Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

84. Central Nervous System Infections

Ramy H. Elshaboury, Elizabeth D. Hermsen, Jessica S. Holt, Isaac F. Mitropoulos, and John C. Rotschafer

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KEY CONCEPTS

The four most likely pathogens of bacterial meningitis in the United States are Streptococcus pneumoniae, group B Streptococcus, Neisseria meningitidis, and Haemophilus influenzae type b, although routine vaccination is having a dramatic effect on the incidence of these pathogens causing infection.

In cases of meningitis, initial findings can include (a) presenting signs and symptoms: fever, headache, nuchal rigidity (the classic triad), Brudzinski’s or Kernig’s sign, and altered mental status; and (b) abnormal cerebrospinal fluid (CSF) chemistries: elevated white blood cell (WBC) count (>1,000 cells/mm³ [<1 × 10⁹/L]), elevated protein (>50 mg/dL [>500 mg/L]), and decreased glucose levels (<45 mg/dL [<2.5 mmol/L).

Two main microbiologic tests that should be obtained include a Gram stain and culture of the CSF. Molecular testing such as polymerase chain reaction, latex coagglutination, and enzyme immunoassay (EIA) tests provide for the rapid identification of several causes of meningitis.

Three primary goals of treatment in meningitis include (a) eradication of infection, (b) amelioration of signs and symptoms, and (c) prevention of the development of neurologic sequelae, such as seizures, deafness, coma, and death.

When selecting antibiotics, the clinician must consider the antibiotic concentration at the site of infection, as well as the spectrum of antibacterial activity. Empirical choices should be based on age, predisposing conditions, and comorbidities. (a) Ceftriaxone or cefotaxime and vancomycin are reasonable initial choices for empirical coverage of community-acquired meningitis in adult patients. (b) Listeria monocytogenes is a common pathogen in infants and elderly; therefore, ampicillin with or without gentamicin should be added empirically to antimicrobial coverage.

Empirical coverage with an appropriate antibiotic should be started as soon as possible when clinical suspicion of meningitis exists. If there is a delay in doing a lumbar puncture (even 30 to 60 minutes), or if the patient is to undergo neuroimaging, the first dose of an antibiotic should not be withheld. Changes in the CSF after initiation of antibiotics usually take 12 to 24 hours.

Antibiotic dosages for the treatment of meningitis should be optimized to ensure adequate CNS penetration.

The duration of antibiotic treatment for meningitis has not been standardized; however, the duration generally is based on the causative organism and the individual case and may range from 7 to 21 days.

Close contacts and relatives of the index case should be assessed for appropriate prophylaxis, particularly for N. meningitidis and H. influenzae meningitis.

Steroid treatment includes dexamethasone 0.15 mg/kg per dose to be given four times daily for 4 days in infants and children older than 2 months of age with proven or strongly suspected bacterial meningitis. Steroids should be started prior to the first dose of antibiotics.

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CNS infections are caused by a variety of pathogens, including bacteria, viruses, fungi, and parasites. Infections are the result of hematogenous spread from a primary infection site, seeding from a parameningeal focus, reactivation from a latent site, trauma, or congenital defects within the CNS. Newer diagnostic techniques have enabled more rapid and definitive diagnoses, thus diminishing the number of unknown “aseptic meningitis” diagnoses and improving targeted therapy. Bacteria resistant to multiple antibiotics present new challenges in the management of meningitis. This chapter presents the etiology, pathophysiology, therapy, and prophylaxis of these infections, concentrating predominantly on bacterial meningitis.

EPIDEMIOLOGY

Approximately 1.2 million cases of acute bacterial meningitis (ABM), excluding epidemics, occur every year around the globe, resulting in ~170,000 deaths.^1,2 Mortality rates for patients with meningitis vary depending on the causative microorganism and age group. About 20% (range 12.3% to 35.3%) of survivors will experience one or more neurologic disabilities.³ Neurologic sequelae frequently associated with ABM include seizures, sensorineural hearing loss, and hydrocephalus. Risk for the development of neurologic sequelae depends on the infecting organism, with pneumococcal meningitis being associated with the highest risk.⁴ Despite the availability of antimicrobial therapy against the most common CNS pathogens, CNS infections continue to have significant morbidity and mortality.

Two findings that have the potential for great epidemiologic impact on bacterial meningitis are the following: (a) passive and active exposures to cigarette smoke are risk factors for bacterial meningitis, especially meningococcal disease,⁵ and (b) children with cochlear implants that include a positioner are at increased risk of bacterial meningitis, specifically pneumococcal meningitis. The incidence of meningitis due to Streptococcus pneumoniae in children with cochlear implants was more than 30 times the incidence in a similar cohort of the U.S. population without implants.⁶ Other risk factors for ABM include respiratory tract infection, otitis media mastoiditis, head trauma, alcoholism, high-dose steroids, splenectomy, sickle cell disease, immunoglobulin (Ig) deficiency, and immunosuppression.

ETIOLOGY

CNS infections are caused by a variety of microorganisms. Historically, CNS infections were primarily community acquired; however, an increasing number of cases are now nosocomial.⁷ Haemophilus influenzae type b was the most commonly identified cause of bacterial meningitis until the introduction of the H. influenzae type b (Hib) conjugate vaccine in 1990, when S. pneumoniae became the most commonly identified cause in the United States (58%), followed by group B Streptococcus (GBS) (18.1%), Neisseria meningitidis (13.9%), H. influenzae (6.7%), and Listeria monocytogenes (3.4%).⁸

Following the release of the heptavalent pneumococcal protein-conjugate vaccine (PCV7) in 2000, the rate of invasive pneumococcal disease steadily dropped from 24.3 cases per 100,000 people in 1999 to 17.3 per 100,000 in 2001 and 13.5 per 100,000 in 2007. The largest impact was in children younger than 2 years of age where a nearly 70% decline in infection rate was reported as a result of implementation in the routine childhood vaccination schedule. Interestingly, the effect carried into the adult population as well with significant reduction in invasive pneumococcal disease across all age groups.^9,10

As a result of the decline of ABM rates in children, the median age of patients increased from 30.3 years in 1998 to 41.3 years in 2007 in the United States.⁸ Both the Hib and pneumococcal vaccines are of limited availability in developing countries where cost is often prohibitive. Thus, rate of invasive disease and case fatalities among children continue to be much higher than in Western countries.

ANATOMY AND PHYSIOLOGY OF THE CENTRAL NERVOUS SYSTEM

Meninges

The skull and vertebrae protect the CNS from blunt or penetrating trauma (Fig. 84–1). The brain is suspended in these structures by cerebrospinal fluid (CSF) and is surrounded by the meninges. The meninges are made up of three separate membranes: dura mater, arachnoid, and pia mater.¹¹ Dura mater, or pachymeninges, lies directly beneath and is adherent to the skull. The other two membranes are referred to collectively as leptomeninges. Pia mater lies directly over brain tissue. Arachnoid, the middle layer, lies between the dura mater and the pia mater. The subarachnoid space, located between the arachnoid and the pia mater, is the conduit for CSF. By definition, meningitis refers to inflammation of the subarachnoid space or spinal fluid, whereas encephalitis is an inflammation of the brain itself. Since infectious microorganisms frequently are an underlying cause of these inflammatory processes, the terms meningitis and encephalitis frequently are used to denote an infectious process. The decision regarding the diagnosis of meningoencephalitis depends on radiographic, laboratory, and clinical information but would refer to inflammation of both tissue and fluid.

FIGURE 84-1 Diagram of the CNS.

Cerebrospinal Fluid

Approximately 85% of the CSF is produced within the third, fourth, and lateral ventricles by the choroid plexus (Fig. 84–1). CSF volume in the CNS is related to patient age: infants have approximately 40 to 60 mL of CSF, older children have 60 to 100 mL, and adults have 115 to 160 mL. Normally, CSF is produced at the rate of approximately 500 mL/day and flows unidirectionally downward through the spinal cord. The CSF is removed by the arachnoid villi and vertebral venous plexus located in the spinal cord and does not recommunicate with the point of production.¹¹

The CSF normally is clear, with a protein content of less than 50 mg/dL (500 mg/L), a glucose concentration of approximately 50% to 60% of the simultaneous peripheral serum glucose concentration, and a pH of approximately 7.4. Also, it typically contains fewer than 5 white blood cells (WBCs)/mm³ (or fewer than 5 × 10⁶/L), all of which should be lymphocytes (Table 84–1). As meninges become inflamed, the constituency of the CSF will change, and these changes can be used diagnostically as markers of infection.

TABLE 84-1 Mean Values of the Components of Normal and Abnormal Cerebrospinal Fluid ^{13,16,19,20,97}

Blood–Brain Barrier/Blood–CSF Barrier

Natural barriers to the exchange of drugs and endogenous compounds among the blood, brain, and CSF are the blood–brain barrier and the blood–CSF barrier (BCSFB) (Fig. 84–2). The blood–brain barrier consists of tightly joined capillary endothelial cells. Drug entry into brain tissue is accomplished by direct passage through the capillary endothelial cells and further penetration of the glial cells that envelop the capillary structure.¹¹

FIGURE 84-2 Schematic representation of a blood–cerebrospinal fluid barrier capillary, brain tissue capillary, and normal tissue capillary (below).

