Chapter 24. Central Nervous System Infections

The incidence of community-acquired central nervous system (CNS) infections is around 35 per 100,000 person-years.1 These infections are often differentiated by the type (ie, meningitis or encephalitis) and cause of infection. Meningitis (aseptic more than bacterial) is the most common type of CNS infection, followed by viral encephalitis.1,2

Bacterial Meningitis

Bacterial meningitis is most common in the pediatric population. Specifically, the incidence ranges from 21 per 100,000 in neonates, 12.5 per 100,000 in children, and 2.6 per 100,000 in adults.3,4,5 The pathogens associated with bacterial meningitis also vary based upon the age of the patient. In neonates and infants less than 3 months of age, the most common isolated bacteria is Streptococcus agalactiae (also known as group B Streptococcus), followed by Escherichia coli, Streptococcus pneumoniae and Listeria monocytogenes.2,6,7 Specifically, early onset meningitis, that with onset in the first week of life is usually associated with pathogens found in the maternal genital tract (eg, S. agalactiae,E. coli, L. monocytogenes). While meningitis occurring from 1 to 4 weeks of age is associated with maternal and community-associated pathogens (eg, S. pneumoniae) or in hospitalized infants, nosocomial pathogens (eg, Staphylococcus aureus, Enterobacter spp.). From 2 to 3 months of age, the likelihood of pathogens from the maternal genital tract decrease and the community-associated pathogens become more prevalent. In children over 3 months old and adults, the most common causes of bacterial meningitis are S. pneumoniae and Neisseria meningitidis.1,2,5,8 Common bacterial causes of meningitis in patients older than 50 years include S. pneumoniae, N. meningitidis, and L. monocytogenes.9

In order to cause meningitis a bacteria must be able to avoid the patient's normal barriers to infection and cause systemic infection. Next, the bacteria are able to cross the blood-brain barrier, multiply, stimulate inflammation in the subarachnoid and ventricular space and cause damage.10 In the neonate, the blood-brain barrier is not well developed and allows bacteria to cross more readily than in an older patient. Neisseria meningitidis and S. pneumoniae are common causes of bacterial meningitis in older infants and adults because they are surrounded by a polysaccharide capsule that assists in avoiding the usual immune system response to bacterial invasion.10 Additionally, when patients are immunosuppressed (by disease, drugs, or functional/anatomical asplenia) or have barriers, such as skin interrupted (eg, cochlear implants, recent trauma) bacteria are more likely to be able to cause disease.

Aseptic Meningitis and Viral Encephalitis

Viral meningitis is the most frequent infectious cause of aseptic meningitis, occurring at a rate of about 17.8 per 100,000 persons per year.1 Viral meningitis is more common in infants less than 1 year old and is more frequent in the summer months.1,9 The most common cause of viral meningitis in children are enteroviruses.11 Two common types of enteroviruses are coxsackie and echoviruses. Additionally, nonviral infectious causes of aseptic meningitis include mycobacterial and spirochetal (eg, Borrelia burgdorferi).2

Viral encephalitis is the least frequent of the CNS infections discussed here, with traditional estimates approximating about 6.3 per 100,000 person-years.1 These numbers are likely slightly higher due to the introduction of newer viruses, especially West Nile virus over the past decade.12 Unfortunately, the majority of encephalitis cases have an unknown etiology.13 The most frequent virus identified is herpes simplex virus (HSV), which has been estimated to occur in about 1 in every 250,000 to 500,000 persons per year.14,15 Other viral causes include: enteroviruses, other herpes viruses (eg, varicella, cytomegalovirus, Epstein-Barr virus, and human herpes virus 6), adenoviruses, arboviruses (eg, West Nile virus, St. Louis encephalitis virus, Eastern equine encephalitis virus, and Western equine encephalitis virus), measles, mumps, and rubella viruses, influenza viruses, bunyaviruses, reoviruses, arenaviruses, and rabies viruses.1,2,11,16

Pathogens that cause aseptic meningitis and viral encephalitis enter the body as they would usually to cause infection (eg, orally for enterovirus, tick bite for B. burgdorferi).17 The pathogen however moves from the usual site of infection via the blood to the CNS where it leads to encephalitis or meningitis.17 Herpes viruses are unusual as they can travel to the CNS by either the blood or travel along the neuron. Additionally, herpes viruses are also unique as they can cause meningitis/encephalitis during initial disease or by reactivation of disease.17 A summary of the typical infectious causes of meningitis and encephalitis by age are shown in Table 24-1.2-9,11-16,18

