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Management of meningitis and encephalitis in the critically ill 

Management of meningitis and encephalitis in the critically ill
Chapter:
Management of meningitis and encephalitis in the critically ill
Author(s):

Simon Nadel

and Johnny Canlas

DOI:
10.1093/med/9780199600830.003.0241
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date: 25 February 2020

Key points

  • Management of CNS infections requires specific antimicrobial agents, plus supportive treatment targeted at intracranial hypertension and other life-threatening complications.

  • It is important that the need for management in an intensive care setting is considered early in the illness.

  • Antibiotic resistance amongst the most common organisms causing bacterial meningitis is becoming more common and antibiotic therapy should be adjusted accordingly.

  • Anti-inflammatory treatment, such as steroids should be started as soon as possible in patients with proven acute bacterial meningitis.

  • In the future, effective vaccines should be available against all the common causes of bacterial meningitis and encephalitis, including Neisseria meningitidis serogroup b.

Introduction

The management of CNS infections requires specific antimicrobial agents to eradicate the infection and supportive treatment targeted at reducing raised intracranial pressure with neuroprotective strategies. Advances in the understanding of the pathophysiology of central nervous system infection have led clinicians to use anti-inflammatory agents in the treatment of bacterial meningitis. Some patients may require tracheal intubation and mechanical ventilatory support for the treatment of increased intracranial pressure, seizures, coma, shock, acidosis, and respiratory depression. This chapter will review the management of meningitis and encephalitis. It will necessarily concentrate on acute bacterial meningitis, as patients with this disease will tend to be more severely ill and are more likely to require intensive care management.

Management

Meningitis

Antimicrobial therapy

The initial management of suspected acute bacterial meningitis depends on early recognition, rapid diagnostic evaluation, and urgent introduction of antimicrobial and adjunctive therapy [1]‌. Antimicrobial therapy should not be delayed by imaging studies in the case of patients with focal neurological signs or papilloedema. Even if lumbar puncture is delayed, the CSF findings will still be important for diagnosis after the start of antimicrobial therapy, and a microbiological aetiology may be obtained by antigen detection or PCR. The longer the delay before starting appropriate antimicrobial therapy, the more likely that the disease will cause sequelae or be fatal. The current recommendation is to commence appropriate antimicrobial treatment for acute bacterial meningitis within 30 minutes of presentation. In cases of suspected meningococcal disease (i.e. presence of a purpuric or petechial rash), antibiotic therapy with parenteral benzylpenicillin is recommended before admission to hospital. In the absence of a rash, prehospital antibiotic treatment is not recommended unless there is a delay in transfer to hospital [2].

Empirical antibiotic therapy should be commenced based on the most likely causative organism for the individual patient, taking into account the patient’s age, vaccination status, immune competence, and local patterns of antimicrobial resistance. In developed countries, most authorities recommend a third generation cephalosporin, such as ceftriaxone or cefotaxime, which have excellent CSF penetration and are active against most pathogens causing acute bacterial meningitis. Ceftriaxone should be avoided in infants who are jaundiced, hypo-albuminaemic, acidotic or born prematurely, as it may exacerbate hyperbilirubinaemia. In addition, it should not be administered at the same time as calcium-containing infusions as this may potentially precipitate cardiopulmonary adverse events [3]‌. Listeria monocytogenes, more common in infants <3 months and adults >50 years, is not sensitive to the cephalosporins. Therefore, the addition of a penicillin (e.g. amoxicillin or ampicillin) is recommended.

In the case of patients who are immunosuppressed, following surgery or where CSF leak is suspected, antimicrobial therapy should be broadened to include other Gram-negative organisms, the staphylococci, any possible opportunistic organisms, or Mycobacterium tuberculosis. In the post-neurosurgical patient, initial therapy must cover the Gram-negative organisms, including coliforms, P. aeruginosa, the skin flora, as well as community-acquired organisms. Broad antimicrobial coverage is essential in these patients. For example, vancomycin and ceftazidime, possibly in combination with an aminoglycoside. Table 241.1 summarizes the empiric choice of antibiotic for meningitis according to age and underlying condition [1]‌.

