Meningitis, encephalitis, and beyond: A practical intensive care unit guide to severe central nervous system infections

Abstract

Infections of the central nervous system can require immediate admission to an intensive care unit (ICU) because of initial severe neurologic presentation or systemic complications or may be encountered during the course of a hospital stay because of secondary complications. Brain infections include community-acquired or healthcare-associated meningitis, ventriculitis, encephalitis, and brain abscesses, which share specific clinical features but have different pathophysiology, risk factors, and outcomes. In this review, we will provide a practice-based overview of severe presentations of brain infections as encountered by the intensivist, focusing on early decision-making, the sequence of diagnostic and management decisions, and encountered complications. We illustrate the review with case examples to offer real-life illustrations of challenging decision-points. Key take-home points include understanding the first-hour priorities for de novo presentation of meningitis and encephalitis with a focus on early initiation of antimicrobial treatment; awareness of limitations in cerebrospinal fluid (CSF)-based diagnostics for early encephalitis and in healthcare-associated meningitis and ventriculitis, and the importance of an expedited, non-CSF-based diagnostic approach to brain abscesses.

Introduction

Brain infections, spanning community-acquired or healthcare-associated meningitis, ventriculitis, infectious encephalitis, and brain abscesses, may present with similar initial clinical features yet risk factors, pathophysiology, associated clinical course, and outcomes differ.

In this review, we provide an overview of brain infections for intensive care providers, focusing on early decision-making, sequence of diagnostic and management decisions, and complications encountered during the clinical course in the intensive care unit (ICU). To offer real-life illustration of challenging decision-points, the review is enhanced by case-based pictorials.

Bacterial Meningitis

Clinical suspicion triggers of bacterial meningitis

Paramount to diagnosis and rapid initiation of management of meningitis is consideration of its presence. Clinical suspicion is often prompted by abrupt onset of headache, malaise, and mental status change like in the illustrated case. High-risk populations, especially those with suppressed immune response, require careful thought as they may not demonstrate typical findings. Only 45% of patients with meningitis have the classic combination of four cardinal signs and symptoms of fever, headache, meningeal irritation, and altered mentation, but up to 95% will have at least two.^[1] Extracranial manifestation may be present depending on the specific pathogen, such as a petechial or purpuric rash (Neisseria meningitidis), pulmonary lesions (tuberculosis or mycoses), or a constellation of endocarditis, pneumonia, and meningitis dubbed “Austrian Syndrome” (Streptococcus pneumoniae). Signs of sepsis/septic shock are often present in adult patients with bacterial meningitis caused by N. meningitidis and S. pneumoniae.

Management of bacterial meningitis

In addition to systemic resuscitation, the goal for administration of antimicrobial therapy when bacterial meningitis is suspected is within the first hour—this may mean prior to obtaining images or laboratory diagnostics—as every hour of delay in administration increases the risk of poor outcome,^[2] while morbidity is reduced if a third-generation cephalosporin is given on presentation to the hospital for patients with all-cause community-acquired meningoencephalitis.^[3] Empiric treatment for suspected community-acquired meningitis in adults generally requires a combination of a third-generation cephalosporin (ceftriaxone 2 g intravenous injection [IV] every 12 h or cefotaxime 2 g IV every 4–6 h, adapted to renal function) and vancomycin 15–20 mg/kg IV every 8–12 h. Ampicillin 2 g IV every 4 h should be added if Listeria monocytogenes is suspected or when age is >50 years; in immunosuppressed patients, cephalosporins should be replaced by cefepime or meropenem if Gram-negative meningitis due to Enterobacteriae or Pseudomonas aeruginosa is suspected. ^[4] Co-empiric coverage for viral encephalitis (largely, herpes simplex virus [HSV] encephalitis) with IV acyclovir (10 mg/kg every 8 h in the absence of altered renal function) is often advisable until further history points and diagnostics are obtained. Corticosteroids can improve outcomes in select patient populations with acute bacterial meningitis:^[5] Mortality due to S. pneumoniae meningitis is reduced with dexamethasone but not for Hemophilus influenzae or N. meningitidis. Corticosteroid therapy is also associated with reduction in hearing loss and short-term neurological sequelae in high-income countries. Corticosteroids, while previously reported to be associated with increased mortality when given for meningitis due to L. monocytogenes,^[1] have more recently also been found to be beneficial for outcomes in listeria meningitis.^[6] Hence, adjunctive dexamethasone should be started together with antibiotics or within 6 h, unless contraindicated, and considered for discontinuation if diagnostic work-up reveals pathogens for which the risk–benefit profile is unfavorable.^[4]

Diagnosis of bacterial meningitis

Analysis of cerebrospinal fluid (CSF) remains the gold standard for diagnosis of central nervous system (CNS) infections. While risk of harm is generally low for gaining CSF via lumbar puncture (LP), concerns for raised intracranial pressure (ICP), due to altered mentation, focal neurological deficits, papilledema, should be evaluated with imaging prior to attempting an LP. Approximately 1% of patients with meningitis will develop cerebral herniation after LP.^[7] Another important consideration prior to LP is ensuring absence of coagulopathy, especially with increasing utilization of direct oral anticoagulants, as their impact on coagulation may not readily be measurable with conventional coagulation testing. Blood cultures should be collected as approximately 70% of patients with meningitis have concomitant bacteremia.^[8] CSF should be evaluated for cell count, glucose, protein levels, Gram stain, bacterial cultures, in addition to rapid polymerase chain reaction (PCR) assays. Commercially available multiplex PCRs (FilmArray meningitis/encephalitis panel) have shown overall percent positive agreement of 97.5% for common bacterial pathogens, 90.1% for viral pathogens, and 52% for Cryptococcus neoformans/C. gattii.^[9] Despite this, up to 10% of investigations will fail to yield a causative pathogen.^[10] Additionally, the overall negative predictive value is mostly reported upwards of 90%, while the positive predictive value varies depending on clinical level of suspicion, and can be much lower – between 37% and 70%.^[11]

