Commonly encountered central nervous system infections in the intensive care unit

Learning objectives.

By reading this article, you should be able to:

• •Recognise the common clinical features associated with CNS infections in intensive care.
• •Identify the organisms causing CNS infection in the community, in the immunocompromised patient or returning traveller, and in patients with healthcare-associated ventriculitis and meningitis.
• •Interpret the results of CSF analysis and neuroimaging appropriately.
• •Select the most appropriate antimicrobial agent and treatment duration based on the clinical features and results of investigations.

Key points.

• •CNS infections account for around 3.9% of infections in the ICU but are associated with significant morbidity and mortality.
• •Early recognition and initiation of treatment are key to the management of CNS infections and improving outcomes.
• •Urgent brain imaging should be performed in patients with clinical evidence of increased intracranial pressure before lumbar puncture, but this should not delay treatment with antibiotics, as a delay is associated with increased mortality.
• •Geographical location and immune status should be considered when determining the likely causative organism.
• •Autoimmune encephalitis should be considered in all patients presenting with suspected CNS infection, particularly when microbiological tests are negative.

Central nervous system infections account for 3.9% of all infections in adult ICUs, at 3.9% of the total. They are associated with up to 29% mortality and often lead to persistent neurological deficits, including cognitive impairment in 32% of adults who survive meningitis.^1,2 Diagnosis can be challenging, and timely management is of the utmost importance. Here, we present an overview of the most commonly encountered CNS infections, including meningitis and encephalitis. We aim to provide a framework to assist with diagnosis and management of such infections, often starting with empirical treatment. We also discuss specific subgroups of patients, including the returning traveller, immunocompromised patients, healthcare-associated ventriculitis and meningitis (HAVM), brain abscess and subdural empyema (SE), in addition to the possible alternative diagnoses when microbiology results are negative. CNS infections in children and neonates are beyond the scope of this article.

Meningitis

Bacterial meningitis is defined as inflammation of the meninges, particularly the pia and arachnoid mater, associated with the invasion of bacteria into the subarachnoid space.³ It is thought that bacterial invasion into the CNS is preceded by high-grade bacteraemia, with invasion occurring at highly vascularised sites, such as the choroid plexus and leptomeningeal blood vessels. A further source of entry is direct access to the CNS in association with local infection, such as sinusitis, or via dural defects (which can be iatrogenic; traumatic, including after surgery or base of skull fracture; or spontaneous). Bacterial invasion results in endothelial activation and leucocyte infiltration. Whilst this limits bacterial invasion, it may also result in neuronal damage and adverse outcomes.³

Clinical presentation

The classical symptoms of meningitis are fever, headache, neck stiffness and altered mental status. Up to 95% of patients will present with two out of four of these symptoms.⁴ Additional signs may include focal neurological deficits, such as cranial nerve palsies, aphasia, hemiparesis, seizures, coma and a rash most commonly associated with Neisseria meningitidis infection.⁴

Epidemiology

The global burden of disease attributable to meningitis remains high. Incidence depends on geographical location, ranging from 0.5 per 100,000 population in Australia to 207 per 100,000 in South Sudan.⁵ The overall mortality from community-acquired meningitis is around 20% and up to 30% for pneumococcal disease.⁶ Vaccination programmes have reduced the incidence significantly, and the number of deaths attributable to meningitis decreased by 21% between 1990 and 2016.⁵

Haemophilus influenzae was previously the most common causative pathogen. It has been near eradicated after successful vaccination programmes worldwide.^5,7 It now accounts for 1–2% of cases of meningitis, usually in association with underlying causes, such as otitis media or sinusitis. At present, Streptococcus pneumoniae is responsible for the majority of cases of meningitis in adults, although the incidence of pneumococcal meningitis has reduced by 25% since the introduction of the vaccine.⁸ However, serotype replacement has been observed, where expansion of non-vaccine serotypes has occurred.⁷ Hyposplenism, alcoholism, human immunodeficiency virus (HIV), and chronic liver or kidney disease predispose to pneumococcal disease.

Neisseria meningitidis is the second most common cause of meningitis, being most prevalent in adolescents. The mean incidence of invasive meningococcal disease in the UK and Ireland is twice that of the rest of Europe (1.33 vs 0.62 per 100,000).⁹ The incidence has been declining over the past two decades with the introduction of vaccination programmes. Listeria monocytogenes is the third most common cause of bacterial meningitis in adults and is more frequent in those aged over 60 yrs. Additional risk factors for Listeria include immunocompromised states, alcohol dependency, diabetes and malignancy. Staphylococcus aureus is encountered infrequently and often in association with endocarditis.⁸

