Bacterial meningitis in the neonate: Clinical features and diagnosis

INTRODUCTION — Bacterial meningitis is more common in the first month than at any other time of life [1]. Despite advances in infant intensive care, neonatal meningitis remains a devastating disease.

The epidemiology, etiology, clinical features, and diagnosis of bacterial meningitis in the neonate will be discussed here. The treatment, prognosis, and complications of neonatal bacterial meningitis are discussed separately, as is bacterial meningitis in older children:

●(See "Bacterial meningitis in the neonate: Treatment and outcome".)

●(See "Bacterial meningitis in the neonate: Neurologic complications".)

●(See "Bacterial meningitis in children older than one month: Clinical features and diagnosis".)

●(See "Bacterial meningitis in children older than one month: Treatment and prognosis".)

EPIDEMIOLOGY

●Incidence – The incidence of bacterial meningitis in neonates (infants <1 month) ranges from 0.25 and 0.32 per 1000 live births, depending upon the definition used [2-6]. The incidence has declined substantially since the 1970s, largely due to prevention of early-onset group B streptococcal (GBS) disease through screening efforts, intrapartum antibiotic prophylaxis, and prompt evaluation of neonates with well-defined maternal risk factors [7]. In the same time period, preterm neonates have accounted for a growing number of cases: as many as 30 percent of all cases of neonatal meningitis in contemporary reports [5,8]. (See "Prevention of early-onset group B streptococcal disease in neonates".)

Bacterial meningitis occurs in as many as 15 percent of neonates with bacteremia. Among infants with invasive GBS disease, 5 to 10 percent with early-onset and approximately 25 to 30 percent of those with late-onset infections have meningitis [9-12]. (See "Group B streptococcal infection in neonates and young infants".)

During the second month after birth, the incidence of meningitis declines by approximately 50 percent; however, these young infants continue to have increased risk relative to older infants and children [13]. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis".)

●Risk factors – Risk factors for neonatal meningitis are largely the same as for neonatal sepsis occurring at sites outside the central nervous system.

Risk factors for early-onset sepsis and meningitis include low birth weight, preterm birth, premature and/or prolonged rupture of membranes, maternal intra-amniotic infection, and others, as discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Maternal risk factors' and "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Risk factors'.)

Risk factors for late-onset infections are not as well established. Meningitis can occur from spread of a gram-negative infection (eg, urinary tract infection progressing to bacteremia and meningitis). (See "Urinary tract infections in neonates".)

In addition, preterm neonates with intraventricular hemorrhage and/or intraventricular hardware are at increased risk of late-onset meningitis [14]. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome".)

In preterm neonates without these risk factors, late-onset meningitis is a rare manifestation of nosocomial infection. In one study of 4731 episodes of late-onset nosocomial infection in preterm neonates (22 to 26 weeks gestation), meningitis accounted for only 3.5 percent of the episodes [15].

ETIOLOGY — In resource-abundant countries, group B Streptococcus (GBS), Escherichia coli, and other gram-negative bacilli are the most common causes of neonatal meningitis [6,8,11,16-21]. In prospective surveillance studies of neonates with sepsis or meningitis within 72 hours of birth, approximately 65 to 75 percent had infection caused by GBS and E. coli [18,22]. When E. coli infection occurs after six days of age, galactosemia should be excluded. (See "Galactosemia: Clinical features and diagnosis" and "Group B streptococcal infection in neonates and young infants", section on 'Epidemiology'.)

Early-onset infections (defined by most neonatologists as those occurring in the first 72 hours after birth, but for GBS, defined as the first six days of life) reflect vertical transmission from maternal genital tract flora [23]. Late-onset infections (acquired after age six days) suggest maternal flora colonizing the neonate or nosocomial or community acquisition as the source of infection [24].

Gram-positive organisms other than GBS (eg, Enterococcus, coagulase-negative staphylococci, Staphylococcus aureus, Listeria monocytogenes, group A Streptococcus, and alpha-hemolytic streptococci) contribute to the total disease burden, particularly among preterm very low birth weight (birth weight <1500 g) infants [25]. However, none of these organisms accounts for more than 1 to 4 percent of cases overall [22,26]. (See "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Etiologic agents'.)

Neisseria meningitidis, Streptococcus pneumoniae, and nontypeable Haemophilus influenzae also rarely cause meningitis in newborn infants.

Anaerobic pathogens, especially Bacteroides fragilis, are a consideration in neonates with clinical and laboratory findings suggestive of meningitis with negative routine culture results [27].

Pasteurella multocida should be considered in the differential diagnosis, especially if contact, typically licking rather than a bite, with companion animals such as dogs and cats is documented [28]. (See "Pasteurella infections", section on 'Epidemiology'.)

In the developing world, the microbiology of bacterial meningitis in neonates varies geographically, but GBS remains a prominent cause [29].