Passage of drugs into the CSF is controlled by the BCSFB. This barrier is created by ependymal cells of the choroid plexus, which function as an active transport system similar to the renal tubular epithelial cells. The inflammatory process associated with meningitis inhibits the active transport system of the choroid plexus.¹² As in the active transport system in the kidney, the secretion of substances out of the choroid plexus also can be inhibited by the administration of probenecid.¹¹

PATHOPHYSIOLOGY OF THE CNS INFECTION

The development of bacterial meningitis occurs following bacterial invasion of the host and CNS, bacterial multiplication with subsequent inflammation of the CNS, specifically the subarachnoid space and the ventricular space, pathophysiologic alterations owing to progressive inflammation, and the resulting neuronal damage.¹³ The critical first step in the acquisition of ABM is nasopharyngeal colonization of the host. Igs such as secretory IgA are found in high concentrations within nasopharyngeal secretions and work to inhibit bacterial colonization. However, the mucus barrier is deteriorated by IgA proteases secreted by the bacteria, which then extend pili that allow adherence to the host cell surface receptors. Bacterial pathogens attach themselves to nasopharyngeal epithelial cells and are phagocytized into the host’s bloodstream. After accessing the patient’s bloodstream, bacteria must overcome the host’s defense mechanisms. Commonly, CNS bacterial pathogens will produce an extensive polysaccharide capsule resistant to neutrophil phagocytosis and complement opsonization. H. influenzae, Escherichia coli, and N. meningitidisstrains lacking polysaccharide capsules are unable to cause meningitis. Capsular polysaccharides activate the alternate complement pathway, which promotes phagocytosis and clearance of infecting pathogens. Patients unable to activate the alternative complement pathway, such as asplenic and sickle cell patients, are predisposed to bacterial infections caused by encapsulated microorganisms and therefore are at increased risk for meningitis.¹³

Although the exact site and mechanism of bacterial invasion into the CNS is unknown, studies suggest that invasion into the subarachnoid space occurs by continuous exposure of the CNS to large bacterial inocula. Bacteremia with inoculum densities of at least 10³ colony-forming units (CFU)/mL (10⁶ CFU/L) appears to be essential for subarachnoid space invasion.¹⁴ Although several sites of bacterial invasion have been theorized, the most plausible sites are the choroid plexus and/or the cerebral microvasculature. Host defense mechanisms within the subarachnoid space are inadequate to combat bacterial pathogens; therefore, bacteria replicate freely within the CSF until either overgrowth occurs or an effective antibiotic regimen is administered that terminates the process.

The effects of meningitis, namely, inflammation within the subarachnoid space and the ensuing neurologic damage, are not necessarily a direct result of the pathogens themselves. The neurologic sequelae occur due to the activation of the host’s inflammatory pathways, which is induced by the pathogens or their products. Bacterial cell lysis and subsequent death can result in the release of cell wall components, such as lipopolysaccharide (LPS), lipid A (endotoxin), lipoteichoic acid, teichoic acid, and peptidoglycan, depending on whether the pathogen is gram-positive or gram-negative (Fig. 84–3). These cell wall components cause capillary endothelial cells and CNS macrophages to release cytokines (interleukin 1 [IL-1] and tumor necrosis factor [TNF]) and other inflammatory mediators (IL-6, IL-8, platelet-activating factor [PAF], nitric oxide, arachidonic acid metabolites [e.g., prostaglandin and prostacycline], and macrophage-derived proteins). Proteolytic products and toxic oxygen radicals are released from the capillary endothelium, causing an alteration in the permeability of the blood–brain barrier. PAF activates the coagulation cascade, and arachidonic acid metabolites stimulate vasodilation. These events propagate other sequential events that lead to cerebral edema, elevated intracranial pressure (ICP), CSF pleocytosis, decreased cerebral blood flow (CBF), cerebral ischemia, and death.^13,14

FIGURE 84-3 Hypothetical schema of pathophysiologic events that occur during bacterial meningitis. (IL-1, interleukin 1; TNF, tumor necrosis factor; PAF, platelet-activating factor; CBF, cerebral blood flow; CSF, cerebrospinal fluid; PGE₂, prostaglandin E₂; ICP, intracranial pressure.)

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Clinical Controversy…

Procalcitonin (PCT) has emerged as a predictive biomarker for invasive infections, including meningitis, owing to specificity to bacterial infections. Elevation of serum PCT levels was mostly studied in lower respiratory tract and bloodstream infections, but some data support its association with bacterial meningitis. Utility of PCT in predicting bacterial meningitis, differentiating bacterial from viral etiologies, and deciding on starting and stopping antibacterial therapy is controversial. More studies are needed to confirm the impact of serum PCT monitoring on clinical outcomes.

CLINICAL PRESENTATION AND DIAGNOSIS

Clinical presentation varies with age, and, generally, the younger the patient, the more atypical and the less pronounced is the clinical picture. Patients may receive antibiotics before a diagnosis of meningitis is made, delaying presentation to the hospital. Prior antibiotic therapy may cause the Gram stain and CSF culture to be negative, but the antibiotic therapy rarely affects CSF protein or glucose.

Signs and Symptoms

Classic signs and symptoms include fever, nuchal rigidity, altered mental status (the classic triad), chills, vomiting, photophobia, and severe headache; Kernig’s and Brudzinski’s signs may also be present but are poorly sensitive and frequently are absent in children (Figs. 84-4 and 84-5).¹⁵ Clinical signs and symptoms in young children may include bulging fontanelle, apneas, purpuric rash, irritability, refusal to eat, and convulsions in addition to those just mentioned.¹⁵ Almost all patients have at least two of the following symptoms: fever, nuchal rigidity, headache, and altered mental status.^4,16 Purpuric and petechial skin lesions typically indicate meningococcal involvement, although the lesions may be present with H. influenzae meningitis. Rashes rarely occur with pneumococcal meningitis.¹⁷

FIGURE 84-4A, B. Brudzinski’s neck signs. Hip and knee flexion occurs as a result of flexion of the neck (B). C–E. Brudzinski’s leg signs. C. Patient’s leg is flexed by examiner (arrow). D. The contralateral leg begins to flex—identical contralateral sign (arrows). E. The contralateral leg now begins to extend spontaneously, resembling a little kick (arrows).

FIGURE 84-5 Kernig’s sign. A. Knees are raised to form a 90° angle relative to the trunk, and the examiner attempts to extend the knees. B. Once the knee angle reaches approximately 135°, contracture or extensor spasm occurs.

Waterhouse-Friderichsen syndrome, a rapid eruption of multiple hemorrhagic lesions associated with a shock-like state, is associated with meningococcal meningitis. Both H. influenzae meningitis and meningococcal meningitis can cause involvement of the joints during the illness. History of head trauma with or without skull fracture or presence of a chronically draining ear is associated with pneumococcal involvement.

Bacterial Meningitis Score

Bacterial Meningitis Score is a validated clinical decision tool aimed to identify children older than 2 months with CSF pleocytosis who are at low risk of ABM. This tool incorporates clinical features such as positive CSF Gram stain, presence of seizure, serum absolute neutrophil count ≥10,000 cells/mm³ (≥10 × 10⁹/L), CSF protein ≥80 mg/dL (≥800 mg/L), and CSF neutrophil count ≥1,000 cells/mm³ (≥1 × 10⁹/L). Treatment is recommended when one or more criteria are present. Certain pediatric patients are excluded including those with purpura, CSF shunt, recent neurosurgery, and Lyme’s disease (LD) and those who received oral or IV antibiotics within 72 hours. This scoring tool was validated in several studies showing high accuracy in excluding ABM. One meta-analysis of eight validation studies between 2002 and 2012 (5,312 pediatric patients) showed the tool to be highly accurate, with combined sensitivity of 99.3%, specificity of 62.1%, and negative predictive value of 99.7%.¹⁸

Laboratory Tests

Several tubes of CSF are collected via lumbar puncture for chemistry, microbiology, and hematology tests. Theoretically, the first tube has a higher likelihood of being contaminated with both blood and bacteria during the puncture, although the total volume is more important in practice than the tube cultured. CSF should not be refrigerated or stored on ice.

Analysis of CSF chemistries typically includes measurement of glucose and total protein concentrations. An elevated CSF protein of ≥50 mg/dL (≥500 mg/L) and a CSF glucose concentration of less than 50% of the simultaneously obtained peripheral value suggest bacterial meningitis (see Table 84–1).

The values for CSF glucose, protein, and WBC concentrations found with bacterial meningitis overlap significantly with those for viral, tuberculous, and fungal meningitis (see Table 84–1). Therefore, CSF WBC counts and CSF glucose and protein concentrations cannot always distinguish the different etiologies of meningitis.

Other Diagnostic Tests^19–22

In patients presenting with new-onset seizures, signs of space-occupying lesions or moderate to severe impairment of consciousness, cranial imaging via magnetic resonance imaging (MRI), or cranial computed tomography (CT) should precede a lumbar puncture. MRI is generally preferred as it more clearly identifies areas of cerebral edemas. In these instances, the withdrawal of CSF fluid from a lumbar puncture reduces counterpressure that may result in compression of the brain from above with risk of brain herniation complicating the clinical course. Neuroimaging should not however delay initiation of antibiotic therapy as doing so can result in a poor outcome in this disease.^23,24MRI is the preferred modality for the diagnosis of encephalitis due to higher specificity and sensitivity (A-I) than CT (B-III) (see Table 84–2 footnotes for rating scale of evidence).

TABLE 84-2 Bacterial Meningitis: Most Likely Etiologies and Empirical Therapy by Age Group^13,19,20

Blood and other specimens should be cultured according to clinical judgment because meningitis frequently can arise via hematogenous dissemination or can be associated with infections at other sites. A minimum of 20 mL of blood in each of two to three separate cultures per each 24-hour period is necessary for the detection of most bacteremia.

Gram stain and culture of the CSF are the most important laboratory tests performed for bacterial meningitis. The Gram stain continues to be the most rapid and accurate method of presumptively diagnosing ABM. When performed before antibiotic therapy is initiated, Gram stain is both rapid and sensitive and can confirm the diagnosis of bacterial meningitis in 75% to 90% of cases. The sensitivity of the Gram stain decreases to 40% to 60% in patients who received prior antibiotic therapy. Culture is required to differentiate the various bacterial etiologies.

Polymerase chain reaction (PCR) techniques can be used to diagnose meningitis caused by N. meningitidis, S. pneumoniae, and Hib. PCR is considered to be highly sensitive and specific, but expense and availability can be limiting. Currently, no U.S. FDA-approved testing is available.

Latex fixation, latex coagglutination, and enzyme immunoassay (EIA) tests provide for the rapid identification of several bacterial causes of meningitis, including S. pneumoniae, N. meningitidis, and Hib. Rapid-identification latex tests work by bringing potential capsular antigens of the pathogen causing meningitis in contact with a specific antibody, causing an antigen–antibody reaction. This capsular antigen–antibody reaction can be observed visually and quickly without waiting for culture results. The sensitivity and specificity of latex fixation and coagglutination tests can vary with the manufacturer of the antibody, density of the antigen present in the CSF, and pathogen being tested. Latex agglutination is most useful for patients who have been treated with antimicrobials and whose CSF Gram stain and culture are negative (B-III).

Diagnosis of tuberculosis meningitis employs acid-fast staining, culture, and PCR of the CSF. PCR testing of the CSF is the preferred method of diagnosing most viral meningitis infections (A-III). The standard diagnostic tests for fungal meningitis include culture, direct microscopic examination of stained and unstained specimens of CSF, antigen detection of cryptococcal or histoplasmal antigens, and antibody assay of serum and/or CSF.

