Managing acute central nervous system infections in the UK adult intensive care unit in the wake of UK encephalitis guidelines

Abstract

The acute central nervous system infections meningitis and encephalitis commonly require management on intensive care units. The clinical features often overlap and in the acute phase–altered consciousness and seizures may also need to be managed. In April 2012, the first UK national guideline for the management of suspected viral encephalitis was published by the British Infection Association and Association of British Neurologists, and other key stakeholders, and included a simple management algorithm. The new guideline results from evidence demonstrating a number of common oversights in the standard management of suspected viral encephalitis in many settings. In combination with British Infection Association meningitis guidelines, evidence-based approaches now exist to facilitate the non-expert managing patients with suspected central nervous system infections. Here we bring together these guidelines and the supporting evidence applicable for intensivists into a single resource.

Introduction: defining the problem

Infective meningitis and encephalitis are the most common forms of suspected central nervous system (CNS) infections that present to intensivists.¹ Less commonly CNS infections cause intracranial abscess, cystic disease (such as neurocysticercosis), or lead to cerebrovascular sequelae such as the diffuse microvascular occlusion of ‘cerebral malaria’ or a vasculitis complicating meningitis or encephalitis).^2,3 Other causes of CNS inflammation, such as antibody-associated autoimmune encephalitis, are increasingly recognised and should be considered in those with appropriate clinical features.⁴

In the western world, the incidence in adults is estimated to be 0.6–4/100,000/year for bacterial meningitis and 5.2–7.6/100,000/year for viral meningitis. Encephalitis demonstrates a similar incidence of 2.73–8.66/100,000/year.^2,5–10 Whilst cases of proven CNS infection are relatively uncommon, suspected cases are common; in some series approximately four patients are routinely investigated for every one case diagnosed.⁹ Nevertheless, a low index of suspicion, with urgent investigation and treatment, is required because delays are associated with a significant increase in morbidity and mortality.^9–17

Infective meningitis is predominantly due to viral or bacterial infection, with viral forms usually following a more benign course.¹⁸ In contrast, in the 30–63% of cases for whom a cause is identified, encephalitis is usually viral and results in serious sequelae.¹⁹ In the UK, of the cases in whom a viral cause is identified, 90% are due to herpes simplex (HSV), varicella zoster (VZV) and enteroviruses.⁵

With the launch of the British meningitis C and pneumococcal vaccination programmes and the British Infection Association (BIA) meningitis guidelines and algorithm in 2003, clinicians now appear to be aware of the importance of urgent investigation and treatment for meningitis.^9,17,20 Mortality rises from 7% to 26% if antibiotics are not administered within the immediate hours following admission, findings mirrored in the intensive care cohort of patients with bacterial meningitis.^16,17,21 Perhaps less widely recognised is that delays in treatment for viral encephalitis dramatically increases morbidity and mortality, particularly if >48 hours from admission.^12,13 Indeed current guidelines recommend treatment within 6 hours of admission.⁸ Time to antiviral therapy represents the single most important modifiable risk factor for poor outcome.^12,13 Without aciclovir treatment, mortality from HSV encephalitis is at least 70% and only 3% of patients survive without sequelae.⁷ However, with timely aciclovir, the mortality is reduced to 10–20% and 40–50% survive without sequelae.⁷ Nevertheless, comparative studies have demonstrated that there are significantly longer delays in suspicion of the diagnosis, delays in investigation and delays in treatment in comparison to suspected meningitis, largely due to a lack of awareness of standards of management.⁹

With an incidence that parallels bacterial meningitis, more severe sequelae if treatment is delayed, and evidence that existing management often falls short of best practice, a national guideline has been developed for the non-specialist (summarized in an algorithm: Figure 1).^8,9,16 As many of these patients will require intensive care input, it is important that intensivists are well versed in how to manage these patients.

Figure 1.

