AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Despite development of effective vaccines, tools for rapid identification of pathogens, and potent antimicrobial drugs, neonatal meningitis contributes substantially to neurological disability worldwide. The persistence of neonatal meningitis results from increasing numbers of infants surviving premature delivery and from limited access to medical resources in developing countries. In addition, the absence of specific clinical findings makes diagnosis of meningitis more difficult in neonates than in older children and adults. Moreover, a wide variety of pathogens are seen in infants because of immaturity of their immune systems and intimate exposure to possible infection from their mothers.

This review focuses on common presentations of treatable bacterial and viral meningitis in the neonatal period, defined as birth to 44 weeks postconceptual age. Common CNS infections caused by bacteria and viruses (eg, herpes simplex, varicella zoster) are emphasized; these may cause either perinatal infection or congenital infection.

Excluded from this discussion are the meningitides caused by HIV and fungi as well as other organisms implicated in congenital CNS damage (eg, cytomegalovirus, toxoplasmosis).

Pathophysiology

Neonates are at greater risk of sepsis and meningitis than other age groups because of deficiencies in humoral and cellular immunity and in phagocytic function. Infants younger than 32 weeks' gestation receive little of the maternal immunoglobulin received by full-term infants. Inefficiency in the neonates' alternative complement pathway compromises their defense against encapsulated bacteria. T-cell defense and mediation of B-cell activity also are compromised. Finally, deficient migration and phagocytosis by neutrophils contribute to neonatal vulnerability to pathogens of even low virulence.

Frequency

United States

The incidence of bacterial meningitis is approximately 0.3 per 1000 live births in industrialized countries. The incidence of herpes simplex virus (HSV) meningitis is estimated to be 0.04-0.2 case per 1000 live births. Varicella zoster virus (VZV) meningitis is even less common (Red Book, 2003).

International

The incidence of neonatal meningitis worldwide cannot be accurately determined because of testing limitations.

Mortality/Morbidity

• Bacterial meningitis: In developed countries, the rate of mortality from bacterial meningitis among neonates has declined from almost 50% in the 1970s to less than 10% in the late 1990s. Morbidities related to neonatal bacterial meningitis are not uncommon. In a prospective sample of more than 1500 neonates surviving until age 5 years, the prevalence of neuromotor disabilities including cerebral palsy was 8.1%, learning disability 7.5%, seizures 7.3%, and hearing problems 25.8% (Bedford, 2001). No problems were reported in 65% of babies who survived group B streptococcal (GBS) meningitis and in 41.5% of those who survived Escherichia coli meningitis.
• HSV meningitis: Mortality among neonates with HSV infection of the central nervous system is 15%. Of these cases, 25-40% will have culture-proven cerebrospinal fluid (CSF) infection. Interestingly, both HSV serotypes (HSV-1 and HSV-2) carry the same risk of mortality, but HSV-2 is more commonly associated with morbidities including cerebral palsy, mental retardation, seizures, microcephaly, and ophthalmic defects (Kimberlin, 2004).
• VZV meningitis: Because VZV meningitis is rare, no epidemiologic data exist on its associated mortality risk. Mortality from neonatal varicella infection is modulated by maternal immunoglobulin antibody. Hence, the risk of mortality in a neonate whose mother develops varicella from 5 days before to 2 days after delivery is roughly 25%. Severity of disease is lessened when maternal varicella develops more than 5 days prior to delivery, assuming a gestational age of greater than 28 weeks (Red Book, 2003). Morbidities associated with maternal primary infection have been described in the context of congenital varicella syndrome, which can include anomalies of the CNS, eyes, limbs, and gastrointestinal tract.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Regardless of the specific pathogen involved, neonatal meningitis is most often caused by vertical transmission during labor and delivery. It occurs most frequently in the days following birth and is more common in premature infants than term infants. Neonatal meningitis occurs in roughly 0.3 per 1000 live births; it is closely associated with sepsis, which is 5 times as common.

When evaluating a neonate for meningitis, consider these 3 key points: (1) be vigilant for maternal infection "set-ups," including prolonged rupture of membranes, fever, and chorioamnionitis, remembering that asymptomatic maternal infection is always a possibility even with screening; (2) early-onset and late-onset bacterial infections have distinctive clinical courses, as detailed below; and (3) in HSV and VZV infections, the presence of skin lesions in a meningitic neonate are the exception more than the rule.