Etiology of bacterial meningitis

The most common bacterial pathogens for community-acquired bacterial meningitis in adults remain S. pneumoniae and N. meningitidis, comprising 53%–72% and 27%–11%, respectively.^[12,13] Other culprit bacteria include H. influenzae (3%–27%) and L. monocytogenes (1%–4%), the latter more prevalent in patients older than 50 years and those with immune deficiencies or alcohol use disorder.^[10,13] Contiguous spread from proximal structures (e.g., facial sinuses, mastoid air cells) or hematogenous dissemination is frequently identified as the path of infection: nearly 52% of adult bacterial meningitis cases can be traced to an otogenic source.^[14]

ICU considerations of bacterial meningitis

Altered mental status places these patients at high risk for respiratory failure and aspiration pneumonia that invokes rapid evaluation of airway compromise, which is an independent predictor of poor outcome.^[3] Half of all patients with community-acquired meningitis will require ICU admission,^[15,16] often due to the requirement for mechanical ventilation, shock, cerebral edema and/or elevated ICP.

Source control—if there is a suspected source for seeding after initial work-up—should be accomplished quickly with joint decision-making between the intensivist, surgical teams, and infectious disease specialists.

Complications of bacterial meningitis

Cerebrovascular complications, likely mediated by inflammatory vasculitis and vasospasm, occur in approximately one-fifth of acute bacterial meningitis.^[17] Ischemic and hemorrhagic stroke complicates 14% of patients with bacterial meningitis and are associated with higher risk of mortality, unfavorable outcomes, and long-term sequelae.^[18] Cerebral vasospasm has been implicated as an underlying mechanism, but it is unclear how to best mitigate this complication, and whether calcium-channel blockers exert the same benefit as for vasospasm observed in subarachnoid hemorrhage. Case reports suggest cerebral blood flow augmentation (such as with inotrope and intra-arterial verapamil) may be beneficial.^[19] Cerebral venous sinus thrombosis, especially of the transverse sinus, frequently occurs with S. pneumoniae simultaneously with otitis media and sinusitis.

When there is suspicion for elevated ICP – anisocoria, persistent or fluctuating coma, increased optic nerve sheath diameter, decreased pupillary reactivity – invasive intracranial monitoring may be considered. While the role of ICP monitoring and CSF diversion in the setting of bacterial meningitis remains a topic of debate, it is estimated that at least two out of five will have elevations in ICP.^[15] Placement of external ventricular drain (EVD) might be beneficial, given its simultaneous ability to divert CSF and monitor ICP and has been reported to be associated with improved outcomes despite its heterogeneous use.^[20] However, this is likely hinging on selection of appropriate patients, as routine use of intracranial devices was not associated with improvements in mortality and morbidity in a large registry-based Danish cohort study.^[21]

Seizures occur in up to 37% of patients with meningitis, with as many as 11% of them progress to status epilepticus.^[3] Focal and subclinical seizures may be dramatically underrecognized given their inconspicuous appearance, especially in healthcare systems without continuous electroencephalographic (EEG) monitoring. In the absence of suspected or confirmed seizures, initiation of antiseizure medications (ASM) is not recommended. In patients with acute-phase seizures, the impact of seizure prophylaxis in the long term remains to be investigated.

Outcomes of bacterial meningitis

While global case fatality decreased from approximately 32% before 1961 to 15% since the 2010s,^[10] bacterial meningitis still poses high morbidity. Hydrocephalus and brain ischemia carry a high risk of poor outcomes,^[22] as are structural abnormalities on neuroimaging. If a patient is comatose and has otogenic meningitis, the odds ratio for poor outcome is 42-fold higher across a range of bacteria.^[23] Other independent risk factors associated with poor outcome include older age, chronic alcohol consumption, lower Glasgow-Coma-Scale score, motor dysfunction, and hemiplegia/hemiparesis and indicators of systemic compromise.^[3] The best predictors of positive outcomes are early initiation of anti-infectious treatment, including obtaining source control, and specifically, early (<24 h) initiation of third-generation cephalosporins, as well as ICU admission with aggressive prolonged supportive therapy.^[3]

Figures 1 and 2 present the clinical course and serial neuroimaging findings of a patient with severe pneumococcal meningitis complicated by cerebral edema, vasculopathy, and cerebral infarction.

Figure 1.

