Central Nervous System (CNS) infections include a wide variety of clinical conditions and etiologies: meningitis, meningoencephalitis, encephalitis, brain and meningeal abscesses, and shunt infections. The focus of this chapter is meningitis. Central nervous system 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 in the CNS.
Passive and active exposure to cigarette smoke and the presence of a cochlear implant that includes a positioner, both increase the risk of bacterial meningitis. CNS infections may be caused by a variety of bacteria, fungi, viruses, and parasites. The most common causes of bacterial meningitis are Streptococcus pneumoniae, group B Streptococcus, Neisseria meningitidis, Haemophilus influenzae, and Listeria monocytogenes,
The critical first step in the acquisition of acute bacterial meningitis is nasopharyngeal colonization of the host by the bacterial pathogen. The bacteria first attach themselves to nasopharyngeal epithelial cells and are then phagocytized into the host’s bloodstream.
A common characteristic of most CNS bacterial pathogens (eg, H. influenzae, Escherichia coli, and N. meningitidis) is the presence of an extensive polysaccharide capsule that is resistant to neutrophil phagocytosis and complement opsonization.
The neurologic sequelae of meningitis occur due to the activation of host inflammatory pathways. Bacterial cell death causes the release of cell wall components such as lipopolysaccharide, lipid A (endotoxin), lipoteichoic acid, teichoic acid, and peptidoglycan, depending on whether the pathogen is gram-positive or gram-negative. These cell wall components cause capillary endothelial cells and CNS macrophages to release cytokines (interleukin-1, tumor necrosis factor, and other inflammatory mediators).
Proteolytic products and toxic oxygen radicals cause an alteration of the blood–brain barrier, whereas platelet-activating factor activates coagulation, and arachidonic acid metabolites stimulate vasodilation. These events lead to cerebral edema, elevated intracranial pressure, cerebrospinal fluid (CSF) pleocytosis, decreased cerebral blood flow, cerebral ischemia, and death.
Clinical presentation and laboratory diagnosis
Meningitis causes CSF fluid changes, and these changes can be used as diagnostic markers of infection. Clinical presentation varies with age; 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.
Classic signs and symptoms include fever, nuchal rigidity, altered mental status, chills, vomiting, photophobia, and severe headache. Kernig and Brudzinski signs may be present but are poorly sensitive and frequently absent in children. Clinical signs and symptoms in young children may include bulging fontanelle, apneas, purpuric rash, and convulsions, in addition to those just mentioned.
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.
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 of 10,000 cells/mm 3 or more (10 × 109/L), CSF protein 80 mg/dL (800 mg/L), and CSF neutrophil count 1000 cells/mm3 (1 × 109/L). Treatment is recommended when one or more criteria are present. An elevated CSF protein of 50 mg/dL or more and a CSF glucose concentration less than 50% of the simultaneously obtained peripheral value suggest bacterial meningitis
The values for CSF glucose, protein, and WBC concentrations found with bacterial meningitis overlap significantly with those for viral, tuberculous, and fungal meningitis and cannot always distinguish the different etiologies of meningitis.
Gram stain and culture of the CSF are the most important laboratory tests performed for bacterial meningitis. 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.
Polymerase chain reaction (PCR) techniques can be used to diagnose meningitis caused by N. meningitidis, S. pneumoniae, and H. influenzae type b (Hib). Latex fixation, latex coagglutination, and enzyme immunoassay tests provide for the rapid identification of several bacterial causes of meningitis, including S. pneumoniae, N. meningitidis, and Hib. The rapid antigen tests should be used in situations in which the Gram stain is negative. Diagnosis of tuberculosis meningitis employs acid-fast staining, culture, and PCR of the CSF.
Eradication of infection with 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. The administration of fluids, electrolytes, antipyretics, analgesia, and other supportive measures are particularly important for patients presenting with acute bacterial meningitis.
Empiric antimicrobial therapy should be instituted as soon as possible to eradicate the causative organism. Antimicrobial therapy should last at least 48 to 72 hours or until the diagnosis of bacterial meningitis can be ruled out. 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. The first dose of antibiotic should not be withheld even when lumbar puncture is delayed or neuroimaging is being performed.
With increased meningeal inflammation, there will be greater antibiotic penetration. 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.
Dexamethasone as an Adjunctive Treatment for Meningitis
In addition to antibiotics, dexamethasone is a commonly used therapy for the treatment of pediatric meningitis. Current recommendations call for the use of adjunctive dexamethasone in infants and children with H. influenzae meningitis. 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.
Clinical outcome is unlikely to improve if dexamethasone is given after the first dose of antimicrobial and should therefore be avoided. If adjunctive dexamethasone is used, careful monitoring of signs and symptoms of gastrointestinal (GI) bleeding and hyperglycemia should be employed.
Neisseria Meningitidis (Meningococcus)
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. N. meningitides meningitis is the leading cause of bacterial meningitis in children and young adults in the United States and around the world. Most cases occur in the winter or spring, at a time when viral meningitis is relatively uncommon.
