Infectious Intracranial Aneurysms

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CHAPTER 379 Infectious Intracranial Aneurysms

The first description of an aneurysm of infectious etiology arising within the intracranial circulation was provided by Church in 1869, when he described an aneurysm in a 13-year-old boy with mitral valve endocarditis.¹ Osler then coined the term mycotic aneurysm during his “Gulstonian Lectures on Malignant Endocarditis” in 1885, when he described an aortic aneurysm that developed in a patient with bacterial endocarditis.² Eppinger acknowledged the significance of infected emboli in the development of these lesions by calling them mycotic-embolic aneurysms.³ The term mycotic aneurysm came to describe all aneurysms of infectious origin and is the terminology that has persisted until recently in the literature to describe aneurysms of infectious etiology. In one of the larger earlier series, Stengel and Wolforth reviewed 34 reported cases of infectious aneurysm in 1923.⁴ Bohmfalk and colleagues replaced mycotic aneurysm with bacterial aneurysm because the underlying infectious cause is most commonly bacterial and not fungal as mycotic would suggest.⁵ They described 85 cases from 1954 to 1978, which remains the largest series to date. Hospital series include those of Frazee and associates,⁶ Monsuez and coworkers,⁷ and Barrow and Prats,⁸ with 13, 12, and 12 patients, respectively. More recently Kannoth and colleagues described 25 cases spanning from 1976 to 2003.⁹ Chun and coauthors reported on 20 cases over a 10-year period.¹⁰ As evidenced by the small number of patients in these series, infectious aneurysms are a rare entity.

Terminology

There is much debate in the literature on what constitutes the appropriate terminology to refer to intracranial aneurysms of infectious etiology. The term mycotic aneurysm has been used historically to describe aneurysms of infectious etiology, but the terminology is misleading because it implies a fungal source, which can be the case but excludes bacteria, viruses, and tuberculous bacilli as possible causative agents. The term infectious aneurysm has replaced mycotic aneurysm as the most frequently used term. However, some object to use of the term infectious because it implies that the aneurysm itself acts as a source of further infection, and therefore other terminology has been suggested, such as infected or inflammatory.¹¹ Because there does not currently appear to be a consensus on the appropriate terminology, infectious aneurysm will be used as an all-encompassing term. An attempt will be made to be specific whenever possible, and fungal aneurysm and bacterial aneurysm will be used to describe an aneurysm of fungal or bacterial etiology, respectively, when the distinction is important.

Epidemiology

Intracranial aneurysms of infectious etiology are rare and represent approximately 2% to 6% of all intracranial aneurysms.¹²^–¹⁴ The incidence may be higher in children, in whom they account for as many as 10% of all intracranial aneurysms.¹⁵ In one series, aneurysms of infectious origin were found in 2% of children with bacterial endocarditis and accounted for 43% of the neurological complications related to endocarditis.¹⁶ A meta-analysis of cerebral aneurysms in children younger than 1 year found aneurysms of infectious etiology to represent 10% of intracranial aneurysms in that age group.¹⁷ Others have found a lower incidence of infectious aneurysms in the pediatric population, with an estimated incidence of less than 5%.¹⁸ The true incidence of these lesions in both the pediatric and adult population is difficult to ascertain because of their rarity. Their propensity to grow or regress rapidly and asymptomatically suggests that they are often undetected and that reported rates probably underestimate the true incidence. In 1916, Fearnsides’ autopsy review reported that 30% of all intracranial aneurysms were infectious.¹⁹ Subsequently, McDonald and Korb reported an incidence of 6.2% based on autopsies.¹⁴ This relative decline has been attributed to the introduction of antibiotic therapy. However, antibiotic therapy can select for more virulent organisms and thus alter the natural history of infectious aneurysms and the effectiveness of current antibiotics. In addition, improved survival of immunocompromised patients may also contribute to the relative increase in the number of fungal aneurysms.

Endocarditis, particularly left-sided valve disease, predisposes patient to infectious aneurysms and neurological complications. More than 80% of patients with intracranial infectious aneurysms carry an underlying diagnosis of endocarditis.⁵ Twenty percent to 40% of patients with endocarditis suffer neurological sequelae. Cerebral infarction is most common and afflicts up to 31% of patients.²⁰ Intracranial hemorrhage occurs in 5%.²¹ Overall, in 1% to 4% of patients with infective endocarditis, an infectious intracranial aneurysm is clinically diagnosed.^6,^7,^12,^22,²³

Intracranial infectious aneurysms may also develop in the absence of endocarditis or intravascular infection. Extravascular infection such as meningitis,²⁴^–²⁶ cavernous sinus thrombophlebitis,^27,²⁸ cerebral abscess,²⁹^–³² subdural empyema,³³ osteomyelitis of the skull,³⁴ and sinus infections^9,^28,³⁵ can potentially extend into the arterial wall and induce arteritis and aneurysm formation. Infectious aneurysms from an extravascular source such as meningitis tend to occur proximally, whereas embolic infectious aneurysms associated with infective endocarditis occur predominantly in distal cerebral arterial regions.⁹ The difference in location and incidence of fungal aneurysms requires a different management approach.

