Chapter 53C Infections of the Nervous System
Bacterial and Fungal
Bacterial Infections of the Central Nervous System
Meningitis
Etiology
Until recently, children had the highest incidence of meningitis, but with the development of an extremely effective vaccine against H. influenzae type b (Hib) and the heptavalent vaccine targeting invasive S. pneumoniae, adults now have the highest incidence of meningitis in developed countries, where it is 5 per 100,000 (Schut et al., 2008). The S. pneumoniae vaccine is not a meningitis vaccine but has decreased the incidence of meningitis by decreasing the incidence of otitis media in children. Though an absolute increase in number of cases of H. influenzae non-b and S. pneumoniae serotypes not in the vaccine (“replacement phenomena”) has been seen, this increase in absolute number is still small (Bender et al., 2010). The incidence of meningitis due to N. meningitidis has decreased with the tetravalent (serogroups A, C, W-135, and Y) meningococcal glycoconjugate vaccine, but the vaccine does not provide lasting immunity and does not include one of the major serotypes, serotype B, as the N. meningitidis group B polysaccharide capsule is poorly immunogenic. There is ongoing work to make the vaccine more efficacious (Riordan, 2010). L. monocytogenes accounts for approximately 8% of cases of acute bacterial meningitis. L. monocytogenes meningitis is uncommon in healthy children and adults. The most common predisposing factors for L. monocytogenes meningitis are age older than 50 years, diabetes, chronic illness, malignancy, and immunosuppressive therapy or an immunosuppressed state.
Table 53C.1 lists the most common bacterial causes of acute or chronic meningitis and diagnostic tests for identifying the organism.
Organism | Blood | Cerebrospinal Fluid |
---|---|---|
Streptococcus pneumoniae | Culture | Gram stain: Gram-positive diplococci in pairs Culture |
Listeria monocytogenes | Culture | Gram stain: Gram-positive rods Culture |
Neisseria meningitides | Culture | Gram stain: Gram-negative diplococcus Culture |
Haemophilus influenzae type b | Culture | Gram stain: Gram-negative coccobacillus Culture |
Mycobacterium tuberculosis | 20-30 mL for AFB stain and culture; PCR | |
Treponema palladium | RPR/VDRL; MHA-TPA | VDRL (non-traumatic tap) |
Coxiella burnetii | Acute and convalescent serologies | |
Brucella spp. | Culture: acute and convalescent serologies | Gram stain: Gram-negative coccobacillus Culture |
Borrelia spp. | ELISA→ if equivocal or +, then IgG and IgM WB (follow CDC guidelines for + WB) | Antibody index: Anti-Borrelia IgG in CSF/anti-Borrelia IgG in serum to total IgG in CSF/total IgG in serum |
Leptospira spp. | Acute and convalescent serologies (MAT only done in reference labs, ELISA and lateral flow dipstick less sensitive and specific) Culture: special media; may need to keep for 8-12 weeks |
Culture: Special media, fastidious |
AFB, Acid-fast bacilli; CDC, Centers for Disease Control and Prevention; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulin; MAT, microscopic agglutination test; MHA-TPA, microhemagglutination assay–Treponema antibody absorption test; PCR, polymerase chain reaction; RPR, rapid plasma reagin test; VDRL, Venereal Disease Research Laboratory test; WB, Western blot test.
Clinical Presentation
The classic symptoms of acute bacterial meningitis are fever, headache, meningismus, and a progressive decrease in the level of consciousness. In a study that evaluated the symptoms in 666 episodes of meningitis in adults, headache was the most common complaint (87%), followed by neck stiffness (83%), fever (77%), and altered mental status (69%). While no single symptom is particularly sensitive or specific, 95% of the patients had two of the four symptoms and only 1% had none. A petechial rash can also be present during acute bacterial meningitis, especially when N. meningitidis is the causative agent, although S. pneumoniae can produce a similar rash (van de Beek et al., 2004). It should be noted that in immunocompromised patients, fever and meningismus may not be present.
Diagnosis
The diagnosis of acute bacterial meningitis depends on recognizing the clinical picture as one consistent with acute meningitis and performing a lumbar puncture (LP) to evaluate for meningeal inflammation and bacteria. The necessity of head computed tomography (CT) prior to performing an LP is often discussed. A head CT prior to LP is recommended in the patient with any of the following: an altered level of consciousness, a focal neurological deficit, new-onset seizure, papilledema (or other signs of increased intracranial pressure), or an immunocompromised state. The utility of imaging is twofold: (1) to evaluate for focal mass lesions and edema that put the patient at risk for uncal herniation and (2) to find those diseases that might mimic acute meningitis but in fact are quite distinct (bacterial abscess, tumor). The imaging modality to use in such patients is CT; the scans can be obtained quickly, and CT is sensitive enough to rule out lesions that predispose patients to herniation. Noncontrast imaging may show no abnormality; postcontrast images will often show diffuse meningeal enhancement. If it is determined that head imaging would be appropriate before LP, and acute bacterial meningitis is high in the differential, the most critical step to take is to obtain blood cultures and begin empirical antibiotics before the patient is sent for imaging. Starting empirical antibiotics quickly is critical because there is burgeoning evidence that a delay in initiating antibiotic treatment for acute bacterial meningitis leads to increased morbidity and mortality (Auburtin et al., 2006; Proulx et al., 2005). If antibiotics are not initiated prior to imaging, it is also clear that imaging prior to LP significantly delays the time to antibiotics (Proulx et al., 2005).