Viral meningitis is usually less severe and progresses more slowly than bacterial meningitis. It is encountered in young adults, particularly young women between the ages of 20 and 40 yrs.⁶ A number of viruses are implicated, the most frequent being enterovirus, herpes simplex virus (HSV) and varicella zoster virus (VZV). In addition, HIV and lymphocytic choriomeningitis virus, a rodent-borne arenavirus, can cause an aseptic meningitis. Less common entities include Epstein–Barr virus (EBV), cytomegalovirus (CMV) and mumps virus. In contrast to encephalitis, it is often HSV 2 rather than HSV 1 that causes viral meningitis. In addition, HSV 2 is the commonest cause of recurrent lymphocytic meningitis, also referred to as Mollaret's meningitis.⁶

Treatment

Bacterial meningitis is a medical emergency. Treatment should be initiated within 1 h of arrival to hospital in tandem with diagnostic interventions.⁸ Antibiotic therapy should not be deferred longer than this to obtain imaging studies, and each hour of treatment delay increases the likelihood of unfavourable outcome by 10–30%.10, 11, 12 Empirical antibiotic therapy should be guided by the likely infecting organisms, local resistance patterns and age of the patient (Box 1). Most guidelines suggest third-generation cephalosporins as first line, as these agents have good penetration of the meninges and are bactericidal against pneumococcus and meningococcus. If in an area with a risk of pneumococcal resistance, vancomycin or rifampicin should be added. Amoxicillin should be added for patients aged >60 yrs or for patients younger than this with additional risk factors for Listeria meningitis.⁶ There is no evidence to guide duration of treatment in adults, and recommendations have been extrapolated from trials in children. Antibiotics can be stopped after as early as 5 days if a patient is deemed to have recovered for meningococcal disease and at 10 days for pneumococcal disease.⁶

Box 1.

Empirical therapy for suspected meningoencephalitis. ∗To be commenced within 1 h. ∗∗If in an area with high levels of pneumococcal resistance to penicillin. ∗∗∗If aged >60 yrs or other risk factors for Listeria infection present.

Empiric Treatment∗

• Cefotaxime 2 g every 4 h or ceftriaxone 2 g every 12 h

• With or without vancomycin 10–20 mg kg⁻¹ every 12 h∗∗

• With or without amoxicillin 2 g every 4 h∗∗∗

• + Aciclovir 10 mg kg⁻¹ every 8 h

• + Dexamethasone 10 mg every 6 h

The use of corticosteroids in acute bacterial meningitis has been examined in a Cochrane review.¹³ This included data from 25 studies in both adults and children (4,121 patients). The authors concluded that corticosteroids significantly reduced hearing loss (13.8% compared with 19.0% in patients receiving placebo) and neurological sequelae (17.9% vs 21.6%).¹³ Mortality was reduced in patients with pneumococcal meningitis (29.9% vs 36.0%) but not the overall group, and treatment only appeared to be beneficial in high-income countries.¹³ In line with this, guidelines recommend that dexamethasone be started shortly before or with the first dose of antibiotics in all patients suspected of having bacterial meningitis. If not given with the first dose of antibiotics, steroids can be given up to 12 h after antibiotics are started. Treatment should be stopped if a pathogen other than S. pneumoniae or Mycobacterium tuberculosis is isolated. Steroids should be continued for 4 days in pneumococcal meningitis. For tuberculous (TB) meningitis, they should be given at high dose for 6–8 days then tapered over 4–8 weeks.^6,8

There is no benefit, and there is potentially an increased risk of harm associated with the use of therapeutic hypothermia in meningitis. There is insufficient evidence to make a conclusion regarding the use of prophylactic anti-epileptics, hyper-osmolar therapies or intracranial pressure-based treatment in meningitis.^6,8

Encephalitis

Encephalitis is defined as inflammation of the brain. It is a pathological diagnosis. However, for practical reasons, surrogate markers of brain inflammation are used, including changes in CSF and imaging.¹⁴ Encephalitis can be infectious, post-infectious or autoimmune. When infectious, entry to the CNS is specific to the pathogen, occurring via retrograde travel along neural pathways or by haematogenous spread. Once across the blood–brain barrier, pathogens enter neural cells, causing release of cytokines, cytotoxicity, inflammation and tissue damage. Autoimmune encephalitis occurs as a result of autoantibodies directed against intracellular or cell surface receptors binding to their target and causing neuronal dysfunction.¹⁵

Clinical presentation

Classical features of encephalitis include fever, headache, altered mental state, focal neurological signs and seizures. In a study of the clinical presentation and causes of encephalitis in England, more than 70% of patients had fever at presentation, with more than 50% having headache, seizures and personality change.¹⁶ The frequency of seizures varies, being most common in autoimmune encephalitis and HSV infection. Focal neurological signs are most common with VZV infection. Gastrointestinal and respiratory symptoms are frequent irrespective of the cause, particularly acute disseminated encephalomyelitis, whereas urinary symptoms are more frequent in M. tuberculosis infection.¹⁶ Features suggesting an autoimmune aetiology are subacute clinical presentation, extrapyramidal signs, intractable seizures and hyponatraemia.¹⁴