TREATMENT

Desired Outcome

Goals for the treatment of CNS infections should include eradication of infection, amelioration of signs and symptoms, preventing morbidity and mortality, initiating appropriate antimicrobials, providing supportive care, and preventing disease through timely introduction of vaccination and chemoprophylaxis. Understanding antibiotic selection and the issues surrounding antibiotic penetration will assist in meeting the goals of treatment.

General Approach to Treatment and Nonpharmacologic and Supportive Therapy

This section discusses issues surrounding the approach to treatment, such as antibiotic penetration within the CNS, duration of antibiotic therapy, and supportive treatments. Until a pathogen is identified, prompt empirical antibiotic coverage is often needed. Based on the patient’s profile (i.e., allergies, age, and concurrent medical conditions), extent of antibiotic CNS penetration,²⁵ and spectrum of activity, appropriate recommendations can be made, and therapy should last at least 48 to 72 hours or until the diagnosis of bacterial meningitis can be ruled out (Tables 84–2 and 84-3). The first dose of antibiotics should not be withheld, even when lumbar puncture is delayed or neuroimaging is being performed. Changes in the CSF after antibiotic administration usually take 12 to 24 hours. Continued therapy should be based on the assessment of clinical improvement, cultures, and susceptibility testing results. Once a pathogen is identified, antibiotic therapy should be tailored to the specific pathogen (Tables 84–4 and 84-5). Throughout the course of treatment, efficacy parameters, such as signs and symptoms, microbiologic findings, and CSF examination, should be followed to evaluate the success of meeting the desired outcomes.

TABLE 84-3 Penetration of Antimicrobial Agents into the CSF^{a, 25}

TABLE 84-4 Antimicrobial Agents of First Choice and Alternative Choice in the Treatment of Meningitis Caused by Gram-Positive and Gram-Negative Microorganisms^16,19,20

TABLE 84-5 Dosing of Antimicrobial Agents by Age Group ^{19–22,89,105}

Supportive care, particularly early in the course of treatment, is critically important. Administration of fluids, electrolytes, antipyretics, and analgesics is indicated for patients presenting with ABM. Additionally, venous thromboembolism prophylaxis and ICP monitoring are often needed. Patients may require the administration of osmotic diuretics such as mannitol 25% or hypertonic 3% saline to maintain an ICP of <15 mm Hg (<2 kPa) and a cerebral perfusion pressure of ≥60 mm Hg (≥8 kPa). Other supportive care measures may include respiratory and circulatory support, GI care, and maintaining normal body temperature. Although supportive care is important initially, appropriate antibiotic therapy (empirical or definitive) should be started as soon as possible.^23,24

Several factors influence the transfer of antibiotic from capillary blood into the CNS, including inflammation of the meninges, which increases antibiotic penetration through damage to tight junctions between capillary endothelial cells and decreases the activity of an energy-dependent efflux pump in the choroid plexus responsible for movement of penicillins and, to a much lesser extent, fluoroquinolones and aminoglycosides (see Table 84–3). Antibiotics having low molecular weights are passed more easily through biologic barriers than compounds of higher molecular weight. Only antibiotics that are nonionized at physiologic or pathologic pH are capable of diffusion. Highly lipid-soluble compounds penetrate more readily than water-soluble compounds. Antibiotics not extensively bound to plasma proteins provide a larger free fraction of drug capable of passing into the CSF. Passage of large, polar antibiotics into the CSF may be assisted, however, by a carrier transport system. Antibiotic dosages in the treatment of CNS infections must be optimized to ensure adequate penetration to the site of infection.

Problems of CSF penetration were traditionally overcome by direct instillation of antibiotics intrathecally, intracisternally, or intraventricularly. Advantages of direct instillation, however, must be weighed against the risks of invasive CNS procedures. Intrathecal administration of antibiotics is unlikely to produce therapeutic concentrations in the ventricles possibly owing to the unidirectional flow of CSF.²⁶Although intraventricular administration from a therapeutic standpoint may be preferred over intrathecal administration, the former requires neurosurgical placement of a subcutaneous reservoir. Intraventricular delivery may be necessary in patients who have shunt infections that are difficult to eradicate or who cannot undergo surgical interventions (A-III).¹⁹ The antimicrobial agents often utilized for ABM treatment have adequate CSF penetration, which has limited the need for direct CNS instillation of antibiotics. The European guidelines for meningitis treatment recommend considering the use of intrathecal or intraventricular antibiotics only in patients who fail conventional treatment.²⁰

Although the length of treatment for bacterial meningitis generally is based on the causative organism, there is no universally accepted standard (Table 84–4). Meningitis caused by S. pneumoniae has been treated successfully with 10 to 14 days of antibiotic therapy. Meningitis caused by N. meningitidis or H. influenzae usually can be treated with a 7-day course of antibiotics. In contrast, a longer duration (≥21 days) has been recommended for patients with L. monocytogenes, gram-negative or pseudomonal meningitis (A-III). Therapy should be individualized, and some patients may require enduring courses.^19,20

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Clinical Controversy…

Patients with ABM often remain hospitalized for the duration of IV antibiotic treatment. Outpatient treatment may be appropriate in certain patients following the acute phase of infection, typically the first 7 days. Decreasing length of stay and hospital-acquired complications has driven the efforts to complete treatment courses in the outpatient setting. However, only certain patients who are at low risk of developing neurologic complications should be considered for outpatient treatment, and close followup should be arranged.

Causative Organisms

S. pneumoniae (Pneumococcus or Diplococcus)

S. pneumoniae is the leading cause of meningitis in patients ≥2 months of age in the United States. Overall case-fatality rate is estimated to be 18%. Despite the decline in rates of pneumococcal meningitis since the introduction of PCV7 vaccination in 2000, case-fatality rate did not significantly change from pre-PCV7 era.⁸ Approximately 50% of cases are secondary infections resulting from primary infections of parameningeal foci, such as the ear or paranasal sinuses. Pneumonia, endocarditis, CSF leak secondary to head trauma, splenectomy, alcoholism, sickle cell disease, and bone marrow transplantation may predispose the patient to the development of pneumococcal meningitis.

Neurologic complications, such as coma, hearing impairment, and seizures, are common with pneumococcal meningitis. The prognosis of pneumococcal meningitis depends on a variety of factors, including chronic comorbidities, low Glasgow Coma Scale Score, focal neurologic deficits on admission, low CSF leukocyte count, pneumonia, bacteremia, and intracranial and systemic complications.²⁷

Based on resistance patterns and the fact that sufficient CSF concentrations of penicillin are difficult to achieve with standard IV doses, penicillin should not be used as empirical therapy if S. pneumoniae is a suspected pathogen. Furthermore, appropriate Clinical Laboratory Standards Institute (CLSI)–approved testing of all CSF isolates for penicillin resistance is recommended. Ceftriaxone and cefotaxime have served as alternatives to penicillin in the treatment of penicillin-resistant pneumococci. Of note, higher cephalosporin minimum inhibitory concentration (MIC) and higher cephalosporin resistance rates were shown in penicillin-resistant isolates.²⁸ Therapeutic approaches to cephalosporin-resistant pneumococcus include the addition of vancomycin and rifampin. However, only data from animal and experimental trials supporting the use of rifampin are available.^29,30 Therefore, the combination of vancomycin and ceftriaxone has been suggested as empirical treatment until the results of antimicrobial susceptibility testing are available (A-III). Vancomycin should not be used alone even for highly penicillin- and cephalosporin-resistant strains (A-III).^19,20 Some pneumococcal strains exhibit tolerance to vancomycin and were linked to increased meningitis mortality.^31,32

Based on concern about the limited therapeutic options for penicillin- and cephalosporin-resistant pneumococcal meningitis, newer agents have been evaluated. Meropenem is approved by the U.S. FDA for the treatment of bacterial meningitis in children aged 3 months and older and has shown similar clinical and microbiologic efficacy to cefotaxime or ceftriaxone. It is currently recommended as an alternative to a third-generation cephalosporin in penicillin-nonsusceptible isolates (B-II). Some caution is warranted with the use of imipenem for CNS infections because of the possibility of drug-induced seizures, especially when not properly dose adjusted for declining renal function. Of note, seizures may be caused by meningitis itself or by imipenem, and the cause is difficult to differentiate. The newer fluoroquinolones represent another therapeutic option owing to favorable activity against multidrug-resistant pneumococci and good penetration into the CSF (B-II).³³

IV linezolid and daptomycin have emerged as therapeutic options for treating multidrug-resistant gram-positive infections. Linezolid in combination with ceftriaxone has been used to treat a limited number of cases of pneumococcal meningitis with outcomes similar to standard treatment.³⁴ The penetration of daptomycin in the CSF was approximately 6% following a 15 mg/kg bolus achieving maximum concentration approximately 4 hours after the dose in a rabbit meningitis model. The 15 mg/kg dose produces similar serum concentrations in rabbits as the 6 mg/kg dose in humans. In this study, daptomycin was able to clear both the penicillin-resistant and the quinolone-resistant pneumococci from the CSF more rapidly than the standard regimen of vancomycin and ceftriaxone.³⁵ Additionally, daptomycin may reduce the inflammatory response caused by cell wall components in pneumococcal meningitis compared with ceftriaxone in animal models.³⁶

Pneumococcal vaccines help in reducing the risk of invasive pneumococcal disease. Virtually all serotypes of S. pneumoniae exhibiting intermediate or complete resistance to penicillin are found in the 23-valent pneumococcal polysaccharide vaccine (PPV23) (Pneumovax 23^®). Due to low vaccination rates among people 65 years of age and older, the U.S. Centers for Disease Control and Prevention (CDC) issued stronger recommendations for the use of the pneumococcal polysaccharide vaccine, calling for vaccination of the following high-risk groups: persons over the age of 65 years; persons aged 2 to 64 years who have a chronic illness, who live in high-risk environments (e.g., Alaskan Natives and residents of long-term care facilities), and who lack a functioning spleen (e.g., sickle cell disease and splenectomy); and immunocompromised persons over the age of 2 years, including those with human immunodeficiency virus (HIV) infection. Additionally, the question of whether or not college students living in dormitories, a possible high-risk environment, should be vaccinated remains debatable. Unfortunately, variability in the host’s ability to mount an immune response to the vaccine limits its usefulness for penicillin-resistant pneumococci in children younger than 2 years of age and in immunocompromised adults.