CLINICAL FEATURES — The clinical presentation of neonatal meningitis is indistinguishable from that of neonatal sepsis without meningitis. The most commonly reported clinical signs are temperature instability, irritability or lethargy, and poor feeding or vomiting [30].

Temperature instability — Temperature instability is the most common finding. Temperature instability encompasses fever (rectal temperature >38°C) or hypothermia (rectal temperature <36°C). Term infants are more likely to have fever, whereas preterm infants are more likely to have hypothermia [31]. Temperature instability is present in approximately 60 percent of neonates with bacterial meningitis [30,32].

Neurologic findings — Neurologic signs of neonatal meningitis may include irritability, lethargy, poor tone, tremors or twitching, and seizures. Irritability is common and present in up to 60 percent of patients [30]. Seizures have been reported as a presenting feature in 20 to 50 percent of infants with neonatal meningitis, more commonly with gram-negative compared with gram-positive pathogens [24]. Seizures usually are focal and may be subtle (eg, lip smacking or eye deviation) [30].

Bulging fontanelle and nuchal rigidity are not common findings at the time of initial presentation but are found in approximately 25 and 15 percent of affected neonates, respectively [30,32]. However, when these findings are present, they should raise concern for meningitis.

Other findings — Other findings of neonatal bacterial meningitis and their approximate frequencies are listed below [30,32]:

●Poor feeding or vomiting – 50 percent

●Decreased activity – 50 percent

●Respiratory distress (tachypnea, grunting, flaring of the nasal alae, retractions, decreased breath sounds) – 33 to 50 percent

●Apnea – 10 to 30 percent

●Change in stool frequency or consistency – 20 percent

EVALUATION

Overview — Evaluation of neonates with suspected sepsis or meningitis should include a review of the prenatal history, delivery, and complete physical examination. Because the clinical presentation of bacterial meningitis in the neonate is nonspecific, neonates with suspected bacterial meningitis should undergo a full laboratory evaluation for sepsis. This includes:

●Complete blood count with differential (optional)

●Blood culture

●Urine culture (if >6 days of age) [32]

●Lumbar puncture (LP) for cerebrospinal fluid (CSF) cell count, protein, glucose, Gram stain, and culture

Examination of the CSF is necessary to establish the diagnosis of bacterial meningitis. (See 'Diagnosis' below.)

There is no specific presentation or laboratory test (other than direct CSF examination) that reliably distinguishes the neonate with serious bacterial infection (bacteremia, urinary tract infection) from the neonate with meningitis. Thus, if a serious bacterial infection is suspected in a neonate, meningitis must also be considered.

The following sections provide a detailed discussion of the CSF examination. Other components of the laboratory evaluation for neonates with suspected sepsis are discussed separately. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Laboratory tests' and "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Evaluation'.)

Lumbar puncture — When signs of sepsis are present in a neonate, an LP should be performed, ideally before or soon after antibiotic therapy is initiated. When clinical instability precludes performing an LP at the time of the initial diagnostic evaluation, antimicrobials should be provided in doses sufficient for the treatment of meningitis, until such time that the infant's condition permits evaluation of the CSF. Empiric treatment is discussed separately. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empiric therapy'.)

Interpretation of cerebrospinal fluid — Interpretation of CSF studies in newborns can be challenging. The range of normal values for CSF parameters is different for neonates than for older infants and children and also varies according to gestational age, chronologic age, and birth weight (table 1) [33-38].

In addition, there is considerable overlap between CSF parameters in neonates with and without bacterial meningitis [32].

Additional features that assist in arriving at a provisional diagnosis include the clinical status of the infant, other laboratory parameters, and the neonate's clinical progression. For infants in whom the initial CSF is obtained so early in the course that CSF findings of bacterial meningitis are not definitive, a repeat LP performed 24 to 48 hours later may provide clarity because signs of inflammation in the CSF increase. When the meninges are inflamed, the second LP always shows a pleocytosis and other parameters are consistent with the diagnosis of meningitis.

Cell count — In the neonate, a CSF white blood cell (WBC) count >15 cells/microL is consistent with meningeal inflammation, and bacterial meningitis should be a consideration (ie, this finding warrants empiric antibiotic therapy pending culture results) [26,35,38-42]. However, it is important to recognize that neonatal meningitis occasionally can occur with normal CSF parameters and some neonates with CSF WBC >15 cells/microL do not have meningitis. In one study, CSF WBC >21 cells/microL had a sensitivity of 79 percent and a specificity of 81 percent to predict culture-proven meningitis [39]. The CSF WBC is typically greater in gram-negative meningitis compared with gram-positive meningitis, but there is overlap in many cases [43]. In a study of 46 infants with group B streptococcal (GBS) meningitis managed in the era of intrapartum antibiotic prophylaxis, the median CSF WBC count was 271 cells/microL [44].

