109: Meningitis

Neonatal meningitis is an infection of the meninges and central nervous system (CNS) in the first month of life. This is the most common time of life for meningitis to occur.

The incidence is ∼0.16–0.45 per 1000 live births in developed countries. The incidence may be higher in underdeveloped countries.

In most cases, infection occurs because of hematogenous seeding of the meninges and CNS. In cases of CNS or spinal anomalies (eg, myelomeningocele), there may be direct inoculation by flora on the skin or in the environment. Neonatal meningitis is often accompanied by ventriculitis, which makes resolution of infection more difficult. There is also a predilection for vasculitis, which may lead to hemorrhage, thrombosis, and infarction. Subdural effusions and brain abscess may also complicate the course.

Most organisms implicated in neonatal sepsis also cause neonatal meningitis. Some have a definite predilection for CNS infection. Group B Streptococcus (GBS) (especially type III) and the gram-negative rods (especially Escherichia coli with K1 antigen) are the most common causative agents. Galactosemia should be considered if E. coli is the causative agent in late-onset meningitis. Other causative organisms include Listeria monocytogenes (serotype IVb), other streptococci (enterococci, Streptococcus pneumoniae), other gram-negative enteric bacilli (Klebsiella, Enterobacter, and Serratia spp), and rarely Neisseria meningitides. In the very low birthweight infant, coagulase-negative staphylococci need to be considered as causative organisms in bacterial meningitis.

With CNS anomalies involving open defects or indwelling devices (eg, ventriculoperitoneal shunts), staphylococcal disease (Staphylococcus aureus and Staphylococcus epidermidis) is more common, as is disease caused by other skin flora, including streptococci and diphtheroids. Many unusual organisms, including Ureaplasma, fungi, and anaerobes, have been described in case reports of neonatal meningitis.

Premature infants with sepsis have a much higher incidence (up to 3-fold) than term infants of CNS infection. The characteristics of some bacteria make them more virulent, especially for neonates (eg, capsular polysaccharide of GBS type III, E. coli K1, and L. monocytogenes serotype IVb all contain sialic acid in high concentrations). Infants with CNS defects necessitating ventriculoperitoneal shunt procedures also are at increased risk.

The clinical presentation is usually nonspecific and indistinguishable from those caused by sepsis. Meningitis must be excluded in any infant being evaluated for sepsis or infection. Signs and symptoms of meningitis include temperature instability (the most common), lethargy, irritability, poor tone, seizures, feeding intolerance, vomiting, respiratory distress, apnea, or cyanotic episodes. Seizures, often focal, can be the presenting manifestation in up to 50% of the cases. Late manifestations of meningitis include a bulging anterior fontanelle and coma. Syndrome of inappropriate antidiuretic hormone may accompany meningitis.

1. Laboratory studies. The clinical presentation of bacterial meningitis in the neonate is nonspecific; therefore, neonates with suspected bacterial meningitis should undergo a full sepsis evaluation including a complete blood count with differential, blood culture, urine culture (if >3–5 days), and lumbar puncture (LP) to examine cerebrospinal fluid (CSF) for Gram stain, culture, protein, glucose, and cell count. CSF examination is critical in the investigation of possible meningitis and the only way to confirm the diagnosis. Approximately 15–50% of all infants with positive CSF cultures for bacteria have negative blood cultures. The technique for obtaining CSF fluid and CSF normal values are discussed in Chapter 35.

   1. Culture. A CSF culture is the gold standard for the diagnosis of bacterial meningitis. It may be positive in association with a normal or minimally abnormal CSF analysis.

   2. CSF pleocytosis is variable. There are usually more cells with gram-negative rods than with GBS disease. Normal values range from 0 to 35 white blood cells (WBCs), some of which may be polymorphonuclear cells. Traumatic LP (>500 red cells/mm³) occur in up to 40% of the attempts, and adjustment of CSF white cells down to account for increased red cells does not improve diagnostic utility of the CSF examination. Reactive pleocytosis may be seen secondary to CNS hemorrhage.

   3. Gram-stained smear can be helpful in making a more rapid definitive diagnosis and identifying the initial classification of the causative agent.

   4. Decreased CSF glucose. CSF glucose level must be compared with serum glucose level. Normal CSF values are one-half to two-thirds of serum values. Typically, neonates with meningitis have CSF glucose level <20–30 mg/dL.

   5. CSF protein is usually elevated (>100–150 mg/dL), although normal values for infants, especially premature infants, may be much higher than in later life, and the test may be confounded by the presence of blood in the specimen.