Table 241.1 Empiric choice of antibiotic for meningitis according to age and underlying condition

Age

Empiric choice of antibiotic (intravenous)

0–3 monthsa,b,c

Broad spectrum cephalosporin and ampicillin:

  • Cefotaxime 100 mg/kg 8-hourly; or

  • Ceftriaxone 80 mg/kg 12-hourly; plus

  • Ampicillin or amoxicillin 100 mg/kg 8-hourly

>3 months–50 yearsb,c

Broad spectrum cephalosporin:

  • Cefotaxime 100 mg/kg 8-hourly (adult 2 g 8-hourly); or

  • Ceftriaxone 80 mg/kg 12-hourly (adult 2 g 12-hourly)

>50yb,c

Broad spectrum cephalosporin and ampicillin:

  • Cefotaxime 100 mg/kg 8-hourly (adult 2 g 8-hourly)

  • Ceftriaxone 80 mg/kg 12-hourly (adult 2 g 12-hourly)

  • Ampicillin or amoxicillin 100 mg/kg 8-hourly (adult 2 g 4-hourly)

Immunocompromised hostc

Ceftazidime and ampicillin or amoxicillin:

  • Ceftazidime 50 mg/kg 8-hourly (adult 2 g 8-hourly)

  • Ampicillin or amoxicillin 100 mg/kg 8-hourly (adult 2 g 4-hourly)

Post-neurosurgery, post-skull trauma, cerebrospinal fluid shunt

Ceftazidime and vancomycin:

  • Ceftazidime 50 mg/kg 8-hourly (adult 2 g 8-hourly)

  • Vancomycin 15 mg/kg 6-hourly (adult 2 g/24 hours)

a In neonates, in particular preterm neonates, drug dosages may have to be adjusted.

b Vancomycin 15 mg/kg 6-hourly (max. 2 g/24 hours, for resistant Streptococcus pneumoniae).

c If cephalosporin-resistant pneumococci are suspected add vancomycin as in b above.

Max., maximum.

Data from Agrawal S and Nadel S, ‘Acute Bacterial Meningitis in Infants and Children. Epidemiology and Management’, Pediatric Drugs, 2011, 13(6), pp. 385–400.

There are now increasing reports of high-level cephalosporin resistance, conferring resistance of S. pneumoniae to the third generation cephalosporins. Factors reported to increase the likelihood of infection with a resistant strain include patient’s age (<10 or >50 years), immunosuppression, prolonged hospital stay, children in day care settings, infection by serotypes 14 and 23, and frequent or prophylactic use of antibiotics.

When S. pneumoniae meningitis is strongly suspected, vancomycin may be included in empirical therapy until the antimicrobial susceptibility of the isolate has been determined. Vancomycin penetrates the CSF adequately in the presence of meningeal inflammation and the combination of vancomycin and a third generation cephalosporin may be synergistic for meningitis caused by a high-level penicillin-resistant S. pneumoniae [1,2].

At present there are no data to suggest that quinolones or extended-spectrum macrolides are beneficial for the empiric therapy of bacterial meningitis. However, early studies with the carbapenem meropenem look promising as single agent therapy for a wide range of pathogens that cause bacterial meningitis. The recommended antibiotics and dosages for the treatment of ABM caused by specific organisms are outlined in Table 241.2.

Table 241.2 Recommended antibiotic therapy for specific pathogens

Organism

Antibiotic (intravenous)

Neisseria meningitidis

Broad spectrum cephalosporin:

  • Cefotaxime 100 mg/kg 8-hourly (adult 2 g 8-hourly)

  • Ceftriaxone 80 mg/kg 12-hourly (adult 2 g 12-hourly)

  • Benzylpenicillin (depending on sensitivity: 300,000 units/kg/day; max. 24 million units/ 24 hours)

Streptococcus pneumoniae

Broad spectrum cephalosporin and vancomycin:

  • Cefotaxime 100 mg/kg 8-hourly (adult 2 g 8-hourly)

  • Ceftriaxone 80 mg/kg 12-hourly (adult 2 g 12-hourly)

  • Vancomycin 15 mg/kg 6-hourly (max. 2 g/ 24 hours)

Haemophilus influenzae

Broad spectrum cephalosporin:

  • Cefotaxime 100 mg/kg 8-hourly (adult 2 g 8-hourly)

  • Ceftriaxone 80 mg/kg 12-hourly (adult 2 g 12-hourly)

Listeria monocytogenes

Ampicillin and gentamicin (synergistic activity):

  • Ampicillin 100 mg/kg 8-hourly (adult 2 g 4-hourly)

  • Gentamicin 7.0 mg/kg 24-hourly (check levels)

Streptococcus agalactiae

Ampicillin and gentamicin (synergistic activity):

  • Ampicillin 100 mg/kg 8-hourly (adult 2 g 4-hourly)

  • Gentamicin 5–7 mg/kg 24-hourly (depending on gestational age and level)

Max., maximum.