Epidemiology

The incidence of infectious encephalitis is thought to range from 1.5 to 7 per 100,000 per year.¹⁷ It varies with geographical location, population and the occurrence of epidemics. The aetiology is unknown in up to 50% of cases. In those with a known aetiology, infectious causes predominate, with HSV being the most frequent pathogen. Herpes simplex virus encephalitis is caused by HSV 1 in 90% of cases. In addition, HSV 2 causes around 10% of HSV encephalitis and is more commonly found in patients who are immunocompromised. Varicella zoster virus is the second most commonly encountered pathogen, followed by enterovirus or M. tuberculosis depending on location.^16,17 Travel and being immunocompromised need to be considered when determining the likely cause, and these factors are discussed in more detail later. Up to one-fifth of cases of encephalitis (initially thought to be infective in aetiology) may in fact be autoimmune, with no underlying organism identified, highlighting the importance of considering and testing for these conditions.¹⁶

Mortality from encephalitis ranges from 4% to 36%, with those who are immunocompromised being at increased risk of death.^16,17 Overall mortality rate has been reported as 12% but substantially higher for those with M. tuberculosis infection (30%) or VZV (20%).¹⁶ The risk of severe disability is nearly 50%, being highest in those with antibody-associated encephalitis followed by HSV.¹⁶ In HSV encephalitis, factors associated with adverse outcome include older age, coma, presence of restricted diffusion on MRI and delay in starting acyclovir.¹⁸

Treatment

Treatment should be initiated within 6 h on clinical suspicion of encephalitis and ideally after CSF sampling and neuroimaging.¹⁴ Acyclovir 10 mg kg⁻¹ three times daily is recommended, as it has good antiviral activity against HSV and VZV, the most common causes of viral encephalitis. The use of acyclovir has reduced mortality of HSV encephalitis from 70% to current levels of 20–30%. It is a relatively safe drug but should be dose adjusted in renal impairment. Treatment should continue for 14–21 days in proven HSV encephalitis and a repeat lumbar puncture (LP) performed at this stage. If CSF polymerase chain reaction (PCR) is still positive for HSV, treatment should continue until a negative result is obtained. Oral valaciclovir can be considered as an alternative to acyclovir after 2–3 weeks.¹⁴ Specific treatments recommended for other viral causes of encephalitis include aciclovir at a higher dose of 10–15 mg kg⁻¹ for VZV; pleconaril and i.v. immunoglobulin (IVIG) may be considered for enteroviral infection of the CNS and ganciclovir for CMV infection. Steroids are not routinely recommended but can be considered for VZV encephalitis with a vasculitic component or under specialist supervision for HSV CNS infection.

Diagnostic investigations for CNS infections

Lumbar puncture

Lumbar puncture is central to the diagnosis. It should be performed within 1 h for patients with suspected bacterial meningitis and within 6 h for suspected encephalitis, in patients in whom it is deemed safe to do so.^6,14 Parameters measured include the opening pressure, CSF appearance, white cell count and differential, protein level, glucose concentration with reference to a concurrent plasma glucose level and Gram stain for bacteria. The characteristic CSF features of the different causes of meningitis are outlined in Table 1. A small proportion of patients with acute bacterial meningitis will have a lower CSF white cell count than predicted.¹⁹ Early enteroviral infection can be associated with a predominance of neutrophils in the CSF. Tuberculosis, listeriosis, brucellosis or partially treated bacterial meningitis may be associated with a lymphocytic CSF pleocytosis.¹⁴ Caution must be applied when interpreting results after a traumatic tap, as the CSF can be contaminated by blood and protein. Various correction formulae can be applied, the most common of which is to subtract 1 mg dl⁻¹ of protein for every 1,000 CSF red blood cells and to allow one additional white blood cell for every 500–1,000 red cells.

Table 1.

Typical CSF characteristics in the immunocompetent patient with meningitis and encephalitis.

Investigation	Normal	Bacterial	Viral	Tuberculosis	Fungal
Opening pressure	10–20 cm	Increased	Normal/mildly increased	Increased	Increased
Colour	Clear	Cloudy	Clear	Cloudy/yellow	Clear/cloudy
White cell count (× 106 L−1)	<5	100–50,000	5–1,000	<500	0–1,000
Differential	Lymphocytes	Neutrophils	Lymphocytes	Lymphocytes	Lymphocytes
CSF/plasma glucose	50–65%	<40%	Normal	<30%	Normal or low
Protein (g dl−1)	<0.45	Increased	Mildly increased	Significantly increased	Increased