Non-contrast CT of head of a 27-year-old man presenting with severe headache, flu-like symptoms, fever, and shock. He is febrile, tachycardic and hypotensive. He rapidly deteriorates to obtundation. His initial head CT shows mild increase in ventricle caliber and parenchymal fullness with mild cerebral edema (A: axial window, B: parenchymal window) and complete opacification of the right middle ear and mastoid air cells (C: axial, bone window). Lumbar puncture reveals CSF with 451 red blood cells, 733 white blood cells (86% polynucleated cells), glucose 63 mg/dL (serum, 133 mg/dL), protein 121 mg/dL. He is started on ceftriaxone, vancomycin, acyclovir and ampicillin. Steroids are added when blood cultures and CSF cultures show gram-positive cocci and eventually grow S. pneumoniae. The patient undergoes right myringotomy and mastoidectomy.

CSF, Cerebrospinal fluid; CT, Computed tomography.

Figure 2.

CT angiogram of the brain on day 3 (A), obtained due to persistent obtundation, shows diffusely reduced cerebrovascular caliber with multifocal irregularities and stenoses, suggestive of diffuse vasculopathy/vasospasm in the setting of bacterial meningitis. MRI brain on day 4 shows multifocal infarcts (B; DWI sequence) and enhancing lesions in the left basal ganglia area (T1-post, not shown), consistent with tissue necrosis. Systolic blood pressure augmentation to >130 mmHg results in improved cerebrovascular velocities (as measured by bedside transcranial Doppler ultrasonography) and is subsequently maintained with norepinephrine. Hospital course is further complicated by persistent obtundation, hypernatremia (due to sodium augmentation for cerebral edema and central diabetes insipidus); hyperchloremia with acute kidney injury; requirement for prolonged mechanical ventilation, ultimately discharge to a long-term-acute-care facility with a tracheostomy and gastrostomy.

CT, Computed tomography; DWI, Diffusion-weighted imaging; MRI, Magnetic resonance imaging.

Viral Encephalitis

Clinical suspicion triggers, context, and etiology of viral encephalitis

Clinical consideration is often prompted by progressive change in mental status and malaise, as in the illustrated case. Nearly 20% of patients with infectious encephalitis are comatose on admission.^[24] Key clinical findings include a combination of convulsions (up to half), focal neurologic findings (53%), and fever (77%).^[25] Overall, approximately 40% of encephalitis cases are infectious,^[25] and viruses represent 82% of identified culprits. Herpes viruses are the most common at nearly two-thirds.^[26] The main aspect of consideration for the intensivist is the context, a concern for encephalitis rises: in de novo admissions from the community, HSV, varicella zoster virus (VZV), and enteroviruses make for up to 90% of identified culprit viruses. However, if altered mentation or new neurologic worsening in a hospitalized patient sparks a differential diagnosis for encephalitis, etiology may include less commonly observed pathogens, especially in the elderly, where VZV and L. monocytogenes are more common,^[27] and in immunosuppressed or transplant populations where human herpesvirus 6 (HHV-6), Epstein Barr virus (EBV), and cytomegalovirus (CMV) must be ruled out.

Management of viral encephalitis

The most important management priority is early initiation of antiviral treatment, usually with IV acyclovir, to cover HSV/VZV until CSF is obtained. IV acyclovir (10 mg/kg, every 8 h, adapted to renal function) should be started immediately; for VZV encephalitis, a higher dose, 15 mg/kg of acyclovir every 8 h, has been recommended.^[28] Outcomes worsen with every hour of treatment delay,^[3] especially in HSV encephalitis.^[29] Additionally, rapid admission to the ICU should be sought, as delays have been linked to poorer 3-month outcomes.^[3] Treatment for HHV-6 and CMV encephalitis is done with ganciclovir and/or foscarnet.^[30] Treatment of influenza encephalitis includes rapid administration of oseltamivir and sometimes high-dose steroids.^[31] Management of other viruses is largely supportive. While not generally recommended, steroids are often used in sicker patients and/or to counter cerebral edema and, perhaps because of that selection bias, have not clearly been found to lead to an outcome benefit in non-high-risk patients.^[32] EEG, either intermittent or continuous, should be performed in all patients with altered mental status or focal neurologic findings to rule out non-convulsive seizures. Epileptiform findings, seizures, or status epilepticus will be found cumulatively in more than half of patients,^[33] and absence of reactivity is a poor prognostic marker for severe HSV encephalitis. Prophylactic administration of ASM is not recommended. No strong data or consensus exists on the potential role of invasive multimodal neuromonitoring for infectious encephalitis, and decisions are best made on a case-by-case basis.

Diagnosis of viral encephalitis

Considerations on safety of LP for CSF analysis are the same as outlined for bacterial meningitis. CSF analysis is the diagnostic pillar and will usually reveal lymphocytic pleocytosis and mildly elevated total protein. However, up to 1 in 4 patients exhibit absence of pleocytosis, and this does not reliably rule out viral encephalitis.^[34] CSF-PCR for herpes viruses is highly sensitive and specific, albeit an initial negative PCR may be seen with early testing in 4% of HSV encephalitis.^[35] MRI brain with contrast is the preferred imaging modality as a head computed tomography (CT) is too insensitive for the various often subtle parenchymal changes seen in encephalitis. While typical imaging findings may be found for different viruses (Table 1),^[24] none of these is diagnostic for viral encephalitis.^[36] Bilateral involvement, restricted diffusion, and possible hemorrhage are associated with unfavorable outcomes.^[22]

Table 1.

Magnetic resonance imaging findings in viral encephalitis.

