Meningitis

Viral Meningitis

Epidemiology and Aetiology

Viruses are the major causes of the aseptic meningitis syndrome, which has been defined as any meningitis (infectious or non-infectious) for which a cause is not apparent after initial evaluation and routine stains and cultures of cerebrospinal fluid (CSF). The most common aetiological agents of the aseptic meningitis syndrome in adults are the non-polio enteroviruses (specifically Coxsackie and echoviruses), which account for 85–95% of cases in which a pathogen is identified.1 These viruses are worldwide in distribution. In temperate climates, infections occur with a peak incidence in the summer and early autumn. Other viral causes of the aseptic meningitis syndrome include arboviruses (e.g. St Louis encephalitis virus, the California encephalitis group of viruses, West Nile virus and the agent of Colorado tick fever), mumps virus, human immunodeficiency virus (HIV) and the herpes viruses [herpes simplex viruses (HSVs) types 1 and 2 and varicella zoster virus (VZV)]. The DNA of HSV (mostly HSV type 2) has been detected in the CSF of patients with recurrent benign lymphocytic meningitis (formerly known as Mollaret’s meningitis).2

Clinical Presentation

Patients with viral meningitis often present with typical symptoms and signs of meningitis, including headache, meningismus, fever and photophobia.1, 3 Symptoms associated with the causative virus may also be present, such as vomiting and diarrhoea with the enteroviruses, vesicular rash with HSV and a mononucleosis-like syndrome with primary HIV infection. The duration of illness in enteroviral meningitis is usually less than 1 week, with many patients reporting improvement after lumbar puncture, probably as a result of a reduction in intracranial pressure.

Diagnosis

In enteroviral meningitis, lumbar puncture usually reveals a lymphocytic pleocytosis (100–1000 cells mm−3), although there may be a predominance of neutrophils early in the course of infection; however, this quickly gives way to a lymphocytic predominance over the first 6–48 h.1, 3, 4 CSF protein is elevated, whereas glucose may be normal or low, although these abnormalities, if present, are usually mild. Similar CSF abnormalities are usually observed in other causes of viral meningitis. Viral cultures are rarely helpful in the aetiological diagnosis of the aseptic meningitis syndrome; in one study of viral cultures on 22 394 CSF samples, virus was recovered from only 5.7% of samples, most of which were enteroviruses (98.4%).5 Acute and convalescent serum titres may be obtained to identify specific aetiological agents but are not helpful in acute diagnosis and management.

The polymerase chain reaction (PCR) has been shown to be useful in the diagnosis of meningitis due to HSV types 1 and 2 and VZV3 and may be helpful in the identification of HIV in the CSF or plasma of patients with meningitis following primary infection. Reverse transcription-polymerase chain reaction (RT-PCR) has also been utilized for detecting enteroviral RNA, with sensitivity ranging from 86 to 100% and specificity from 92 to 100% in the diagnosis of enteroviral meningitis.1, 3, 4

Therapy

Viral meningitis is usually a self-limited illness and in the majority of cases only supportive therapy is indicated.1, 3 Pleconaril, a novel compound that integrates into the hydrophobic pocket of picornaviruses, has been shown to have beneficial effects on the clinical, virological, laboratory and radiological parameters in patients with severe enterovirus infections. In one randomized, multi-centre, double-blind, placebo-controlled trial of 607 patients with enteroviral meningitis, pleconaril shortened the course of illness especially early in the disease course.6 Pleconaril, however, has not achieved approval by the US Food and Drug Administration (FDA) because it induces CYP3A enzyme activity and has the potential for drug interactions; therefore, the sponsor has not sought approval. In cases associated with HSV infection (most often an initial infection with HSV type 2), treatment of the genital infection with antiviral therapy (e.g. acyclovir) often results in resolution of the meningitis.

Bacterial Meningitis

Epidemiology and Aetiology

Although numerous bacterial pathogens have been reported to cause meningitis in the elderly, certain agents are isolated more frequently.3 Streptococcus pneumoniae is the most common cause of bacterial meningitis in the elderly. A contiguous (e.g. sinusitis, otitis media or mastoiditis) or distant (e.g. endocarditis or pneumonia) site of infection is often identified. More serious pneumococcal infections occur in elderly patients and in those with underlying conditions such as asplenia, multiple myeloma, alcoholism, malnutrition, diabetes mellitus and hepatic or renal disease. S. pneumoniae is also the most common aetiological agent of meningitis in patients with basilar skull fracture and CSF leak. In the USA, the overall mortality rates for pneumococcal meningitis have ranged from 19 to 26%. In one study of 352 episodes of community-acquired pneumococcal meningitis in adults, 70% of cases were associated with an underlying disorder and the overall in-hospital mortality rate was 30%;7 in patients aged 60 years or older, death was more likely secondary to systemic complications. For this reason, the 23-valent pneumococcal vaccine is recommended for all patients over the age of 64 years and for those in groups at high risk for serious pneumococcal infection.