In 2000, a heptavalent pneumococcal protein-conjugate vaccine (PCV7) (Prevnar^®) was approved for use in children 2 months of age and older. Use of the vaccine has significantly reduced invasive pneumococcal infections, including sepsis and meningitis, as well as possible cost savings.^9,37 Moreover, the vaccine is safe and effective in low-birth-weight and preterm infants.³⁸ In the decade following the introduction of PCV7, rate of invasive disease caused by non-PCV7 strains increased considerably, especially serotype 19A.⁹ This led to the development of a newer vaccine with expanded coverage. Ultimately, the FDA approved a 13-valent pneumococcal conjugate vaccine (PCV13) (Prevnar 13^®) in 2010 for childhood vaccination. Current recommendations are for all healthy infants younger than 2 years of age to be immunized with the PCV13 at 2, 4, 6, and 12 to 15 months. The CDC has issued a recommendation that all persons with cochlear implants receive age-appropriate vaccination with the pneumococcal conjugate vaccine, pneumococcal polysaccharide vaccine, or both.³⁹ In 2011, the FDA approved the use of PCV13 in adults 50 years and older as PCV13 was shown to produce antibody levels that are either comparable to or higher than the levels achieved by PPV23, for the 13 serotypes included in PCV13. Final recommendations from the CDC regarding the routine use of PCV13 in adults will be forthcoming.

N. meningitidis (Meningococcus)

N. meningitidis is a leading cause of bacterial meningitis among children and young adults in the United States and around the world.^8,40 The source of infection usually is an asymptomatic carrier. Five of the 13 serogroups of N. meningitidis (A, B, C, Y, and W-135) are primarily responsible. Clusters of meningococcal disease, defined as two or more cases of the same serogroup that are closer in time and space than expected for the population or group under observation, generally are associated with crowding as in schools, dormitories, and military barracks.⁴¹ Although some of these clusters have been due to serogroup B, the majority has been due to serogroup C. Serogroup A, although associated with meningococcal outbreaks in Africa and Asia, is a rare cause of disease in the United States. Serogroup Y, although frequently associated with pneumonia, is emerging as an important cause of invasive meningococcal disease in select areas.⁴² Overall, N. meningitidis accounted for 13.9% of all meningitis cases in the United States during 2003 to 2007, most cases in persons aged 2 to 18 years. According to recent estimates, the case-fatality rate is approximately 10%.⁸

Initially, patients are colonized and, at some point, develop bacteremia, which most likely occurs prior to hospital admission. Meningitis occurs after the bacteria seed into the meninges. After the acute phase of meningitis has resolved, there is a unique immune reaction that distinguishes meningococcal meningitis from other bacterial causes. The patient develops a characteristic immunologic reaction of fever, arthritis (usually involving large joints), and pericarditis approximately 10 to 14 days after the onset of disease and despite successful treatment. At this time, examination of the synovial fluid reveals a large number of polymorphonuclear cells, elevated protein concentrations, normal glucose concentrations, and sterile cultures. The reaction may last a week or longer, and no additional antibiotic therapy is required; however, patients may benefit from nonsteroidal antiinflammatory agents and supportive care.^17,43

Seizures and coma are uncommon with meningococcal meningitis. Patients may behave aggressively and often are maniacal. They may develop deafness and transiently impaired ocular movements. Deafness unilaterally or, more commonly, bilaterally may develop early or late in the disease course. Hearing loss secondary to sensory nerve damage (sensorineural hearing) is usually permanent, whereas conductive hearing impairment, such as damage to the tympanic membrane, is often reversible.^17,43

The presence of petechiae may be the primary clue that the underlying pathogen is N. meningitidis. Approximately 60% of adults and up to 90% of pediatric patients with meningococcal meningitis have purpuric lesions, petechiae, or both.¹⁷ Patients may have an obvious or subclinical picture of disseminated intravascular coagulation (DIC), which may progress to infarction of the adrenal glands and renal cortex and cause widespread thrombosis and rapid death.

Third-generation cephalosporins (i.e., cefotaxime and ceftriaxone) are the recommended empirical treatment for meningococcal meningitis (A-III) (see Table 84–4). When final culture results are available, penicillin G or ampicillin is recommended for penicillin-susceptible isolates. Meropenem and fluoroquinolones are also suitable alternatives for the treatment of penicillin-nonsusceptible meningococci (A-III).^19,20

N. meningitidis is spread by direct person-to-person close contact, including respiratory droplets and pharyngeal secretions. Close contacts of patients contracting N. meningitidis meningitis are at an increased risk of developing meningitis. Close contacts include daycare center contacts, members of the household, or anyone who has been exposed to respiratory or oral secretions through activities such as coughing, sneezing, or kissing. Household contacts of people who have sporadic disease are at increased risk for meningococcal meningitis compared with overall population. Secondary cases of meningitis usually develop within the first week following exposure, but may take up to 60 days after contact with the index case.⁴⁴ Young children are at the greatest risk of contracting N. meningitidis; however, all ages are at risk, especially close contacts exposed via household, daycare, or military contact.

Prophylaxis of close contacts should be started only after consultation with the local health department. In general, rifampin, ceftriaxone, ciprofloxacin, or azithromycin is given for prophylaxis. A systematic review of available data suggests an increased rate of rifampin-resistant isolates.⁴⁵ Also, cases of ciprofloxacin-resistant isolates were reported in North America.⁴⁶ For regions with reported ciprofloxacin resistance, one dose of azithromycin 500 mg is recommended for prophylaxis. Further discussion of who should receive prophylaxis is beyond the scope of this chapter; interested readers can refer to the recommendations of the CDC and recommendations of the American Academy of Pediatrics.

Two meningococcal vaccines are available for routine immunization. Both vaccines contain antigens to serogroups A, C, Y, and W-135, but lack activity against serogroup B. Meningococcal polysaccharide vaccine (MPSV4) is preferred for adults 56 years and older who have an indication for immunization, while meningococcal conjugate vaccine quadrivalent (MCV4) is preferred for individuals 55 years and younger. Typically, adolescents receive a primary dose of MCV4 at age 11 or 12, and a booster dose at age 16. Please refer to Chapter 102 for Vaccine chapter in this book for further information on meningococcal vaccination and target high-risk groups.

H. influenzae

Historically, Hib was the most common cause of meningitis in children 6 months to 3 years of age. Since the introduction of effective vaccines, the incidence of Hib disease in the United States has declined dramatically. Widespread vaccination of infants and children has effectively decreased the incidence of bacterial meningitis due to H. influenzae in children between the ages of 1 month and 5 years, resulting in a significant decline in all cases of bacterial meningitis.⁸ In children older than 3 years and adults, meningitis caused by H. influenzae may indicate a parameningeal focus of infection such as middle ear infection, paranasal sinus infection, or CSF leakage. Spread of the organism occurs through direct spread from infected sinuses, draining of these areas via the veins, or bacteremia originating from the local focus of infection.⁴⁷

Because approximately 20% of H. influenzae strains are ampicillin-resistant, a third-generation cephalosporin is recommended empirically until susceptibilities are available (A-I). If the organism is susceptible to ampicillin, the patient can be switched to ampicillin and the cephalosporin discontinued (A-III). Third-generation cephalosporins (cefotaxime and ceftriaxone) are active against β-lactamase–producing and non–β-lactamase–producing strains of H. influenzae. In addition, they are relatively free of toxicity and do not require serum concentration monitoring. Cefepime (A-I) and fluoroquinolones (A-III) are suitable alternatives regardless of β-lactamase activity.^19,20

Prophylaxis is to protect close contacts from the index case by eliminating nasopharyngeal and oropharyngeal carriage of H. influenzae. Invasive disease should be reported to the local public health department and the CDC. Prophylaxis of close contacts should be started only after consultation with the local health department. Widespread vaccination has limited the need for chemoprophylaxis. Further discussion of who should receive prophylaxis is beyond the scope of this chapter; interested readers can refer to the recommendations of the American Academy of Pediatrics.

Vaccination includes a series of doses and usually is begun in children at 2 months of age. In addition to pediatric immunization, the vaccine also should be considered in patients older than 5 years of age with the following underlying conditions: sickle cell disease, asplenia, and immunocompromising diseases. Refer to Chapter 102 for further information on vaccine dosing and administration.

Group B Streptococcus (Streptococcus agalactiae)

GBS is a leading cause of neonatal meningitis in the United States and around the world.^8,48 The causative organism, S. agalactiae, is a gram-positive bacterium with β-hemolytic properties that is often implicated in neonatal sepsis, pneumonia, and meningitis. GI and genitourinary colonization in pregnant women is common. Neonates acquire this infection through vertical transmission while passing through the vaginal canal during birth.

Early onset infections are those occurring within the first week of life, while late-onset infections occur after the first week of the child’s birth. Universal prenatal screening and intrapartum antimicrobial prophylaxis of colonized pregnant women have significantly decreased rate of early onset invasive disease.⁴⁹ While rates of GBS meningitis in the United States did not change significantly during 1998 to 2007, including cases in patients <2 months of age, most cases during 2002 to 2007 were late-onset infections that are not affected by intrapartum prophylaxis.⁸

Ampicillin and penicillin G are the recommended agents for the treatment of presumed GBS (A-III). Addition of an aminoglycoside should also be considered for confirmed GBS meningitis.¹⁹ GBS continues to be susceptible to ampicillin and penicillin; however, reports of isolates with increased MIC have been published.^49,50

Investigations are undergoing to develop vaccines to reduce maternal colonization and prevent fetal transmission of GBS. Clinical trials have shown promising results; however, to date there are no licensed vaccines available for GBS.

L. monocytogenes

L. monocytogenes is a gram-positive diphtheroid-like organism. This disease primarily affects neonates, alcoholics, immunocompromised adults, and the elderly, while infections in healthy individuals are extremely rare. L. monocytogenes is implicated in approximately 10% of meningitis cases in those older than 65 years of age and carries a case-fatality rate of approximately 18% in the United States.⁸

Transmission usually involves colonization of the patient’s GI tract with the organisms, which then penetrate the gut lumen. Coleslaw, unpasteurized milk, Mexican-style soft cheese, ready-to-eat foods, and raw beef and poultry all have been identified as sources of this foodborne pathogen.¹³ If a sufficient cell-mediated immune response (T lymphocytes, macrophages) is not produced, bacteremia, meningitis, meningoencephalitis, or cerebritis may develop. Infection of the CNS may be diffuse or localized, possibly involving the cerebral hemispheres, thalamus, and brain stem.