National guidelines algorithm for the management of suspected viral encephalitis. Reproduced from the Association of British Neurologists and British Infection Association National Guidelines with permission from Elsevier.⁸

Clinical features

A thorough assessment of clinical features seeks to answer three questions:

• 1. Could this be a CNS infection?

• 2. If a CNS infection, what is the aetiology?

• 3. Can a diagnostic lumbar puncture (LP) be performed safely to establish the aetiology?

• 1. The classical clinical features of encephalitis include headache, altered mental state, focal neurological deficits and seizures in the context of fever or recent febrile illness. However, these clinical features have been shown to have too low a negative predictive value alone to reliably exclude CNS infection.^8,9 Much of the ambiguity arises from patients presenting with encephalopathy: the clinical syndrome of altered mental status manifest as altered consciousness, cognition, personality or behaviour, which has a very wide differential diagnosis. Psychiatric phenomena are not uncommon in infective and non-infective encephalitis and can be misleading early on in the illness.⁸ Encephalopathy may also be erroneously attributed to drugs or alcohol.⁷ This ambiguity leads to a significantly longer delay to suspicion and investigation as compared with meningitis especially in the elderly for whom altered mental state is often attributed to systemic sepsis but in whom the incidence of HSV encephalitis is higher, given the bimodal distribution.^7,8 Fever at admission is often used to help rule-in CNS infection under these circumstances. However, fever is absent in 10% of patients with HSV encephalitis.^12–14 A history of a prodromal febrile illness or subsequent documented fever may be useful where fever is absent at initial assessment.⁸ Notably, of patients with proven encephalitis a proportion have diarrhoea, vomiting, urinary or respiratory symptoms.⁴ Therefore, investigation should be undertaken to exclude CNS infection even if these symptoms are present, unless there is an established extra-CNS infection with significant complications (e.g. hypoxia or severe metabolic acidosis) to explain encephalopathy.⁷ Infection outside of the CNS should not cause significant encephalopathy in an otherwise fit individual unless significant complications have arisen.

Owing to the clinical (and histopathological) overlap that may occur between cases of meningitis and encephalitis, both may present in a similar manner, giving rise to the concept of meningoencephalitis. This is especially true in the intensive care setting since a patient with meningitis referred for higher level care will often have been referred for the same reasons as a patient with encephalitis.

• 2. Clinical features may point towards the potential aetiology of encephalitis or meningitis. Foreign travel history must be established due to the geographical restrictions of many pathogens and subsequent investigation should be guided by expert advice.⁸ This will also include urgent investigation for common diseases that mimic encephalitis. Malaria is the most common and geographically widespread example, and is important to consider as outcomes are also related to time to commencing antimalarials.²²

Identifying patients with immunocompromise broadens the number of potential pathogens and HIV itself can cause an acute meningitis or encephalitis at seroconversion or a more insidious dementing illness characterized by psychosis and seizures.^8,23 Therefore, the British HIV Association (BHIVA) guideline, supported by the ABN/BIA encephalitis guideline, recommend HIV testing in all patients presenting with encephalitis or meningitis.^8,23

Finally, subacute presentation and atypical features (such as extrapyramidal signs e.g. dystonias involving the face and arm, or choreoathetosis) suggest an autoimmune cause.^8,24,25

• 3. The role of clinical features in determining the safety of a LP is outlined below.

Initial investigation and management

CSF analysis is by far the most useful tool in establishing or excluding meningitis and encephalitis from the list of potential diagnoses. National guidelines advise that an LP is performed urgently unless clear clinical contraindications are present.⁸ Initial CSF findings of opening pressure, white cell count (WCC) and differential, protein and CSF: blood glucose ratio provide quick evidence for or against a CNS infection and direct treatment towards a viral or bacterial pathogen. Moreover, early CSF Gram stain has a sensitivity and specificity of 60–90% and 97%, respectively, for bacterial meningitis, and subsequent culture can also identify antibiotic sensitivities; CSF PCR has an even greater sensitivity and specificity in excess of 95% for viral encephalitis, when performed in the appropriate timeframe.⁸