Fungal or “true” mycotic aneurysms are rare. However, the incidence of these lesions has recently increased as a result of more patients with immunocompromised states. Prolonged steroid use, immunosuppressive therapy, immunodeficient states, and exposure to broad-spectrum antibiotics have been implicated in their development.^8,^35,³⁶ In addition, fungal aneurysms can occur secondary to contiguous spread of postoperative fungal infection.³⁷ More aggressive use of immunosuppressive therapy and broad-spectrum antibiotics, along with an increasing population of immunocompromised patients, may explain the resurgence of fungal intracranial aneurysms.

Pathophysiology

The pathophysiology of infectious aneurysms is dependent on the causative agent, mechanism of spread, and the timeliness of diagnosis and initiation of appropriate therapy. Infectious agents can spread by several different mechanisms. There can be endovascular spread with infectious intracranial aneurysms occurring as a result of septic emboli, as is seen with bacterial endocarditis. As described previously, infectious intracranial aneurysms can be divided into those derived from intravascular infection and those that find their infectious origin in the extravascular space. Intravascularly derived infectious aneurysms are usually bacterial but may rarely be fungal.³⁸ Because of their embolic etiology, intravascularly derived infectious aneurysms tend to form in locations where blood flow is maximal and the vascular anatomy favors the lodging of embolic particles, such as vessel branch points in the distal vasculature. The most common location is the distal middle cerebral artery (MCA), where more than 60% of emboli lodge.^34,³⁹ This contrasts with classic berry aneurysms, which tend to form on large basal vessels as solitary lesions. Because the origin of infectious aneurysms is most commonly mitral valve septic vegetations, numerous emboli can lead to multiple aneurysms in as many as 30% of patients.⁴⁰

Unlike infectious aneurysms originating from an intravascular source, infectious aneurysms from an extravascular source are more likely to occur in the proximal intracranial arteries from contiguous infectious spread at the base of the brain. Usual locations include the intracavernous internal carotid artery, the midbasilar artery, and the vertebral artery. Although most bacterial aneurysms arise as a result of intravascular embolism, nearly all fungal aneurysms find their origin in the extravascular space. These “true” mycotic aneurysms tend to be larger and more fusiform in shape with a higher association of occlusion of the vessel than occurs with bacterial aneurysms.^36,^37,^41,⁴²

The precise mechanism of aneurysm formation probably varies depending on the infectious agent, immune status of the host, and time course of initiation of antibiotic therapy. Some animal models have shed light on the possible pathogenesis. Nakata and associates introduced bacteria into a canine aorta that had been isolated by clamps to demonstrate the role of stasis and sepsis in vascular destruction of the vasa vasorum.⁴³ However, this theory has been questioned because of the relative absence of vasa vasorum in cerebral arteries, particularly in the most distal segments, where infectious aneurysms are prone to form.^44,⁴⁵ Molinari designed a study to evaluate the exact role of septic emboli in the cerebral circulation by injecting bacteria-coated silicone rubber particles into the internal carotid artery. They found that the entire process, including embolization, arteritis, aneurysm formation, and hemorrhage, occurred within a couple of days. Interestingly, they also found that the inflammatory process involved the adventitia and muscularis primarily despite delivery of the bacteria to the intimal surface. The elastica and intima were the last to be affected, thereby supporting stasis and sepsis of the vasa vasorum and perhaps leakage into the Virchow-Robin spaces.⁴⁴

The pathologic changes produced by either septic embolization or contiguous spread are similar. Infiltration of the adventitia and media by polymorphonuclear leukocytes is accompanied by marked intimal proliferation. Thrombosis of the involved vessel may occur but is not necessary for the formation of an aneurysm. Some fungal infections such as aspergillosis and mucormycosis have a tendency to directly invade blood vessel walls. The angioinvasive nature of Aspergillus is directly related to its capacity to digest elastic tissue through production of the enzyme elastase.^35,⁴⁶ The tendency of Aspergillus for intramural growth is directly related to the fusiform shape seen with fungal aneurysms, as opposed to the more saccular shape seen with bacterial aneurysms.³⁵ Focal arteritis, whether bacterial or fungal, gives rise to a severely weakened and necrotic vessel wall, with aneurysmal dilation or frank vessel wall disintegration leading to hemorrhage. Thus, hemorrhage can occur as a result of necrotic vasculitis and does not necessarily indicate the presence of an infectious aneurysm. Intracranial infectious aneurysms are typically friable and often not separable from the surrounding parenchyma, which plays an important role in surgical planning. Antibiotic treatment may reverse this damage by inducing reparative fibrosis of the aneurysmal wall and parent artery,⁴⁵ but it does not necessarily preclude rupture of the aneurysm.

