Clinical manifestations

Presentation and course

The signs of meningitis in the neonate are nonspecific (53; 04; 36). The infant may become irritable or lethargic and often develops poor feeding. Vomiting or diarrhea may occur. The patient may be afebrile, but may also develop either fever or hypothermia, may become tachypneic – at times with outright respiratory distress – or may have apneic spells (53; 04; 36). Seizures may occur, but these may be subtle or fragmentary. Multifocal clonic movements, brief tonic spasms, and fragmentary stereotypic movements such as buccolingual movements, limb stiffening, and “bicycling movement” may all represent neonatal seizures. Apnea may represent an epileptic phenomenon, and neonates may also have electrographic seizure activity on electroencephalography without recognizable clinical signs. Older literature emphasized the importance of a high-pitched “meningeal” cry, but this is often absent. The presence of a bulging fontanel is a late sign, indicating significantly increased intracranial pressure (27). Nuchal rigidity is rarely present in the newborn with meningitis (67; 53; 04). The neonate’s level of consciousness may deteriorate from lethargy to obtundation to stupor and coma. Deterioration in the level of consciousness is a sign of raised intracranial pressure.

Prognosis and complications

Focal neurologic deficits may develop as a result of arterial cerebrovascular disease, intracranial hemorrhage, or developing brain abscess. Generalized seizure activity and status epilepticus may be due to fever, hyponatremia, anoxia from decreased cerebral perfusion, or toxicity from antimicrobial agents. The presence of focal clonic seizures or seizures with a consistent focal onset suggests localized cerebral injury. Involvement of cranial nerves by the exudate may result in cranial nerve palsies, in particular, involving the second, third, sixth, seventh, or eighth cranial nerves. Hearing loss due to the meningitis may be due to direct involvement of cranial nerve VIII or to purulent labyrinthitis. In contrast to adult meningitis, where concomitant brain abscess is rare, brain abscess may occasionally occur in neonatal meningitis; this association is particularly strong, with infections caused by Citrobacter sp (40).

Clinical vignette

A 10-day-old neonate was brought to the emergency department for a seizure. The parents complained that the baby had been irritable and not eating for 24 hours. On examination, the neonate was febrile and lethargic. Examination of the cerebrospinal fluid revealed 50 white blood cells/mm3, 80% polymorphonuclear leukocytes, a protein concentration of 190 mg/dL, and a CSF:serum glucose ratio of 0.4. Empiric antimicrobial therapy was initiated with ampicillin and cefotaxime. Cerebrospinal fluid Gram stain demonstrated a Gram-negative bacillus, and Escherichia coli grew in culture. Antimicrobial sensitivity tests demonstrated the organism was resistant to ampicillin, but susceptible to the cephalosporins. CSF culture was negative on repeat lumbar puncture performed 24 hours after the initiation of antimicrobial therapy.

Biological basis

Etiology and pathogenesis

Etiological agents. The most common organisms associated with neonatal meningitis in the developed world are Streptococcus agalactiae (group B streptococci), followed in order of frequency by E coli, other Gram negatives, and L monocytogenes (53; 44; 59; 52; 29; 04; 19; 48; 36; 08). In a Canadian study of E Coli and S agalactiae each accounted for one third of cases of bacterial meningitis in early onset meningitis. In numerous studies S agalactiae is the most common pathogen, including 59% of cases of neonatal meningitis overall from France and 52% of cases from United Kingdom (19; 37; 47). Other bacteria identified include E coli (28%), other Gram-negative organisms (4%), N meningitides (3%), and L monocytogenes (1.5%) (19). In term infants, S agalactiae accounted for 77% of cases and E coli for 28%, and in late-onset meningitis for 50% versus 33%. In contrast, E coli was more commonly isolated in preterm infants (45% vs. 33% for S agalactiae) and accounted for 54% of cases in very preterm infants (58; 19). However, in a study of 6956 very low birth weight infants with late-onset sepsis, where the likelihood of nosocomial infection is much higher, the major organism was coagulase-negative Staphylococcus species (48% of cases) followed by coagulase-positive Staphylococcus aureus (8% of cases) and E coli (5% of cases) (11). Less common causes include Neisseria meningitidis, Klebsiella species, Streptococcus pneumoniae, Cronobacter sp, Mycoplasma hominis, or Candida species (53; 44; 59; 52; 29; 12; 25; 04; 19; 56; 30; 49; 02; 47). Burkholderia pseudomallei, the agent of melioidosis, remain a cause of neonatal meningitis in some underdeveloped countries (61). In recent years, the agent Elizabethkingia meningoseptica (previously Chrysobacterium meningosepticum) and Elizabethkingia anopheles group have been associated with neonatal meningitis in multiple locations worldwide (32; 31). Laboratory differentiation of these two species is difficult, and it is thought that some cases previously thought to be caused by E meningoseptica are actually caused by E anopheles (31).