Cerebrospinal fluid lactate has been suggested as a useful aid in distinguishing bacterial from viral CNS infections, with a cut-off level <2 mmol L⁻¹ essentially ruling out bacterial disease. It has a sensitivity of up to 98%, but this decreases to less than 50% in those pre-treated with antibiotics, limiting its usefulness in this context.²⁰

A CSF Gram stain can have additional value in the presence of negative CSF culture and when antibiotics have been given before the LP. It has a sensitivity of between 50% and 99% depending on the causative organism and prior antibiotic treatment, being highest for pneumococcal and meningococcal meningitis. It may be the only positive microbiological finding.^6,8,21

Cerebrospinal fluid culture is the gold standard for diagnosis of bacterial meningitis. It is positive in up to 85% of patients if the LP is done before the start of antibiotics. The positivity rate differs according to the causative agent, being highest for H. influenzae, followed by S. pneumoniae and then meningococcal disease.²¹ Cerebrospinal fluid culture allows sensitivities to be performed to guide antibiotic therapy. Diagnostic yield drops with prior treatment with antibiotics, with CSF sterilisation occurring in as little as 2 h for meningococcal disease and 4 h for pneumococcal meningitis.²²

Polymerase chain reaction should be performed on CSF in all patients with suspected meningitis and encephalitis. Meningococcal and pneumococcal PCR should be sent in all patients with suspected meningitis and CSF PCR for HSV 1 and 2, VZV and enteroviruses in suspected encephalitis or viral meningitis, as this will identify up to 90% of known causes of viral meningoencephalitis.^6,14,23 It has incremental value over CSF Gram stain and culture. More recently, the development of multiplex PCR assays has enabled concurrent testing for an array of bacterial, viral and fungal pathogens responsible for CNS infection. This allows rapid and simple processing of samples, requiring only a small volume of CSF, with results available in 1–2 h.²⁴ Polymerase chain reaction may be negative in early HSV encephalitis; therefore, a repeat LP at 24–48 h is recommended if clinical suspicion remains high. If PCR is not performed early in cases of suspected HSV encephalitis, CSF and serum HSV-specific immunoglobulin G antibody testing is a further tool to confirm diagnosis. Herpes simplex virus-specific antibodies can be detected in CSF from around 10 to 14 days after the onset of illness and can be used to establish diagnosis from Days 10–12. The decision to perform antibody testing should be in conjunction with microbiology or infectious diseases. Further CSF microbiological testing depends on immune status, geography and travel history (outlined in Table 2).

Table 2.

Additional diagnosis and investigations to consider in specific groups of patients. ∗All investigations in this section should be performed irrespective of the cause of immunosuppression. ^†Investigations for returning traveller and autoimmune encephalitis are specific to the condition under consideration. Acute disseminated encephalomyelitis (ADEM), John Cunningham virus (JC), Myelin oligodendrocyte glycoprotein (MOG), White cell count (WCC).

Group	Disorder	Investigations to consider
All patients		CSF opening pressure CSF WCC and differential CSF protein Paired CSF and serum glucose CSF Gram stain Blood and CSF cultures CSF PCR for meningococcus, pneumococcus, HSV 1 and 2, VZV and enterovirus
Immunocompromised patients∗	HIV After transplant Haematological malignancy Immunosuppressant therapy	CMV and EBV PCR HHV 6/7 PCR JC virus PCR HIV serology Toxoplasma serology with or without PCR Cryptococcal antigen/India ink stain Aspergillus PCR Galactomannan CSF M. tuberculosis culture and acid-fast bacilli PCR
Returning traveller†	Cerebral malaria Flaviviridae Japanese encephalitis Dengue encephalitis St Louis encephalitis West Nile encephalitis Tick-borne encephalitis Togaviridae Eastern encephalitis Western encephalitis Venezuelan encephalitis Reoviridae Colorado tick fever Rhabdoviridae Rabies encephalitis Chandipura virus Henipaviridae Nipah virus	Rapid blood antigen test Thick and thin blood films CSF PCR/serology CSF PCR/serology CSF PCR/serology CSF PCR/serology CSF PCR/serology CSF serology CSF serology CSF serology CSF PCR/serology CSF PCR/serology CSF serology CSF PCR/serology
Autoimmune encephalitis†	Anti-NMDA receptor encephalitis Anti-VGKC complex encephalitis Bickerstaff's encephalitis Paraneoplastic encephalitis Hashimoto's encephalitis ADEM	Anti-NMDA receptor antibodies Anti-VGKC complex antibodies Anti-GQ1b antibodies ANNA 1/Anti-Hu ANNA 2/Anti-Ri Anti-Ma1/Anti-Ma 2 Anti-amphiphysin Anti-thyroid peroxidase antibodies MOG antibodies

Contraindications to LP

Contraindications to LP are outlined in Box 2. Brain imaging should be performed before LP when there is a concern for increased intracranial pressure to prevent cerebral herniation. The indications for imaging are the presence of focal neurological signs, papilloedema, continuous or uncontrolled seizures and a Glasgow Coma Scale (GCS) score ≤12.^6,26 Antibiotics should not be delayed to obtain LP and imaging, as this can lead to increased mortality.¹² The majority of patients presenting to ICU will have a reduced level of consciousness necessitating brain imaging, so empirical therapy should be started whilst awaiting imaging studies and LP.