Data from Agrawal S and Nadel S, ‘Acute Bacterial Meningitis in Infants and Children. Epidemiology and Management’, Pediatric Drugs, 2011, 13(6), pp. 385–400.

The duration of antimicrobial therapy is dependent on the age and immune status of the patient, the aetiological agent, and the clinical course or development of complications. There is no universally accepted standard. As little as 7 days of therapy or shorter is appropriate for uncomplicated meningococcal meningitis. For meningitis due to H. influenzae, 10 days is the accepted duration, while for pneumococcal meningitis it is 14 days. Meningitis due to L. monocytogenes should be treated for 14 days, extending to 21 days in the immunocompromised host. Neonatal Gram-negative meningitis should be treated for at least 21 days following CSF sterilization. For meningitis due to Streptococcus agalactiae, at least 14 days treatment is recommended, depending on the clinical course.

The duration of therapy may need to be extended as a result of complications, such as the development of brain abscess or subdural empyema, prolonged fever, or the development of nosocomial superinfection. In such cases, the duration of therapy should be individualized. Current recommendations in the UK are summarized in Table 241.3.

Table 241.3 Current UK guidelines for empirical and specific therapy in bacterial meningitis in children

Age group

Empirical therapy

Specific therapy

>3 months

Ceftriaxone or cefotaxime:

  • +/– vancomycin

  • 7 days for N. meningitides

  • 10 days for Hib

  • 14 days for S. pneumonia

Ceftriaxone

<3 months

Cefotaxime + amoxicillin/ampicillin

GBS

≥14 days cefotaxime or penicillin or ampicillin + gentamicin

Gram-negative organisms

21 days cefotaxime or ceftriaxone or meropenem +/– gentamicin

Listeria monocytogenes

  • 21 days amoxicillin/ampicillin + gentamicin for first 7 days

  • +/– vancomycin

Unconfirmed

  • ≥14 days amoxicillin/ampicillin + cefotaxime

  • Consider Aciclovir

GBS, for Group B Streptococci.

Data from National Institute for Health and Clinical Excellence. Bacterial meningitis and meningococcal septicaemia: management of bacterial meningitis and meningococcal septicaemia in children and young people younger than 16 years in primary and secondary care. (Clinical guideline 102) 2010. www.nice.org.uk/CG102.

Anti-inflammatory treatment

Despite effective antimicrobial therapy, neurological morbidity and mortality remains a major consequence of acute bacterial meningitis (ABM). This is partly due to the damaging process within the brain that is mediated by activation of host inflammatory pathways, triggered by the release of endotoxin and other bacterial constituents. This is often accentuated by the use of powerful bactericidal antibiotics, and this has led to the hypothesis that injury to the brain may be reduced by the use of anti-inflammatory treatment.

The role of adjunctive corticosteroids in ABM has been widely studied in the last three decades. Initial trials showed a clear benefit from dexamethasone, with decrease in neurologic sequalae, particularly nerve deafness [4]‌.

In 2007, a Cochrane analysis published a review of 20 randomized clinical trials on the safety and efficacy of corticosteroid use in ABM. According to this analysis, adjuvant corticosteroids were associated with lower case fatality rates, lower rates of severe hearing loss, and fewer long-term neurological sequelae. In children, the beneficial effects of corticosteroid use were less convincing, although there was a trend towards reduced hearing loss and short-term neurological sequelae in non-Hib meningitis, with the effect statistically significant in high-income countries compared with low-income countries. Subgroup analysis suggested that the case fatality rate was reduced by adjuvant steroids in patients with pneumococcal meningitis and that hearing loss was reduced in patients with Hib meningitis [5]‌.

In the absence of any potentially significant harmful effects, dexamethasone is recommended for use in children with confirmed or suspected ABM above 3 months of age in the UK [2]‌ and above 6 months of age in the US [6]. The recommended dosage is 0.6 mg/kg/day in four divided doses for 4 days, commencing prior to or simultaneously with the first dose of antibiotic, or within 4 hours of antibiotic administration.