Virus	MRI characteristics	Brain areas
Herpes simplex 1 [88]	T2 hyperintensity, restricted diffusion, SWI (hemorrhage or petechial), parenchymal swelling	Mesial temporal, frontal lobes
Herpes simplex 2 [88]	T2 hyperintensity, restricted diffusion, SWI	Diffuse
Varicella zoster [89]	T2 hyperintensity, restricted diffusion, SWI (petechial)	Cerebral cortex, thalami, basal ganglia, cerebellum
Human herpesvirus 6 [90]	T1 hypointensity, T2 hyperintensity, diffusion restriction	Mesial temporal (hippocampus, amygdala), insula, frontal lobe
Cytomegalovirus [88,91]	Variable: enhancing lesions, diffusion restriction, parenchymal swelling	Variable
Influenza virus [92]	Brain edema; T2 hyperintensity; DWI restriction	Diffuse (edema); deep grey (symmetric); corpus callosum
West Nile virus [93]	T2 hyperintensity, restricted diffusion	Deep structures (basal ganglia, thalami, midbrain), cerebral peduncles, substantia nigra

DWI, Diffusion-weighted imaging; MRI, Magnetic resonance imaging; SWI, Susceptibility-weighted imaging.

ICU considerations and complications of viral encephalitis

Requirement for mechanical ventilation, either primary neurogenic due to poor mental status or ICP, or secondary due to aspiration and subsequent hypoxic failure, is the most prominent intensive care need, reaching 50%.^[25] Predictors for need of ventilation are higher admission SOFA score, elevated ICP, lower GCS score, and thrombocytopenia.^[37] Ventilator-related complications, seen in up to half, are mostly pneumonia and atelectasis. Morbidity with higher mortality further stems from elevated ICP, status epilepticus, and autonomic instability.^[38,39] Other common ICU complications include urinary tract infections, venous thromboembolism, or pressure sores at reported frequencies on the lower average spectrum.^[37] Specific viruses may have a propensity for specific complications, for example, bleeding for dengue or chikungunya, flaccid paralysis, and neurogenic respiratory failure for West Nile. Another important consideration for viral infections is their ability to trigger intense immune responses, including autoimmune encephalitis. The mechanisms for this are variable, including innate immune pathway activation and molecular mimicry.^[[40], [41], [42]^] While autoimmune encephalitis after HSV is usually a delayed phenomenon associated with anti-NMDA-receptor antibody synthesis, immune activation after other viruses may present as a continuum to the acute illness with disproportionate worsening or lack of improvement in acute viral encephalitis.

Outcomes of viral encephalitis

ICU mortality may reach 1 in 4, while >80% of survivors can experience a good outcome.^[37] In a large observational series, functional independence at 3 months was observed in only half, irrespective of the etiology.^[25] However, recovery trajectories and sequelae vary depending on the underlying cause of encephalitis.

Figures 3 and 4 illustrates the clinical course and serial MRI findings of a patient with influenza-associated encephalopathy/encephalitis.

Figure 3.

MRI of the brain without contrast, showing faint FLAIR hyperintensity (A) without convincing DWI restriction (B) in the bilateral mesial temporal lobes (no correlation on ADC maps; not shown), obtained on day of presentation of a 69-year-old woman with malaise, fever, and rapidly worsening confusion, requiring intubation after suffering a generalized seizure. She is started on ceftriaxone, vancomycin, acyclovir and levetiracetam.

ADC: Apparent diffusion coefficient; DWI, Diffusion-weighted imaging; FLAIR, Fluid-attenuated inversion recovery; MRI, Magnetic resonance imaging.

Figure 4.

Due to persistent coma, MRI brain is repeated with contrast on day 4, and shows bilateral signal intensity changes of the mesial temporal lobes, insula, left medial frontal lobes (A) and anterior cingulate gyri with abnormal enhancement (B), sparing the basal ganglia, and additional involvement of the brainstem and cerebellum as well as small foci of susceptibility artifact within the bilateral temporal lobes (C), thalami, and bilateral cerebellum (not shown). CSF shows 2 white blood cells, no red blood cells, total protein of 193 mg/dL, and glucose of 103 mg/dL (serum glucose 120 mg/dL). CSF-PCR (meningoencephalitis PCR Panel) and CSF cultures are negative. However, pneumonia panel PCR testing is positive for Influenza A. The patient is started on oseltamivir. Additional CSF and serum studies reveal profound elevation of IL-6, a cytokine involved in the innate inflammatory immune response after influenza. The patient is therefore treated with a dose of tocilizumab. Three weeks after admission, she is discharged to rehabilitation with a tracheostomy and gastrostomy, awake, able to interact to simple commands, and starting to regain motor function. By the time of discharge from rehabilitation one month later (i.e., 7 weeks after her initial presentation), she ambulates, and both tracheostomy and gastrostomy have been removed.

CSF, Cerebrospinal fluid; MRI, Magnetic resonance imaging; PCR, Polymerase chain reaction.