CSF findings in viral encephalitis are generally more modest than those seen in bacterial meningitis. CSF pressures are usually only modestly elevated in viral encephalitis in contrast to very high pressures in up to 40% of those with bacterial meningitis.^3,8 In viral infection the CSF WCC is around 10–100 × 10⁶/L and lymphocyte predominant in contrast to 100–10,000 × 10⁶/L and polymorph predominant in bacterial meningitis.^3,8 A normal WCC may occur within the first few days of illness in viral encephalitis (and in those with immunocompromise, in whom cell counts cannot be relied upon).⁵ Equally a raised WCC with polymorph predominance more suggestive of bacterial disease may occur early on in viral encephalitis.⁸ Early, atypical findings usually become typical on repeat LP 24–48 hours later. Conversely, a lymphocyte predominance with modest cell counts can occur in bacterial disease: brucellosis, listeriosis, tuberculosis and partially treated bacterial meningitis.⁸ In these circumstances, except for partially treated bacterial meningitis, CSF lactate <2 mmol/l has been reported to be useful to exclude bacterial disease with a negative predictive value (NPV) of 94–96%.^7,26,27 Prior treatment with antibiotics, particularly for prolonged periods, significantly reduces this NPV and in one study produces a sharp decline in culture positivity to zero at 8 hours, although bacterial PCR remains reliable and cost-effective for up to 96 hours.^20,28,29

Viral PCR may be negative in early encephalitis. However, the PCR is likely to be positive if the LP is repeated 24–48 hours later, if still within 2–10 days of onset of the illness.⁸ PCR requests should be for HSV, VZV and enteroviruses. If there is immunocompromise or foreign travel, early expert advice should be sought to guide other requests. In patients presenting more than 10 days after illness onset, CSF: serum viral antibody ratio (Rieber’s formula) is calculated using CSF and blood samples paired in time to demonstrate intrathecal synthesis of virus-specific antibody to provide post hoc evidence of CNS infection (‘paired oligoclonical bands’ in the algorithm).⁸

Beyond 48 hours of treatment with aciclovir, levels of microbial DNA/RNA fall and PCR results may be reported as ‘low levels’. Under these circumstances, CSF: serum antibody ratios may again be useful to clarify the diagnosis after day 10 of onset of illness.

Some have raised questions around the risk of cerebral herniation when performing LP in critically ill patients with suspected CNS infection.³⁰ The incidence of brain herniation occurring in patients with bacterial meningitis (with or without lumbar puncture as part of their management) is estimated at around 5%.³⁰ There is little data to support a corresponding incidence for encephalitis.⁸ The incidence of herniation following LP as an investigation for any pathology, in which a temporal but not necessarily causal relationship is demonstrated, is estimated by a number of authors at around 1%.^30–32 However, this is based on case series and retrospective cohort studies many of which predate the widespread availability of CT and consist of a heterogeneous group of patients with both infectious and non-infectious aetiologies, and includes many with features of raised intracranial pressure (ICP).^30–32

Clinical features have been demonstrated to be at least as accurate at predicting this risk as CT imaging of the brain.³² These clinical contraindications are listed in Figure 1 alongside those indicating cardiorespiratory instability making LP impractical, and coagulopathy increasing the risk of a vertebral canal haematoma. Given that most intensive care patients are likely to have such clinical features, almost all will require CT and/or stabilisation prior to LP according to the guidelines. A number of small studies of patients with bacterial meningitis suggest the sensitivity of CT for warning impending herniation after LP is surprisingly low and varies between 20% and 80%.³⁰ As such, the guidelines advise performing LP on a case by case decision in those with clinical signs suggestive of possible brain shift causing or caused by raised ICP contraindicating LP but with a normal CT. Given the high mortality and morbidity associated with inadequately treated CNS infection, particularly in those already requiring intensive care support, the potential benefits of performing the LP may outweigh the potential risks in many with clinical signs suggestive of possible brain shift but a normal CT scan. Particularly so that, in an era of increasing antibiotic resistance, targeted antimicrobial therapy can be given.