Incidence of L. monocytogenes meningitis tends to peak in the summer and early fall. As with gram-negative meningitis, presentation may be subtle and insidious, and clinical suspicion should prompt lumbar puncture. L. monocytogenes produces primarily a mononuclear CSF response.⁵¹ One common laboratory error seen with L. monocytogenes is a tendency to misidentify the organism on Gram stain as a diphtheroid, Streptococcus, or a poorly staining gram-negative rod.

Treatment of L. monocytogenes meningitis with penicillin G or ampicillin may result in only a bacteriostatic effect and possible persistence of infection. Usually the combination of penicillin G or ampicillin with an aminoglycoside results in a bactericidal effect. Patients should be treated for a minimum of 3 weeks (A-III).¹⁹ European guidelines for meningitis treatment recommend considering combination therapy for the first 7 to 10 days of treatment, with the remaining course of therapy completed with penicillin G or ampicillin alone.²⁰ Despite in vitro activity against L. monocytogenes, vancomycin was associated with high failure rates.⁵² Third-generation cephalosporins lack in vitro activity against L. monocytogenes. Trimethoprim–sulfamethoxazole and meropenem may be effective alternatives because adequate CSF penetration is achieved (A-III).^19,20

Gram-Negative Meningitis

During the last several years, the incidence of gram-negative bacillary meningitis, excluding H. influenzae, has been increasing in both children and adults. E. coli is a leading cause of bacterial meningitis in neonates up to 3 months of age.⁵³ Several factors predispose patients to the development of gram-negative meningitis: congenital defects involving the CNS, accidental cranial trauma, neurosurgery, the use of antimicrobial agents with exclusive gram-positive activity preoperatively in neurosurgery, any form of communication between the skin and subarachnoid space (such as a dermal sinus), diabetes, malignancy, urinary tract infection in neonates, cirrhosis, parameningeal infection, spinal anesthesia, advanced age, immunosuppression, and hospitalization in general.

Elderly debilitated patients are at an increased risk of gram-negative meningitis but typically lack the classic signs and symptoms of the disease. Nuchal rigidity may be difficult to detect secondary to cervical arthritis. Presence of a low-grade fever and changes in mental status without other obvious cause should prompt consideration of meningitis and a lumbar puncture. Neonates are also at risk for gram-negative meningitis with E. coli and Klebsiella pneumoniae, which are responsible for 40% to 50% of cases.⁵³

Treatment of gram-negative meningitis is complex because of the variety of organisms that can infect the CNS. The treatment of meningitis due to Pseudomonas aeruginosa remains a unique problem because antibiotics showing good antibacterial activity, such as antipseudomonal penicillins and aminoglycosides, penetrate the CSF poorly. Furthermore, many isolates of P. aeruginosa are resistant to multiple, if not all, commonly used agents, and this trend in resistance is increasing. Initially, cases of P. aeruginosa meningitis should be treated with an extended-spectrum β-lactam such as ceftazidime or cefepime (A-II), or alternatively aztreonam, ciprofloxacin, or meropenem (A-III). The addition of an aminoglycoside—usually tobramycin—to one of the above agents should also be considered (A-III).^19,20 Since aminoglycosides penetrate the CSF poorly, their inclusion is predominantly to aid in the treatment of extracerebral infections. If multidrug-resistant Pseudomonas is suspected initially, intraventricular administration of an aminoglycoside should be considered along with IV administration. Preservative-free forms of gentamicin and tobramycin are available and should be used for direct administration into the CSF. Since CSF flows unidirectionally with gravity, intraventricular aminoglycoside administration is more likely to produce therapeutic concentrations throughout the CSF than intrathecal administration. While intraventricular administration of aminoglycosides is considered for treatment of P. aeruginosa meningitis, this method produced higher mortality in a sample of infants treated for gram-negative bacillary meningitis.⁵⁴ Thus, intraventricular administration of aminoglycosides to infants is not recommended routinely.

Multidrug-resistant Pseudomonas and Acinetobacter infections are of concern to clinicians because of the limited therapeutic options available. This concern has led to the reemergence of the use of older antibiotics, such as colistin and polymyxin B. Colistin can be used, both IV and intrathecally, in the treatment of multidrug-resistant Pseudomonas or Acinetobacter CNS infections.⁵⁵ Furthermore, synergistic activity with the combination of colistin and ceftazidime against multidrug-resistant P. aeruginosa was demonstrated in an in vitro model.⁵⁶ The use of colistin should be reserved for only the most severe cases.

Other gram-negative organisms causing meningitis, excluding P. aeruginosa and Acinetobacter spp., most likely can be treated with a third- or fourth-generation cephalosporin, such as cefotaxime, ceftriaxone, ceftazidime, or cefepime. Ceftazidime, however, may not be the best choice of empirical antibiotic for situations where the offending organism is not known initially because of its lack of reliable gram-positive coverage. Cefotaxime should be used in place of ceftriaxone in the neonatal period because of the potential for the displacement of bilirubin from albumin-binding sites.

Trimethoprim–sulfamethoxazole is useful in the management of the Enterobacteriaceae family and also may be useful in the management of L. monocytogenes (A-III). One advantage of trimethoprim–sulfamethoxazole is that its penetration into the CSF does not depend on meningeal inflammation. Trimethoprim–sulfamethoxazole is not bactericidal, which may be a disadvantage. Fluoroquinolones have good penetration into the CSF and are effective in animal models of both gram-negative and gram-positive meningitis; however, there are limited data on their efficacy in clinical practice. Ciprofloxacin is recommended as an alternative agent for the treatment of E. coli, other Enterobacteriaceae, and P. aeruginosa (A-III). Cefepime, meropenem, and aztreonam represent other therapeutic options for the treatment of gram-negative bacterial meningitis (A-III).^19,20

CSF cultures may remain positive for several days or more with a regimen that eventually will be curative. Therapeutic efficacy can be monitored through bacterial colony counts every 2 or 3 days, which should decrease progressively over the period of therapy. Therapy for gram-negative meningitis should be continued for a minimum of 21 days from the start of treatment with an effective agent.^19,20

Bacillus anthracis

B. anthracis is a large, endospore-forming, aerobic, gram-positive bacterium capable of producing infection via the cutaneous, pulmonary, or GI routes. Cases of meningitis have been reported following both cutaneous and inhalational infections. Prior to the bioterrorism-related outbreak of 11 inhalational and 12 suspected or confirmed cases of cutaneous anthrax in 2001, only 18 sporadic cases had occurred in the United States in the 20th century, with the last occurrence in 1976.⁵⁷

The major neurologic complication of anthrax infection is fulminant, rapidly fatal hemorrhagic meningoencephalitis. The inhalational form of anthrax seems to be a potent inducer of neurologic symptoms, and death usually occurs within a week for those with neurologic complications.⁵⁷ B. anthracis typically is susceptible to penicillin, amoxicillin, erythromycin, doxycycline, and ciprofloxacin. The bioterrorism-related strain was susceptible to the fluoroquinolones, rifampin, tetracycline, vancomycin, imipenem, meropenem, chloramphenicol, clindamycin, and the aminoglycoside, but resistant to third-generation cephalosporins and trimethoprim–sulfamethoxazole. Ciprofloxacin or doxycycline plus one of the aforementioned antibiotics, preferably clindamycin to limit toxin production, is the currently recommended regimen for the treatment of inhalational anthrax, but doxycycline is not recommended for the treatment of anthrax meningitis owing to poor CNS penetration, compared with MIC of most bacterial pathogens, and recent in vitro resistance.^57,58

Dexamethasone as an Adjunctive Treatment for Bacterial Meningitis In addition to antibiotics, dexamethasone is a commonly used therapy in the treatment of meningitis. Corticosteroids inhibit the production of TNF and IL-1, both potent proinflammatory cytokines. In trials that measured inflammatory mediators, lower levels of TNF, PAF, or IL-1 were detected in patients treated with dexamethasone.^59–61 A series of clinical studies assessing the efficacy of corticosteroid therapy for the initial treatment of bacterial meningitis indicate conflicting results.^59–63 A systematic review in 2004 shows treatment with corticosteroids reduces both mortality and neurologic sequelae in adults with community-acquired bacterial meningitis.⁶⁴ However, subsequent large randomized clinical trials show conflicting results. A fundamental problem with corticosteroid investigations to date is that the majority of patients in the trials had H. influenzae meningitis, which has decreased dramatically following the introduction of polysaccharide conjugate vaccines. Additionally, the majority of studies examining dexamethasone use for pneumococcal meningitis were conducted before widespread penicillin-resistant pneumococcus emerged or in parts of the world where penicillin resistance is minimal.

A systematic review of 24 randomized controlled trials of corticosteroid use in ABM showed that corticosteroids significantly reduced hearing loss and neurologic sequelae, but did not reduce overall mortality, nor were associated with beneficial effects in low-income countries. Subgroup analyses showed reduced mortality in pneumococcal meningitis and reduced severe hearing loss in H. influenzaemeningitis.⁶⁵ Another meta-analysis of five randomized, double-blinded, placebo-controlled trials of dexamethasone for ABM in patients of all ages showed that adjunctive dexamethasone did not seem to significantly reduce death or neurologic disability.⁶⁶ Thus, adjunctive corticosteroid use in the management of ABM remains controversial.

Most clinical trials on the use of adjunctive dexamethasone in bacterial meningitis have involved children. A retrospective analysis of pediatric patients with pneumococcal meningitis and one unblinded, noncontrolled trial suggested that adjunctive steroids may decrease the neurologic sequelae and mortality associated with S. pneumoniae meningitis.^60,67 A meta-analysis in 1997 suggested benefits in H. influenzae meningitis and, if commenced with or before antibiotics, suggested benefit for pneumococcal meningitis in childhood.⁶⁸

Current recommendations call for the use of adjunctive dexamethasone in infants and children with H. influenzae meningitis (A-I). The recommended IV dose is 0.15 mg/kg every 6 hours for 2 to 4 days, initiated 10 to 20 minutes prior to or concomitant with, but not after, the first dose of antimicrobials (A-I). Clinical outcome is unlikely to improve if dexamethasone is given after the first dose of antimicrobial and should therefore be avoided (A-I). For infants and children 6 weeks of age and older with pneumococcal meningitis, adjunctive dexamethasone may be considered after weighing the potential benefits and possible risks (C-II).^19,69 If adjunctive dexamethasone is used, careful monitoring of signs and symptoms of GI bleeding and hyperglycemia should be employed. Moreover, the use of dexamethasone may interfere with the interpretation of clinical response to treatment, such as resolution of fever.