Persons at risk for infection (including meningitis) with Listeria monocytogenes are the elderly (≥50 years of age), those with underlying malignancy, alcoholics, those receiving corticosteroids, immunosuppressed adults (e.g. transplant recipients) and patients with diabetes mellitus and iron overload disorders.3 Cases have also been reported in patients receiving treatment with anti-tumour necrosis factor alpha agents. Although L. monocytogenes is an unusual cause of bacterial meningitis in the USA, it is associated with high mortality rates (15–29%). Outbreaks of Listeria infection have been associated with the consumption of contaminated coleslaw, raw vegetables and milk, with sporadic cases traced to contaminated cheese, turkey franks, alfalfa tablets and processed meats; this points to the intestinal tract as the usual portal of entry. However, the incidence has been decreasing, likely as a result of a decrease in the prevalence of Listeria in ready-to-eat foods.

Bacterial meningitis caused by aerobic Gram-negative bacilli (e.g. Klebsiella species, Escherichia coli, Serratia marcescens, Salmonella and Pseudomonas aeruginosa) is found in the elderly, occurring after head trauma or neurosurgical procedures and in patients with Gram-negative bacteraemia.3, 8 Some cases have been associated with disseminated strongyloidiasis in the hyperinfection syndrome, in which meningitis caused by enteric bacteria occurs secondary to seeding of the meninges during persistent or recurrent bacteraemias associated with migration of infective larvae; alternatively, the larvae may carry enteric organisms on their surfaces or within their own gastrointestinal tracts as they exit the intestine and subsequently invade the meninges.

Other bacterial species are less common causes of bacterial meningitis in the elderly.3 Neisseria meningitidis may cause meningitis during epidemics (caused by serogroups A and C) or in sporadic outbreaks (serogroup B), although meningitis caused by this microorganism is more common in children and adults. There is an increased incidence of neisserial infections, including that caused by N. meningitidis, in persons with deficiencies of the terminal complement components (C5, C6, C7, C8 and perhaps C9), although the case fatality rates in these patients are lower than in those with an intact complement system. Hemophilus influenzae meningitis in elderly adults is associated with concurrent infections such as sinusitis, otitis media and pneumonia and underlying conditions such as chronic obstructive pulmonary disease, asplenia, diabetes mellitus, immunosuppression and head trauma with CSF leak. Meningitis caused by Staphylococcus aureus is usually found in the early postneurosurgical period or after head trauma or in patients with CSF shunts; other underlying conditions include diabetes mellitus, alcoholism, chronic renal failure requiring haemodialysis, injection drug use and malignancies. Staphylococcus epidermidis is the most common cause of meningitis in patients with CSF shunts. The group B streptococcus (Streptococcus agalactiae) may cause meningitis in adults; risk factors include age greater than 60 years, diabetes mellitus, cardiac disease, collagen vascular disorders, malignancy, alcoholism, hepatic failure, renal failure, previous stroke, neurogenic bladder, decubitus ulcers and corticosteroid therapy.

Clinical Presentation

The classic symptoms and signs in patients with bacterial meningitis include headache, fever and meningismus; these are seen in more than 85% of patients.3 In a review of community-acquired meningitis in adults, the classic triad of fever, nuchal rigidity and change in mental status was found in only two-thirds of patients. Other findings include cranial nerve palsies (∼10–20%), seizures (∼30%) and Kernig’s and/or Brudzinski’s signs. However, in a prospective study that examined the diagnostic accuracy of meningeal signs in adults with suspected meningitis, the sensitivity of Kernig’s sign was 5%, Brudzinski’s sign 5% and nuchal rigidity 30%, indicating that the presence of these signs did not accurately distinguish patients with meningitis from those without meningitis. In another review of 696 episodes of community-acquired bacterial meningitis, the triad of fever, neck stiffness and altered mental status was found in only 44% of patients,9 although 95% presented with at least two of four symptoms (fever, headache, stiff neck, altered mental status).

