Brain Abscess

This chapter includes an accompanying lecture presentation that has been prepared by the authors: .

Epidemiology

Incidence and Risk Factors

Before the advent of infection with HIV, brain abscess was not common, with an incidence of 0.3 to 1.3 cases per 100,000 persons per year in the United States. This incidence translates to approximately 1500 to 2500 cases per year in the United States; incidence in developing countries is higher. Even in later series, the incidence has similarly ranged from 0.4 to 0.9 cases per 100,000 population, with higher rates in immunocompromised patients. In a recent 14-year epidemiologic review of 6027 cases of brain abscess in Taiwan, the overall incidence was 1.8 cases per 100,000 person-years and increased with age. There is a male preponderance of 2:1 to 3:1, and the median age at infection is between 30 and 40 years of age. ^, Differences in age are based on the primary site of infection—when the abscess is from an otitic focus, the patient is generally younger than 20 years or older than 40 years of age, and when the abscess is secondary to a focus in the paranasal sinuses, the patient is usually between 30 and 40 years of age. Later studies suggest that the predisposing conditions for patients with brain abscess have changed, with a decline in the incidence of otogenic abscesses and an increase in the percentage that occur following head trauma and neurosurgery. The incidence of brain abscess was found to decrease in one study in South Africa as a result of improvements in socioeconomic standards and availability of health care services. In this review of 973 patients, the mean age was 24 years, and 75% of patients were men; the most common predisposing conditions were otorhinogenic (∼39%) and traumatic (∼33%).

About 25% of brain abscess cases occur in children, mostly secondary to an otitic focus or in those with congenital heart disease; in one review from the University of Virginia Children’s Hospital for the years 2000 to 2007, an average of only 1.5 children per year were admitted to the inpatient pediatric service with a primary diagnosis of brain abscess. In a later series of 27 children, the most common predisposing conditions were sinusitis, meningitis, and traumatic brain injury.

Brain abscess may occur after a cranial operation. It was reported in only 0.2% of 1587 operations in one study and in 10 of 16,540 cranial procedures performed by 25 neurosurgeons in another review ; a small percentage of patients require a second operation to treat the infection. Occasionally brain abscess may develop years after neurosurgery.

Brain abscess is more commonly reported in patients who are immunocompromised, including those who are infected with HIV, are receiving chemotherapy for cancer, are receiving immunosuppressive therapy after organ transplantation, or have undergone prolonged corticosteroid therapy.

Pathogenesis

Organisms can reach the CNS through spread from a contiguous source of infection (25% to 50% of cases), hematogenous dissemination (20% to 35% of cases), or trauma. ^, ^, ^, Brain abscess is cryptogenic in about 10% to 35% of patients. ^, Sources of a contiguous focus of infection include the middle ear, mastoid cells, and paranasal sinuses. Brain abscess that results from otitis media usually localizes to the temporal lobe or cerebellum; in one review, 54% were in the temporal lobe, 44% in the cerebellum, and 2% in both locations. Later series, however, have demonstrated that cases of brain abscess secondary to otitis media have been decreasing, although intracranial complications may be increased in patients in whom appropriate treatment of otitis media is neglected. In patients with brain abscess secondary to paranasal sinusitis, the frontal lobe is the predominant site. When the abscess is a complication of sphenoid sinusitis, the temporal lobe or sella turcica is usually involved. Dental infections, particularly of the molar teeth, can lead to brain abscess ^, ; these often occur in the frontal lobe, but temporal lobe extension has been reported.