In adults, the evidence for use of steroids in ABM is less convincing. However, in severe ABM, there are theoretical grounds for using steroids at the same recommended dosage as previously mentioned, without evidence of a worse outcome. The benefit of dexamethasone appears to be greatest if it is administered early in the course of the illness, preferably prior to antibiotic administration. There have been few side effects documented in patients receiving dexamethasone. In particular, there have been no reports of delayed CSF sterilization or treatment failure, although gastrointestinal bleeding has been observed in a small proportion of patients. However, the early reports of a beneficial effect of dexamethasone in bacterial meningitis should be interpreted with caution. There are no good data on the use of adjunctive steroid therapy in neonatal, post-neurosurgical or traumatic meningitis.

Supportive care

Antibiotic administration is only one component of the overall management of patients with meningitis. Neurological derangement often co-exists with circulatory insufficiency, impaired respiration, metabolic derangement, and convulsions. Measures to detect and correct any co-existing physiological derangement are probably important in improving the prognosis.

Neuroprotective strategies

All patients with bacterial meningitis are likely to have raised ICP as part of their disease process. Signs of raised ICP include altered level of consciousness, altered pupillary responses, hyper- or hypotension, reduction in resting pulse rate, altered respiratory pattern, and focal neurological signs. Papilloedema is a late sign. Patients with raised ICP due to bacterial meningitis and other intracranial infections should be assessed for airway, breathing, and circulation. The management is generally as for other causes of intracranial hypertension.

Fluid management

Fluid therapy should be guided by clinical assessment of hydration status. Over 50% of children with ABM have hyponatraemia at presentation, often attributed to increased secretion of antidiuretic hormone (ADH), and this may be a marker of severe disease contributing to cerebral swelling. By restricting intravenous fluid administration in the presence of SIADH, the risk of developing cerebral oedema is likely to be diminished.

In general, enteral fluids or feeds should be used where appropriate, and isotonic fluid when intravenous therapy is required. In developing world settings with high mortality and where children present late, full maintenance fluid therapy was associated with reduced spasticity, seizures, and chronic severe neurological sequelae [7]‌.

Sedation and control of convulsions

Seizures occur within 48 hours of presentation in 20–30% of patients with bacterial meningitis. Seizures are especially dangerous in patients with raised ICP, as they result in increased metabolic demands, an increase in cerebral blood flow and may precipitate a further increase in ICP. Convulsions may be difficult to detect in patients who are treated with neuromuscular blocking agents for artificial ventilation. In such patients electrical monitoring should be used to detect seizure activity. The use of anticonvulsant treatment in non-ventilated patients may precipitate respiratory arrest and careful observation of respiration and ventilation could be undertaken during the treatment of seizures. Short- acting benzodiazepines can be used to control acute seizures, and standard anti-epileptic agents for longer term control.

Encephalitis

It may not always be possible to isolate the organism that causes encephalitis. In such circumstances, it is prudent to commence treatment with broad-spectrum antimicrobials and to cover the more likely causative agents. There are some specific therapies available for specific organisms as described in the following sections. Appropriate supportive intensive care may be required including the use of neuroprotective strategies. Newer antiviral agents are continually being identified and may be useful in the future treatment of specific encephalitides. Where organisms which cause encephalitis are endemic, such as Japanese B virus, vaccination programmes are very effective in reducing prevalence of disease.

Mycoplasma pneumoniae encephalitis

In patients with Mycoplasma pneumoniae encephalitis, a temporal clinical improvement has been reported in children treated with antibiotics. On the other hand some children recover without antimicrobials [8]‌. It is not clear whether encephalitis due to M. pneumoniae is an acute-infectious process or a post-infectious/auto-immune process. However, it is probably prudent to treat suspected or confirmed M. pneumoniae encephalitis with antimicrobials with activity against mycoplasma. Macrolides are considered the antibiotic of choice despite their poor penetrance of the blood brain barrier. Azithromycin has been found to achieve a high concentration in brain tissue [9].

Herpes simplex encephalitis

Aciclovir is the treatment of choice in Herpes simplex encephalitis. The current standard of care for adults and children over the age of 12 months is intravenous aciclovir at a dose of 500 mg/m2 every 8 hours for 21 days. In infants <12 months, the recommended dose is 20 mg/kg every 8 hours for 21 days. Shorter duration of treatment increases the risk of relapse. Neonatal HSV infection may require a longer duration of therapy. With this regimen, mortality from neonatal HSV encephalitis has fallen to 5%. 40% of survivors develop normally. Outcome is dependent upon age of patient, level of consciousness at presentation, duration of encephalitis, and viral load. If presenting Glasgow Coma Score (GCS) <7, outcome is universally poor. Where treatment was instituted less than four days following the onset of symptoms, the survival at eighteen months increased from 72% to 92% [10].