Clinical Presentation

The clinical presentation of a patient with a CNS infection is dependent upon age. Neonates and young infants with meningitis or encephalitis may have only nonspecific symptoms such as poor feeding, fever, or irritability. Older children and adults with meningitis usually present with the classic signs of meningitis including a temperature more than 101.3°F, headache, neck stiffness, altered consciousness. Other symptoms including seizures are less common.19 Older children and adults are more likely to also have positive Kernig or Brudzinski signs. Similar to meningitis, patients with infectious encephalitis usually have fever, headache, altered consciousness, and seizures, but they also have specific focal neurologic signs.19

Diagnosis

Meningitis is diagnosed based on symptoms plus laboratory data from the cerebrospinal fluid (Table 24-2).18,19 These laboratory data assist in the differentiation between viral and bacterial meningitis. Generally, in bacterial meningitis the cerebrospinal fluid (CSF) is cloudy, CSF white blood cell count (WBC) elevated (often > 1000 cells/mm3) with a predominance of neutrophils, the CSF glucose concentration is decreased (< 40 mg/dL) with a CSF:serum glucose ratio of ≤ 0.4, while the CSF protein is elevated (> 100 mg/dL).18-20 In viral meningitis the CSF WBC is also increased (although not usually as high) with a monocytic or lymphocytic predominance. Additionally, the CSF glucose and protein concentrations are less likely to be abnormal. It is important to note that these are the usual findings, as 10% patients with enteroviral meningitis have a predominance of neutrophils while some patients with bacterial meningitis may not, especially if they have received prior antibiotic therapy.18,20

The Gram stain and culture from the CSF is another tool used to assist in differentiating the type of meningitis. The Gram stain is more likely to be positive in patients with high concentrations of bacteria in the CSF. When the Gram stain is positive, many practitioners find it helpful in focusing antibiotic therapy.18 In most patients with bacterial meningitis, an organism will be grown from the CSF culture.18 There are two significant limitations of the CSF culture. First, the results are not quickly available, so empiric antibiotic therapy must be determined prior to culture results. Secondly, patients that received prior antibiotic treatment are less likely to grow bacteria.18,20 Additionally, as enteroviruses are the most likely cause of viral meningitis, enteroviral polymerase chain reaction (PCR) and/or culture is useful to assist in solidifying a diagnosis of viral meningitis.18,20

It is much more difficult to identify a causative pathogen in infectious encephalitis.13,16 Since many etiologies of encephalitis exist, initial testing is often based on patient history and common pathogens.13,16 Tests often include bacterial and fungal cultures of the CSF fluid, PCR of common viruses (including HSV and enterovirus). Additional cultures (blood, respiratory, stool), serologic testing, or other tests are also often performed.13,16

The focus for prevention of neonatalmeningitis has been to decrease exposure to pathogens in the birth canal.21 Specifically, rates of early group B streptococcal meningitis have decreased significantly by identifying and treating mothers colonized with the bacteria with either IV penicillin or ampicillin during the delivery period.21

Vaccination against common bacteria is the primary means of prevention of some CNS diseases including meningitis in older infants and adults. Specifically, the vaccines against encapsulated bacteria (ie, Haemophilus influenzae type b, N. meningitidis, S. pneumoniae) decrease the likelihood of bacterial meningitis. The H. influenzae type b (Hib) vaccine has had such efficacy in reducing systemic infections due to this pathogen that it is no longer a common cause of bacterial meningitis in developed countries. The meningococcal vaccines and pneumococcal vaccines can also provide some protection against the strains covered by the vaccines. Vaccine specifics are provided in Table 24-3.22 Vaccine recommendations are updated annually and available at www.cdc.gov/vaccines. Currently there is no meningococcal vaccine approved for patients less than 2 years old and the pneumococcal conjugate vaccine's minimum age is 6 weeks.

Additionally, other routine vaccinations including measles, mumps, rubella (MMR), and varicella are thought to have decreased encephalitis infections due to these organisms.22 All of these vaccines are subcutaneous, live-virus vaccines included in the routine immunization schedules for children older than 1 year. Adverse reactions to the live vaccines are most likely to occur between days 5 and 12. Injection site reaction, fever and rash are most common, occurring in 5% to 33% of patients.22 Transient arthralgias and arthritis have also been reported in about one-fourth of postpubertal females.22 Rare adverse effects include thrombocytopenia (MMR) anaphylaxis, and CNS dysfunction.22 Cases of disseminated disease in immunocompromised patients receiving the vaccines have been reported. Since both vaccines contain live viruses, neither should be given to patients with most immunodeficiencies (some HIV patients can receive the vaccines and patients with isolated humoral immunodeficiency may be able to receive varicella vaccine), immunosuppressing conditions (including radiation and medications), those who are pregnant, and in those with moderate to severe illness.22 Additionally, vaccines should be avoided in patients with a prior allergic reaction to the vaccine or its components. Both the MMR vaccine and the varicella vaccine contain neomycin and gelatin, so both should be avoided in patients allergic to either component.22 It is also important to note that although there is much hype that surrounds vaccines and autism, multiple scientific groups have independently investigated the scientific data and have not found any link between any vaccine and autism.22