Hematogenous dissemination to the brain generally leads to multiple multiloculated abscesses, which are associated with higher mortality than abscesses from contiguous foci of infection. ^, ^, The higher mortality may be related to a failure to establish an early diagnosis or to the complexity of the anatomy of the abscess (i.e., multiple and multiloculated). The most common sources in adults are chronic pyogenic lung diseases (especially lung abscess), bronchiectasis, empyema, and cystic fibrosis. Other distant sources of infection are wound and skin infections, osteomyelitis, pelvic infections, and intra-abdominal infections ; they can also occur after esophageal dilation or sclerosing therapy for esophageal varices. Cyanotic congenital heart disease (especially in patients with tetralogy of Fallot and transposition of the great vessels) is another predisposing factor that accounts for 5% to 15% of brain abscess cases. Even higher percentages are reported in pediatric series, ^, although with advances in cardiovascular surgery, cyanotic congenital heart disease is a less common predisposing factor. Brain abscess occurs in less than 5% of patients with infective endocarditis despite the presence of continuous bacteremia ; one study found brain abscess in 14 of 198 critically ill patients with infective endocarditis. In another study of 44 cases of left-sided endocarditis in patients who required valve replacement surgery, MRI was performed in 29 patients who had no neurologic signs or symptoms ; brain abscess was found in 6 patients (21%), ranging in size from 6 to 35 mm. There is also a significant likelihood of brain abscess in patients with hereditary hemorrhagic telangiectasia. The abscesses are almost always observed in patients with coexisting pulmonary arteriovenous malformations, perhaps because the malformations allow septic emboli to cross the pulmonary circulation without capillary filtration ; the risk ranges from 5% to 9% and is 1000 times greater than in the general population. In a recent study of 445 consecutive patients with CT-confirmed pulmonary arteriovenous malformations (including 403 with hereditary hemorrhagic telangiectasia), 37 experienced a cerebral abscess.

Trauma can lead to brain abscess formation as a result of an open cranial fracture with dural breach or foreign body injury or as a sequela of neurosurgery. The incidence of traumatic brain abscess in the civilian population ranges from 2.5% to 10.9%, and reports have included brain abscess secondary to compound depressed skull fractures, dog and horse bites, rooster pecking, tongue piercing, and injuries from lawn darts and pencil tips. Nosocomial brain abscess has been seen after halo pin insertion, after electrode insertion to localize seizure foci, in patients with malignant glioma treated by placement of Gliadel wafers in the tumor bed to release carmustine, after placement of deep brain stimulation hardware, as a result of ICP monitors, ^, and after embolization of arteriovenous malformations. ^,

In combat-related injuries, the incidence of brain abscess after head trauma ranges from 3% to 17%, and the abscess usually occurs secondary to retained bone fragments or contamination of initially uninfected missile sites with bacteria from skin, clothes, or the environment. However, the importance of retained bone fragments in the pathogenesis of infection has been questioned. In a study from Croatia of 160 penetrating craniocerebral injuries caused by war missiles, in which 21 skull base injuries were treated surgically, only the accessible retained bone or metallic fragments were removed; the retained foreign bodies did not seem to increase the infection rate except in patients who suffered an in-driven cluster of bone fragments or leakage of CSF. These findings were confirmed in another retrospective study from Croatia in which intracranial débridement in 88 patients with brain missile wounds removed only accessible bone or metallic fragments ; there were 9 cases of brain abscess, and the presence of retained fragments was not responsible for an increased rate of infection. Similar results were found in another study of 43 patients who survived low-velocity missile injuries to the brain during military conflicts and had retained fragments; suppurative sequelae were seen in 6 patients, and only 2 progressed to brain abscess.

Etiology

Numerous infectious agents have been reported to cause brain abscess. The probable infecting pathogen depends on the pathogenesis of the infection (see earlier) and the presence of various predisposing conditions ( Table 56.1 ). This chapter focuses on important bacterial and fungal causes of brain abscess. Protozoal and helminthic causes (e.g., Trypanosoma cruzi, Taenia solium, Entamoeba histolytica, Schistosoma spp., Microsporidia spp., and Paragonimus spp.) are discussed in other chapters of this text. The most important protozoal cause of brain infection is Toxoplasma gondii, which is seen primarily in patients infected with HIV; this organism and the approach to CNS mass lesions in patients infected with HIV are also discussed in other chapters of this text (see Chapter 58 ).