CT scan changes consistent with encephalitis are unreliable early on, for example a lesion consistent with HSV encephalitis only occurs in 20–85%.⁸ A second scan will almost always show an abnormality but may take up to a week to develop. In HSV encephalitis this typically involves the temporal lobes. The primary role of CT is in quickly identifying alternative diagnoses (e.g. intracranial bleeding), particularly where history is unavailable. In those patients who demonstrate hydrocephalus, investigation for additional pathogens should be undertaken, particularly TB and Cryptococcus, when there is the appropriate travel/exposure history and/or immunocompromise.³³

Diffusion-weighted magnetic resonance imaging (MRI) within 48 hours (ideally within 24 hours) of admission is recommended in the encephalitis guidelines.⁸ It is markedly more sensitive than CT within this time frame for detecting focal changes consistent with encephalitis, for example HSV encephalitis lesions are present in 90%, and other subtle focal changes may help quickly redirect investigation and treatment where CT is normal and basic initial CSF investigations are equivocal.⁸ A neuroradiologist opinion may be of value. The guidelines advise that all patients with suspected encephalitis should be referred to the neurology team within 24 hours of admission and this will facilitate such interactions at a time when decisions about further investigation and treatment are being made based on initial findings.⁸

The same neuroprotective targets and strategies used to prevent secondary brain injury in traumatic brain injury are recommended for all patients (such as maintaining a mean arterial pressure of 80 or more to maintain cerebral perfusion pressure).^5,34,35 Acute glucose control avoiding >10 mmol/l, amongst patients with CNS infections, potentially reduces the burden of functional disability in patients who survive.³⁶ High-grade fever appears to be an independent risk factor for poor outcome, increased length of stay and mortality in a range of neurocritical care patients.³⁷ Randomised controlled trials are lacking in this patient cohort to strongly recommend targeted temperature management (to normothermia) with surface or intravascular cooling devices but many experts advocate it.⁵ ICP monitoring is not routinely recommended even if there are clinical signs of raised pressure.³⁴ Repeat CT imaging and early consultation with a neurosurgical unit is recommended if there are clinical signs of raised ICP with a view to monitoring and medical and/or surgical management targeting maintenance of cerebral perfusion pressure.³⁴ No strong evidence exists for this approach improving mortality or morbidity and this recommendation is based on case reports and series, and extrapolation from limited studies in patients with meningitis. Some advocate decompressive craniectomy in those with rapid non-dominant hemispheric swelling as a cohort who may respond well to such surgical management.^5,35 Indications for intensive care admissions are similar as for any neurologically obtunded patient – a depressed conscious level (10–25% develop coma), status epilepticus, respiratory failure from secondary lung insults such as aspiration and severe electrolyte disturbances than can accompany intracranial disease.^5,35

Transfer to tertiary neurological units is considered appropriate in the following circumstances: where face-to-face specialist neurological review is not possible within 24 hours of admission; where access to MRI and EEG (see below) is not available (EEG is many hospitals remains unavailable); where significant diagnostic delay occurs, is inconclusive or the patient fails to respond to therapy.⁸ There is convincing evidence that neurocritical care units both reduce mortality and improve functional outcomes in patients with neurological disease, as compared with the general ICU.³⁸

