Intracranial and Intraventricular Abscess – Neurosurgical Management

1. Introduction

A brain abscess (BA) is a focal infection of brain parenchyma most frequently caused by bacteria in an individual with underlying risk factors [1, 2]. Occurring at an estimated incidence of 0.33–1.3 per 100,000 per year [3, 4, 5], BAs occur more frequently in men than women, with a median age of 30 to 40 years [2, 6]. Symptoms and presentation vary drastically based on size, location, and number of foci. Lesions are typically supratentorial, with less than 10% occurring below the tentorium cerebelli [7].

The presence of an intracranial abscess can be life threatening, especially if intraventricular rupture occurs, often leading to massive cerebral edema, herniation syndrome, and death [8]. Mortality rate for uncomplicated BA is cited 0–20% [9], but intraventricular rupture of brain abscess (IVROBA) can be rapidly fatal due to malignant cerebral edema and herniation. IVROBA can occur in anywhere from 0.3–35% [10] of BA and carries a mortality rate greater than 80% [8, 11]. As neurosurgical technology has advanced, the treatment of intracranial and intraventricular abscess has evolved. With new treatment modalities for intracranial infection, in addition to ever-changing bacteria with new patterns of antibiotic resistance, it is crucial to continually adapt and refine our approach to managing this life-threatening condition.

2. Abscess formation and pathogenesis

An intracranial abscess initially begins as an area of cerebritis, secondary to iatrogenic introduction of an infection, hematogenous spread from an infection elsewhere in the body, or from an immunocompromised state, making the host more susceptible to infection [12]. Synergistic effects have been noted between aerobic and anaerobic bacteria, especially once the blood brain barrier has been violated [9]. The early cerebritis stage lasts approximately 3 days, followed by progressive or late cerebritis which over the course of an additional 4 to 5 days becomes a capsule (Figure 1) [12]. The early encapsulation phase of the bacteria takes place over days 10 through 13 of the initial infection, ending in the late capsulation phase which persists after 2 weeks of untreated infection [12]. If the abscess abuts the ventricular system (Figure 1), the capsule is thinnest where it contacts the ventricle [12], making this area not only the most likely source of spread of the infection, but also the most lethal, as intraventricular rupture sets off an inflammatory cascade that can lead to increased intracranial pressure and, eventually, to cerebral herniation syndrome and death as previously mentioned [14]. Within an encapsulated abscess, several histologic patterns are expected, most importantly a necrotic core of infection, followed by a layer of inflammatory cells, including fibroblasts, neutrophils, and macrophages (Figure 2) [12]. The remaining capsule is a thick layer of collagen surrounded by neovascularization, gliosis, and cerebral edema, which results in mass effect on neighboring structures, midline shift, and elevated intracranial pressure [12]. Bacterial pathogens are by far the most common etiology of BA, and it is of paramount importance to identify the source of the bacteria as this will guide diagnostic work up and eventual therapeutic management [9]. In a meta-analysis of 123 studies (n = 9699 patients) on BA, 68% of patients had a positive culture, 77% of which were monomicrobial. The most cultured pathogens were Staphylococcus aureus (13%), Streptococcus viridans (13%), Proteus species (7%), and Bacteroides species (6%) [6]. Streptococcus intermedius is a particularly prevalent species of S. viridans in BA [15] and oral streptococci of the S. milleri group has also shown dominance across the literature [15]. With regard to post operative infections, S. aureus has been shown in additional literature reviews to be the most common, with S. intermedius the most frequently isolated bacteria to form a BA amongst all comers [16]. Fungal pathogens account for only 1% of all BAs [6], and occur almost exclusively in the immunocompromised or those who have undergone prior transplant [17]. While the bacteria listed above are the most frequently isolated, it is likely that the abscesses are polymicrobial and that early initiation antibiotics and lack of standardized sample processing and culture technique affect results [9].