TABLE 56.1

Predisposing Conditions and Probable Etiologic Agents in Brain Abscess

Predisposing Condition	Possible Microbial Causes
Otitis media or mastoiditis	Streptococci (aerobic or anaerobic), Bacteroides spp., Prevotella spp., Enterobacteriaceae
Sinusitis (frontoethmoidal or sphenoidal)	Streptococci, Bacteroides spp., Enterobacteriaceae, Haemophilus spp., Staphylococcus aureus
Dental infection	Mixed Fusobacterium , Prevotella , Actinomyces , and Bacteroides spp.; streptococci
Penetrating trauma or secondary to neurosurgical procedure	Staphylococcus aureus , Enterobacteriaceae, Clostridium spp.
Lung abscess, empyema, or bronchiectasis	Fusobacterium , Actinomyces , Bacteroides , and Prevotella spp.; streptococci; Nocardia spp.
Bacterial endocarditis	S. aureus , streptococci
Congenital heart disease	Streptococci, Haemophilus spp.
Immunocompromised state
Neutropenia	Aerobic gram-negative bacilli, Aspergillus spp., Mucorales, Candida spp., Scedosporium spp.
Transplantation	Nocardia spp., Aspergillus spp., Candida spp., Mucorales, Scedosporium spp., Toxoplasma gondii, Enterobacteriaceae, Listeria monocytogenes , Mycobacterium tuberculosis
Human immunodeficiency virus (HIV) infection	Listeria monocytogenes , Nocardia spp., Mycobacterium spp., Cryptococcus neoformans , T. gondii

Bacteria

The most common bacterial causes of brain abscess are streptococci (aerobic, anaerobic, and microaerophilic), which are isolated in up to 70% of cases. ^, ^, They include organisms in the Streptococcus anginosus ( milleri ) group, which normally reside in the oral cavity, appendix, and female genital tract. Staphylococcus aureus is isolated in 10% to 20% of cases, most commonly after cranial trauma or infective endocarditis. Enteric gram-negative bacilli (e.g., Proteus spp., Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa, and Enterobacter spp.) are isolated in 23% to 33% of patients; predisposing factors include otitis media, bacteremia, neurosurgical procedures, and an immunocompromised state. ^, ^, Anaerobes (especially Bacteroides and Prevotella spp.) have more often been isolated after proper culture techniques and are found in 20% to 40% of patients, frequently in mixed culture. ^, ^, Multiple organisms are cultured in 14% to 28% of cases with positive culture results. ^, The incidence of negative culture results has ranged from 0% to 43% ^a

a References 2, 3, 14–18, 20, 24, 64, 66.

; previous use of antimicrobial therapy may account for such results. In one review and meta-analysis of 123 studies including 9699 patients with brain abscess, streptococci were the most commonly cultured bacteria (34% of cases), followed by staphylococci (18% of cases) and enteric gram-negative bacilli ; almost one-fourth of cases were polymicrobial, and 32% had negative culture results.

Other species are less commonly isolated in patients with bacterial brain abscess but should be considered in those with certain underlying conditions. For example, brain abscess caused by Listeria monocytogenes is uncommon (<1% of cases) but accounts for about 10% of cases of CNS listeriosis ^, ; Listeria should be considered in patients who are immunocompromised (e.g., those with leukemia, lymphoma, HIV infection, and conditions requiring corticosteroids or other immunosuppressive agents). Salmonella species may cause brain abscess in patients who are bacteremic or in the presence of underlying illnesses such as sickle cell disease or chronic granulomatous disease (CGD). Brain abscess caused by Nocardia species may occur as part of a disseminated infection in patients with cutaneous or pulmonary disease; most have defects in cell-mediated immunity as a result of corticosteroid therapy, organ transplantation, HIV infection, or neoplasia. ^, Rare cases of Nocardia brain abscess have also been seen in pregnant women. Other bacteria that cause brain abscess include Streptococcus pneumoniae, group A streptococci, Haemophilus influenzae, Burkholderia pseudomallei, and Actinomyces species. ^, ^, ; actinomycotic brain abscess should be considered in patients with head trauma, previous surgery, and otorhinologic infections and with a long duration of neurological symptoms but no fever. Brain abscess caused by H. influenzae, S. pneumoniae, and L. monocytogenes may be seen in patients with bacterial meningitis complicated by cerebritis during the clinical course. When meningitis is caused by certain facultative gram-negative organisms (e.g., Citrobacter diversus ), concomitant brain abscess is observed in more than 75% of cases. ^, ^, Mycobacterium tuberculosis and nontuberculous mycobacteria have increasingly been observed to cause brain abscess, ^, ^, with cases reported in patients with HIV infection and solid organ transplants ; when the caseous core of a CNS tuberculoma liquefies, a tubercular abscess will result. However, tuberculous brain abscesses can be seen in both immunocompromised and immunocompetent patients ^, ; in one series of 715 patients with brain abscess in India, 60% of patients had infection with M. tuberculosis . In another prospective series from India of 93 patients with intracranial tuberculosis, tuberculomas were 10 times more common than abscess.