Physical

• Bacterial meningitis, early onset
• • Symptoms appearing in the first 48 hours of life are referable primarily to systemic illness rather than meningitis. These include temperature instability, episodes of apnea or bradycardia, hypotension, feeding difficulty, hepatic dysfunction, and irritability alternating with lethargy.
  • Respiratory symptoms can become prominent within hours of birth in GBS infection; however, the symptom complex also is seen with infection by E coli or Listeria species.
• Bacterial meningitis, late onset
• • Late-onset bacterial sepsis is more likely to be associated with neurologic symptoms. Most commonly seen are stupor and irritability, which Volpe describes in more than 75% of affected neonates.
  • Between 25% and 50% of neonates will exhibit the following neurological signs: seizures; bulging anterior fontanel; extensor posturing/ opisthotonus; focal cerebral signs including gaze deviation and hemiparesis; cranial nerve palsies. Nuchal rigidity per se is the least common neurologic sign in neonatal bacterial meningitis, occurring in fewer than 25% of affected neonates (Volpe, 2001).
• HSV meningitis: Early features may mimic those associated with bacterial meningitis, including pallor, irritability, high-pitched cry, respiratory distress, fever, or jaundice, progressing to pneumonitis, seizures, hepatic dysfunction, and disseminated intravascular coagulopathy (DIC).
• VZV meningitis: Neonates with VZV infection may present with a vesicular rash, typically 9-15 days after their mothers develop a rash. However, Mustonen (1998) and Pignotti (2004) reported 5 neonates who had no cutaneous symptoms despite having culture-proven VZV meningitis. Complications include pneumonitis, hepatic dysfunction, and DIC.
• Emerging pathogens: As cases of neonatal enteroviral sepsis are increasingly recognized and as enteroviridae have been implicated in aseptic meningitis in other age groups, there will likely be a role for reporting and identification of more virulent serotypes as they affect infants (CDC, 2004).

Causes

• Bacterial meningitis: Among US neonates, group B Streptococcus is the most commonly identified organism, implicated in roughly 50% of all cases of bacterial meningitis, and E coli accounts for another 20%: identification and treatment of maternal genitourinary infections is thus an important prevention strategy. Listeria monocytogenes is the third most common pathogen, with 5-10% of cases: it is unique because it exhibits transplacental transmission (Heath, 2003).
• HSV meningitis: As many as 95% of viral infections caused by HSV result from intrapartum transmission, with occasional postnatal exposure by oropharyngeal shedding or cutaneous shedding of virus by parents or hospital contacts. Late presentation in the second postnatal week is more commonly seen than early presentation of disseminated disease.
• VZV meningitis: Viral infections by VZV result from respiratory spread by patients with chickenpox or from contact with vesicular lesions; 25% of neonates whose mothers develop varicella during the last 3 weeks of pregnancy will also develop the infection.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Bacterial meningitis in neonates almost always occurs with sepsis but is difficult to distinguish clinically from sepsis alone, as both present with a constellation of symptoms that indicate systemic illness. Therefore, treatment is started on the basis of presumed infection rather than proven infection. Because the goal in the neonate is to manage any life-threatening condition responsive to intervention, the differential diagnosis includes disorders of cardiac, pulmonary, and metabolic functions.

Other CNS problems may present in a manner that simulates meningitis. These include hemorrhage and stroke, the latter of which has also been reported in the context of VZV intracranial arteriopathy. Also, hypoxic-ischemic encephalopathy or cerebral edema associated with nonhemorrhagic trauma may present a confounding picture.

Additionally, bacterial or viral meningitis always should be considered among disorders that cause shock, DIC, or hepatic failure in neonates; however, by the time these conditions develop, the opportunity for successful intervention may have passed. Therefore, consideration of meningitis remains prudent whenever a neonate demonstrates even slight lethargy or irritability.

