Infections of the Nervous System: Bacterial and Fungal

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Chapter 53C Infections of the Nervous System

Bacterial and Fungal

Prior to the modern antimicrobial era, bacterial and fungal infections of the central nervous system (CNS) were almost universally fatal. Fortunately, with the advent of antimicrobial therapy, improved neurosurgical techniques, and modern imaging, the diagnosis and treatment of CNS infections has improved significantly, and mortality rates have declined. Even with these advancements in modern medicine, diagnosing CNS infections can be difficult, and a delay in diagnosis and treatment can lead to increased morbidity and mortality. Thus, it is important to quickly recognize when CNS infections should be high on the differential diagnosis.

When considering an infectious cause of a CNS disorder, it is important to know predisposing conditions for infection such as geographic residence, travel history, occupational and recreational activities, recent sinus or middle ear infections, chronic medical illnesses, vaccination history, and the immune status of the patient. As a general rule, the immunocompromised individual will be susceptible to the same organisms that cause disease in the immunocompetent person but will also be susceptible to organisms that are rarely or never seen in the immunocompetent host. In addition, the clinical manifestations in immunocompromised patients may be subtle or even absent, as they may not generate a brisk immune response to the pathogen. Thus, in these patients the differential must always be broader and the bar lower for starting empirical treatment. The immune status of a patient is particularly important when considering fungal diseases.

Bacterial Infections of the Central Nervous System

Bacteria are prokaryotic organisms that make up the majority of the earth’s biomass. They are everywhere and colonize all human mucosal and skin surfaces, where they generally serve as symbiotes. Only rarely are bacteria pathogenic. The pathogenic bacteria that cause CNS infections can be acquired in a variety of ways: from simple colonization that becomes invasive (Streptococcus pneumoniae, Haemophilus influenzae), via contaminated food (Listeria monocytogenes), as a complication of a systemic infection, from a neurosurgical procedure, or via a contiguous focus of infection (skin, sinuses, or middle ear infections). Most pathogenic bacteria have a variety of virulence factors that partially explain why they cause disease, but various host factors (low immunoglobulin levels, impaired T-cell immunity, complement deficiencies) also play a role.

Meningitis

Etiology

Bacterial meningitis can be divided into acute bacterial meningitis and chronic meningitis. Classically, acute community-acquired bacterial meningitis has been most commonly caused by S. pneumoniae, Neisseria meningitidis, H. influenzae type b, and L. monocytogenes. In meningitis associated with mastoiditis, sinusitis, or otitis media, anaerobes can often play a role. S. pneumoniae, N. meningitidis, and H. influenzae type b are all colonizers of the nasopharyngeal mucosa, and this is the route of entry for these bacteria. L. monocytogenes is usually acquired via contaminated food.

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.

Subacute or chronic meningitis is caused by a much more diverse group of organisms, and more typically by fungi than bacteria, with the exception of Mycobacterium tuberculosis. The worldwide leading cause of chronic bacterial meningitis is M. tuberculosis, especially given its endemic state in many countries around the world. Other bacterial etiological agents include nontuberculous mycobacteria, Treponema pallidum (syphilis), Coxiella burnetii, Brucella spp., Leptospira spp., Francisella tularensis, Actinomyces spp., Ehrlichia chaffeensis, and Anaplasma phagocytophilum.

Table 53C.1 lists the most common bacterial causes of acute or chronic meningitis and diagnostic tests for identifying the organism.

Table 53C.1 Meningeal Pathogens and Their Diagnostic Tests

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.

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.

The cell count, protein and glucose concentrations are also helpful in differentiating acute bacterial meningitis from viral meningitis. In general, acute bacterial meningitis will present with a CSF pleocytosis with a predominance of neutrophils, a mild to moderate CSF protein elevation, and a low CSF glucose concentration (or low CSF/serum glucose ratio, usually ≤0.3.) Viral meningitis will generally present with a CSF pleocytosis with a lymphocytic predominance, normal to mild elevation in protein concentration, and normal CSF glucose concentration or CSF/serum glucose ratio. There have been no prospective studies showing that these parameters alone or in combination have a sensitivity of 100% 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.

Table 53C.2 Empiric Antibiotics for Bacterial Infections of the CNS

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)
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