Protein — In the neonate, a CSF protein of >125 to 150 mg/dL in preterm and >100 mg/dL in term infants is consistent with bacterial meningitis [41,45], but CSF protein values are highly variable in neonates both with and without meningitis [35,36,39]. In a study that analyzed data on nearly 3500 noninfected term neonates (age 0 to 28 days), the median CSF protein concentration was 66 mg/dL (95^th percentile value 118 mg/dL) [38].

Causes of elevated CSF protein that should be considered in the neonate without CSF pleocytosis include parameningeal infections (eg, brain abscess), congenital infections, and intracranial hemorrhage [46]. (See "Bacterial meningitis in the neonate: Neurologic complications" and "Overview of TORCH infections" and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Risk factors, clinical features, screening, and diagnosis" and "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome".)

Glucose — A CSF glucose concentration <30 mg/dL (1.7 mmol/L) in a term infant or <20 mg/dL (1.1 mmol/L) in a preterm infant is consistent with bacterial meningitis in the neonate, but CSF glucose values are highly variable in infants both with and without meningitis [35,36,38]. The ratio of CSF to serum glucose is not useful in acutely ill neonates (their serum glucose may be increased secondary to stress or administration of intravenous glucose before the time of evaluation).

Gram stain — The presence of an organism on CSF Gram stain can suggest the diagnosis of bacterial meningitis and has the advantage of providing a presumptive etiologic diagnosis before culture results are available. However, the absence of organisms on Gram stain does not exclude the diagnosis. Approximately 20 percent of neonates with culture-confirmed bacterial meningitis have negative Gram-stained smears, especially those whose illness is caused by L. monocytogenes. Neonates with culture-proven meningitis can have negative Gram-stained smears if the concentration of organisms in the CSF is low [47].

Polymerase chain reaction — Molecular methods are increasingly used to assist in the diagnosis of central nervous system infections in infants and children. Multiplex or panel-based nucleic acid amplification tests are now available that test for multiple bacterial and viral pathogens simultaneously in a single CSF sample (eg, FilmArray meningitis/encephalitis panel [BioFire]) [48,49]. These tests are highly sensitive and specific, though false-positive and false-negative results can occur. In a study that analyzed 62 CSF samples from infants <3 months old, the multiplex panel assay was more sensitive than bacterial culture, which was attributed to several infants having received prior antimicrobial therapy before CSF was obtained [49].

If a multiplex panel is performed, it should be used in conjunction with standard microbiologic tests (eg, cultures of CSF and blood). Multiplex panels do not detect all causes of central nervous system infection, nor do they provide any information on antimicrobial susceptibility of the pathogen.

Traumatic lumbar puncture — Adjustment of CSF WBC in the setting of a traumatic LP does not improve diagnostic utility and can result in loss of sensitivity with only a marginal gain in specificity [50]. Neonates in whom the LP is traumatic should be treated presumptively for meningitis, pending results of CSF culture. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Antimicrobial therapy'.)

Evaluation for herpes simplex virus — Evaluation for herpes simplex virus (HSV) infection is often warranted in neonates undergoing evaluation for bacterial meningitis, particularly those with concerning signs and symptoms of meningitis and/or CSF pleocytosis. The evaluation for neonatal HSV infection is discussed in detail separately. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)

DIAGNOSIS — Neonatal meningitis should be suspected in any infant younger than one month of age who presents with clinical findings of sepsis or meningitis and in neonates who have positive blood cultures. The clinical findings can be subtle and/or limited to isolated fever or hypothermia. (See 'Clinical features' above.)

Isolation of a bacterial pathogen from the cerebrospinal fluid (CSF) in culture or with molecular methods confirms the diagnosis of bacterial meningitis. Concomitant blood cultures often are positive for the same organism as the CSF culture but can be negative in up to one-third of cases [2,25,33,39]. Pending culture results, neonates who have undergone evaluation for sepsis and meningitis should be hospitalized and treated with antibiotics for presumed sepsis and meningitis. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empiric therapy'.)

The CSF culture may be negative in some neonates with bacterial meningitis whose lumbar puncture (LP) was delayed until after antibiotic administration (eg, unstable, critically ill infants). In such infants, a diagnosis of bacterial meningitis may be made if the initial blood culture grows a pathogen (eg, E. coli) and the CSF obtained 24 to 36 hours after initiation of antibiotic therapy is abnormal (eg, neutrophilic pleocytosis, decreased glucose, and/or elevated protein).