Hematologic spread of infection is quoted to represent between 30 and 40 percent of intracranial abscesses, with sources from the mouth, lungs, and heart being the most common [12]. Infective endocarditis, commonly caused by S. aureus or oral Streptococci, can present as cryptogenic abscess without major symptoms or bilateral disease given the dissemination from the heart. Congenital malformations of the cardiopulmonary circulation, such as pulmonary arteriovenous malformations [18] and extracardiac shunts [19], can predispose patients to BA [12]. Otogenic BA arise in the setting of chronic middle ear inflammation [20] and typically affect the temporal lobe (55%) and cerebellum (28%), with Proteus mirabilis isolated in up to 79% of cases [21]. Odontogenic infections, arising from poor dental hygiene, have a predilection for the frontal and temporal lobes given anatomical proximity; however bacterial spread is also hypothesized to be carried by the middle meningeal artery [16]. Interestingly, odontogenic pathogens are becoming a more common cause of BA, up to 32% in one study [3]. Dental plaque can contain more than 350 different bacterial subtypes and gingival infection and/or infection of the upper molars has been shown to place patients at higher risk for brain abscess formation [16].

3. Patient presentation and characteristics

Classic, although rare, presentation includes a nonspecific triad of headache, fever, and neurological deficits; the presence of all three is only seen in about 20% of cases [6, 22]. In the nation-wide cohort study by Bodilsen et al., most individuals studied had symptom onset 3 days prior to admission, 40% were immunocompromised and 82% had an unspecified neurologic deficit [23]. When subcategorized, motor or sensory loss was more common than cranial nerve palsy, and approximately 25% of patients presented with concern for seizure activity [23]. Compared to the Danish cohort, the literature reports a longer duration of symptoms prior to admission, 8 days on average, possibly due to access and cost of healthcare [5, 12, 22]. This emphasizes the need for increased awareness on the part of patients and providers, especially those who are at high risk for BA formation. On average each patient waited nearly 5 hours prior to first imaging and 4 days for their first neurosurgical procedure, with most undergoing two neurosurgical interventions on average [22]. With regard to imaging modality of choice a prospective study of 115 patients, of which the majority had a brain abscess, demonstrated that magnetic resonance imaging (MRI) with diffusion –weighted imaging (DWI), had a positive predictive value of 98% and a negative predictive value of 92%, emphasizing its utility in differentiating between abscess and metastatic disease [1]. While MRI is preferred, a post-contrast computed tomography (CT) can be used expeditiously to elucidate if an intracranial abscess may be present (Figure 3) [9]. CT or MRI imaging typically demonstrates a ring-enhancing lesion, with MRI revealing a bright lesion with surrounding hypodense rim with surrounding edema as mentioned [24]. Other nonspecific findings on presentation include nausea/vomiting, altered consciousness, seizures, cerebellar involvement, gait instability, and meningeal signs [2, 6]. The nonspecific presenting symptoms might explain why only about 17% of patients with BA have central nervous system (CNS) infection listed as their admission diagnosis and requires increased vigilance on the part of the provider to keep a BA in their differential when an individual presents with any source of infection [1, 22]. As mentioned above, immunocompromised state, post-solid organ or hematologic transplant, and/or use of immunosuppressant medications, congenital cyanotic heart disease and arteriovenous malformations are all predisposing conditions to BA [1, 22]. More commonly, odontogenic or otologic infections, endocarditis, head trauma or history of neurosurgery, cancer, diabetes mellitus and alcohol abuse can also lead to BA [22].

4. Medical management

The mainstay of medical management is early initiation of empiric antibiotics, with prompt transition to targeted therapy upon resulting cultures; however, 6 weeks of polymicrobial coverage is recommended in non-endocarditis cases as more often than not BA are truly polymicrobial (Figure 4) [9]. Expedited treatment may reduce mortality from BA from 40–10% [16]. While blood and, if safely able, CSF cultures, are obtained from patients presenting with concern for BA, a causative bacterium is not always isolated, with sterile cultures cited at approximately 25% [24]. If the solitary abscess is less than 1 centimeter (cm) in size, empiric broad spectrum antibiotics can be continued for 6–8 weeks without neurosurgical aspiration, followed by a prolonged course of oral antibiotics [16]. In clinically stable patients, antibiotic administration may be postponed until definitive neurosurgical management, provided such intervention occurs promptly (within 24 hours) and blood cultures are drawn [22].