If pneumococcal meningitis is suspected or proven, it is recommended that adults receive dexamethasone 0.15 mg/kg (up to 10 mg) every 6 hours for 2 to 4 days with the first dose administered 10 to 20 minutes prior to first dose of antibiotics (A-I). Similar to the pediatric population, clinical outcome is unlikely to improve if dexamethasone is given after the first dose of antibiotics and should therefore be avoided (A-I).^19,20 It is often difficult to ascertain the responsible pathogen on presentation; therefore, some clinicians recommend initiating dexamethasone in all adult patients presenting with meningitis (B-III). Dexamethasone is not routinely recommended for patients with ABM due to other bacterial etiologies.^19,20

Routine use of dexamethasone in meningitis is not without controversy. A potential concern is that adjunctive dexamethasone therapy may reduce the penetration of antibiotics into the CSF by inhibiting meningeal inflammation. In early experimental models of meningitis, steroids decreased the CSF concentrations of ampicillin, rifampin, vancomycin, and gentamicin.^61,70 Ceftriaxone and vancomycin penetration into CSF was unaffected by concurrent dexamethasone administration in pediatric patients.^71,72 More recent data show that appropriate concentrations of vancomycin in CSF may be obtained even when adjunctive dexamethasone is used, but the small number of subjects studied limits the generalization of these findings. Also, measured serum and CSF levels, with and without dexamethasone, were based on a 15 mg/kg loading dose followed by a continuous infusion of 60 mg/kg/day according to the European guidelines, which is not the standard of care in the United States.⁷³

Bacterial Brain Abscess

Approximately 1,500 to 2,500 cases of brain abscess occur annually in the United States, with decreasing incidence due to contiguous spread of infection from the oropharynx, middle ear, and paranasal sinuses and increasing incidence due to contiguous spread from cranial trauma or neurosurgical procedures.^74,75 Other sources of infection include hematogenous spread from distant foci of infection, such as endocarditis or intraabdominal infection.

The clinical presentation varies depending on the number, size, and location of the abscess(es). Headache, mental status changes, focal neurologic deficits, and fever are the most common symptoms of brain abscess, but seizures and nausea and vomiting may also be seen.⁷⁵ Diagnosis of brain abscess can be facilitated by CT or MRI, with preference given to MRI due to the ability to better differentiate cerebral tumor, stroke, and abscess.⁷⁶ Lumbar puncture is not routinely recommended in patients with brain abscess, while CT-guided aspiration and biopsy can be both diagnostic and therapeutic.

The etiology of brain abscess depends on the initial site of infection. Those arising from spread of infection from oropharynx, middle ear, and paranasal sinuses are commonly caused by streptococci and oral anaerobes (e.g., Actinomyces spp., Bacteroides spp., Fusobacterium spp., Peptostreptococcus). Staphylococci and aerobic, gram-negative bacilli are commonly involved in postoperative abscesses or those following head trauma. P. aeruginosa and Nocardia spp. can also cause brain abscesses but are more commonly seen in immunocompromised patients.^75,76

Because brain abscesses are commonly polymicrobial, empirical antimicrobial therapy should include antibiotics with activity against gram-positive, gram-negative, and anaerobic organisms. For example, the regimen could include vancomycin plus a third- or fourth-generation cephalosporin plus metronidazole, depending on risk factors. A carbapenem (such as meropenem) could replace the cephalosporin and metronidazole. De-escalation of therapy should occur once a causative organism is identified. While no consensus on treatment duration for brain abscesses exists, duration of therapy should be determined for each individual patient and should include consideration of the causative pathogen, size of abscess, use of surgical treatment, and response to therapy.⁷⁵ Because seizure is a common complication of brain abscesses, anticonvulsant therapy is recommended for at least 1 year and may be discontinued when an EEG shows no epileptic activity.⁷⁶ The benefit of dexamethasone in the treatment of brain abscess is unclear and is not routinely recommended.

Cryptococcus neoformans

Cryptococcus spp. are encapsulated soil yeasts acquired by inhalation of spores from the environment leading to CNS infection and less commonly pulmonary disease. The two main pathogenic species are C. neoformans and C. gattii. While cryptococcal infections mainly affect persons with underlying impaired immunity such as HIV-positive (approximately 85% of cases) and HIV-negative immunosuppressed patients, infections in nonimmunosuppressed individuals have been reported in North America.⁷⁷ Globally, approximately 958,000 cases of cryptococcal meningitis occur annually, resulting in 3-month case-fatality rate of over 600,000.⁷⁸

The incubation period in acquired immunodeficiency syndrome (AIDS) patients may be very short, as opposed to a relatively normal host, in whom it may be very long. Symptoms of C. neoformansmeningitis are insidious and may be present for varying periods, depending on the host involved, before the definitive diagnosis is made. Fever and a history of headaches are the most common symptoms, although altered mentation and evidence of focal neurologic deficits may be present. Examination of the CSF usually reveals mildly elevated WBCs, primarily lymphocytes (see Table 84–1). Diagnosis is based on the presence of a positive CSF, blood, sputum, or urine culture for C. neoformans. Organisms may be seen by microscope when stained with India ink and are more likely to be seen in AIDS patients compared with other hosts. An additional rapid test helpful in diagnosis is latex agglutination, which detects the presence of cryptococcal antigens. Latex agglutination is associated with overall sensitivities and specificities of 93% to 100% and 93% to 98%, respectively.⁷⁷ A cryptococcal antigen detection test needs to be considered in any patient presenting initially with meningitis. Risk factors predictive of a poor outcome include lethargy at presentation, nonimmunosuppressed patients, high CSF cryptococcal antigen titer, low CSF WBC count, low CD4 cell count, fungemia, and elevated CSF pressure.^77,79–81

Rapid sterilization of CNS through rapid fungicidal activity is the main approach of induction therapy, which ranges from 2 to 6 weeks, followed by consolidation therapy for 8 weeks. Despite poor penetration into the CSF, amphotericin B has long been the drug of choice for the treatment of acute cryptococcal meningitis due to its rapid fungicidal activity.⁷⁹ Amphotericin B 0.7 mg/kg/day combined with flucytosine 100 mg/kg/day for 2 weeks (A-I) is more effective than amphotericin alone (B-II) for HIV-positive patients.⁸² Additionally, this combination is associated with the most rapidly fungicidal activity, when compared with amphotericin alone, in combination with fluconazole or in combination with fluconazole and flucytosine.⁸³

Unfortunately, in the AIDS population, flucytosine is often poorly tolerated, causing bone marrow suppression and GI distress. Careful monitoring of hematologic parameters, therapeutic drug monitoring (TDM), and dose adjustment for patients with renal insufficiency are recommended to avoid flucytosine-associated toxicities. Amphotericin B alone (B-II) or in combination with high-dose fluconazole (B-I) may be a reasonable alternative to standard treatment.^84,85 Lipid formulations of amphotericin B at higher doses (3 to 5 mg/kg/day) can be used for HIV-positive patients with or predisposed to renal dysfunction (B-II) and are recommended for organ transplant recipients (B-III).⁸⁶

Azole therapy is the most studied alternative regimen for the treatment of C. neoformans meningitis in HIV-positive patients. Fluconazole and itraconazole have been studied as monotherapy with mixed results. If used alone or in combination with flucytosine, higher fluconazole doses of 800 to 2,000 mg/day are recommended due to higher success rates (B-II).⁸⁷ To note, the rate of fluconazole resistant C. neoformans has been increasing in recent years.⁸⁸Itraconazole has limited utility in induction therapy due to limited CSF levels of active drug (C-II). Generally, itraconazole suspension is preferred due to better absorption, and TDM is recommended to ensure optimal drug levels.⁸⁹Voriconazole in combination with amphotericin B shows similar rate of clearance of cryptococcal CFU in CSF samples compared with standard therapy.⁸⁵ Posaconazole has demonstrated clinical activity against cryptococcal and other fungal infections of the CNS in patients with refractory disease or otherwise intolerant to standard antifungal agents. Posaconazole appeared well tolerated at oral doses of 800 mg/day and may be an alternative in the treatment of fungal CNS infection due to C. neoformans.^90,91 More data are needed to determine what role the new azole antifungal agents will play in future treatment of cryptococcal meningitis.

HIV-positive persons often require extended maintenance or suppressive therapy, minimum of 12 months, because of high relapse rates following primary therapy (induction and consolidation phases) for C. neoformans. A large multicenter, controlled trial compared fluconazole 200 mg/day (A-I) and amphotericin B 1 mg/kg/wk (C-I) in the prevention of relapse. Two percent of patients receiving fluconazole versus 18% of patients on amphotericin B relapsed. In addition, the amphotericin B group had significantly more frequent bacterial infections, bacteremia, and drug-related toxicity.⁹² Fluconazole (A-I) is superior to itraconazole (C-I) in the prevention of relapse.⁹³ Current guidelines recommend continuing maintenance therapy until immune reconstitution takes place. Guidelines for the prevention of opportunistic infections in HIV-infected persons are updated frequently and can be found at www.aidsinfo.nih.gov. Readers interested in treatment guidelines for cryptococcal meningitis in HIV-negative immunosuppressed, such as transplant recipients, and nonimmunosuppressed individuals are encouraged to review the Infectious Diseases Society of America guidelines for the management of cryptococcal disease.⁸⁹

Viral Encephalitis

Encephalitis is defined by the presence of an inflammatory process of the brain in association with clinical evidence of neurologic dysfunction.²¹ Patients with metabolic disturbances, organ dysfunction, and noninfectious encephalitis, including postimmunization encephalitis or encephalomyelitis, can have similar clinical presentation to those with infectious encephalitis. Several infectious organisms have been identified to cause encephalitis, with viral etiologies being the most commonly diagnosed.^94–96 Additionally, meningoencephalitis is a term commonly used to describe meningeal inflammation along with encephalitis.