Intracranial aneurysms of infectious etiology demonstrate dynamic cycles of formation, enlargement, regression, and resolution. In his canine model, Molinari demonstrated that although there was a decrease in the rate of rupture in the first week, aneurysms were still present in dogs euthanized at 7 days. This suggests that the natural course of an infectious aneurysm is altered by antibiotic treatment. In addition, antibiotic therapy changed the nature of the aneurysms so that they were tough, fibrotic, and less likely to rupture.⁴⁵ Clinical studies have further underscored the dynamic manner in which infectious aneurysms develop and resolve.^47,⁴⁸ The behavior of an infectious aneurysm can range from abrupt rupture despite appropriate antibiotics to spontaneous resolution with appropriate therapy, thus making it difficult to stereotype the natural history.

Microbiology

Streptococcus viridans and Staphylococcus aureus are responsible for 57% to 91% of infectious intracranial aneurysms.⁴⁹ Other bacterial organisms have also been cultured, including enterococci, coagulase-negative staphylococci, Haemophilus, Actinobacillus, Cardiobacterium hominis, Acinetobacter, Eikenella corrodens, Kingella, Pseudomonas, Neisseria, and Corynebacterium.^{6–8,26,49–54} Multiple organisms are found in less than 5% of patients.⁵⁵ Despite multiple blood or cerebrospinal fluid (CSF) cultures, at least 12% to 19% of patients fail to grow an organism.^55,⁵⁶

Extravascular infections that predispose to intracranial aneurysms include meningitis, cavernous sinus thrombophlebitis, osteomyelitis, tonsillitis, pharyngitis, sinusitis, and wound infection, as well as drug abuse. Bacterial organisms cultured from these infections include S. aureus, Mycobacterium tuberculosis, pneumococci, Pseudomonas, Brucella, Neisseria, and other species that inhabit potential portals to the intracranial space.

As mentioned previously, aneurysms of fungal etiology usually occur in immunocompromised hosts. Aspergillus is the most common fungus cultured, followed by Phycomycetes and Candida albicans. Intracranial fungal aneurysms attributable to Cryptococcus, Coccidioides, Petriellidium boydii, Pseudallescheria boydii, Nocardia asteroides, and fungi causing chromoblastomycosis have also been reported.^35,^36,^41,^42,⁵⁷^–⁵⁹ Aspergillosis of the central nervous system usually occurs as a result of direct infection via the paranasal sinus or indirectly by hematogenous infectious spread, most commonly from the lungs.⁵⁸ Direct spread of a fungal infection associated with an aneurysm after craniofacial and other neurosurgical procedures has also been described.^60,⁶¹

Clinical Findings

The signs and symptoms in patients with infectious aneurysm are highly variable. A high index of suspicion is required in those with risk factors for infectious intracranial aneurysms and new neurological symptoms or signs. Patients may have clinical manifestations referable to numerous underlying disease processes, but it is the combination of the underlying disease process and new neurological findings that should raise suspicion. However, infectious intracranial aneurysms can be asymptomatic and the diagnosis can be challenging.

The majority of patients with infectious intracranial aneurysms also have left-sided subacute bacterial endocarditis. The overall incidence of infectious intracranial aneurysms has remained stable at 2 to 6 cases per 100,000 people per year despite changes in therapy and underlying conditions. Classically, rheumatic heart disease and related valvular abnormalities were an important predisposing factor. Recently, new risk factors such as prosthetic valves, elderly sclerotic valve disease, nosocomially acquired bloodstream infections, and intravenous drug abuse have become the most important predisposing factors.^49,⁶² The most common manifestation is a focal neurological deficit, which occurred in 48% of patients in one larger series.⁹ This finding is in contrast to other intracranial aneurysms, which are much less likely to be accompanied by focal signs or symptoms.⁶³ Not all neurological complaints signify the presence of an aneurysm. In fact, neurological manifestations are common in patients with endocarditis, with only a minority ultimately referable to an infectious aneurysm. Signs of subarachnoid or intracranial hemorrhage in the setting of endocarditis should raise strong suspicion of an infectious aneurysm. The signs and symptoms of hemorrhage are present in 57% of patients with infectious aneurysms and are otherwise uncommon in those with endocarditis.⁵⁹ However, intracranial hemorrhage can occur in the setting of bacterial endocarditis in the absence of a demonstrable aneurysm.²¹ Symptoms may include focal neurological deficit, headache, meningismus, seizure, or change in mental status.

Patients with intracranial aneurysms caused by extravascular infection are initially seen with a wide array of symptoms and signs referable to the site of infection. Patients are often immunocompromised. Underlying disease processes include systemic lupus erythematosus, near drowning, Burkitt’s lymphoma, meningitis, sinusitis, tonsillitis, pharyngitis, osteomyelitis, and infection from previous intracranial surgery. Intracavernous internal carotid aneurysms associated with cavernous sinus thrombophlebitis can cause exophthalmos, ophthalmoplegia, and ocular pain.