Healthcare-related Meningitis and Ventriculitis

Clinical suspicion triggers and predisposition of healthcare-related meningitis and ventriculitis

Headache, fever, meningeal irritation, seizures, altered mental status, or nausea in a post-neurosurgical patient may be part of the clinical course, but are very non-specific. Fever in neurocritical ill patients is highly prevalent, and is a manifestation of the brain injury itself in nearly half.^[43] In essence, healthcare-related meningitis/ventriculitis should come to mind in anyone with even non-specific neuro-infectious signs or symptoms who has had a neurosurgical intervention or has a neurosurgical device. Risk factors for post-neurosurgical meningitis include underlying disease – tumor surgery, severe head injury, and subarachnoid hemorrhage pose the highest risk – experience in surgical techniques, CSF leaks, concomitant infection at incisional sites, perioperative steroid use, and concomitant EVD placement.^[44] Well-established risk factors for EVD-related infections include insertion technique, lack of infection control bundles, duration of catheterization, presence of intraventricular hemorrhage, diabetes mellitus, and site leakage, while the role of CSF sampling frequency is not uniformly confirmed as an independent risk factor.^[45,46] Risk calculators, incorporating various factors with different area-under-the-curve (AUC) (0.76–0.89) are available.^[[47], [48], [49]^] The biggest impact on infection prevention with reduction to rates of <5% is the implementation of bundles, with hand hygiene and pre-insertion antibiotics constituting the most common bundle elements.^[50] The type of EVD, silver-impregnated or antibiotic-coated, seems to shift the pathogen profile rather than reduce infections overall.^[[51], [52], [53]^] Bolt-mounted EVDs overall possess higher catheter accuracy, better mechanical reliability, and reduced CSF leakage with similar infectious and hemorrhagic complications,^[54] and, combined with silver-impregnation, may have a favorable profile.^[55] Additionally, insertion in the ICU may carry higher infection risk when compared with insertion in the operating room.^[55] Clinical practice guidelines recommend peri‑insertional antibiotics (typically consisting of a single dose of antibiotic with coverage against Staphylococcus species, such as cefazolin) and protocolized sterile placement techniques.^[56] The benefit of antibiotic prophylaxis beyond this time frame is questionable and may come at the cost of increased infection with resistant organisms or Clostridium difficile.^[53,57]

Epidemiology of healthcare-related meningitis and ventriculitis

Postoperative meningitis occurs in up to 9% of all patients undergoing cranial neurosurgery, and the frequency of EVD-related infection ranges from 2% to 36%, depending on the diagnostic method, study population, and modifiable risk factors.^[58] Of note, definition heterogeneity for nosocomial and EVD-related infections is omnipresent and weakens available data, including meta-analyses.^[59] Nonetheless, morbidity and mortality – 40% for all healthcare-related ventriculitis^[60] and reaching up to 80% depending on the pathogen – render EVD-related infections a dreaded complication.^[61] While common pathogens used to be cutaneous Gram-positive organisms such as coagulase-negative staphylococci, Staphylococcus aureus, and Propionibacterium acnes, Gram-negative pathogens including P. aeruginosa, Acinetobacter baumanii, and Enterobacteriaceae are now making for half or more of pathogens^[44,62] in CSF cultures, and are more challenging to treat due to increasing drug resistance.^[61]

Diagnosis of healthcare-related meningitis and ventriculitis

Diagnosis and management of healthcare-related meningitis and ventriculitis remain challenging, and many management recommendations are based on expert opinion due to a lack of rigorous data^[63] (Table 2). Interpretation of clinical findings and CSF parameters are often difficult. CSF parameters are affected by prior brain injury, neurosurgical procedures, and previous or ongoing antibiotic administration, and are thus unreliable.^[63] CSF cultures remain the most important test to establish a diagnosis of healthcare-related meningitis and ventriculitis, recognizing that CSF cultures are often negative (an estimate of sensitivity revealed <60%) and that the CSF culture should be held for 10 days to allow slow and delayed pathogen emergence.^[63] In a study assessing 1828 patients with EVDs with biweekly surveillance CSF sampling, CSF profiles were not discriminative for aseptic vs. infectious inflammation, and nearly a third was started on antibiotics because of concern of infection, while only 4% yielded a positive CSF culture.^[64] Important considerations for CSF sampling include increased infection risk with frequent proximal sampling; distal sampling may be an alternative,^[65] and better diagnostic profile of lumbar-puncture-obtained CSF.^[66] The cell index – CSF cell counts in relation to serum counts – has failed to reveal convincing reliability.^[67] Various CSF biomarkers aim at better diagnostic ability of healthcare-related CNS infections; to date, no single CSF parameter can reliably predict or exclude healthcare-related CNS infections. Elevated CSF lactate, procalcitonin, or their combination, may be useful in diagnosing healthcare-related CNS infections, and elevated serum procalcitonin may be useful in differentiating CSF abnormalities due to surgery or ICH from those due to bacterial infection.^[68] CSF lactate cutoff values between 1.9 mmol/L and 5.4 mmol/L have been reported to diagnose nosocomial bacterial EVD-infection, but no single standard exists.^[69]

Table 2.

Diagnosis of healthcare-related meningitis and ventriculitis^[63].

Diagnostic indices	Considerations for interpretation
CSF parameters (cell count, protein, glucose)	Affected by brain injury, neurosurgical procedures, antibiotics → interpretation difficult
Cell index (CSF/serum)	Limited data; unreliable; required repeated CSF sampling
CSF lactate	Possibly helpful, however variable cut-off values (1.9–5.4 mmol/L)
Nucleic acid amplification tests	Limited data; no current multiplex PCR approved in this context
CSF culture	Gold standard; often negative; allow up to 10 days to culture

CSF, Cerebrospinal fluid; PCR, Polymerase chain reaction.