Box 2.

Contraindications to lumbar puncture, adapted from the National Institute for Health and Care Excellence recommendations.²⁵

Contraindications to lumbar puncture

• •Signs suggesting raised intracranial pressure, or reduced or fluctuating level of consciousness
• •Relative bradycardia and hypertension
• •Focal neurological signs
• •Abnormal posture or posturing
• •Unequal, dilated or poorly responsive pupils
• •Papilloedema
• •Abnormal ‘doll’s eye’ movements
• •Shock
• •Extensive or spreading purpura
• •After convulsions until stabilised
• •Coagulation abnormalities, or coagulation results outside the normal range, or platelets below 100 × 10⁹ L⁻¹ or receiving anticoagulant therapy
• •Local superficial infection at the lumbar puncture site
• •Compromised respiratory function

Despite the mentioned recommendations, there is controversy over the level of consciousness at which to safely perform an LP. Levels range from a GCS score of less than 13 to less than 8, with some simply stating ‘altered level of consciousness’. Swedish guidelines for the management of meningitis removed altered level of consciousness from their list of recommendations for CT and in a subsequent study showed that there was earlier initiation of antibiotics and a lower mortality associated with this change.²⁷ There is also disagreement over whether immunocompromised states should be included as an indication for CT. Immunocompromised patients may be more at risk for mass lesions, but there is no evidence that they are more likely to be at risk of herniation if they do not have clinical features associated with space-occupying lesions. However, it remains an indication for imaging in some guidelines.^6,8,14 The authors would generally proceed with LP before CT if there were no clinical features suggesting space-occupying lesion. It is also important to follow guideline recommendations for timing of LP in relation to anticoagulant therapy.

Blood tests

All patients with suspected CNS infection should have blood cultures within 1 h of presentation to hospital, ideally before antibiotics are given. Blood cultures are positive in up to 74% of patients and can be useful in patients in whom LP is contraindicated or delayed for imaging to be performed. Serum PCR is recommended for meningococcus and pneumococcus and can remain positive for several days after antibiotics. Serum markers of inflammation, including C-reactive protein and procalcitonin, are useful markers to monitor the progress of infection and inflammation. Serum lactate and plasma glucose will allow interpretation of the CSF result.^6,8 An HIV test should be sent in all patients with suspected CNS infection for a number of reasons. These include the fact that patients with advanced HIV can present with more uncommon CNS pathogens, they are more susceptible to a number of typical CNS infections and HIV seroconversion can present as a self-limiting meningoencephalitis.¹⁴

Imaging

Neuroimaging is used as a diagnostic tool to rule out space-occupying lesions and to detect complications of CNS infection. Initial CT in bacterial meningitis is usually normal. Contrast-enhanced CT and MRI may show leptomeningeal enhancement, but subarachnoid signal hyperintensity on MRI has the highest sensitivity for diagnosis of bacterial meningitis.^28,29 Complications of meningitis, including cerebral oedema, hydrocephalus, SE, abscess and encephalomalacia, can be identified on imaging. The source of meningitis can also be revealed, such as sinusitis, otitis media, skull base fracture or recent intervention.²⁸

Imaging is recommended as soon as possible in suspected encephalitis. CT is abnormal shortly after admission in 25–80% of patients with HSV encephalitis. MRI is the investigation of choice and should be performed within 48 h of admission if the patient's condition allows.¹⁴ Early MRI is abnormal with gyral oedema and cortical/subcortical hyperintensity being seen in up to 90% of cases.^14,28 Restricted diffusion can be seen in the inferomedial temporal and inferior frontal lobes, spreading to the cingulate gyri and insular cortex. Changes are usually bilateral and asymmetrical but can be unilateral early in the disease process. Haemorrhage may be seen in subacute infection.²⁸ The most common finding in VZV encephalitis is a large-vessel vasculopathy. This can appear as an ischaemic or haemorrhagic infarct or intracranial vascular abnormalities on CNS imaging.¹⁴

Findings on imaging in TB meningitis include enhancement of the basilar cisterns and occasional calcification of the basal meninges and periventricular hypodensity. There may be secondary hydrocephalus. Tuberculomas can form once infection spreads to the brain parenchyma, producing solid caseating lesions.^28,29