Meningitis due to S agalactiae occurs at two points in time: within the first 48 hours of the postnatal period, or at seven days to six weeks of age (52; 48). Cases occurring in the immediate postnatal period represent acquisition of the agent from the mother at the time of birth, and meningitis often occurs as part of a systemic infection; cases in older infants more frequently occur as an isolated meningitis. S agalactiae cases of late onset disease have been noted to be increasing in France since 2013 (51). In the United States, late onset disease rates are higher than early onset disease (0.23 per 1000 live births vs. 0.31 per 1000 live births) (46).

The incidence of neonatal meningitis associated with these and other organisms in the developing world may vary significantly according to geographic location, with higher incidence and higher mortality in developing nations (18; 36).

Pathogenesis. In cases of early-onset meningitis, the neonate becomes infected from the mother’s genitourinary tract; late-onset meningitis may be of nosocomial origin (36). Abnormalities of pregnancy and delivery, including prematurity, premature rupture of membranes, traumatic delivery, and caesarian section, are known risk factors (70). Meningitis in the newborn is usually associated with sepsis. Cases of S agalactiae sepsis and meningitis may occasionally be due to mastitis and infected breast milk (68). Cronobacter species may exist as contaminants of infant formula and have been associated with sepsis, enterocolitis, and meningitis, predominantly in infants under four weeks of age (30; 69). Despite extensive research dating back over 50 years, the precise sequence of events involved in meningeal invasion in neonatal meningitis is not fully understood. Studies by Kim indicate that entry of E coli across the blood-brain barrier requires a high level of bacteremia, followed by entry of the organism into brain microvascular endothelial cells and movement across these cells into the subarachnoid space (33). Meningeal infection in neonatal meningitis is frequently accompanied by ventriculitis.

Multiplication of bacteria within the subarachnoid space and ventricles initiates a cascade of events in which multiplication and lysis of bacteria are followed by the release of bacterial cell wall components. These, in turn, induce meningeal inflammation by stimulating the production of inflammatory cytokines and chemokines, in particular, tumor necrosis factor alpha (TNF-alpha) within the CSF space. TNF-alpha and IL-1 act synergistically to alter the permeability of the blood-brain barrier. The alteration in blood-brain barrier permeability during bacterial meningitis results in vasogenic cerebral edema and allows leakage of serum proteins and other molecules into the CSF. In a landmark clinical study, intraventricular administration of gentamicin in Gram-negative meningitis was found to greatly amplify this process, with increased inflammation and consequent increase in mortality (43; 45; 42).