The epidemiology of viral encephalitis in the United States has changed dramatically since the mid-1960s because of the introduction of large-scale polio, rubella, varicella, and mumps immunization programs. Worldwide, mumps remains a causative agent of viral encephalitis in countries with low vaccination rates. Poliomyelitis, once a significant cause of encephalitis, is now confined to only a few less developed countries. Common causes of viral encephalitis and meningoencephalitis in the United States include herpes simplex virus (HSV), West Nile virus, and the enteroviruses. Additionally, viral encephalitis cases are caused by a variety of other pathogens, such as arboviruses, adenoviruses, influenzae virus A and B, rotavirus, corona virus, cytomegalovirus (CMV), varicella-zoster, Epstein-Barr virus, and lymphocytic choriomeningitis. To note, a confirmed or probable pathogen is not identified in the majority of encephalitis cases.^94–96

Viral encephalitis is acquired primarily by hematogenous spread or, alternatively, by neuronal spread of the causative pathogen. After entry into the host, viral replication occurs, resulting in dissemination through the reticuloendothelial system or vasculature. Infection of the capillary endothelial cells and choroid plexus may provide a conduit for CNS infections. Viruses such as polio, herpes, and varicella-zoster also may gain access to the CNS by axonal retrograde transmission from peripheral nerve endings. Once a virus gains access to the CNS, the course of infection depends on the virulence of the particular virus and the host immune response. Subsequent neuronal injury is caused by direct cell damage due to viral replication, but inflammatory and immune-mediated responses also contribute to neurologic damage.^16,97

In contrast with purulent meningitis, host response to viral encephalitis is mediated primarily through cytotoxic T lymphocytes. Increases in concentrations of IL-1, IL-6, and interferon (INF)-α, -β, and -γ may occur. While cytokine assays are available for investigational use, they are not used routinely in the clinical diagnosis of viral encephalitis.^16,97

The clinical syndrome associated with viral encephalitis generally is independent of viral etiology and may vary depending on the patient’s age. Common signs in adults include headache, mild fever, nuchal rigidity, malaise, drowsiness, nausea, vomiting, and photophobia. Only fever and irritability may be evident in the infant, and ABM must be ruled out as a cause of fever when no other localized findings are observed in a child. Duration of symptoms generally is 1 to 2 weeks, and specific manifestations outside the meninges also can occur depending on the viral etiology.

Laboratory examination of the CSF usually reveals a pleocytosis with 100 to 1,000 WBCs/mm³ (100 × 10⁶ to 1,000 × 10⁶/L), which are primarily lymphocytic; however, 20% to 75% of patients with viral encephalitis may have a predominance of polymorphonuclear cells on initial examination of the CSF. On repeat lumbar puncture, 90% of patients presenting initially with a predominance of neutrophils experience a shift to a predominance of mononuclear cells. Other laboratory findings include normal to mildly elevated protein concentrations and normal or mildly reduced glucose concentrations (see Table 84–1).^16,97

As mentioned before, pathogens responsible for viral encephalitis are often not identified.^94–96 Poor laboratory recovery of viral pathogens and limited treatment options for viral encephalitis made the need for specific identification of pathogens of questionable value. Advances in diagnostic laboratory techniques and the potential for decreased costs associated with longer duration of hospitalization for patients with unconfirmed viral encephalitis have led to a reevaluation of the need for confirmatory pathogen diagnosis. When clinical signs warrant pathogen identification, appropriate laboratory diagnostic techniques, including PCR and serologic testing, should be undertaken (A-III). Molecular methods are preferred to conventional laboratory tests, such as viral cultures and brain biopsy, in the diagnosis of viral encephalitis owing to improved sensitivity and specificity, higher yield, and rapid results.^21,22

Supportive and symptomatic treatments of patients with viral encephalitis are of great importance due to limited treatment options for most viral etiologies. Such treatments may include seizure control, hemodynamic management, venous thromboembolism prevention, ICP management, and secondary bacterial infection prevention. Corticosteroid therapy is generally not recommended in most viral encephalitis cases; however, treatment should be considered for patients with cerebral edema and increased ICP.^21,22

Although there are numerous pathogenic causes of viral encephalitis, much of the clinical presentation, diagnosis, and treatment are similar. The most commonly isolated viral etiologies are described here.

Both herpes simplex virus type 1 (HSV1) and herpes simplex virus type 2 (HSV2) are considered the most common treatable causes of viral encephalitis. HSV1 is associated with encephalitis in adults, whereas HSV2 is associated predominantly with encephalitis in newborns.^94–96 An HSV infection of the CNS most likely is spread via retrograde movement from the dorsal root ganglion. Sexually active adults acquire herpes simplex meningitis during or after an attack of genital or rectal herpes, whereas neonates acquire the virus during passage through the vaginal canal of mothers with active herpes infection. HSV PCR testing on CSF specimens should be performed for all patients with presumed encephalitis (A-III). Moreover, repeat testing should be considered for patients with an initial negative test after 3 to 7 days (B-III). Establishing the correct diagnosis as early as possible is paramount because of high mortality rate without treatment (approaches 70%), and unlike other viral etiologies, specific and effective therapy is available. As a result, empirical therapy of suspected HSV encephalitis while laboratory results are pending is necessary. Delaying antiviral therapy has been consistently associated with unfavorable outcomes and increased mortality across several studies. In one retrospective study of 184 patients with HSV encephalitis, administration of IV acyclovir within first day of hospital admission was associated with a lower mortality rate (13% vs. 31%).²⁴ Additionally, a clinical decision to treat may need to be made regardless of test results.

Acyclovir is the drug of choice for herpes simplex encephalitis. In adult patients with normal renal function, acyclovir is usually administered as 10 mg/kg IV every 8 hours for 2 to 3 weeks (A-I).^21,22 Higher doses of acyclovir (20 mg/kg IV every 8 hours) have been used in neonates and are associated with lower mortality rates (A-I).⁹⁸ Herpes virus resistance to acyclovir has been reported with increasing incidence, particularly in immunocompromised patients with prior or chronic exposures to acyclovir, ranging from 3.5% to 10% in immunocompromised patients.⁹⁹ The alternative treatment for acyclovir-resistant HSV is foscarnet. The dose for patients with normal renal function is 40 to 60 mg/kg infused over 1 hour every 8 to 12 hours for 3 weeks, with the higher dose typically reserved for HIV-infected individuals.²² Ensuring adequate hydration is imperative to decrease risk of acyclovir- and foscarnet-induced nephrotoxicity. In addition, patients receiving foscarnet should be monitored for seizures related to alterations in plasma electrolyte levels.

Because of the recent epidemic in the United States, a separate discussion of the West Nile virus is warranted. Although West Nile virus is transmitted primarily by mosquitoes, transmission of the virus via blood products, organ transplantation, transplacental transfer, and breast milk has been documented. Similar to the other arboviruses, the incubation period for West Nile virus ranges from 3 days to 2 weeks. Infection with West Nile virus is asymptomatic in most adults or causes a mild flu-like syndrome characterized by fever, malaise, myalgia, and lymphadenopathy. Typically, less than 1% of patients develop neurologic disease, of which approximately two thirds have encephalitis, with the remainder having meningitis without encephalitis. Many patients develop a maculopapular, erythematous rash, which is more common in children than in adults and is uncommon in other forms of viral encephalitis. The other neurologic manifestations include fever, nausea, vomiting, headache, altered mental status, movement disorders, and/or a syndrome much like poliomyelitis.¹⁰⁰ The primary risk factor for this manifestation seems to be advanced age, but alcohol abuse, diabetes, hypertension, immunosuppression, and cardiovascular disease were also identified as potential risk factors for neuroinvasive disease and worse outcomes.^100,101 The poliomyelitis syndrome is characterized by an early prodromic phase of fevers and weakness followed by the sudden onset of flaccid paralysis. Among patients hospitalized with West Nile virus, the mortality rate is approximately 10% to 15%, whereas patients with encephalitis and weakness have a mortality rate of 30%. CSF examination of West Nile virus encephalitis typically shows pleocytosis and a slightly elevated CSF protein concentration. Several diagnostic methods have been developed for West Nile virus, including a PCR assay and enzyme-linked immunosorbent assay (ELISA) tests. However, serologic tests (ELISA) can cross-react with other flaviviruses causing a false-positive result. Moreover, serum IgM antibodies for West Nile virus can persist for up to 1 year, leading to confusion regarding whether the infection is an acute or previous infection. Ribavirin has shown inhibitory effects on the West Nile virus in neural tissue cultures, but this has not been studied in controlled trials. Finally, DNA vaccines were studied in animals and have shown positive results.¹⁰⁰ Treatment is typically supportive, including treatment for seizures and increased ICP, and in the majority of cases, the disease is self-limiting.^21,22

CMV has emerged as a major cause of morbidity and mortality in immunocompromised patients, including HIV-infected individuals and transplant recipients on immunosuppressants. CNS infections with CMV are often difficult to treat, with higher failure rates and poor outcomes. Combination therapy with ganciclovir and foscarnet (B-III) is recommended for induction treatment due to the higher failure rates and lack of survival benefits when monotherapy with either agent is utilized. Ganciclovir 5 mg/kg every 12 hours and foscarnet 60 mg/kg every 8 hours (or 90 mg/kg every 12 hours) for 3 weeks are recommended during the induction phase, followed by maintenance phase with either agent (B-III).^21,22 Other interventions that may improve survival outcomes include the initiation of HAART in untreated HIV-infected patients and reduction of immunosuppression intensity in transplant recipients.

HIV encephalitis is a common CNS complication associated with AIDS. Frequently, patients may complain of headache, photophobia, or stiff neck at the time of presumed seroconversion. As the disease progresses neurologic symptoms are frequently reported secondary to other opportunistic infections. Diagnosis of viral encephalitis is difficult because mental status and neurologic examinations are not sensitive enough to detect early changes. Direct evidence of HIV encephalitis can be obtained through CSF culture, p24 antigen testing, or qualitative or quantitative PCR for HIV RNA. Diagnostic workup of other potential copathogens, such as HSV, Toxoplasma gondii, Mycobacterium tuberculosis, Aspergillus spp., and Cryptococcus, also should be performed. Refer to Chapter 103 for a complete discussion of infectious complications in HIV-positive individuals.