Approximately 10 to 14 days after the onset of the disease and despite successful treatment, the patient develops a characteristic immunologic reaction of fever, arthritis (usually involving large joints), and pericarditis. The synovial fluid is characterized by a large number of polymorphonuclear cells, elevated protein concentrations, normal glucose concentrations, and sterile cultures. Deafness unilaterally, or more commonly bilaterally, may develop early or late in the disease course.
Treatment and prevention
Aggressive, early intervention with high-dose IV crystalline penicillin G, 50,000 units/kg every 4 hours, is usually recommended for treatment of N. meningitides meningitis. Close contacts of patients contracting N. meningitidis meningitis are at an increased risk of developing meningitis. Prophylaxis of contacts should be started only after consultation with the local health department.
In general, rifampin, ceftriaxone, ciprofloxacin, or azithromycin is given for prophylaxis. For regions with reported ciprofloxacin resistance, one dose of azithromycin 500 mg is recommended for prophylaxis.
Streptococcus Pneumoniae (Pneumococcus or Diplococcus)
S. pneumoniae is the leading cause of meningitis in patients 2 months of age or older in the United States. Neurologic complications, such as coma and seizures, are common.
The treatment of choice until susceptibility of the organism is known is the combination of vancomycin plus ceftriaxone. Penicillin may be used for drug-susceptible isolates with minimum inhibitory concentrations of 0.06 mcg/mL or less, but for intermediate isolates ceftriaxone is used, and for highly drug-resistant isolates a combination of ceftriaxone and vancomycin should be used.
A high percent of S. pneumoniae is either intermediately or highly resistant to penicillin. Meropenem is recommended as an alternative to a third-generation cephalosporin in penicillin nonsusceptible isolates. IV linezolid and daptomycin have emerged as therapeutic options for treating multidrug-resistant gram-positive infections.
VA heptavalent conjugate vaccine is available for use in infants between 2 months and 9 years of age. Current recommendations are for all healthy infants younger than 2 years of age to be immunized with the heptavalent vaccine at 2, 4, 6, and 12 to 15 months.
The Centers for Disease Control and Prevention (CDC) recommends use of 23-valent pneumococcal vaccine (PPV 23) for persons over 65 years of age; persons 2 to 64 years of age who have achronic illness, who live in high-risk environments, and who lack a functioning spleen; and immunocompromised persons over 2 years, including those with human immunodeficiency virus (HIV) infection. All healthy infants younger than 2 years of age to be immunized with the 13-valent pneumococcal conjugate vaccine (PCV13) at 2, 4, 6, and 12 to 15 months.
In the past, H. influenzae was the most common cause of meningitis in children 6 months to 3 years of age, but this has declined dramatically since the introduction of effective vaccines. Because approximately 20% of H. influenzae are ampicillin resistant, many clinicians use a third-generation cephalosporin (cefotaxime or ceftriaxone) for initial antimicrobial therapy. Once bacterial susceptibilities are available, ampicillin may be used if the isolate proves ampicillin sensitive. Cefepime and fluoroquinolones are suitable alternatives regardless of β-lactamase activity.
Prophylaxis of close contacts should be started only after consultation with the local health department and the CDC. Vaccination with Hib conjugate vaccines is usually begun in children at 2 months. The vaccine should be considered in patients older than 5 years with sickle cell disease, asplenia, or immunocompromising diseases.
L. monocytogenes is a gram-positive, diphtheroid-like organism and is responsible for 10% of all reported cases of meningitis in those older than 65 years.
The combination of penicillin G or ampicillin with an aminoglycoside results in a bactericidal effect. Patients should be treated a minimum of 3 weeks. Combination therapy is given for at least 10 days with the remainder completed with penicillin G or ampicillin alone.
Trimethoprim–sulfamethoxazole and meropenem may be an effective alternative because adequate CSF penetration is achieved with these agents.
Gram-Negative Bacillary Meningitis
Elderly debilitated patients are at an increased risk of gram-negative meningitis but typically lack the classic signs and symptoms of the disease. Optimal antibiotic therapies for gram-negative bacillary meningitis have not been fully defined. Meningitis caused by Pseudomonas aeruginosa is initially treated with an extended-spectrum β-lactam such as ceftazidime or cefepime (A-II), or alternatively aztreonam, ciprofloxacin, or meropenem. The addition of an aminoglycoside— usually tobramycin—to one of the above agents should also be considered
If the pseudomonad is suspected to be antibiotic resistant or becomes resistant during therapy, an intraventricular aminoglycoside (preservative-free) should be considered along with IV aminoglycoside. Gram-negative organisms, other than P. aeruginosa, that cause meningitis can be treated with a third- or fourth-generation cephalosporin such as cefotaxime, ceftriaxone, ceftazidime, or cefepime. Therapy for gram-negative meningitis is continued for a minimum of 21 days. CSF cultures may remain positive for several days or more on a regimen that will eventually be curative.