Meningeal inflammation results in the formation of a purulent exudate in the subarachnoid space. The purulent exudate obstructs the flow of CSF through the ventricular system and diminishes the resorptive capacity of the arachnoid granulations in the dural sinuses. This leads to obstructive and communicating hydrocephalus and interstitial edema. Involvement of cranial nerves by the exudate may cause cranial nerve palsies, in particular, involving cranial nerve VIII. The inflammatory process may also affect arteries. The resulting arteritis may cause focal or multifocal ischemia and stroke, with significant increase in mortality and long-term morbidity. Two major patterns of stroke have been reported in neonatal meningitis: occlusion of deep perforating arteries causing infarcts in basal ganglia, thalamus, and periventricular white matter; and superficial patchy infarcts involving the cortical surface (28). Cerebral ischemia resulting from alterations in cerebral blood flow causes cytotoxic edema. The combination of interstitial, vasogenic, and cytotoxic edema leads to raised intracranial pressure and coma. In addition, bacteria and the inflammatory cytokines induce the production of excitatory amino acids, reactive oxygen and nitrogen species (free oxygen radicals, nitric oxide, and peroxynitrite), and other mediators that induce massive apoptosis of brain cells. The inflammatory mediators, IL-1, TNF, and IL-6, stimulate oligodendrocyte cell death and white matter injury resulting in periventricular leukomalacia (01). Hearing loss due to purulent labyrinthitis is common in children surviving acute infection.

Epidemiology

The reported incidence of neonatal meningitis varies from 2 to 10 cases per 10,000 live births (34; 53). This number of rising cases worldwide has been strongly related to measures of poverty, with the greatest burden of disease in the Sahel region of west and central Africa (20; 63). The risk for premature and very low birth weight infants is considerably higher (57). Neonates acquire the most common organisms that cause meningitis, S agalactiae and E coli, from their mother’s genitourinary tract, and neonatal infection becomes more likely where there is complicated or abnormal delivery. Premature rupture of membranes is associated with a greater risk of intrauterine infection and subsequent neonatal sepsis and meningitis (01; 36). One in four women carries S agalactiae in her genitourinary tract. Recognition of this risk factor and the widespread institution of intrapartum chemoprophylaxis have been associated with a significant decline in the incidence of vertical transmission of S agalactiae infections and subsequent meningitis (26). Gram-negative organisms are now the predominant pathogens of neonatal sepsis in some institutions, and ampicillin-resistant Escherichia coli is a common cause of febrile illness, including meningitis, in the neonate (09).

Prevention

Neonatal meningitis is unique among meningitides in that exposure occurs at a defined point in time with a fairly predictable range of organisms. For this reason, intrapartum antibiotic treatment of women has resulted in a significant decline in the incidence of early-onset meningitis due to S agalactiae. The U.S. Centers for Disease Control and Prevention recommends universal screening of all women at 35 weeks’ gestation or later and intrapartum chemoprophylaxis for carriers of group B streptococcus (54). Intravenous administration of ampicillin or penicillin during delivery to women colonized with group B streptococci has reduced the incidence of serious infections caused by group B streptococcus (09). The identification and treatment of maternal vaginal and urinary tract infections is critical to the prevention of neonatal meningitis.

Differential diagnosis

The differential diagnosis of neonatal bacterial meningitis in the term infant includes sepsis without meningitis, viral encephalitis, brain abscess, congenital malformations of the nervous system, head or brain trauma, and, in tropical regions, neonatal malaria. In premature infants, hypoxic-ischemic encephalopathy and subependymal-intraventricular hemorrhage should also be included in the differential diagnosis (50).