Additional considerations should include drug withdrawal, inborn errors of metabolism (including aminoacidopathies, organic acidurias, urea cycle disorders, and mitochondrial disease), and GI problems such as necrotizing enterocolitis or perforated bowel.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CSF and blood cultures
• • Suspected bacterial infection is confirmed often, but not uniformly, by positive results of cultures of CSF or blood. CSF cultures should be obtained in all symptomatic infants; despite the close relationship between bacterial sepsis and meningitis, it has been estimated that 15-30% of infants with CSF-proven meningitis will have negative blood cultures (Malbon, 2006).
  • A recent study from Duke emphasized that no single CSF value can be relied upon to exclude neonatal meningitis except CSF culture (Garges, 2006).
  • The onus is on the clinician to justify initiation of antimicrobial and antiviral therapy regardless of the CSF values.
• Polymerase chain reaction: Polymerase chain reaction (PCR) assay is a powerful diagnostic tool with excellent sensitivity and specificity. It permits identification of GBS antigen in urine or in cerebrospinal fluid, and it is the criterion standard for identification of HSV and enteroviral infection in CSF.
• Latex particle agglutination: Rapid screening is available with latex particle agglutination (LGA) test of urine, which can be performed for GBS, E coli, and Streptococcus pneumoniae. Unfortunately, the presence of GBS antigen does not prove invasive disease.
• Fluid culture of cutaneous lesions: If vesicles are present on the skin, evaluation for HSV or VZV infection should include cultures of fluid from vesicles on the skin. Swabs of the nasopharynx, conjunctiva, and rectum have also been used to identify these agents. DNA from HSV, VZV, or enteroviruses can be identified from either vesicles or CSF using PCR.
• CSF analysis
• • Interpretation of CSF findings is more difficult in neonates than in older children, especially in premature infants whose more permeable blood-brain barrier causes higher levels of glucose and protein.
  • The classic finding of decreased CSF glucose, elevated CSF protein, and pleocytosis is seen more with gram-negative meningitis and with late gram-positive meningitis; this combination also is suggestive of viral meningitis, especially HSV.
  • Only if all 3 parameters are normal does the lumbar puncture provide evidence against infection; no single CSF parameter exists that can reliably exclude the presence of meningitis in a neonate (Garges, 2006).
  • Bacterial meningitis commonly causes CSF pleocytosis greater than 100 WBC/µL, with predominantly polymorphonuclear leukocytes gradually evolving to lymphocytes.
  • In neonates with viral meningitis, the picture may be similar but with a less dramatic pleocytosis. HSV meningitis, particularly, may be associated with a large number of RBCs in the CSF.
• Maternal investigation: Particularly if a mother is symptomatic, bacterial or viral cultures can provide valuable adjunctive information.

Imaging Studies

• Brain MRI
• • MRI is the neuroimaging modality of choice to identify focal areas of infection, infarction, secondary hemorrhage, cerebral edema, hydrocephalus, or, rarely, abscess formation. It should be considered in the context of focal neurological abnormalities, persistent infection, or clinical deterioration. Sinovenous occlusions, ventriculitis, and subdural collections are best discussed with MRI.
  • Follow-up MRI scans are useful in following the resolution of the infection as well as in contributing to prognostication. If available, MR spectroscopy can add important information on the metabolic function of the neonatal brain.
• CT scan
• • Although CT carries the risk of exposing the neonatal brain to radiation, the rapidity and ease with which it can be obtained makes it useful in decision-making for potential neurosurgical interventions, such as ventriculostomy for hydrocephalus or surgical drainage of empyema or abscess.
• Cranial ultrasonography: Cranial ultrasonography provides an alternative imaging modality for critically ill neonates, but it does not provide optimal detail in all circumstances. However, it is low risk and thus useful for monitoring ventricular size for hydrocephalus during the acute phase of meningitis.
• Chest radiography: Chest radiograph provides important information about the lung parenchyma and cardiac silhouette. Meningitis or sepsis may occur with pneumonia but may be distinguishable from surfactant deficiency, pulmonary hypertension, and obstructive cardiac disease.

Other Tests

• Electroencephalography (EEG)
• • EEG is not an essential part of the initial diagnostic process; however, in neonates who are unresponsive or have seizures presenting as episodes of apnea, bradycardia, or rhythmic focal movements, EEG monitoring provides useful information to guide treatment with anticonvulsant drugs.
  • Not surprisingly, infants with normal or mildly abnormal EEGs had better outcomes, while those with moderate-to-markedly abnormal EEGs were more likely to die or to suffer adverse outcomes (Klinger, 2001).