However, elderly patients with bacterial meningitis, especially those with underlying conditions (e.g. diabetes mellitus or cardiopulmonary disease), may present insidiously with lethargy, confusion, anorexia, no fever and variable signs of meningeal inflammation.3 In one review, confusion was very common in elderly patients on initial examination and occurred in 92 and 78% of those with pneumococcal and Gram-negative bacillary meningitis, respectively. There may be a history of an antecedent or concurrent illness such as sinusitis, otitis media or pneumonia. In the elderly patient, an altered or changed mental status should not be ascribed to other causes until bacterial meningitis has been excluded by CSF examination.

Diagnosis

The diagnosis of bacterial meningitis rests with CSF examination following lumbar puncture.3 CSF characteristics of bacterial meningitis include an elevated opening pressure in virtually all patients. The white blood cell count is elevated in untreated bacterial meningitis (usually 1000–5000 cells mm−3) with a neutrophilic predominance, although lymphocytes may predominate in L. monocytogenes meningitis (∼30% of cases). Elevated protein (100–500 mg dl−1) and decreased glucose (<40 mg dl−1) levels are also typically observed; a CSF: serum glucose level of ≤0.4 mg dl−1 is found in the majority of patients with acute bacterial meningitis.

The CSF Gram stain provides rapid and accurate identification of the causative organism in 60–90% of patients with bacterial meningitis, with a specificity of almost 100%. Bacteria are observed in 90% of cases of meningitis caused by S. pneumoniae, but in only about one-third of patients with L. monocytogenes meningitis.3 CSF cultures are positive in 70–85% of patients overall. The probability of identifying the organism in CSF cultures may decrease in patients who have received prior antimicrobial therapy.

Several rapid diagnostic tests are available to aid in the aetiological diagnosis of bacterial meningitis.3 Latex agglutination tests detect the antigens of H. influenzae type b, S. pneumoniae, N. meningitidis, E. coli K1 and S. agalactiae. The overall sensitivity ranges from 50 to 100% (somewhat lower for N. meningitidis because of the limited immunogenicity of the group B meningococcal polysaccharide), although these tests are highly specific. However, the routine use of latex agglutination for the aetiological diagnosis of bacterial meningitis has recently been questioned and is no longer routinely recommended, because the results do not appear to modify the decision to administer appropriate antimicrobial therapy and false-positive tests have been reported.10 Latex agglutination may be most useful for the patient who has been pretreated with antimicrobial therapy and whose CSF Gram stain and cultures are negative, although it must be emphasized that a negative test does not rule out infection by a specific meningeal pathogen. An immunochromatographic test for the detection of S. pneumoniae in CSF has been found to have an overall sensitivity of 95–100% in the diagnosis of pneumococcal meningitis,11 but more studies are needed to assess the usefulness of this test.

Nucleic acid amplification tests (e.g. PCR) have been used to amplify DNA from patients with bacterial meningitis caused by several pathogens. In one study, broad-based PCR demonstrated a sensitivity of 100%, a specificity of 98.2%, a positive predictive value of 98.2% and a negative predictive value of 100%.3 The sensitivity and specificity of PCR in CSF for the diagnosis of pneumococcal meningitis are 92–100% and 100%, respectively.11 There are some problems with false-positive results, but further refinements in PCR may demonstrate its usefulness in the diagnosis of bacterial meningitis in patients who have already received antibiotics and when the CSF Gram stain, bacterial antigen tests and cultures are negative.

Antimicrobial Therapy

In patients suspected of having bacterial meningitis, blood cultures should be obtained and a lumbar puncture done immediately. If purulent meningitis is present, targeted antimicrobial therapy should be initiated on the basis of results of Gram staining (i.e. vancomycin and a third-generation cephalosporin if Gram-positive diplococci are seen). However, if no aetiological agent can be identified or if there is a delay in the performance of the lumbar puncture, empirical antimicrobial therapy should be initiated on the basis of the patient’s age and the underlying disease status.3, 10 In patients who are immunosuppressed and have a history of central nervous system (CNS) disease, focal neurological deficits or seizures or if papilloedema is found on funduscopic examination, a computed tomographic (CT) scan is recommended prior to lumbar puncture, with empirical antimicrobial therapy initiated before scanning. Empirical therapy for elderly patients with suspected community-acquired bacterial meningitis should include vancomycin, ampicillin and a third-generation cephalosporin (see the following text for specific recommendations). Once the meningeal pathogen has been identified, antimicrobial therapy can be modified for optimal treatment (Table 117.1); recommended dosages for CNS infections are shown in Table 117.2.