Recent Infectious Disease Society of America guidelines for bacterial meningitis and encephalitis provide treatment recommendations.13,18 Specifically, empiric antibiotic therapy recommendations for bacterial meningitis are based upon age.18 The IV route of administration is recommended for treatment of all patients with bacterial meningitis.

In neonatesempiric therapy should include ampicillin plus either gentamicin or cefotaxime.18 The ampicillin is necessary to cover for L. monocytogenes. Patients between 1 month old and 50 years old should receive vancomycin plus either cefotaxime or ceftriaxone. Adult patients over the age of 50 years should receive ampicillin in addition to the vancomycin and cefotaxime or ceftriaxone. Again the ampicillin is to provide additional coverage against the L. monocytogenes. Further, monotherapy with IV ceftriaxone is recommended in patients with aseptic meningitis with a suspicion of Lyme meningitis (as long as there is no concern for HSV).23

It is important to note that the recommendation of adding vancomycin to the antibiotic regimen when S. pneumoniae is a likely pathogen is due to the possibility of multidrug resistant S. pneumoniae (ie, resistant to the third generation cephalosporins). Although most pneumococcal isolates continue to be susceptible to the third generation cephalosporins, increases in nonsusceptibility for some serotypes, including serotype 19A have been reported.24,25,26 Therefore, vancomycin should be added to any empiric meningitis antibiotic regimen where S. pneumoniae is a likely pathogen. Finally, once the pathogen is identified and susceptibilities are determined therapy should be appropriately narrowed.18

The use of dexamethasone in bacterial meningitis has been debated. In theory, the dexamethasone would decrease the inflammation, which is thought to be the cause for many of the resultant meningitis sequalae.18 Some, however, are concerned with using dexamethasone because when inflammation is decreased the penetration of medications into the CNS is also diminished. In children, dexamethasone has only demonstrated benefit against H. influenzae meningitis. Since this pathogen is no longer a common cause of meningitis in children, no consensus exists regarding the routine use of dexamethasone in children.18 Initially shown in one randomized controlled trial, and recently reinforced by a meta-analysis, dexamethasone when given with or before the first antibiotic dose has decreased mortality and improved outcomes in adults with pneumococcal meningitis.18,27

Current Infectious Disease Society of America guidelines suggest that IV acyclovir be started on all patients with suspected encephalitis, pending appropriate tests. This recommendation stems from the significantly lower rates of mortality observed in patients that received acyclovir therapy early in the course of their disease (ie, < 4 days vs ≤ 4 days). The guidelines also suggest that addition of doxycycline be considered if age, location, and seasonally appropriate for tick-borne diseases.13 Finally, therapy should be directed against specific pathogen when results are available.13

In general, these medications are well tolerated. Allergic reactions are possible with any medication, but appear more often with the beta-lactams which include: ampicillin, penicillin, ceftriaxone, and cefotaxime. Since most antibiotics can alter the bacterial flora of the gut, it is important to remember that this could result in drug interactions with warfarin and contraceptives. Gentamicin is associated with nephrotoxicity and ototoxicity which is more common when it is given for long durations or with other toxic medications. Vancomycin can also be associated with nephrotoxicity in high doses and/or with other concurrent nephrotoxic medications. Patients receiving vancomycin should have trough concentrations monitored, with goals of 15 to 20 μg/mL for CNS infections and as such should be monitored for signs of nephrotoxicity (eg, serum creatinine, urine output, etc).18,28 Acyclovir is monitored for its ability to cause nephrotoxicity and bone marrow suppression. This nephrotoxicity is caused by acyclovir precipitating in the renal tubules and more common with the high doses often used in treating encephalitis, but can be minimized by maintaining patient hydration and infusing it slowly. Doxycycline often causes upset stomach. If patients go home while on medications, they should avoid the sun. Patients taking aluminum, calcium, magnesium, or iron containing products should take them 2 hours before or after doxycycline because they can decrease the concentrations of the antibiotic. With a short-course of dexamethasone, the likelihood of adverse effects is reduced, patients should be monitored for gastrointestinal bleeding or hyperglycemia.