Diagnostic workup

The diagnosis of bacterial meningitis is based on examination of the cerebrospinal fluid. Normal opening pressure in the neonate is 50 mm H2O or less. The normal CSF white blood cell count in the full-term neonate is 0 to 30 cells/mm3, of which 60% may be polymorphonuclear leukocytes. The normal CSF protein concentration is less than or equal to 150 mg/dL (34; 53). The normal CSF:serum glucose ratio is 0.81 (16; 23). It can be difficult to differentiate infected from uninfected CSF in the neonate. A CSF white blood cell count that is higher than 30 cells/mm3 and a CSF:serum glucose ratio lower than 0.5 strongly suggests bacterial meningitis. Microorganisms can be detected on Gram stain of CSF in 80% of cases of meningitis due to group B streptococcus or E coli, but the Gram stain is often negative in neonates with L monocytogenes meningitis due to the relatively low numbers of bacteria in the CSF (53). Cerebrospinal fluid cultures are usually positive. The latex particle agglutination assays that detect antigens of group B streptococcus and the E coli K1 antigen in CSF are no longer recommended as part of the routine diagnostic CSF studies for neonatal meningitis because a negative bacterial antigen test does not rule out infection. However, the latex particle agglutination assay may be helpful in the neonate who has been pretreated with antimicrobial therapy and whose Gram stain and CSF culture are negative.

Multiplex polymerase chain reaction (PCR) panels have been developed to provide a diagnosis within hours. An analysis of such a panel (BioFire Diagnostics LLC, Salt Lake City, UT, U.S.) shows a 90% sensitivity for detection of all pathogens (viral, bacterial, and yeast), and a 97% specificity (60). Included pathogens on these panels are frequently E coli, H influenzae, L monocytogenes, N meningitidis, S pneumoniae, and S agalactiae. However, there are no good data available showing that rapid diagnostic tests alter management or outcomes of patients with suspected bacterial meningitis.

Blood cultures are usually positive, and the peripheral white blood cell count is increased. The serum sodium concentration may be low. Acute phase reactants, such as the C-reactive protein and erythrocyte sedimentation rate, are usually abnormal. Serum procalcitonin levels of 0.5 ng/mL or greater are predictive of bacterial infection (13). The serum procalcitonin level is minimal in viral infections (21).

Positive cultures on repeat lumbar puncture have been reported in 22% of infants with neonatal meningitis, in particular, during the first week of treatment (22; 36). Detection of organisms on repeat lumbar puncture is associated with higher mortality.

Management

Antibiotic treatment. In most neonates, initial empirical antimicrobial therapy is based on the possibility that the meningitis is due to either group B streptococcus, ampicillin-resistant Gram-negative bacilli, or Listeria monocytogenes. Treatment over the years has included a combination of ampicillin and an aminoglycoside or, because gentamicin may not reach therapeutic levels in CSF, ampicillin and a third- or fourth-generation cephalosporin (ie, cefotaxime). Many centers will use all three agents (ampicillin, gentamicin, and cefotaxime) until antibiotic susceptibilities become available (15). This is due in part to likelihood of systemic sepsis as well as meningitis and also to the emergence of cephalosporin-resistant Gram-negative organisms such as Enterobacter, Klebsiella, and Serratia species (07). In some very low birth weight infants, particularly those older than one week of age, consideration should include coverage of coagulase-negative staphylococcus or other staphylococcal organisms. In this instance, vancomycin should replace ampicillin. Treatment regimens for cefotaxime and ampicillin are shown in Table 1 (62; 36).

Table 1. Treatment Regimens

Antibiotic	Infants 0 to 7 days	Infants 8 to 28 days
Cefotaxime	100 to 150 mg/kg per day given every 8 to 12 hours	150 to 200 mg/kg per day given every 6 to 8 hours
Ampicillin	150 mg/kg per day given every 8 hours	200 mg/kg per day given every 6 to 8 hours
Gentamicin	5 mg/kg per day given every 12 hours	7.5 mg/kg per day given every 8 hours
Vancomycin	20 to 30 mg/kg given every 8 to 12 hours	30 to 45 mg/kg given every 6 to 8 hours