Fungi

In recent years, the incidence of fungal brain abscess has been increasing as a result of the increased use of corticosteroid therapy, broad-spectrum antimicrobial therapy, and immunosuppressive agents. Candida species have been the most prevalent fungi but are often not discovered until autopsy; these fungi cause microabscesses, macroabscesses, noncaseating granulomas, and diffuse glial nodules. Risk factors for candidal brain abscess include the use of broad-spectrum antimicrobial agents, corticosteroids, and hyperalimentation; premature birth; malignancy; neutropenia; CGD; diabetes mellitus; thermal injury; CARD9 deficiency: and the presence of a central venous catheter.

CNS aspergillosis is reported in 10% to 20% of patients with invasive disease. ^, ^, ^, The lungs are the usual primary site of infection, with dissemination to the CNS occurring by direct extension from an area that is anatomically adjacent to the brain or by hematogenous dissemination. The most important underlying immune defect in patients with invasive aspergillosis is neutropenia (e.g., in those who have an underlying malignancy), but this infection may also be seen in patients with hepatic disease, diabetes mellitus, CGD, Cushing syndrome, HIV infection, injection drug use, organ transplantation, and bone marrow transplantation, as well as after craniotomy and in patients receiving long-term corticosteroid therapy. Genetic predisposition to invasive aspergillosis has been identified, including genetic variants of some pattern recognition receptors, cytokines, chemokines, and immune receptors.

CNS infections caused by the Mucorales group are among the most fulminant infections known. Diabetes mellitus, usually associated with acidosis, is the most common predisposing condition (∼70% of cases), but disease may also be seen in patients with acidemia from profound systemic illness (e.g., sepsis, severe dehydration, severe diarrhea, chronic kidney disease), hematologic neoplasms, renal transplantation, injection drug use, and use of deferoxamine. ^, Over the last two decades, this pathogen has also emerged as an important cause of CNS disease in recipients of solid organ and hematopoietic stem cell transplantation. CNS disease results from direct extension from the rhinocerebral form, after open head trauma, or after hematogenous dissemination. Bilateral involvement of the basal ganglia has been reported in injection drug users; Rhizopus arrhizus is the most common isolate.

Scedosporium species may cause CNS disease in immunocompetent and immunocompromised hosts. ^, These organisms may enter the CNS by direct trauma, hematogenous dissemination, or direct extension from infected sinuses. One case has also been reported in a patient after extracorporeal membrane oxygenation. An association between near-drowning and subsequent CNS infection has been found because these organisms are present in contaminated soil, water, and sewage.

Many other fungal species have been reported to cause brain abscess, including Cryptococcus neoformans, the endemic mycoses ( Coccidioides spp., Histoplasma spp., Blastomyces dermatitidis, and Fusarium spp.), and many of the melanized, or dematiaceous, fungi. It is beyond the scope of this chapter to review all fungal causes of brain abscess, and more detail can be found in other sources. ^,

Experimental Models of Infection

Numerous animal models have been developed to study the pathogenesis and pathophysiology of brain abscess. Some large-animal models were created by direct implantation of bacteria into the brain; however, these models were limited by lack of reproducibility, they required multiple steps and an agar vehicle to initiate infection, and they were quite expensive. Another method used embolization of contaminated pliable cylinders implanted into the carotid artery but required concomitant cerebral injury for abscess formation, and the accompanying brain infarction caused a high mortality rate, even in uninfected control animals.