It is clear that rising to these standards (specifically expert neurological input, MRI and EEG facilities) remains a problem. A recent ABN survey of acute neurology services in UK based on standards set by a 2011 Royal College of Physicians publication demonstrated that the average availability of an acute expert neurological opinion remains as low as 30% of days, with MRI and EEG access at best around 22% and 52% of hospitals, respectively, in most district general hospitals.³⁹ Wide service provision variation exists across the country and barriers include fundings systems that fail to recognize multidisciplinary involvement in patient caseloads; an existing unbalanced focus of resources on neurology outpatient services; limited access MRI and EEG facilities including equipment and training facilitating MRI in critically ill patients (MRI safe and conditional equipment), consultant neurologist numbers across the UK and tertiary neurological unit bed availability.³⁹ Neuro-intensive care facilities in many regions have large neurosurgical patient burdens which may not infrequently present a barrier to transfer to tertiary units. The recent 2014–2015 Department of Health Mandate sets out a directive to address these wide variations in service provision from hospital to hospital.⁴⁰

Further investigation and management

A repeat LP is indicated 24–48 hours after the first if initial CSF findings are normal or atypical despite clinical suspicion, particularly early in the disease. Close liaison with experts in microbiology/virology/infectious diseases is valuable at this stage to consider whether any additional tests are worth performing.

Seizures and status epilepticus, including non-convulsive status (CNS infections are one of the most common causes), can occur in a proportion of patients with CNS infections.²⁴ However, there is no evidence to support primary prophylaxis.²⁴ The approach is the same as for any case of status.⁵ Relatively strong evidence favours lorazepam as first line, followed by a non-sedating maintenance drug, even if the first-line agent terminates the seizure.^35,41 These second-line options are phenytoin, valproate or levetiracetam, with more evidence available for the former two.⁴² Status epilepticus that is refractory to these medications should be managed in the ICU setting with infusions of sedatives. No one sedative is favoured by evidence. Where available, 24 hours of EEG-monitored deep sedation, with evidence of burst suppression or no EEG evidence of seizures, can be followed by a wake-up trial.⁴² EEG is of particular use in the diagnosis and establishment of seizure-freedom, in those with non-convulsive (NCSE) or subtle-motor status epilepticus⁷.

EEG has two important roles in the ICU setting. Firstly, determining the presence or absence of seizure activity in a patient failing to wake from a sedation break.²⁴ In addition, a normal EEG suggests a non-organic primary psychiatric cause for failure to wake.⁸ Interestingly, in a small retrospective study of 236 ICU patients with coma due to a number of common aetiologies ranging from anoxic-ischaemic encephalopathy to complications of alcohol abuse, 8% demonstrated EEG features of NCSE suggesting EEG is an underutilized tool in ICU.⁴³ Encephalitis is one of the most common causes of NCSE.⁵

With the expansion in the availability of blood serum testing, it is increasingly important to exclude non-infectious mimics of CNS infections, particularly autoimmune encephalitis (Table 1).⁵ This can occur de novo or be a paraneoplastic or post-infectious phenomenon. The most common form is limbic encephalitis associated with either anti-N-methyl-D-aspartate (NMDA) receptor or anti-voltage gated potassium channel (VGKC)-complex antibodies.^5,8 CSF protein is often normal with a normal WCC in anti-VGKC cases and a modest lymphocytosis in anti-NMDA cases.⁸ Other non-infectious encephalitides are described in Table 1. Other mimics to consider are CNS vasculitis and pseudomigraine with pleocytosis.⁴⁷ Encephalopathy or delirium (including ‘sepsis associated encephalopathy’) amongst patients emerging from severe, complicated critical illness of any cause is well-recognised and can sometimes raise the question of encephalitis even where the presenting illness was not neurological in nature. The clinical spectrum can range from acute to long-term and mild cognitive deficits through to severe obtundation with features of non-specific encephalopathy on EEG and a variety of changes on MRI.⁴⁸ It is a diagnosis of exclusion.

Table 1.