Empiric antibiotic regimens typically consist of vancomycin, a third-generation cephalosporin, and metronidazole which can later be narrowed according to cultures; however, this remains controversial [16]. In patients with acquired immunodeficiency syndrome (AIDS), an empiric regimen of sulfadiazine, pyrimethamine, and leucovorin targets Toxoplasma gondii. If a fungal pathogen is suspected, liposomal amphotericin B and flucytosine may be utilized [24]. Antibiotics are administered intravenously for 6 to 8weeks [16]. Complete surgical removal of abscess and capsule can reduce required duration [24]. Early transition to oral antibiotics may decrease risks associated with prolonged hospitalization [25], but overall efficacy has not been proven. Importantly, conversion to an oral regimen, depending on the causative bacteria, may lead to increased drug toxicity, antibiotic resistance, and diarrheal infection with Clostridium difficile, further complicating patient recovery [22]. Importantly, side effects and toxicity from intravenous medications also pose a risk which must be weighed against the benefits of prolonged treatment and narrowed as soon as medically appropriate [9].

Adjunctive treatments have been studied, however are not yet included in standard of care management. Corticosteroids have a well-established role in the treatment of bacterial meningitis, with a demonstrated reduction in mortality [26]. Initial animal studies suggested impaired antibiotic penetration [27] and delayed capsule formation [28]. A more recent systematic review and meta-analysis found a non-statistically significant mortality benefit [29]. Despite a paucity of robust data supporting their use, corticosteroids are recommended in cases of life-threatening edema with mass effect [9]; however, use of high dose steroids may alter the radiographic findings, namely surrounding ring enhancement/edema, leading to false sense of improvement [30]. If utilized in these scenarios, duration should be minimized to mitigate the sequelae of immunosuppression [30]. Hyperbaric oxygen therapy has shown promise in small trials [31], potentially via improved antibiotic bactericidal activity [32].

5. Surgical management

Stereotactic aspiration is the treatment of choice for abscesses greater than 1 cm in diameter, regardless of location given significant advancement in technology and stereotaxis; open surgical management is first considered for lesions larger than 2.5 cm however other factors should be considered for open surgery including causative bacterium and superficial, easily accessible location [1]. Exceptions to stereotaxic aspiration include imaging without evidence of central cavitation, periventricular lesions, lesions with significant mass effect/impending herniation and lesions in patients with human immunodeficiency virus (HIV) with probable toxoplasmosis, who can be treated with antimicrobials following antibody results [1]. Resection may be considered for superficial abscesses in non-eloquent tissue, especially in cases of suspected tuberculosis, fungal, or branching bacteria; ultrasonography has grown in popularity for superficial lesions if stereotaxis is not available [1]. A systematic review and meta-analysis of 124 cases found that in superficial non-eloquent locations, resection was associated with several positive characteristics including decreased postop residual abscess, decreased re-operation rate, shorter duration of both post-op antibiotics and length of hospital stay, and higher rate of improved neurologic status at 1 month [33]. However, mortality and neurologic status at 3 months did not differ between those treated with aspiration versus resection [34].

At the index procedure, following maximum aspiration of the abscess, leaving a drain within the abscess cavity may promote decreased reoperation rates and allow for intracavitary antibiotic delivery, neither of which are currently included in standard management [1]. As mentioned, intracavitary antibiotic delivery has been used for refractory fungal abscesses but the literature has not proven this treatment to be effective across this pathology [24]. Indications for excision after initial stereotaxic drainage include failure to improve in 7 days, altered mental status, symptomatic elevated intracranial pressure, progressively expanding abscess, especially if migrating towards the ventricle, or if there is failure of abscess shrinkage within 2 weeks’ time [24]. Several studies have explored the feasibility of bedside twist drill aspiration, specifically in peripherally located abscesses sized less than 2.5 cm [35]. A series of 103 patients treated with bedside twist drill aspiration found a mortality rate of 4.8% [36], comparable to the reported mortality rate of typical aspiration.

6. Complications

Acute complications, including intraventricular rupture and herniation, are discussed below. Aside from acute new neurologic deficit, decision making regarding interval imaging can vary. In their review in The New England Journal of Medicine, Brouwer et al. suggest interval cranial imaging following 1–2 weeks of initial management if clinical improvement is not apparent with biweekly imaging until improvement is seen, up to 3 months after initiation of therapy [1]. For individuals with either an identifiable or unidentifiable bacteria, septic emboli may cause remote infarcts in various organs, including the brain, with areas of ischemia prone to subsequent abscess formation, complicating treatment and recovery [24].