The fourth-generation cephalosporin, cefepime (50 mg/kg every 12 hours), can be used instead of cefotaxime (14). As noted above, standard guidelines recommend a combination of ampicillin and gentamicin as one regimen of empiric therapy of neonatal meningitis or a combination of ampicillin plus cefotaxime (62; 64). It has been suggested that therapeutically adequate serum levels of gentamicin with peak levels below toxic range can be achieved in premature infants by administering gentamicin at doses of 3 mg/kg in infants under 35 weeks of gestation and 4 mg/kg in infants 36 weeks of gestation (24). Data concerning the effectiveness of this regimen in neonatal meningitis are limited. Aminoglycosides have nephrotoxicity and can cause hearing loss and vestibular dysfunction. Thus, aminoglycosides should be discontinued as soon as possible if antibiotic susceptibilities permit it. Intraventricular administration of gentamicin should not be used (42; 55). Occasional strains of Gram-negative enteric bacilli are resistant to the aminoglycosides (53).

Once the antibiotic sensitivities of an organism are known, antimicrobial therapy can be modified accordingly. Uncomplicated meningitis due to group B streptococci is treated for 14 days, whereas that due to Gram-negative bacilli is treated for a minimum of 21 days after sterilization of CSF cultures (53). Meningitis due to L monocytogenes requires treatment for at least 21 days. The neonate with Gram-negative meningitis should undergo repeat lumbar puncture to document sterilization of the CSF after 24 to 48 hours of treatment (62).

Organisms of the Elizabethkingia group (E meningosepticum and E anopheles) have proven resistant to many antibiotics (32). Suggested empiric agents, guided by in vitro susceptibility data, have included vancomycin, rifampicin, piperacillin-tazobactam, trimethoprim-sulfamethoxazole, and minocycline (32).

Use of dexamethasone. Although dexamethasone has been recommended in the treatment of children and adults with bacterial meningitis, there have been insufficient randomized controlled trials of meningitis in newborns to assess the drug’s efficacy in this population (65). However, in a randomized controlled trial from India involving 80 patients with neonatal meningitis randomized to receive either dexamethasone or placebo, use of dexamethasone significantly reduced mortality, CSF cell counts, and CSF concentrations of IL-1β and tumor necrosis factor α (TNF-alpha) (41). These results, although promising, have not yet been confirmed by other investigators.

Subdural effusions in neonatal meningitis. A sterile subdural effusion may develop in the course of bacterial meningitis in the newborn, but is much less common in neonates than in older infants or children. In neonates, the effusion is not usually associated with clinical symptomatology or neurologic sequelae. When necessary, these may be treated with subdural taps, but this is rarely needed. In one case, an effusion not responsive to serial subdural punctures was reported to respond to acetazolamide (06).

Outcomes

Infection during the perinatal and neonatal periods remains a dangerous condition and an important contributor to an adverse neurodevelopmental outcome (01; 19; 10; 36). Current mortality in Western countries is 13% to 16% overall, but approaches 25% in small-for-gestational-age or premature infants, regardless of the causative organism (19). Mortality in developing nations is significantly higher. Approximately 50% of neonates with bacterial meningitis have neurologic sequelae, including cerebral palsy, epilepsy, cognitive impairment, neuromotor problems, and hearing loss (39; 35). Bacterial meningitis may be complicated by hydrocephalus, cytotoxic and hypoxic-ischemic injury, and ischemic and/or hemorrhagic stroke. Infants may be left with motor deficits, cognitive disorders, seizures, visual impairment, and long-term cognitive impairment. Stroke in the presence of neonatal meningitis is a highly adverse prognostic indicator: in one series, the presence of stroke was associated with a rate of death or serious neurologic outcome approaching 75% (28). In a study of patients with meningitis ages one month to 18 years, absence of CSF pleocytosis and elevated protein were associated with worse prognosis, as was meningitis associated with S pneumoniae (38).

Special considerations

Pregnancy

Maternal colonization with group B streptococci or E coli and maternal genital tract infections are risk factors for neonatal infection. Risk of neonatal meningitis is increased with premature or complicated labor and with premature rupture of membranes. Prenatal or intrapartum treatment of S agalactiae colonization is of major importance in preventing neonatal meningitis caused by that organism.