The administration of intrapartum antibiotic prophylaxis for an adequate duration (≥4 hours before delivery) prevents at least 80 percent of cases of early-onset group B streptococcal (GBS) disease [7]. If the infant is infected and the bacterial pathogen is susceptible to the antimicrobial agent that the mother received, the blood culture in the infant may be sterile despite a clinical course that suggests neonatal sepsis. Such infants usually have undergone an LP (clinical status permitting), and, if so, increased CSF cell count and protein concentration can be used to establish the presumptive diagnosis of meningitis if the CSF culture is sterile. The administration of intrapartum antibiotic prophylaxis has not resulted in "missed" sepsis in healthy-appearing infants. (See "Prevention of early-onset group B streptococcal disease in neonates" and "Management of neonates at risk for early-onset group B streptococcal infection", section on 'Management of the neonate'.)

DIFFERENTIAL DIAGNOSIS — If blood and cerebrospinal fluid (CSF) cultures are negative for bacterial pathogens in the neonate with suspected meningitis based on clinical or laboratory data, the differential diagnosis of aseptic meningitis should be reviewed, particularly with the aim of identifying treatable entities [32]:

●Bacterial infections – Partially treated bacterial meningitis, bacterial infection with a parameningeal focus (brain or epidural abscess), congenital tuberculosis

●Viral infections – Herpes simplex meningoencephalitis, congenital cytomegalovirus, enteroviruses, rubella, lymphocytic choriomeningitis, congenital varicella

●Spirochetal infections – Syphilis

●Parasitic infections – Toxoplasmosis, Chagas disease

●Mycoplasma infections – Mycoplasma hominis infection, Ureaplasma urealyticum infection

●Fungal infection – Candidiasis, coccidioidomycosis, cryptococcal

●Trauma – Subarachnoid hemorrhage, traumatic lumbar puncture (LP)

●Malignancy – Teratoma, medulloblastoma, choroid plexus papilloma and carcinoma

Additional evaluation that may be helpful in distinguishing among the differential diagnostic possibilities includes review of the prenatal and perinatal history, with particular attention to maternal illness and contacts, animal exposures, and travel; examination of the infant for focal signs of disease (eg, ophthalmologic examination); neuroimaging; and radiographic examination of the long bones. Definitive diagnosis may require culture, antigen detection, polymerase chain reaction, and/or serology. Treatment for some of these conditions may be warranted, pending definitive results. (See "Overview of TORCH infections".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bacterial meningitis in infants and children".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Bacterial meningitis is more common in the first month than at any other time of life. Risk factors for neonatal meningitis are largely the same as for neonatal sepsis more broadly (eg, low birth weight, preterm birth, premature and/or prolonged rupture of membranes, maternal intra-amniotic infection). (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Maternal risk factors' and "Clinical features and diagnosis of bacterial sepsis in preterm infants <34 weeks gestation", section on 'Risk factors'.)

●Microbiology – Group B Streptococcus (GBS) and Escherichia coli are the most common bacteria causing neonatal meningitis. (See 'Etiology' above.)

●Clinical features – Signs of neonatal meningitis include (see 'Clinical features' above):

•Fever (rectal temperature >38°C) or hypothermia (rectal temperature <36°C)

•Irritability

•Lethargy

•Poor feeding or feeding intolerance

•Bulging fontanelle

•Nuchal rigidity is observed in a minority of affected infants

Neonatal meningitis should be suspected in any infant <1 month of age who presents with signs of sepsis since the early clinical features are indistinguishable.

●Evaluation – Evaluation of neonates with suspected sepsis or meningitis should include (see 'Evaluation' above):

•Review of the prenatal and birth history

•Complete physical examination

•Full laboratory evaluation for sepsis including:

-Complete blood count with differential (optional)

-Blood culture

-Urine culture (if >6 days of age)

-Lumbar puncture (LP) for cerebrospinal fluid (CSF) cell count, protein, glucose, Gram stain, and culture

●Interpretation of CSF findings – Neonatal bacterial meningitis is characterized by the following CSF findings (table 1) (see 'Interpretation of cerebrospinal fluid' above):

•CSF white blood cell (WBC) count >15 cells/microL with a predominance of polymorphonuclear leukocytes

•Elevated CSF protein concentration

•Decreased CSF glucose concentration

●Empiric therapy – Pending culture results, neonates who have undergone evaluation for sepsis and meningitis should be hospitalized and treated with antibiotics for presumed sepsis and meningitis, as discussed separately. (See "Bacterial meningitis in the neonate: Treatment and outcome", section on 'Empiric therapy'.)

●Diagnosis – The diagnosis of neonatal bacterial meningitis is confirmed by isolation of a bacterial pathogen from the CSF by culture or molecular methods. If the LP is delayed until 24 to 36 hours after initiation of antibiotics, the diagnosis can be made on the basis of abnormal CSF parameters (eg, neutrophilic pleocytosis, decreased glucose, elevated protein) and isolation of a pathogen from the blood. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of bacterial meningitis in the neonate includes infectious and noninfectious causes of aseptic meningitis. (See 'Differential diagnosis' above.)