Autoimmune encephalitides.^{3,5,8,24,25,44–46}

Autoimmune mechanism	Name	Distinguishing features	Useful investigations
Antibodies to neuronal membrane proteins	Anti-NMDA receptor Limbic Encephalitis	-associated malignancy in 20–50%: usually teratomas (often ovarian, hence female predominance) -Psychiatric phenomena -orofacial dyskinesia and choreoatheotosis -autonomic dysfunction	Serum anti-NMDA receptor antibodies
	Anti-VGKC-complex Limbic Encephalitis	-associated malignancy in 10% (thymoma or small-cell lung cancer) -psychiatric features -focal unilateral faciobrachial dystonic seizures, may be pathognomic in those with antibodies to the leucine-rich glioma 1 (LGI1) subunit -SiADH	Serum anti-VGKC-complex antibodies: Antibodies to LGI1 subunit typically cause CNS manifestations, whilst those targeting contactin 2 associated protein (CASPR2) predominantly cause peripheral nerve hyper-excitability
	Bickerstaff encephalitis	-brainstem features: ataxia, ophthalmoplegia -Guillain-Barre variant (post-infectious)	Anti-GQ1b antibodies (a type of anti-ganglioside antibody)
Antibodies to intracellular neuronal proteins	Paraneoplastic Limbic encephalitides	-features of limbic involvement: psychiatric and memory deficits -may preceed malignancy	Onconeuronal antibodies: Anti-Hu Anti-Ma2 Anti-CV2 Anti-amphyphysin Anti-Ri
Associated with antibodies but unknown mechanism	Hashimoto’s Encephalopathy	-encephalopathy alongside gait abnormalities, tremor, seizures, psychiatric phenomena -steroid responsive	-Anti-thyroid peroxidase antibodies (thyroid function may still be normal)
No known antibody association	Acute Disseminated Encephalomyelitis	-post-infectious -associated myelopathy -age <50 years	Typical demyelinating lesions on MRI
	Rasmussen’s Encephalitis	-may be post-infectious -strict unilateral hemispheric features/seizures	Typical MRI unilateral hemispheric changes

Treatment

Just as initial empirical treatment exists for bacterial meningitis, empirical treatment with aciclovir within 6 hours of admission is recommended based on the most common treatable pathogens, HSV and VZV.⁸ As aforementioned, bacterial meningitis is concomitantly treated in these critically ill patients according to BIA guidelines based on age and UK-prevalent sensitivities amongst the major pathogens until CSF results are available and conclusive. Occasionally local sensitivities may apply and indicate the need for the addition of vancomycin to ceftriaxone to cover beta-lactam-resistant pneumococcal strains. Early liaison with local microbiology services is again advised. Comprehensive, new UK guidelines for the management of meningitis are due to be published later this year.

Of additional note, VZV may require higher doses of aciclovir, for patients in whom renal function can tolerate this. Due to bioavailability, the intravenous route is the only route currently recommended as capable of generating adequate CSF concentration, and therefore there is currently no recommended role for the enteral pro-drug valaciclovir. For patients with suspected encephalitis who are immunocompromised, the initial treatment approach with aciclovir is the same, with the exception that early expert advice is advised to guide additional investigation and treatment for opportunistic infections. For example, if cytomegalovirus is suspected or identified then ganciclovir is recommended.⁸ However, no equivalent antiviral therapy has been established for many other forms of viral encephalitis, such as enteroviruses, and therefore treatment is mainly supportive.

To determine when aciclovir can be stopped in adults with HSV encephalitis a repeat LP is advised after 14 days of treatment in the immunocompetent and after 21 days in those with immune compromise.⁸ If the CSF remains positive for HSV by PCR, then it is advised that the intravenous aciclovir is continued with the LP repeated after 7-day intervals to determine that the CSF has become negative for HSV by PCR. Aciclovir can precipitate within the distal convoluted tubule leading to crystal nephropathy and acute renal failure in between 12% and 49% of patients.⁴⁹ ICU patients are at risk and in such cases volume resuscitation to euvolaemia and loop diuretics are advised and renal replacement therapy may be required, but in general the nephropathy is reversible.⁴⁹

Steroids are not recommended routinely early in the management of suspected encephalitis or in proven HSV encephalitis, although they may be considered for use by experts under specific circumstances, whilst the results of a current randomized controlled trial are awaited. In other encephalitides, steroids may be recommended, particularly when there is a vasculitic component, for example in some cases of VZV encephalitis.