Human immunodeficiency virus encephalitis can present as multiple symmetric sub-centimetre foci that spare cortical U fibres. This can progress to chronic HIV encephalopathy with brain atrophy, ventricular enlargement and more extensive white matter abnormality.²⁸ Progressive multifocal leukoencephalopathy (PML) shows up as asymmetric small scattered white matter lesions involving the subcortical and periventricular white matter, and the cortex is usually spared. Advanced disease presents with large confluent lesions extending to U fibres.^28,29 Cryptococcal infection can have a wide spectrum of findings on neuroimaging, although it usually appears as multiple non-enhancing hypodense cysts in the basal ganglia. Cryptococcomas, which can be a solid mass or disseminated lesions in the midbrain and basal ganglia, are found in a small number of cases.²⁹ Toxoplasmic encephalitis will show as multiple ring-enhancing lesions located in the basal ganglia, thalami and corticomedullary junction. The ‘eccentric target’ sign is considered specific for toxoplasmosis. The main differential for these appearances is CNS lymphoma.²⁸

Electroencephalogram

An EEG does not need to be requested routinely but should be performed if there is suspicion of seizure activity, particularly if there is concern for subtle motor or non-convulsive seizures. It should also be performed to look for encephalopathic changes if there is doubt as to whether mildly altered behaviour is secondary to an organic or psychiatric cause.¹⁴

The EEG can be abnormal in up to 80% of those with diagnosed encephalitis. Changes include diffuse or generalised high-amplitude slow waves, spike-and-wave activity, bilateral slow triphasic waves and periodic lateralised epileptiform discharges (PLEDs). The PLEDs were once thought to be pathognomonic of HSV encephalitis but can be seen in a multitude of disorders.^14,30 Changes located in the temporal lobe are also suggestive of HSV encephalitis. An extreme delta brush pattern (rhythmic delta activity with superimposed bursts of beta-frequency activity) on EEG is highly suggestive of anti-N-methyl d-aspartate (NMDA) receptor encephalitis. Other findings in autoimmune encephalitis, which are less specific, include frontal intermittent rhythmic delta activity, excess beta activity, generalised rhythmic delta activity and PLEDs.³⁰

Specific groups of patients

Immunocompromised patient

The population of immunocompromised patients is increasing. Any immunosuppressed patient presenting with new neurological symptoms should be considered to have a CNS infection, and investigation and treatment should be instituted rapidly, as these are associated with a poor prognosis. The causative organism varies according to the cause of immunosuppression. In patients with HIV infection, the most likely causes are HIV encephalitis, cerebral toxoplasmosis, tuberculous meningitis, cryptococcal meningitis and PML.³¹ Cytomegalovirus, EBV and human herpesvirus (HHV) 6 and 7 encephalitis are also more common.¹⁴ With solid organ transplantation, the greatest risk of CNS infection is within the first year, and CNS aspergillosis, cryptococcal meningitis, mucormycosis, Nocardia infection and PML are common causes. The probability of CNS infection is greater again in patients with haematological malignancy, particularly after allogenic stem cell transplant.³¹ Central nervous system infection with common pathogens, such as S. pneumoniae, is also increased in patients who are immunocompromised. Computerised tomography is recommended before LP in the majority of guidelines.^8,14 MRI should be performed as soon as is feasible. Additional microbiological testing that should be considered is outlined in Table 2.

Returning traveller

Returning travellers are at risk of CNS infection from a variety of pathogens not commonly encountered in the UK and western Europe; these patients should be investigated and managed in consultation with a tropical and infectious disease specialist (Table 2). Pathogens vary with geographical location, season and climate; the most commonly encountered infections are cerebral malaria and TB meningitis.¹⁴ The geographical distribution of arthropod-borne viruses depends on the life cycle and activity of their insect vectors, and infections frequently occur in epidemics. Japanese encephalitis is probably the most prevalent cause of viral encephalitis worldwide and is encountered in Asia. Arboviral encephalitides encountered in the USA include western equine, eastern equine, Californian and St Louis encephalitis. West Nile virus is now endemic in the USA, and Venezuelan encephalitis is found in South America.¹⁵ Dengue fever has rarely been found to cause encephalitis in travellers returning from endemic areas. Of the tick-borne fevers, Colorado tick fever virus can be found in North America and tick-borne encephalitis virus in eastern Europe. The incidence of rabies encephalitis has substantially reduced as a result of vaccination. A second Rhabdoviridae, Chandipura virus, has caused outbreaks of encephalitis in India, and Nipah virus, a paramyxovirus more commonly encountered in Malaysia, has caused outbreaks in Kerala in recent years.

CNS mimics

There has been increasing recognition of non-infectious mimics of encephalitis in recent years with the availability of new biomarkers, and the diagnosis should be considered in all patients presenting with suspected encephalitis.^14,32 These can be autoimmune, paraneoplastic or post-infectious. A more subacute presentation, extrapyramidal features, intractable seizures and hyponatraemia can be suggestive.