BA are not without morbidity, as permanent cranial nerve palsies, vision loss, hemiparesis, learning/cognitive deficits, and hydrocephalus are amongst the life-changing side effects of BA diagnosis and treatment [30]. Most importantly, the aftereffects of BA formation regarding neuropsychological and psychological testing are not well researched [1]. Excision of BA can cause an increased risk of epilepsy (41 vs. 20%), which subsequently increases mortality; however routine empiric use of antiepileptic medications on presentation is still under investigation [23]. Interestingly, BA has also been associated with increased risk of cancer in the first 10 years after diagnosis (HRR 2.09 [95% CI 1.79–2.45]) [37].

7. Prognosis

A nationwide, population-based cohort study in Denmark from 2007 to 2020 (n = 485 cases) reported a 6% mortality rate at discharge to 12% at 6 months [22]. Prognostic factors impacting overall mortality from BA include IVROBA, abscess size larger than 3 cm, and age older than 65 years of age, with oral flora having a favorable impact on mortality in this study possibly secondary to susceptibility to oral antibiotic regimens [22]. Above all else, prevention of IVROBA is most critical; however, immunocompromised state, hematologic spread, and age above 65 have been associated with mortality specifically within 6 months following hospital discharge and/or poorer prognosis [22, 34]. Factors associated with poor outcome in surgically managed patients include diabetes, ventricular rupture, and supratentorial abscesses located in eloquent brain [38]. In the population of patients managed nonoperatively, neck stiffness or meningismus, septic shock and lower admission Glasgow Coma Score (GCS) were associated with poorer prognosis [39]. For the immunocompromised s/p hematologic or solid organ transplant, fungal BA hold a near 100% mortality rate [24]. Without IVROBA, since the increased utilization of CT/MRI, the mortality from BA has decreased from 40 to 60% to approximately 10%, although morbidity remains high [24]. Favorable prognostic factors across the literature have included GCS of 12 or greater as well as absence of criteria for septic shock [39].

8. Intraventricular abscess

Primary intraventricular abscess typically forms via slow growth from an area of cerebritis or ventriculitis [8]. A longitudinal single-center study on BA between 1986 and 2005 in Taiwan identified 179 patients with bacterial brain abscess, 62 of whom had IVORBA (45 on initial presentation, 17 later in hospital course). Pathogens implicated in IVORBA included Synema viridans (n = 10), mixed infection (10), and Klebsiella (6), although 13 cases had negative cultures [40]. Regardless of etiology, patients present with severe HA, meningeal irritation, and rapid deterioration usually within 10 days of the first presentation of meningeal signs [41]. emphasizing the importance of early diagnosis and treatment. Importantly, up to 34.6% of patients with BA can have concomitant meningitis, clouding the clinical picture and potentially complicating diagnosis [40]. Radiographic clues for IVROBA found on CT include intraventricular debris layering within the occipital poles and/or temporal horns, as well as ependymal enhancement within the ventricle (Figure 5) [41, 42].

Several factors can increase the risk of intraventricular rupture. For example, when compared to unilocular abscess, the risk of rupture is 4.2 times higher in multiloculated BA [10]. Strikingly, every 1 millimeter (mm) reduction in distance to ventricle has been associated with increased risk of rupture by 10% [40]. The proposed mechanism for preferential rupture into the ventricles rather than subarachnoid space is differential blood supply, resulting in reduced thickness of the abscess wall along the ventricles as previously mentioned [8]. Abscesses originating from hematogenous spread and those located in the temporal lobe have been shown to rupture the fastest [10, 39]. As such, aggressive CT-guided aspiration of deep abscesses, especially located in the parieto-temporal region improves outcome [14]. The danger of IVROBA is not limited to the days following the event, as it has been associated with 3.48 increase in relative risk for mortality 6 months after hospital discharge [22]. Identifying patients at risk for rupture is critical to optimize medical management and prioritize surgical intervention for BA with high-risk features, such as proximity to the ventricles.