For those with a travel history to a malaria-endemic area, empirical antimalarial therapy should be considered early. Again, expert advice should be sought early to advise on any additional investigation and empirical treatment.

Autoimmune encephalitis is treated with intravenous methylprednisolone and/or immunoglobulins or plasmapharesis in the acute phase, with subsequent adjunctive immunosuppressants, although no long-term protocols have yet been established. Delays in treatment of autoimmune encephalitis are important in determining outcomes although the urgency is less so than for viral encephalitis. For example, in the largest series of patients with autoimmune encephalitis due to NMDA receptor antibodies, delays of >40 days to starting immune-suppression were associated with a worse outcome in those with a primarily autoimmune process, and delays of >3 months have been associated with a worse outcome in those with paraneoplastic disease. Nevertheless, as it may take 2–3 weeks from obtaining the serum sample to receiving the antibody result, in many cases when an autoimmune encephalitis is suspected, and an infectious process has been excluded, treatment may need to commence before the antibody results are known.⁵⁰

Conclusions

CNS infections, meningitis and encephalitis are medical emergencies requiring early identification and treatment, often requiring intensive care input. Significant clinical and histopathological overlap exist and a broad differential often complicates assessment in those with encephalitis. LP is pivotal to establishing a diagnosis and directing treatment towards the responsible pathogen. The last 10–20 years has seen dramatic improvements in the management of meningitis with vaccination programmes and national guidelines. It is hoped that the development of UK national guidelines for encephalitis will see improvements in the management of these conditions in which delays in diagnosis and treatment are associated with significant morbidity and mortality

Learning points

A low index of suspicion is required early amongst critically ill patients presenting with encephalopathy to allow prompt, simultaneous investigation for both meningitis and encephalitis using UK management algorithms for both.

BIA UK algorithms and guidelines for managing meningitis and encephalitis are available at: http://www.britishinfection.org/content/clinical-guidelines#emmen

It is appropriate to refer patients with suspected encephalitis to a neurologist within 24 hours of admission. Transfer to a specialist neurocritical care unit is indicated where: access to a neurologist in <24 hours is not possible; there is no access to MRI/EEG; diagnostic failure or poor response to therapy occurs.

For cases of encephalitis for whom a cause can be identified (up to 63%), 90% are due to HSV, VZV and enteroviruses.

CSF should be sent for standard microscopy/culture, biochemistry and a sample sent for HSV, VZV and enterovirus PCR. All patients should be tested for HIV.

Immunocompromise and/or foreign travel should prompt early discussion with a neurologist and microbiologist to determine additional CSF testing. CSF testing with normal/equivocal initial results should be repeated at 24–48 hours to avoid false negatives.

Subacute or atypical features (psychiatric phenomena, orofacial dyskinesias, faciobrachial dystonic seizures or choreoathetosis) prompt consideration of autoimmune encephalitis. The most common is Limbic encephalitis due to anti-NMDA or to anti-VGKC antibodies tested with serum blood samples. These take 2–3 weeks to process. Treatment may commence prior to acquisition of results and has good outcomes.

Empirical treatment of adults with encephalitis is with intravenous aciclovir 10 mg/kg (dose adjusted in renal failure) within 6 hours of suspicion. Standard medical techniques to maintain cerebral perfusion pressure should be employed.

Patients with clinical or radiological signs of raised ICP should be referred to a neurosurgeon although routine ICP monitoring is not currently recommended. Decompressive craniectomy may be considered in selected patients.

CNS infection is one of the most common causes of non-convulsive status. EEG should be used in a patient failing to wake from sedation or with refractory seizures to optimize anticonvulsant/sedative therapy.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.