The most recognised autoimmune encephalitis is anti-NMDA receptor antibody-associated limbic encephalitis. It is more common in young females and can be associated with ovarian teratoma. It can occur post-HSV encephalitis and should be considered in anyone with a protracted course or relapse after HSV encephalitis. Anti-voltage-gated potassium channel (VGKC) limbic encephalitis is also well recognised and tends to occur in older males. In a small proportion of patients, it is associated with an underlying malignancy, most commonly small-cell lung cancer or a thymoma.¹⁴ Bickerstaff's brainstem encephalitis is another autoimmune encephalitis with antibodies to neuronal cell surface antibodies, in this case anti-GQ1b antibodies. It can present with brainstem features, such as ataxia and ophthalmoplegia. It is considered a Guillain–Barré variant and can follow a preceding viral illness.

Paraneoplastic encephalitides are associated with antibodies against intracellular neuronal components. These include anti-neuronal nuclear antibody (ANNA)-1/Hu, ANNA-2/Ri, Ma-1, Ma-2 and anti-amphiphysin. Thymoma, small-cell lung cancer and neuroendocrine tumours are the most frequently associated malignancies, and encephalitis can precede the onset of malignancy. Acute disseminated encephalomyelitis is an immune-mediated post-infectious encephalitis associated with multifocal demyelination, encephalopathy, ataxia, optic neuritis and cranial nerve involvement. It is usually temporarily associated with vaccination or a preceding viral illness, and myelin oligodendrocyte glycoprotein antibodies can be found, although not in all cases.³² Hashimoto's encephalopathy is another mimic of CNS infection and should be considered in patients with features of an autoimmune thyroiditis and positive thyroid peroxidase antibodies.³²

Early detection and treatment are key to management of these disorders and improve prognosis (Table 2). Treatment comprises immunosuppression with high-dose steroids, usually methylprednisolone; IVIG; and consideration of plasmapheresis in patients with an incomplete response. Rituximab and cyclophosphamide should also be considered early in those with a failed or partial response to immunotherapy.³² All patients with an autoimmune encephalitis should be screened for underlying malignancy.¹⁴

Healthcare-associated ventriculitis and meningitis

Healthcare-associated ventriculitis and meningitis refers to CNS infection in the setting of neurosurgical devices or procedures and after head trauma. It can occur at the time of index hospitalisation or months to years later. Healthcare-associated ventriculitis and meningitis is considered a discrete entity from community meningitis because it differs in terms of pathogenic mechanisms and the spectrum of organisms involved.³³ Incidence varies according to device/procedure, but all are associated with significant morbidity and mortality.

Healthcare-associated ventriculitis and meningitis should be suspected in any patient after neurosurgical intervention or head trauma with new onset fever, lethargy, nausea, mental status change, seizures or signs of meningeal irritation. Depending on the site of device insertion or the procedure, there may be erythema, tenderness, wound discharge or evidence of inflammation, for example peritonitis with ventriculoperitoneal shunt. Gram-negative bacteria and S. aureus are more commonly encountered in HAVM. Other typical organisms include coagulase-negative staphylococci and Cutibacterium acnes.³³

A CSF sample should be sent if there is clinical suspicion for HAVM with the same parameters measured as for community meningitis. A CSF culture is the most important investigation to establish diagnosis of HAVM. However, a negative culture or Gram stain and normal CSF biochemistry do not rule out infection. Prolonged CSF culture up to 10 days may be necessary for growth of C. acnes. Diagnosis can be difficult because clinical signs and symptoms can be variable and CSF changes subtle, making it difficult to distinguish between infection and postoperative or post-device placement change. Additional diagnostic CSF to consider are CSF lactate and PCR, including 16s rRNA PCR. Cerebrospinal fluid β-d-glucan and galactomannan may be useful if fungal meningitis is a concern.³³ Frequent routine sampling of extra-ventricular drains (EVDs) should not be performed, as this increases the risk of infection.³⁴ Imaging is usually performed but not mandatory for diagnosis, with MRI being the investigation of choice.

Empirical therapy is targeted at frequently encountered organisms and includes drugs that penetrate the CNS, achieve adequate CSF concentration and are bactericidal. The recommended regimen is vancomycin and an anti-pseudomonal beta-lactam antibiotic i.v. Intraventricular antimicrobial agents can be considered in patients with a poor response to i.v. therapy. In the majority of cases, this use is off-label but is included in guidelines. Penicillins and cephalosporins should not be given intrathecally, as they are associated with neurotoxicity. Removal of an EVD or shunt will be required in the majority of cases, where these are present. The timing of shunt reinsertion depends on the causative organism, with longer courses needed for S. aureus and Gram-negative bacilli, the presence of CSF abnormalities and time from negative CSF culture. Treatment should be in close collaboration with microbiology and neurosurgical teams.