Nucleic acid amplification tests, such as 16S PCR, on CSF may increase the ability to identify a pathogen, lower false positive clinical diagnoses, and decrease the time to making a specific diagnosis; yet these methods lack standardized assays, workflows, and agreed-upon cut-off values.^[70,71] Importantly, the only two currently FDA-approved multiplex PCR assays to detect pathogens in CSF (BioFire FilmArray Meningitis/Encephalitis [M/E] panel and QIAstat-Dx Meningitis/Encephalitis) are geared toward community-acquired meningitis/encephalitis and do not cover the major culprit pathogens for healthcare-related meningitis and ventriculitis. In a recent study repurposing a blood-based multiplex PCR test (BioFire Blood Culture Identification 2) for diagnosis of healthcare-related meningitis and ventriculitis, the specificity for identification of pathogens reached 90%, while sensitivity was low at 50% when the CSF sample Gram-stain was negative.^[72] CSF markers that are being explored for aiding in the diagnosis of healthcare-related CNS infections include CSF levels of IL-1β, TNF-α, IL-6, and IL-8,^[73] but are not yet available or validated in a larger scheme. Novel diagnostic approaches include color-based, machine-learning-enhanced CSF analysis for early infection detection.^[74]

Management and impact on outcomes of healthcare-related meningitis and ventriculitis

Empiric antibiotic therapy must cover the most likely pathogens, that is, include Gram-negative coverage, and penetrate the blood–brain and blood–CSF barriers. Guidelines recommend vancomycin, plus either an anti-pseudomonal cephalosporin or carbapenem,^[63] with fluoroquinolones or aztreonam as the alternative in the case of beta-lactam allergy. Early device removal and avoiding implantation of a second device will shorten illness duration^[75] and potentially improve outcomes,^[76] yet, depending on the clinical situation, this may not always be possible or advised. The duration of treatment for healthcare-related meningitis is mostly based on common practice rather than true evidence, and commonly spans 21 days for Gram-negative, and 10–14 days for Gram-positive meningitis.^[63] No consensus exists on indications for intrathecal treatment, and no antibiotic is FDA-approved for intrathecal use. Off-label application is considered as rescue or adjunct therapy for severe ventriculitis, persistently positive CSF cultures, multi-drug-resistant pathogens, intolerance of systemic antibiotic administration, or when device removal is not feasible. Treatment of multidrug-resistant ventriculitis with adjuvant intrathecal colistin, which is less afflicted by pathogen resistance for Acinetobacter baumannii and P. aeruginosa,^[61] resulted in improved infection control and reduced mortality in a small single-center series,^[77] and thus could potentially be considered as a rescue regimen in individual cases. If the hardware is in place, removal and subsequent extended treatment is endorsed.^[63] If an EVD is removed or exchanged, the duration of therapy is sometimes shortened, while therapy for 10–14 days is usually suggested if the catheter is retained. Differentiation of a true infection from a contamination or device colonization will affect the therapeutic approach and is also addressed in the guidelines.^[63] Prophylactic catheter exchange has not shown benefit and is not routinely performed.^[78] Ventricular lavage, that is, flushing the infected ventricular system and thereby removing inflammatory debris, improving CSF circulation, and enhancing antibiotic penetration, has emerged as an adjunct management strategy for severe ventricular infection, with lower mortality, shortened length of hospitalization, and potentially better neurologic outcomes.^[79]

Brain Abscesses

Clinical suspicion triggers and source of brain abscesses

Headaches constitute the most common presenting symptom in up to 70%, followed by altered mentation (around 65%), focal neurologic findings (around 60%), and seizures (25%–35%).^[80] By the time of admission to the ICU, a suspicion or consideration of brain abscess is usually established through the combination of symptoms and initial imaging results, often in the form of a non-contrast head CT scan that reveals a circular hypodense lesion. Most brain abscesses, that is, up to 50%, originate through local spread from infections of the teeth, ear, mastoid, or the parafacial sinuses.^[80] Hematogenous spread, estimated etiology in 20%–35%, stems from pneumonia, pulmonary arteriovenous malformations, bronchopleural fistulas, or heart disease such as endocarditis, or cyanotic heart disease in children. Direct introduction from trauma or neurosurgical procedures often occurs delayed,^[81] while no source can be identified in up to 35% of cases. Anatomically, the frontal lobes are most often affected.

Management priorities: Maximizing diagnostic yield early

The ideal and recommended modality to delineate the features of such mass lesions and differentiate from other ring-enhancing brain lesions – namely, primary and secondary brain cancers – is gadolinium-enhanced MRI, as early as possible.^[82] The typical features of brain abscesses on MRI are that of ring-enhancement, and elevated signal intensity on diffusion-weighted imaging (DWI) from abscess pus, along with poor apparent diffusion coefficient (ADC).^[83] The diagnostic performance in distinction of brain abscess from ring-enhancing tumors through DWI/ADC is excellent, with a pooled sensitivity and specificity of 92% each in a recent systematic review,^[84] while recognizing that differentiation based on DWI/ADC falls short in 8% of cases. From a practical perspective, it is important to assess whether a patient can safely lie flat without motion for a contrasted MRI scan; if there are concerns, especially about airway protection, intubation may be necessary to obtain optimal imaging data. As opposed to other types of brain infections, immediate antimicrobial therapy may not be recommended if a brain abscess is considered, for two reasons: (1) the main differential diagnoses are non-infections (i.e., brain tumors, strokes), and (2) diagnostic yield may decline when antibiotics precede the acquisition of tissue. Withholding antimicrobials until further diagnostics are obtained of course does not apply if there are systemic symptoms or an expected delay of surgical diagnosis.^[82]

Approach to diagnostic sequence and management of brain abscesses

Once a presumptive diagnosis of brain abscess is established by the combination of symptoms and imaging, the most pressing management decisions are (1) whether to treat surgically or conservatively, and (2) which symptom management is required. A summary of the approach to managing brain abscesses is provided in Table 3.