Other viral encephalitides (enterovirus, rabies virus, arthropod-borne virus)

The enteroviruses include polioviruses, Coxsackie viruses, and echoviruses. They are known to cause both encephalitis and aseptic meningitis, and the management for these cases is supportive. Rabies virus encephalitis is virtually always fatal. It can be prevented by appropriate immunization even when exposure has occurred [11]. The management is generally supportive. Encephalitis due to arthropod-borne viruses is very common worldwide. There are no specific therapies for these apart from supportive care of organ failure.

Enterovirus 71 encephalitis

Enterovirus 71 (EV71) causes major outbreaks of hand, foot, and mouth disease (HFMD), most frequently affecting children. Although present throughout the world, the largest outbreaks of disease have been seen in the Asia–Pacific region and neurological manifestations range from aseptic meningitis to acute flaccid paralysis and brainstem encephalitis.

Brainstem encephalitis, especially affecting the medulla and associated with cardiopulmonary dysfunction has become the most notable feature in EV71 epidemics in Asia. Children typically present with a brief febrile illness and mild neurological signs, which may progress to myoclonic jerks, after which they develop signs of tachycardia, poor perfusion, and tachypnoea that rapidly develop into acute, intractable cardiac dysfunction, and fulminant pulmonary oedema or haemorrhage.

Post-mortem examination and MRI studies of children with EV71 brainstem encephalitis showed extensive inflammation of gray matter of the spinal cord and the whole medulla oblongata.

Treatment of complications

Complications of CNS infections vary according to the aetiological agent, duration of symptoms prior to initiation of appropriate therapy, and the age and immune status of the patient. Early complications are seizures, haemodynamic instability, SIADH, or other dysregulation of the hypothalamic-pituitary axis (such as diabetes insipidus), an acute increase in ICP, profound shock, and DIC. Neonates with any form of bacterial meningitis are likely to develop shock and DIC. Children may suffer severe and permanent neurological sequelae, or mild subtle behavioural disturbance. The most common complication of bacterial meningitis is sensorineural hearing loss.

Focal neurological signs including hemiplegia and quadriplegia may develop in the early stages of meningitis, but are more common in the later stages. Vasculitis and thrombosis may explain these clinical findings. Awareness of other conditions that require acute neurosurgical intervention is necessary. These include the development of subdural empyema, brain abscess, and acute hydrocephalus. Subdural effusions are more common after Haemophilus influenzae meningitis, but can occur with any organism. They usually resolve spontaneously, but the presence of significant and persistent neurological symptoms including seizures, paresis, raised ICP, and development of empyema are indications for drainage. Cerebral abscess must also be considered in any child who deteriorates neurologically, usually following the acute phase of bacterial meningitis, and is often accompanied by persistent fever. Table 241.4 is a summary of risk sequelae from bacterial meningitis worldwide [12].

Table 241.4 Risk of sequalae from bacterial meningitis in adults and children globally

Risk after:

S. pneumonia (%)

Hib (%)

N. meningitidis (%)

Hearing

7.5

3.2

2.6

Motor deficit

5.8

2.2

1.0

Behavioural problems

4.6

2.1

0.6

Cognitive difficulties

4.2

1.1

1.6

Epilepsy

2.5

1.5

0.5

Visual disturbances

1.1

0.5

1.5

At least one sequelae

34.7

14.5

9.5

Multiple impairments

5.7

2.6

1.3

Reprinted from Lancet Infectious Diseases, 10(5), Edmond K et al., ‘Global and regional risk of disabling sequelae from bacterial meningitis: a systematic review and meta-analysis’, pp. 317–28. Copyright 2010, with permission from Elsevier.

Conclusion

The successful introduction of vaccines against encapsulated organisms that cause bacterial meningitis has significantly reduced the incidence in developed countries, but there is still a substantial burden of disease in developing countries. Molecular diagnostics are being increasingly used in the diagnosis of non-bacterial encephalitides. Clinical trials on vaccines against Neisseria meningitidis serogroup B and newer antimicrobial agents against resistant pneumococcal strains and other viral pathogens are underway. However, there remains limited information on optimum duration of antimicrobial therapy, indications for corticosteroid treatment and optimum fluid therapy. Clinical trials to evaluate best therapies, optimal duration of treatment, adjunctive therapies, neuroprotective agents and new vaccines are urgently needed.

References

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