Procedures

• Lumbar puncture
• • Lumbar puncture is indicated to evaluate CSF in all neonates suspected of having sepsis or meningitis, even in the absence of neurological signs.
  • Many clinicians are reluctant to perform a tap on a critically ill infant. Although the theoretical complications of lumbar puncture include trauma, brain-stem herniation, introduction of infection, and hypoxic stress, none of these occurred in a meta-analysis of more than 10,000 infants who underwent lumbar puncture (Malbon, 2006). Meningitis, however, increases the risk of death in neonates. Stoll (2004) reported 23% mortality in babies with CSF-proven meningitis versus 9% mortality in neonates whose lumbar puncture results were not consistent with meningitis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Although evaluation and treatment of perinatal infection often begins before birth, discussion of antenatal interventions is beyond the scope of this review. However, early initiation of antimicrobial drugs is essential; a confirmed diagnosis of meningitis seldom is established before treatment is started. Recommended agents are discussed in the section on Medication.

• Corticosteroids have been shown to reduce long-term sequelae, particularly hearing loss, in older infants with Haemophilus influenzae type B meningitis and S pneumoniae infection. However, dexamethasone is not recommended for neonates with meningitis (Chaudhuri, 2004).
• Supportive care is focused on supporting blood pressure to maintain adequate cerebral perfusion and on preventing secondary brain injury. Meticulous fluid management is important to minimize cerebral edema and to respond to inappropriate antidiuretic hormone (ADH) secretion. Neither steroids nor hyperosmolar agents have been proven to be helpful. The syndrome of inappropriate ADH secretion may cause hyponatremia and hypo-osmolality, which may increase lethargy and seizures while further increasing intracranial pressure.
• Management of seizures is a common challenge in neonates with meningitis. Phenobarbital and phenytoin remain the current drugs of choice, with benzodiazepines utilized as adjunctive therapy. Respiratory dysfunction, DIC, and nutritional deficiencies require management by experienced neonatologists.
• Lumbar puncture, especially for CSF culture and sensitivity, should be repeated 24-36 hours after the initial study to monitor the course of the infection and guide further treatment decisions. With persistent infection in the lumbar CSF or with clinical deterioration not explained by other complications, a diagnostic tap of the lateral ventricle should be performed to determine the presence of ventriculitis. This may occur, especially with gram-negative bacteria, in the absence of pleocytosis in the lumbar CSF or with sterile CSF.
• A negative HSV-PCR test in the initial CSF sample is an acceptable endpoint for discontinuation of empiric acyclovir treatment.
• Infants with partially treated bacterial meningitis should be managed on a case-by-case basis, based on their clinical presentation. These infants should be observed for at least 48 hours after treatment is discontinued.

Surgical Care

• Ventriculostomy
• • Ventriculostomy with external drainage may be required with the development of acute hydrocephalus secondary to obstruction of CSF flow.
  • Ventriculostomy with intermittent administration of intraventricular antibiotic may be required for the management of ventriculitis.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Aggressive antimicrobial intervention is lifesaving in neonates with suspected meningitis. Because distinguishing viral from bacterial meningitis is difficult early in the clinical course, a combination of agents is often necessary, providing coverage for both types of infection.

While consensus exists that acyclovir is the preferred antiviral therapy, the best antibacterial therapy is a matter of some disagreement. The combination of ampicillin and gentamicin is a common regimen, but selection of antibiotics should be considered in light of local patterns of practice based upon antibacterial drug sensitivities and hospital policies.

Drug Category: Antiviral agents

These recommendations are for treatment of HSV and VZV meningitis; acyclovir is preferred for the treatment of both of these infections.

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting. Either gram-positive or gram-negative organisms may cause bacterial sepsis and meningitis. Combination therapy is necessary.

Drug Category: Anticonvulsants

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Brainstem auditory evoked response testing: Because of the potential for hearing loss, neonates with meningitis should undergo brainstem auditory evoked response (BAER) testing at 4-6 weeks after discharge (Wellman, 2003).