2. Imaging studies are recommended to detect the complications of meningitis, especially when the clinical course is complicated. Infection with certain microorganisms such as Citrobacter koseri and Enterobacter sakazakii predispose for the development of brain abscesses. The most useful and noninvasive method of imaging is ultrasonography, which provides information regarding ventricular size, inflammation (echogenic strands), and the presence of hemorrhage. Computed tomography (CT) or magnetic resonance imaging (MRI) are useful in detecting cerebral abscesses and later in the treatment course in identifying areas of encephalomalacia that may dictate prolonged therapy.

General supportive measures like ventilation/oxygenation, cardiovascular support, intravenous dextrose, and anticonvulsant therapy are considered essential components of managing the neonate with bacterial meningitis. Isolation precautions for all infectious diseases, including maternal and neonatal precautions, breast-feeding, and visiting issues, can be found in Appendix F.

1. Drug therapy. For drug dosages and other pharmacologic information, see Chapter 148. (Note: Dosages for ampicillin, nafcillin, and penicillin G are doubled when treating meningitis.)

   1. Empirical therapy. Optimal antibiotic selection depends on culture and sensitivity testing of the causative organisms. Ampicillin and gentamicin are usually started as empirical therapy for suspected early sepsis. If meningitis is suspected, cefotaxime should be added. For hospitalized infants with late-onset presentation, empiric therapy consists of vancomycin (cover gram-positive organisms, especially coagulase-negative staphylococci) and gentamicin with the addition of cefotaxime when CSF findings suggest meningitis (extended coverage of gram-negative rods). Lastly, for the infant <60 days who is coming from home to the emergency department, the empiric therapy consists of ampicillin and cefotaxime.

   2. Gram-positive meningitis (GBS and Listeria). Penicillin or ampicillin is the drug of choice. These infections usually respond well to treatment for 14 days of therapy.

   3. Staphylococcal disease. Because of the increased prevalence of methicillin-resistant staphylococci both in the nosocomial setting and in the community, vancomycin should be substituted for penicillin or ampicillin as initial coverage.

   4. Gram-negative meningitis. Most clinicians would use ampicillin plus cefotaxime plus an aminoglycoside as initial therapy. Further therapy is dictated by sensitivity results. “Double” gram-negative coverage is maintained for 10 days after sterility of CSF. Subsequently, cefotaxime can be continued alone to complete 21 days of therapy. There is an emerging problem with multidrug-resistant enteric microorganisms (especially Klebsiella pneumoniae); for this situation, the drug of choice is meropenem. (See Chapter 148.) Studies have shown no advantage for intrathecal or intraventricular gentamicin.

   5. Repeat lumbar puncture 48 hours into antibiotic therapy is recommended to document CSF sterilization. Persistence of infection may indicate a focus, such as obstructive ventriculitis, subdural empyema, or multiple small-vessel thrombi. Infants with repeat positive CSF cultures after initiation of appropriate antibiotics are at risk for complications as well as a poor outcome. In general, ∼3 days are required to sterilize the CSF in infants with gram-negative meningitis, whereas in gram-positive meningitis, sterilization usually occurs within 36–48 hours. Follow-up CSF examination is recommended until sterility is documented. External ventricular drainage may be indicated in certain cases complicated by ventriculitis. Treatment should continue until 14 days after cultures are negative or for 21 days, whichever is longer.

   6. Adjunctive therapy. Contrary to childhood meningitis, dexamethasone does not seem to improve the outcome of neonatal meningitis. Other therapies focusing on enhancing the immune system in the newborn, such as hematopoietic growth factors or intravenous immune globulins, do not seem to help either.

2. Supportive measures and monitoring for complications. Head circumference should be measured daily, and neurologic examination should be performed frequently. Imaging studies (especially MRI) are helpful for prognosis and guiding the length of therapy. Hearing and vision evaluation should be done in all neonates who develop meningitis. All of them should undergo long-term neurodevelopmental follow-up.

The mortality rate has decreased over the past 15 years to 3–13%, compared with 25–30% from earlier decades. There is a higher incidence (20–50%) of neurodevelopmental sequelae in survivors, and this figure has not changed over the years. Factors predictive of death or serious sequelae include preterm birth, neutropenia, seizures persisting more than 72 hours after hospitalization, focal neurologic deficits, initial inotropic support, delayed sterilization of the CSF, and parenchymal lesions (abscess, thrombi, infarcts, and encephalomalacia) on neuroimaging studies.