To reduce risk of HAVM, periprocedural prophylactic antibiotics are recommended at the time of CSF shunt or EVD insertion and for neurosurgical procedures. Antimicrobial-impregnated shunts have been shown to reduce the risk of HAVM.³⁵ Patients with a base of skull fracture and CSF leak should also receive pneumococcal vaccination, as pneumococcus is a significant pathogen in this setting.

Brain abscess

A brain abscess is a localised infection in the brain. It starts as an area of cerebritis, which develops into an encapsulated collection of pus. The incidence is believed to be between 0.3 and 0.9 cases per 100,000 population in developed countries, being more common in men and from ages 30–40 yrs old.³⁶ The most common source is a contiguous focus of infection, such as otitis media, mastoiditis, sinusitis and meningitis. Abscesses can also follow haematogenous spread of endocarditis, pulmonary or dental infection or after neurosurgery or cranial trauma.³⁶ Presenting features include headache, fever, focal neurological deficit and seizures, depending on the abscess location. Causative organisms depend on the source of infection and are often polymicrobial in nature. Bacteria are responsible for more than 95% of abscesses in immunocompetent patients with streptococcal species, anaerobes, Gram-negative bacilli and staphylococci being commonly encountered. In immunocompromised patients, including HIV infection, cryptococcus, TB, fungi and rarer bacterial pathogens, such as Nocardia, should be suspected.³⁷ Diagnostic work-up should include imaging with contrast-enhanced CT showing a rim-enhancing lesion surrounded by vasogenic oedema. Magnetic resonance imaging is preferable if available. Stereotactic aspiration of abscesses greater than 1 cm should be performed, if possible, to aid with diagnosis and guide antimicrobial treatment. Empiric treatment comprises a third-generation cephalosporin (e.g. ceftriaxone) in combination with metronidazole for a duration of 6–8 weeks.^36,37 Indications for neurosurgical drainage include abscesses greater than 2.5 cm in size, periventricular lesions at risk of intraventricular rupture and those caused by difficult-to-treat bacteria or fungi. With timely diagnosis and treatment, a cure rate of up to 90% can be expected.³⁶

Subdural empyema

Subdural empyema is a focal infection consisting of a collection of pus between the dura and arachnoid membranes. It is typically associated with spread of craniofacial infections, such as sinusitis or otitis. It can also develop post-trauma or post-neurosurgical procedures. Symptom onset can be rapid and includes headache, fever, signs of meningeal irritation and raised intracranial pressure, focal neurologic deficits and seizures.³⁶ The causative organisms depend on the underlying source but include streptococci (with Streptococcus milleri being common), staphylococci, Gram-negative bacteria and anaerobes.³⁸ MRI is the imaging modality of choice, similar to brain abscess, as CT is less sensitive. Lumbar puncture is generally contraindicated, given the risk of herniation.³⁷ Management of SE should be instituted promptly with a combined medical and surgical approach. Empirical antibiotic therapy should be tailored to the source of infection, local guidelines and resistance patterns but typically includes a third-generation cephalosporin, vancomycin and metronidazole.³⁸ Surgical intervention should be performed to decompress the brain and evacuate the collection. With timely diagnosis and management, mortality can be as low as 6–9%.³⁸

Conclusions

Central nervous system infections account for a small but not insignificant proportion of ICU infections and are associated with substantial morbidity and mortality. Maintaining a high index of suspicion along with early recognition and treatment are key to improving outcomes. Guidelines for empirical treatment should be followed when initiating antimicrobial therapy, and epidemiological factors and local resistance patterns are taken into account when selecting appropriate therapy. Cerebrospinal fluid analysis and neuroimaging are the main diagnostic tools, and immune status, travel history/geographical location and neurosurgical interventions should be taken into consideration when conducting investigations to establish the causative pathogen. In patients with atypical presentation, negative microbiological testing and poor response to antimicrobial therapy, autoimmune encephalitis should be considered in the differential diagnosis.

Declaration of interest

The authors declare that they have no conflicts of interest.

Biographies

Aisling McMahon FJFICMI, FCAI is a consultant intensivist and anaesthetist in the Mater Misericordiae University Hospital.

Ian Conrick-Martin FJFICMI, FCAI, MRCPI is the director of critical care in the Mater Misericordiae University Hospital Dublin, which includes the National Isolation Unit. This facility cares for patients from across Ireland, who have hazardous and highly infectious diseases. As such, he commonly encounters patients requiring treatment for a number of complex infectious conditions. He has previously worked in the Royal Brompton and Birmingham Hospitals.

Matrix codes: 1E01; 2C03; 3C00

Level 2: 2C03: Diagnosis and management of shock, infection and sepsis

Level 3: 3C00: Adult ICM

MCQs

The associated MCQs (to support CME/CPD activity) will be accessible at www.bjaed.org/cme/home by subscribers to BJA Education.