Table 117.1 Specific antimicrobial therapy for meningitis.

aCefotaxime or ceftriaxone.

bAddition of rifampin should be considered; see text for details.

cAddition of an aminoglycoside should be considered.

dThe value of these antimicrobial agents has not been established.

eIntravenous and intraventricular administration.

fSee text for indications of utilizing a lipid formulation of amphotericin B.

Table 117.2 Recommended dosages of selected antimicrobial agents for central nervous system infections in adults with normal renal and hepatic function.

aNeed to monitor peak and trough serum concentrations.

bCan increase dosage to 1.5 mg kg−1 per day in severely ill patients.

cHigher dose recommended for pneumococcal meningitis.

dOral administration.

eMaintain serum concentrations from 50 to 100 μg ml−1.

fDosage based on trimethoprim component.

gMay need to monitor cerebrospinal fluid concentrations in severely ill patients.

hLoad with 6 mg kg−1 i.v. every 12 h for two doses.

For the treatment of bacterial meningitis in elderly persons, choices of antimicrobial therapy should be based on prevalent trends in antimicrobial susceptibility. For meningitis caused by S. pneumoniae, therapy in recent years has been significantly altered by changes in pneumococcal susceptibility patterns.3, 10 Numerous reports from around the world have documented strains of pneumococci that are of intermediate susceptibility [minimal inhibitory concentration (MIC) range 0.1–1.0 μg ml−1] and highly (MIC ≥2.0 μg ml−1) resistant to penicillin G; susceptible strains have MICs ≤0.06 μg ml−1. On the basis of these trends and because achievable CSF concentrations of penicillin are inadequate to treat these resistant isolates, penicillin can never be recommended as empirical therapy for patients with suspected or proven pneumococcal meningitis, pending results of susceptibility testing. As an empirical regimen, we recommend the combination of vancomycin plus a third-generation cephalosporin (either cefotaxime or ceftriaxone). If the isolate is susceptible to penicillin, high-dose intravenous penicillin G or ampicillin is adequate. If the isolate is of intermediate susceptibility to penicillin, only the third-generation cephalosporin need be continued. However, if the pneumococcal isolate is highly resistant to penicillin, the combination of vancomycin and the third-generation cephalosporin should be continued, because vancomycin therapy alone may not be optimal therapy for patients with pneumococcal meningitis. Any patient who is not improving as expected or has a pneumococcal isolate for which the cefotaxime/ceftriaxone MIC is ≥2.0 μg ml−1 should undergo a repeat lumbar puncture to document sterility of CSF after 36–48 h of therapy;10 this may be especially important for patients who are also receiving adjunctive dexamethasone therapy (see the following text). Some experts have also recommended the addition of rifampin for these highly resistant strains, although clinical data are lacking. In patients not responding, administration of vancomycin by the intraventricular or intrathecal route is a reasonable adjunct. Newer fluoroquinolones (e.g. moxifloxacin) that have in vitro activity against S. pneumoniae may have utility in the treatment of pneumococcal meningitis;3, 10 the newer fluoroquinolones (specifically moxifloxacin), combined with either a third-generation cephalosporin or vancomycin, may emerge as an option in the treatment of bacterial meningitis.

Adjunctive Therapy

Despite the availability of effective antimicrobial therapy, the mortality and morbidity from bacterial meningitis have not changed significantly over the past 30 years. A major factor contributing to increased morbidity and mortality is the generation of a subarachnoid space inflammatory response following antimicrobial-induced bacterial lysis;3 therefore, several clinical trials were performed to examine the effectiveness of adjunctive dexamethasone in attenuating this inflammatory response in patients with bacterial meningitis. Most of these studies were conducted in infants and children with predominantly H. influenzae type b meningitis and supported the routine use of adjunctive dexamethasone in this patient population.3, 10 In a prospective, randomized, double-blind trial in 301 adults with bacterial meningitis, adjunctive dexamethasone was associated with a reduction in the proportion of patients who had unfavourable outcomes and in the proportion of patients who died; the benefits were most striking in the subgroup of patients with pneumococcal meningitis and in those with moderate-to severe disease as assessed by the admission Glasgow Coma Scale score. Despite these results, the use of adjunctive dexamethasone in the treatment of bacterial meningitis in the developing world has been more controversial. In one randomized, double-blind, placebo-controlled trial in adolescents and adults in Vietnam with confirmed bacterial meningitis (most often caused by Streptococcus suis), adjunctive dexamethasone was associated with reduction in the risk of death or disability.12

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