Table 3.

Approach to management for brain abscesses.

Principle	Details
Maximize diagnostic yield early	•MRI •Source identification
Decision for or against surgical approach	•Neurosurgical approach when applicable and feasible •Biopsy/aspiration/resection
Symptom management	•Cerebral edema •Elevated intracranial pressure •Seizures •Systemic symptoms related to infection and CNS dysfunction
Source control	•Antimicrobial treatment •Local control/surgery

CNS, Central nervous system; MRI, Magnetic resonance image.

Laboratory work-up of brain abscesses

Routine laboratory-based diagnostic tests should include blood cultures, assessment of inflammatory burden (e.g., C-reactive protein, erythrocyte sedimentation rate), and, if in context, HIV-testing.^[82] CSF analysis via LP is usually of low yield, as the abscess wall prevents spilling into the CSF space, and may come at high risk, if brain compression and mass effect are present, and is thus not routinely recommended. Additional imaging should target the identification of source, for example, through thorax imaging or pulmonary angiogram, especially in the case of multifocal or recurrent abscesses.^[82] Pulmonary arterio-venous malformations predispose to brain abscesses by creation of a right-to-left shunt that bypasses the normal filtering function of the lungs, allowing bacteria to directly enter the brain via systemic circulation. Bacteria often stem from infections, mostly in the oral space that evade capillary trapping in the lungs.

Surgical diagnosis and management of brain abscesses

Surgical management offers three main advantages: it is the best approach to obtain a firm diagnosis and detailed microbiologic data, allows decompression of space-occupying lesions, and reduces bacterial inoculum. In >80% of cases, neurosurgical management of brain abscesses is strongly recommended as soon as possible, ideally within a 24-h timeframe, in all patients in whom feasible and indicated^[82] with a conditional recommendation to withhold antimicrobials until tissue is obtained.^[82] The different surgical approaches are biopsy and sampling, aspiration, or full resection of the brain abscess. Intraventricular rupture of brain abscess carries a high mortality, up to 80%, and subtotal resection of the abscess wall is often employed in abscesses that are ill-formed or within 1 cm of the ventricle wall. The less invasive surgical modalities, biopsy and aspiration, still allow the diagnostic advantage but also carry a risk of spillage and no clear advantage in outcomes of treatment. Overall, aspiration is the most commonly chosen modality, in about two-thirds, while about one in five will undergo craniotomy with resection and 13% will be treated with antimicrobials only.^[85] Recognizing that data on brain abscesses and management are most available from Denmark and European countries, while slim from North America or Asian continents, a large Danish study assessing 1-year mortality of patients with brain abscesses from 1982 to 2016 showed that mortality was higher (24%) in patients treated conservatively vs. those treated with neurosurgery (14%), with an adjusted mortality ratio for surgically treated patients of 0.78 (95% CI: 0.62–0.97),^[86] although an updated analysis from 2007 to 2020 revealed that aspiration or excision of brain abscess was not associated with improved 6-month mortality.^[80] As such, the decision-making for or against neurosurgical approach also needs to balance the yield of already available data and the risk of the surgery. Surgical approach may not be needed if there are positive blood culture results and a strong impression that the bacteremia seeded and caused the abscess; in case of an existing diagnosis, such as neurocysticercosis, or if the detected lesions are small or may represent early cerebritis and the neurologic exam is good (usually, with a Glasgow Coma Scale Score of >12). Surgical risk may further outweigh benefits if the abscess location is inaccessible or in an eloquent brain area, if the characteristics are challenging by shape, surrounding edema, or size, or if there is high rupture risk, especially with proximity of the abscess to the ventricle wall where the abscess wall is often thinner.^[80] While causing less neuronal damage and afflicted with lower surgical risk and morbidity than abscess resection, aspiration may not be complete, and the risk of relapse can be as high as 32%. Indications for excision after initial aspiration and drainage are lack of clinical improvement (ideally in the short term, i.e., within 1 week), abscess growth, or evidence of elevated ICP.

ICU complications of brain abscesses

Immediate management requirements may also occur through the mass impact of the abscess, and/or its surrounding cerebral edema: Tissue damage in brain abscesses is primarily caused by the acute inflammatory host response to the invading pathogen. Corticosteroids, often dexamethasone 10 mg IV followed by 4 mg IV every 6 h, may reduce mass effect and cerebral edema and is therefore recommended for patients with severe symptoms, peri abscess edema, or impending herniation, although high-quality randomized controlled trials have yet to be performed.^[82] Although there is potential risk of lowering antibiotic penetration with steroids, mortality was overall not affected under administration of dexamethasone in a pooled analysis of existing data.^[87]

Seizures may be caused by either the abscess itself or the impact on surrounding cortex. About one-third of patients with brain abscesses will present with new-onset seizures, which should be managed with ASM in addition to addressing the abscess. Primary prophylaxis against seizures is generally not recommended.^[82] Seizure risk is higher for frontal abscesses, large abscess size, surgical management, and in case of prior history of neurosurgery or strokes.^[86] In patients with poor neurologic condition, evaluation with (continuous) EEG should routinely be considered to avoid missing non-convulsive seizures or status epilepticus.