A better animal model involved the use of mice or rats and consisted of a simple, one-step, easily reproducible procedure for consistent production of brain abscess. Infection was produced by the injection of 1 μL of saline containing a fixed inoculum of bacteria through a bur hole and into the frontal lobe of the brain. ^, With this model, brain abscess was achieved in a one-step process at a specific site with the injection of bacteria alone, the inoculum could be regulated in terms of both volume and number of organisms, the number of injected bacteria and the number of bacteria that remain viable in the tissue could be quantified at a later time, and there was precise control of the injection site, thereby reducing tissue trauma with minimal (or no) infection in the subarachnoid space. This model also simulated human infection in that the abscess was produced in the white matter at the white and gray matter junction and migrated toward the ventricle, a shift in intracranial contents occurred, and there was minimal histologic evidence of meningitis; the abscess capsule was asymmetrical, being more complete on the cortical than on the ventricular side, perhaps because the increased vascularity of normal cortical gray matter allowed greater fibroblast proliferation and collagen helix formation. In addition, development of the abscess paralleled clinical disease with the initial development of cerebritis and massive white matter edema followed by encapsulation.

In another animal model, brain abscess was produced in a rat by direct intracerebral injection of agarose beads laden with S. aureus . This method was also easy, reproducible, effective, and associated with a low mortality rate, and the histologic features of the experimental abscesses were similar to those observed in other animal models and in humans. These models have been useful in delineating the early events in brain abscess formation with respect to bacterial virulence factors and the host defense mechanisms involved in brain abscess formation; these concepts are reviewed in greater detail subsequently.

Initiation of Infection

The brain appears to be significantly more sensitive to infection than many other tissues. In a rat model of experimental brain abscess, injection of 10 ⁴ colony-forming units (CFUs) of S. aureus or 10 ⁶ CFUs of E. coli failed to cause infection in the skin, but abscess formation in brain tissue was induced by a level as low as 10 ² CFUs of either organism. The brain may also be more susceptible to infection by different organisms; in the experimental rat model, strains of E. coli were more virulent (i.e., led to abscess formation at lower inocula) than P. aeruginosa, S. aureus, or Streptococcus pyogenes . In addition, E. coli strains possessing the K1 antigen were more infective than strains without this antigen, thus indicating that certain encapsulated strains may be more virulent in brain abscess formation. Furthermore, inoculation of Bacteroides fragilis or streptococci such as Streptococcus intermedius failed to lead to abscess formation in rats, even though these organisms account for a high percentage of isolates from brain abscesses in humans; this finding may be explained by the fact that brain abscess is often the result of a contiguous focus of infection, and the synergistic infectivity of mixed populations of anaerobes plus a facultative organism may be necessary to establish infection. ^, In an experimental dog model of brain abscess formation, inoculation of B. fragilis with Staphylococcus epidermidis in mixed culture caused a virulent reaction, although each organism was not tested separately. The role of other bacterial virulence factors in the pathogenesis of brain abscess formation has not been elucidated. However, the role of virulence factor production in the development of brain abscess was demonstrated by the inability of heat-inactivated S. aureus to induce proinflammatory cytokine or chemokine expression in an experimental mouse model; alpha toxin was identified as a key virulence factor for survival of S. aureus in the brain and subsequent development of brain abscess.

Brain abscess may also develop in patients with bacterial meningitis, a rare complication except in human neonates with meningitis caused by C. diversus . Pathologically, there is cerebral necrosis and liquefaction, along with vasculitis of small vessels and hemorrhagic necrosis of adjacent tissue with a propensity for contiguous inflammation in the cerebral white matter, which may reflect the effects of endotoxin in the small penetrating vessels in this area; the typical abscess with capsule formation was not present. The pathogenesis was investigated in an infant rat model in which infection was initiated with the production of a high-grade bacteremia, infiltration of the leptomeninges, and subsequent development of ventriculitis. Brain abscesses were found exclusively in the periventricular white matter, apparently from disruption of the ventricular ependymal lining with direct extension of the infection into the parenchyma. The virulence factors responsible for the propensity of this organism to cause brain abscess are undefined, although one study reports that a minor 32-kD outer membrane determinant may be a marker for strains that are more likely to produce ventriculitis and brain abscess; strains that lacked the 32-kD outer membrane protein caused more bacteremia, meningitis, and death.