The gold standard for the diagnosis of acute bacterial meningitis is identification of the meningeal pathogen in Gram stain and/or culture of cerebrospinal fluid (CSF). The culture may take 48 to 72 hours to be positive. The organism may also be cultured from blood. Newer diagnostic techniques include polymerase chain reaction (PCR) assays for use on CSF. The real-time multiplexed PCR on CSF specifically determines whether S. pneumoniae, H. influenzae, or N. meningitides are present (Corless et al., 2001). The conserved-sequence bacterial 16S rRNA is a broad-based PCR that if positive requires a second step to identify the specific pathogen detected (Schuurman et al., 2004). Identification can be accomplished either by pathogen-specific PCR or by sequencing of the 16S rRNA band that is amplified. The advantages to PCR-based diagnostics are improved sensitivity and shorter times to diagnosis, but the disadvantages are that these tests are not routinely available, and antibiotic sensitivity data, which is essential, can only be obtained from culture. Thus, at this time in many hospitals, Gram stain and culture remain the best tools for diagnosing acute bacterial meningitis.
Diagnosis of chronic infectious meningitis is much more complicated, and the number of tests required to determine the specific etiology is often much higher. Lumbar puncture is important in documenting meningeal inflammation, although if there are clinical signs or symptoms consistent with increased intracranial pressure, neuroimaging should be done prior to LP. Unlike acute bacterial meningitis, in this scenario, magnetic resonance imaging (MRI) with and without contrast is the study of choice because of increased sensitivity of MRI compared to CT, and because there is less urgency to start empirical treatment and obtain CSF for diagnostic studies. Depending on the CSF abnormalities, certain etiologies may be more or less likely. For example, a mononuclear predominance with a mildly decreased glucose concentration and increased protein concentration suggests tuberculous meningitis, while a CSF pleocytosis with a mononuclear predominance and a normal glucose concentration and either a normal or mildly elevated protein concentration is more consistent with neurosyphilis. To distinguish between just these two possibilities, one would need to send serum and CSF tests for syphilis (see Table 53C.1) and high-volume CSF AFB smear, culture, and PCR for M. tuberculosis.
A noninfectious etiology of meningitis that has a clinical presentation and CSF and neuroimaging abnormalities similar to bacterial meningitis is neoplastic meningitis. Neoplastic meningitis is called carcinomatous meningitis when the leptomeninges are seeded with malignant cells from solid tumors, most commonly melanoma, breast or lung cancer, and leukemic or lymphomatous meningitis from hematological malignancies. The CSF in neoplastic meningitis can range from being completely normal in all routine parameters (cells, protein and glucose concentrations) to having a moderately elevated pleocytosis (<500 cells/mm3) and protein concentration as well as an impressive hypoglycorrhachia. The differences in these CSF parameters are often reflective of the extent of meningeal involvement, with normal CSF parameters occurring in those patients with a low burden of neoplastic meningeal disease. While the gold standard for the diagnosis of neoplastic meningitis is a positive conventional cytological analysis or flow cytometry for neoplastic cells, the sensitivity of these tests is poor. To increase the yield of CSF analytical cytologies, the following is recommended: send high volumes of CSF (>10 mL), send a minimum of two high-volume CSF samples (obtained at different time points), make sure the cytological evaluation can be done on the same day the sample is collected, and if possible, obtain the CSF from a source close to any abnormalities on neuroimaging (Chamberlain et al., 2009). While waiting to determine whether a chronic meningitis is neoplastic in origin, CSF should also be sent for bacterial and fungal smears and cultures, and PCR should be done to rule out common causes of viral meningitis.
Management
Acute bacterial meningitis is treated initially with empirical antibiotics, which can be narrowed once the specific organism and its antibiotic sensitivities have been determined. Choosing the appropriate empirical antibiotic depends on the likely organism, which is dependent upon the patient’s age and risk factors. Table 53C.2 identifies which empirical antibiotics should be used for specific patient populations, and Table 53C.3 gives the appropriate CNS dosing for these antibiotics. Antibiotic therapy is modified when the antimicrobial sensitivity tests results are available.
Disease Entity | Organisms | Empiric Antibiotics |
---|---|---|
Bacterial Meningitis | ||
Age < 50 and no risk factors for Listeria | S. pneumoniae, N. meningitidis | Vancomycin + ceftriaxone or cefotaxime or cefepime |
Age > 50 and/or risk factors for Listeria | As above + L. monocytogenes | As above + ampicillin |
Sinusitis, mastoiditis, or otitis predisposing cause of meningitis | As above (depending on age and risk factors) + anaerobes | As above (depending on age and risk factors) + metronidazole |
Brain abscess | S. aureus, aerobic and anaerobic streptococci, oral and GI flora (including Bacteroides spp) | Vancomycin + ceftriaxone or cefotaxime or cefepime+ metronidazole |
Nocardia | Trimethoprim-sulfamethoxazole | |
Spinal epidural abscess | Staphylococcal spp, streptococcal spp, enteric gram negative bacilli | Vancomycin + ceftriaxone or cefotaxime or cefepime |
Any of the above | M tuberculosis (high suspicion) | Four drug therapy (isoniazid, rifampin, ethambutal, pyrazinamide) |