Complications

• Regardless of etiology, meningitis in neonates can progress rapidly to serious complications. These include cerebral edema; hydrocephalus; hemorrhage; ventriculitis, especially with bacterial infection; and cerebral infarction. Cerebral edema, hydrocephalus, and hemorrhage each may cause increased intracranial pressure, with potential for secondary ischemic injury to the brain because of decreased brain perfusion.
• Cerebral edema results from vasogenic changes, cytotoxic cell injury, and, at times, inappropriate antidiuretic hormone (ADH) secretion.
• Hydrocephalus develops as a result of debris obstructing CSF flow through the ventricular system or dysfunction of arachnoid villi.
• Hemorrhage occurs in regions of infarction or necrosis and should be suspected in a neonate with new focal neurological findings or clinical deterioration.
• Ventriculitis results in sequestration of infection to areas poorly accessible to systemic antimicrobial drugs. Inflammation of the ependymal lining of ventricles often obstructs CSF flow. Thus, all of these complications are interactive, making effective management difficult.
• Cerebral infarction, both focal (arterial) and diffuse (venous), may complicate recovery.
• Necrotizing lesions secondary to HSV meningitis can be deleterious to the developing brain.

Prognosis

• Survivors of neonatal meningitis are not only more likely to have moderate-to-severe disabilities than children who had meningitis after one month of age, they are also more likely to have subtle problems, including visual deficits, middle-ear disease, and behavioral problems (Bedford, 2001).
• Poor prognostic indicators include low birth weight, significant leukopenia or neutropenia, high CSF protein, and coma.
• In addition to coma and leukopenia, seizures lasting longer than 72 hours and the need for inotropes predict moderate/severe disability or death with 88% sensitivity and 99% specificity (Klinger, 2000).
• Use of acyclovir has reduced morbidity and mortality due to HSV infections. Yet neurological sequelae are likely to be seen in 50% of neonates with HSV meningitis.
• Brain MRI, both in the acute and convalescent phases of illness, is a good modality to assist in determining prognosis.
• Although neonatal meningitis is an acute infectious process, significant complications may result. These include residual epilepsy, cognitive impairment, hearing loss, visual impairment, spastic paresis, and, occasionally, microcephaly. Some of these disorders may be difficult to detect during infancy.
• • Hearing, for example, is difficult to evaluate without the child's cooperation, and then assessment may be limited to behavioral response to sounds. Brainstem auditory evoked response (BAER) testing does not evaluate all dimensions of hearing, but this test, which can be performed reliably in sedated infants, only slightly overestimates hearing loss, which occurs in 30% of survivors of bacterial meningitis and 14% of survivors of nonbacterial meningitis (Bao, 1998). Subtle impairment of sound discrimination may not be readily apparent.
  • Similarly, cognitive impairment may not be apparent until the child has started school or advanced into higher grades when more complex analysis of information is necessary (Stevens, 2003). Careful screening for neurological deficits must be conducted as part of routine pediatric care over the period of many years, and the responsible physician should be attentive to possible problems with perception, learning, or behavior that may result from neonatal infection.

Patient Education

• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center . Also, see eMedicine's patient education article Brain Infection.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Delays in diagnosis and initiation of treatment are the most critical pitfalls.
• Failure to perform a lumbar puncture and detect infection in a neonate with mild fever and minimal, nonspecific clinical findings is problematic; all neonates in whom meningitis might be the cause of symptoms should undergo CSF examination.
• • In a 2001 survey of pediatricians, "meningitis or other infectious disease" and "newborn conditions other than congenital vision/hearing loss" were the two most frequent bases reported for malpractice suits (Berger and Deitschel, 2004). From a risk-management perspective, it is important to remain mindful that "the most prevalent condition for which claims were filed against pediatricians was neurologic impairment of an infant. Thirty percent of claims paid were for this condition alone. However, the second most prevalent condition, meningitis, resulted in a higher percentage of paid claims (46%) and a higher total and average indemnity" (Berger and Deitschel, 2004).
• Delay in treatment because of equivocal laboratory screening tests or because findings are altered by prior partial treatment may cause significant harm.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Stoll BJ, Hansen N, Fanaroff AA, et al. To tap or not to tap: high likelihood of meningitis without infection in very low birthweight infants. Pediatrics. 2004;113:1181-6. [Medline].
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Article Last Updated: Sep 29, 2006