Other Etiologies

M. tuberculosis

M. tuberculosis is the primary cause of tuberculous meningitis and remains the most life-threatening form of extrapulmonary tuberculosis.¹⁰² The incidence of tuberculosis in general has decreased to 3.3 cases per 100,000 individuals in the United States in 2011,¹⁰³ with only 138 cases of tuberculous meningitis reported to the CDC in 2010.¹⁰⁴

The CDC recommends an initial regimen of four drugs for empirical treatment of M. tuberculosis. This regimen consists of isoniazid, rifampin, pyrazinamide, and ethambutol 15 to 20 mg/kg/day (maximum 1.6 g/day) for the first 2 months, generally followed by isoniazid plus rifampin for the remaining duration of therapy.¹⁰⁵ The recommended therapy for HIV-positive individuals is the same as for immunocompetent patients, although rifabutin may be considered in place of other rifamycins in an effort to minimize drug interactions with protease inhibitors and non-nucleoside reverse-transcriptase inhibitors. Therapy in HIV-negative and HIV-positive patients should be individualized based on susceptibility patterns and guidelines from the CDC and the American Thoracic Society, which are updated frequently and available on the Internet (www.cdc.gov/nchstp/tb/pubs/mmwrhtml/maj_guide.htm). Patients with M. tuberculosis meningitis should be treated for 9 months or longer with multiple-drug therapy, and patients with rifampin-resistant strains should receive 18 to 24 months of therapy.

Tuberculous meningitis has a mortality rate of 10% to 50% despite early diagnosis and treatment. The level of patient consciousness at the start of therapy is the most useful prognostic indicator. Patients who are comatose at the beginning of therapy have a mortality rate of approximately 75%. Other negative prognostic factors include old age, poor nutrition, evidence of miliary disease, high initial CSF protein concentrations, presence of hydrocephalus, and evidence of elevated ICP. Between 10% and 30% of patients surviving the disease have physical or mental sequelae, including deafness, vertigo, and short-term memory loss.^106,107

Treponema pallidum (Neurosyphilis)

Infection of the CNS by T. pallidum can occur at any stage of the disease, although it is most commonly seen in tertiary syphilis many years, even decades, after the initial exposure. The incidence of late latent syphilis, which includes neurosyphilis, according to the CDC has remained approximately 6 cases per 100,000 for the last decade. Patients with neurosyphilis may be asymptomatic, or present with signs and symptoms consistent with acute meningitis. Diagnosis is based on CSF findings, neurologic manifestations, and serologic evidence of exposure.¹⁰⁸ Aqueous penicillin G is recommended for treatment as 3 to 4 million units every 4 hours or 18 to 24 million units as a continuous infusion for a duration of 10 to 14 days. CSF examination should be repeated every 6 months until the cell count and protein has returned to normal.¹⁰⁹ For further reading on the manifestations and treatment of syphilis, we refer you to Chapter 95.

Primary Amoebic Meningoencephalitis (PAM)

PAM is a very rare form of CNS infection caused by Naegleria fowleri, a unicellular parasite that lives in warm stagnant fresh or brackish waters, and potentially well water. Humans acquire PAM when water is insufflated through the nostrils usually while swimming.^110,111 The pathogen attaches to the olfactory nerve and migrates through the cribriform plate into the brain. Within a few days N. fowleri will begin to multiply in numbers as the pathogen consumes the olfactory bulb. The patient may have problems properly identifying odors (parosmia), progressing to an inability to smell (anosmia), and then will lose taste sensation (ageusia). Trophozoites may be seen in the CSF at this time and are often missed visually but can be confirmed using PCR methods.¹¹² The disease becomes rapidly progressive as the parasite moves further into the brain and meninges causing fever, headache, neck rigidity, nausea, emesis, and possibly seizures. Unfortunately, even if PAM is recognized prospectively, the clinical prognosis is not good. Most cases of PAM are misdiagnosed or the diagnosis is made at autopsy. PAM is almost always a fatal event, which makes defining optimal management practices speculative at best. Most of the available PAM literature consists of case reports or summaries of case reports. Treatment of PAM usually consists of high-dose amphotericin B therapy. In some cases, azithromycin, rifampicin, and fluconazole have been added as adjuvants with some success.¹¹³ Chlorpromazine has been shown to be highly effective in vitro and in animal models against N. fowleri; however, the clinical utility of the drug in humans is unknown.

T. gondii

Toxoplasmic encephalitis (TE) is caused by the protozoan T. gondii. Approximately 22.5% of the U.S. population 12 years and older has been infected with T. gondii. In other parts of the world, up to 95% of populations are infected. The primary routes of transmission are foodborne, animal-to-human (cats serving as the definitive host), mother-to-child (congenital), blood transfusions, and organ transplantation.¹¹⁴TE is typically caused by the reactivation of disease in immunocompromised patients, especially those with AIDS, or intrauterine infection in newborns. Clinical manifestations include extrapyramidal signs and symptoms, headache, seizures, confusion, hemiparesis, cranial nerve abnormalities, or fever.²¹ In congenital toxoplasmosis, patients may also present with hydrocephalus, intracerebral calcification, microcephaly, convulsions, or chorioretinitis.^21,115 Definitive diagnosis of TE requires a clinical sample via a brain biopsy; therefore, TE is presumptively diagnosed on the basis of clinical symptoms, positive serology for anti-Toxoplasma immunoglobulin G (IgG) antibodies, and identification of space-occupying lesions on CT, MRI, or other radiologic imaging. In patients with AIDS, MRI typically shows multiple ring-enhancing lesions. T. gondii can also be detected by PCR in CSF; however, the sensitivity is low (50%) and the result is usually negative once treatment has started.^21,115,116 First-line treatment for TE in adults consists of pyrimethamine plus sulfadiazine plus leucovorin (A-I). Leucovorin is typically added to the treatment regimen to reduce the likelihood of hematologic toxicity associated with pyrimethamine. In patients who are unable to tolerate sulfadiazine, clindamycin may be used as an alternative (A-I). Other alternative treatment options include trimethoprim–sulfamethoxazole (B-I), atovaquone plus pyrimethamine plus leucovorin (B-II), atovaquone plus sulfadiazine (B-II), atovaquone monotherapy (B-II), or pyrimethamine plus leucovorin plus azithromycin (B-II). Treatment recommendations are the same in pediatric patients; however, several of the alternative regimens have not been studied in children.^21,115,116

Borrelia burgdorferi

LD is caused by the spirochete B. burgdorferi and is the most common tick-borne infection in North America and Europe.¹¹⁷ Lyme neuroborreliosis (LNB) is an infectious disorder of the nervous system caused by B. burgdorferi and has been reported in up to 10% to 15% of patients with untreated LD. CNS involvement includes meningitis, myelitis, cerebral vasculitis, and encephalitis. Clinical manifestations include fever, headache, fatigue, photosensitivity, phonosensitivity, confusion, hemiparesis, cranial neuropathy (facial neuropathy being the most common), cerebellar ataxia, ocular flutter, apraxia, opsoclonus-myoclonus syndrome, or Parkinson’s-like symptoms. Poliomyelitis-like syndromes and acute stroke-like symptoms caused by cerebral vasculitis have been documented in single case reports but are considered rare. Unlike the European LD, the North American LD is also characterized by a skin rash called erythema migrans.^117–119 Currently there is no international consensus for the diagnosis of LNB. Diagnosis is primarily based on the presence of neurologic symptoms without other obvious reasons, CSF analysis (lymphocytic pleocytosis, moderately elevated protein, normal glucose), intrathecal B. burgdorferi antibody production, blood and CSF serologic testing (ELISA plus Western blot), and MRI demonstrating areas of inflammation.^21,117,118 PCR testing for detection of B. burgdorferi in CSF has a sensitivity of less than 10% to 30% and has an unknown specificity; therefore, it is not routinely recommended. Parenteral treatment with ceftriaxone once daily is recommended as first-line treatment of LNB. Patients with cranial neuropathy without clinical signs of meningitis may be treated with oral amoxicillin, doxycycline, or cefuroxime axetil. The European Federation of Neurological Societies (EFNS) guidelines also recommend oral doxycycline as a first-line option for patients with symptoms confined to the meninges, cranial nerves, nerve roots, or peripheral nerves based on its CSF penetration, ability to achieve CSF concentrations above the MIC, and several Class III studies showing similar short- and long-term efficacy to various parenteral regimens.¹¹⁸ Alternative parenteral options to ceftriaxone include cefotaxime or penicillin G. For patients intolerant to β-lactams, doxycycline oral or IV is suggested.

EVALUATION OF THERAPEUTIC OUTCOMES

Signs and Symptoms

Because of the potential for rapid deterioration associated with meningitis, signs and symptoms of fever, headache, meningismus (e.g., nuchal rigidity, Brudzinski’s or Kernig’s sign), vital signs, and signs of cerebral dysfunction should be evaluated every 4 hours for the initial 3 days and then daily thereafter. The Glasgow Coma Scale should be used in severely ill patients. Trends in improvement and resolution rather than single evaluations in time are more important in monitoring the signs and symptoms of meningitis.

Microbiologic Findings

CSF and blood samples for Gram stain, cultures, and sensitivity testing should be taken prior to starting antibiotic therapy. If lumbar puncture is delayed, however, antibiotics should be started. Although the CSF cultures may be negative, antibiotic therapy rarely interferes with the protein and/or glucose concentrations in the CSF. Furthermore, if the laboratory is made aware of the antibiotic therapy, steps can be taken to diminish the effects of the antibiotic during the detection process. Gram stain results can be obtained immediately and can guide empirical antibiotic treatment. Identification of the organism can be made within 24 hours, and sensitivities should be available within 48 hours. Repeat cultures should be performed to help determine if sterilization is achieved. A second tube of blood should be taken to allow for latex agglutination tests of antigens to common meningeal pathogens (H. influenzae, S. pneumoniae, N. meningitidis, E. coli, and GBS) if the Gram stain has not been helpful.

CSF Examination

In bacterial meningitis, the CSF WBC count usually is greater than 1,000 cells/mm³ (1,000 × 10⁶/L), the CSF protein concentration is elevated, and the CSF glucose concentration (hypoglycorrhachia) is often low (<45 mg/dL [<2.5 mmol/L] or 50% to 60% of a simultaneous blood glucose value). Viral encephalitis, in contrast, results in relatively normal CSF protein and glucose levels and typically does not result in greater than 90% polymorphonuclear leukocytes (PMNs) in the CSF (see Table 84–1).

ABBREVIATIONS

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