Special Considerations

Although ceftriaxone has similar antibacterial coverage to cefotaxime, it is not recommended in neonates because of the potential to displace bilirubin, possibly leading to kernicterus. Ceftriaxone when administered, at high doses with IV calcium containing solutions has been associated with causing lethal precipitates in neonates and young infants.29 As such IV ceftriaxone should not be administered to any neonate nor should it be used in any young infant within 48 hours of any calcium containing IV. Additionally, patients of any age with trauma to the brain, CNS surgery, or who are immunocompromised are at risk for meningitis as a result of additional pathogens, including pseudomonas, and will require more broad-spectrum initial therapy.18

If a neonate is determined to have herpes simplex virus infection, even of just the skin, they should be treated similarly to if they have encephalitis, because disseminated infection is common and can have devastating consequences if it is not appropriately managed.13

Antibiotic prophylaxis for N. meningitidis is recommended for close contacts (those who live in the same household, seated next to a patient on prolonged airplane travel, children in day care with a patient, and those exposed to oral secretions of a patient). Either intramuscular ceftriaxone, oral rifampin, or oral ciprofloxacin can be used.22

Additionally, vaccination with any meningococcal vaccine is recommended for control of community outbreaks of N. meningitidis types A, C, Y, or W135.22Haemophilus influenzae is now a rare cause of meningitis in developed countries due to routine vaccination. Since H. influenzae invasive disease was most common in young children (that are now immune) or immunocompromised individuals, chemoprophylaxis of contacts is limited to a small group of patients. Specifically, chemoprophylaxis with rifampin should be provided to individuals exposed, if they have incompletely immunized young children or immunocompromised close contacts. Additionally, if more than one day care attendee has H. influenzae type b invasive disease (such as meningitis) everyone that attends or works in the day care should receive oral rifampin.30 No prophylaxis is recommended for pneumococcal or viral meningitis. Unimmunized persons exposed to measles, mumps, or varicella who do not have contraindications of receiving the vaccine should receive it as soon as possible.22 Additionally, IV immune globulin or hyper immune globulins (ie, VariZig for varicella) can be used for immunocompromised patients exposed to these viruses.

Special Considerations

When choosing an agent for meningococcal prophylaxis a few considerations should be made. Intramuscular ceftriaxone is painful and should not be used in patients less than 1 month of age. Rifampin is a microsomal enzyme inducer, can color body secretions, and requires compounding if a suspension is required. Finally, although the fluoroquinolones have been used extensively in children, they are still not recommended to be used as first-line agents.31

• Bacterial meningitis is a serious infection that causes significant morbidity and mortality.
• Preventative measures against meningitis include preventative perinatal care and appropriate routine vaccinations.
• Pneumococcal conjugate vaccine should be given to all infants beginning between 6 and 8 weeks of age.
• Pneumococcal polysaccharide 23 valent vaccine should be given to any patient over 2 years old that (1) has a chronic disease (including adult asthma), (2) is immunocompromised, or (3) is an adult and smokes.
• Varicella and measles, mumps and rubella vaccines should not be given to persons who are immunocompromised, pregnant, or allergic to anything included in the vaccines (including neomycin or gelatin).
• MCV4 should not be given to patients that have a history of Guillain-Barré syndrome if they are not at considered high risk for meningococcal disease.
• Prompt empiric IV antibiotic therapy is necessary when bacterial meningitis is suspected.
• Antibiotic therapy should be chosen based upon common age-related pathogens.
• Ampicillin with either gentamicin or cefotaxime is recommended to cover the group B Streptococcus, E. coli, and L. monocytogenes that are likely in neonates.
• Vancomycin and either ceftriaxone or cefotaxime are recommended for empiric therapy against S. pneumoniae and N. meningitidis in older infants, children, and adults.
• In addition to the common bacteria that cause meningitis in adults, L. monocytogenes, is possible in older adults, as such ampicillin should be added to therapy in patients older than 50 years.
• Controversy exists regarding whether dexamethasone should be used in pediatric bacterial meningitis since H. influenzae is now uncommon.
• Dexamethasone has shown to improve mortality and other clinical outcomes in adult patients with pneumococcal meningitis.
• If dexamethasone is used, it should be given before or with the first dose of antibiotics.
• Viral meningitis is commonly caused by enterovirus and is usually self-limiting.
• When herpes simplex is considered as a possible cause of a CNS infection IV acyclovir should be started.
• Chemoprophylaxis with rifampin, ceftriaxone, or ciprofloxacin is recommended for certain N. meningitidis contacts.
• No chemoprophylaxis is recommended for contacts of patients with S. pneumoniae meningitis.