9. Treatment of IVROBA

Additional treatment considerations are required when BA is complicated by intraventricular rupture. Pending up on the clinical status of the patient following abscess rupture, the role of external ventricular drain (EVD) placement and intrathecal antibiotics remains controversial [10, 43]. More often than not patients with IVROBA decline rapidly to a comatose state, partially due to the rise in intracranial pressure [43]. Mortality secondary to IVROBA has been estimated between 84 and 100% and has not declined as the mortality of unruptured brain abscesses has declined [8, 43]. Some authors suggest that emergent placement of an EVD, followed by ventricular irrigation and intrathecal antibiotic therapy plays a role in overall survival however given the high mortality, this treatment strategy remains underexplored [8, 39]. In reviewing case studies of IVROBA survivors present within the neurosurgical literature, Omar et al. describes varying methods of antibiotic delivery including intravenous, intrathecal via EVD or lumbar drain, and into the abscess cavity directly as well as varying methods of drainage from needle aspiration to open decompressive craniectomy [10]. Antibiotic courses ranged from 31 to 180 days intravenously and up to 42 days via intrathecal administration, which some authors feel decreases the likelihood of ventricular septations [10]. The authors summarize that 67% of surviving patients required EVD placement with 29% eventually requiring ventriculoperitoneal shunt placement [10]. Of note the length of EVD drainage ranged amongst institutions as did the prevalence of systemic alone versus systemic and intrathecal antibiotics; 43% of survivors receiving both systemic and intraventricular therapies [10]. Zeidman et al. describes a case of survival from IVROBA with combined medical and surgical management including immediate craniotomy with abscess and ventricular irrigation and debridement followed by an extensive course of intravenous and intrathecal antibiotics with routine exchange of the ventriculostomy catheters [43]. This case taken with the systematic literature review by Omar et al. highlights the need for further research into the standard of care for the neurosurgical emergency that is IVROBA.

Intrathecal antibiotics are more often utilized for ventriculitis and/or meningitis as they reliably result in sterilization of the cerebrospinal fluid and have demonstrated safety both via ventricular catheter and lumbar drain [14]. Takeshita et al. published a protocol for both intrathecal and intravenous antibiotic therapy that reduced mortality rate from IVROBA in their study to 38.7% [14]. The authors describe aspiration for abscesses larger than 2 cm with placement of an EVD if the patient demonstrated hydrocephalus and or ventriculitis, with VPS placement delayed for 8 weeks [14]. Of clinical importance, the authors paid attention to, often subtle, meningeal signs and noted that IVROBA was associated with progressive headache, decline in neurologic status, and increased meningeal signs [14].

Aside from neurologic decline, cerebral herniation syndromes and malignant cerebral edema, additional complications from IVROBA include septic arteritis, noncommunicating hydrocephalus with possible trapped ventricles and ventricular septations or loculations that prevent physiologic circulation of cerebrospinal fluid [11]. While early aggressive ventricular irrigation at the index surgery may help prevent this complication [11, 44], patients may require further procedures such as ventriculoperitoneal shunt placement or endoscopic exploration to break up the septations [11]. Although patients with meningitis and ventriculitis who were treated with intraventricular or intrathecal antibiotics had lower relapse rates, the standard of therapy administration is not well supported by the literature [10]. A retrospective cohort study (n = 105) demonstrated an 88.4% CSF sterilization rate in ICU patients with meningitis or ventriculitis who were treated with intraventricular antibiotics [45]. Remes et al. studied IVT via external ventricular drain (EVD) or lumbar drain (LD) in post-neurosurgical patients with meningitis and ventriculitis with similar efficacy. Most notably, the study reported a mean time to CSF sterilization of 2.2 and 2.6 days in EVD and LD groups, respectively [30].

With the evolution of neurosurgical technology and increased sophistication of our intracranial pressure monitors, continuous ventricular irrigation has been introduced for the management of intraventricular hemorrhage, ventriculitis, amongst other pathologies. For example, Hess et al. reports a case of IVROBA treated successfully with intraventricular vancomycin via a bilateral IRRAflow® catheter [46]. Prospective studies are needed to establish the optimal patient population, as well as the efficacy and safety of this route of administration.

10. Conclusion

IVROBA remains at the top of the list of neurosurgical emergencies given its high mortality rate however the persistent difficulty in diagnosing BA requires increased awareness on the part of all providers to consider BA in the differential for all patients, especially those with an infection. As neurosurgical technology has advanced, the mortality rate for BA has decreased, with a role for both medical and surgical management. Preventing IVROBA requires ongoing research and dedication to reduce the mortality, and hopefully at the same time morbidity, of BA for all patients.