Stages of Infection

The temporal course and pathologic consequences of brain abscess were examined in a canine model of infection after inoculation with α-hemolytic streptococci. Four stages of infection were identified ( Table 56.2 ): early cerebritis, late cerebritis, early capsule formation, and late capsule formation ( Figs. 56.1 to 56.3 ). These stages are somewhat arbitrary but are useful in the classification and comparison of virulence among different organisms in the production of brain abscess. Similar neuropathologic findings were described in an experimental model of anaerobic brain abscess, but capsule formation could not be divided into early and late stages because of delayed encapsulation. S. aureus was found to be more virulent than α-hemolytic streptococci, with a greater amount of necrosis and total area of involvement, a longer course of progression to resolution, and longer times to reach a stable size and to contain the necrotic region within a collagenous capsule. Inflammation with histologic evidence of extension of inflammation, necrosis, and edema beyond the capsule was also observed, findings similar to those after inoculation with B. fragilis .

TABLE 56.2

Histopathologic Findings in the Stages of Brain Abscess Formation

Data from Tunkel AR, Scheld WM. Pathogenesis and pathophysiology of bacterial infections. In: Scheld WM, Whitley RJ, Durack DT, eds. Infections of the Central Nervous System . 2nd ed. Philadelphia: Lippincott-Raven; 1997;297–312; Britt RH, Enzmann DR, Yeager AS. Neuropathological and computerized tomographic findings in experimental brain abscess. J Neurosurg . 1981;55(4):590–603.

	Early Cerebritis (Days 1–3)	Late Cerebritis (Days 4–9)	Early Capsule Formation (Days 10–13)	Late Capsule Formation (Day 14 and Later)
Necrotic center	Acute inflammatory cells; bacteria present on Gram stain	Enlarging necrotic center reaching maximal size	Decrease in necrotic center	Further decrease in necrotic center
Inflammatory border	Acute inflammatory cells	Inflammatory cells, macrophages, and fibroblasts	Increased numbers of fibroblasts and macrophages	Further increase in number of fibroblasts
Cerebritis and neovascularity	Rapid perivascular infiltration of neutrophils, plasma cells, and mononuclear cells	Maximal extent of cerebritis; rapid increase in new vessel formation	Maximal degree of neovascularity	Cerebritis restricted to outside of collagen capsule; reduced neovascularity
Collagenous capsule	Reticulin formation begins by day 3	Appearance of fibroblasts with rapid formation of reticulin	Evolution of mature collagen	Capsule completed by end of second week
Reactive gliosis and cerebral edema	Marked cerebral edema	Prominent cerebral edema; appearance of reactive astrocytes	Regression of cerebral edema; increase in reactive astrocytes	Regression of cerebral edema; marked gliosis outside capsule by third week

Capsule formation occurs in a delayed fashion (see Table 56.2 ). In all of these studies, capsule formation was less prominent on the ventricular surface than on the cortical surface. ^, ^, Differences in vascularity between the cortical gray matter and white matter might allow greater fibroblast proliferation more superficially (i.e., on the cortical surface). Alternatively, fibroblasts responsible for the capsule collagen may need to migrate from the meninges, thereby accounting for the delay in capsule formation and the greater density of the capsule on its superficial surface. This thinner aspect of the capsule on its “deeper” surface probably explains the tendency for brain abscesses to rupture into the ventricular system rather than into the subarachnoid space. However, the histopathologic sequence of brain abscess formation was found to be different in an experimental rat model after inoculation with E. coli ; the histopathologic findings supported an alternative hypothesis that brain abscesses tend to rupture intraventricularly because the infectious process is directed along the major white matter tracts (areas of lower tissue resistance) rather than as a result of asymmetric collagen deposition. However, the question of rupture of brain abscess requires further study.

The histopathologic findings in brain abscesses after direct implantation differ from those produced by intracarotid embolization because metastatic abscesses induce only transient midline displacements, inflammatory cell infiltration is reduced, and collagen formation is slower around proliferating capsular vessels; this difference may have patient care implications because a lower level of encapsulation contributes to mortality.

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