Antimicrobial therapy of brain abscesses

Recommendations for initial broad antibiotic coverage of brain abscesses based on presumed etiology and target pathogens are outlined in Table 4 and in recent guidelines.^[82] Duration of antibiotics is generally for 6–8 weeks IV, balancing risk of relapses and recurrence with individual factors including tolerance, drug toxicity, and healthcare costs.^[82] As antibiotics require longer-term IV access, maintenance of reliable peripheral IV access and transition to a peripherally inserted central catheter may be necessary to complete treatment. Studies evaluating early transition to oral antibiosis are ongoing.

Table 4.

Empiric antimicrobial therapy for brain abscesses based on presumed source.

Etiology	Covering	Antibiotic
Oral, otogenic or sinus	Mixed, oral	metronidazole + ceftriaxone/cefotaxime cefepime (if pseudomonas suspected)
Hematogenous	S. aureus, S. viridans or other streptococci	vancomycin/linezolid
	gram-negative	metronidazole + ceftriaxone/cefotaxime/cefepime
	gram positive + negative	vancomycin + metronidazole + cefepime
Post-op neurosurgical	S. aureus, streptococci, enterococci, P. aeruginosa	vancomycin + meropenem (or cefepime/ceftazidime)
Penetrating head trauma	S. aureus + enterobacterales spp Tap water contamination	vancomycin+ceftriaxone/cefotaxime/cefepime (+ metronidazole if paranasal sinuses involved)
Unknown source	broad	Vancomycin + metronidazole + ceftriaxone/cefotaxime/cefepime

Considerations for ICU course and outcome of brain abscesses

Data on complications of patients with cerebral abscesses during ICU course are slim. Close attention needs to be paid to neurologic status, as lack of improvement or worsening may indicate a lack of response to chosen therapy, progression of accompanying symptoms (ICP, seizures, cerebral edema), or even intraventricular rupture of abscess – the latter expectedly with abrupt decline and high morbidity. At discharge, more than one-third of patients will still rely on assistance,^[80] and proactive planning for rehabilitation measures may facilitate disposition.

Figures 5 and 6 demonstrate a case of brain abscess and its clinical evolution and neuroimaging findings from diagnosis through treatment and follow-up.

Figure 5.

Non-contrast CT of the head of a 39-year-old man with headaches 3 weeks after a dental extraction, showing a large, cystic-appearing hypodense left parieto-occipital mass lesion, with global cerebral edema and brain compression with effacement and left-to-right shift of the left lateral ventricle (A) and subsequent MRI of the brain with and without contrast showing a ring-enhancing (B, T1-post-contrast sequence), DWI-hypointense (C, DWI sequence) and FLAIR-hypointense (D, T2 FLAIR-sequence) lesion with small surrounding edema.

CT, Computed tomography; DWI, Diffusion-weighted imaging; FLAIR, Fluid-attenuated inversion recovery.

Figure 6.

CT head of the 39-year-old man with left parieto-occipital mass lesion after neurosurgical aspiration and drainage, showing hemorrhagic post-operative products in the aspiration cavity (A). Intravenous injection antimicrobial coverage (vancomycin, metronidazole & ceftriaxone) is initiated. Upon abscess culture growing Staphylococcus warneri, a bacterium found as component of healthy human microbiome of skin and mucosae, antibiotic regimen is narrowed to intravenous injection vancomycin. However, headaches and malaise recur one week later (B), and the patient requires neurosurgical abscess resection. He continued to have speech and motor impairment with gait difficulties and was discharged to rehabilitation with a peripherally inserted central line for antibiotic continuation for 6 weeks.

CT, Computed tomography.

Conclusions

Brain infections represent a management emergency. For bacterial meningitis and viral encephalitis, the initial diagnostic and management pathway overlaps, with early antimicrobial treatment initiation at its core. The management of brain abscess, on the other hand, hinges on early acquisition of MRI imaging to further guide diagnostic and therapeutic approach. Requirement for ICU admission is generally determined by level of consciousness, ability to maintain respiratory function, and/or presence of cerebral edema or elevated ICP among possible complications. Early initiation of appropriate treatment, especially with antibiotics, is key for outcomes. A summary of key diagnostic considerations, priorities and pitfalls is outlined in Figures 7 and 8.

Figure 7.

Flowchart depicting diagnostic pathway

Figure 8.

Key priorities and pitfalls in diagnosis and management of meningitis, encephalitis, healthcare-related meningitis and ventriculitis, and brain abscesses.

CRediT authorship contribution statement

Katharina M. Busl: Writing – review & editing, Writing – original draft, Data curation, Conceptualization. Nate Ordway: Writing – original draft, Data curation. Romain Sonneville: Writing – review & editing, Supervision, Data curation.

Managing Editor: Jingling Bao