Chapter 117: Meningitis in Infants and Children

Meningitis is an inflammation of the leptomeninges, tissues that cover the brain and spinal cord. Untreated bacterial meningitis has a mortality of nearly 100%, so treat suspected bacterial meningitis promptly. Unfortunately, even with rapid antibiotic treatment, long-term neurologic sequelae occur. Viral meningitis has a range of severity. Mild cases resolve without sequelae. However, some viruses, such as herpes virus, can cause severe infections. Meningoencephalitis is an inflammation of the brain as well as the meninges. It is less common than meningitis but can be devastating.

The most common causes of bacterial meningitis vary with the child's age. In neonates, important organisms are group B Streptococcus, Escherichia coli, and Listeria monocytogenes. Other gram-negative bacteria can be occasional causes of meningitis as well. In infants >1 month old and children, the leading organisms are Neisseria meningitides, Streptococcus pneumoniae, and Haemophilus influenzae type b. Vaccination programs have had a huge impact on the epidemiology of bacterial meningitis in developed countries. Prior to the widespread use of H. influenzae type b (Hib) conjugate vaccines, H. influenzae type b was the most common cause of bacterial meningitis in children in the United States. Since the introduction of Hib vaccines, the incidence of H. influenzae type b meningitis has decreased by 99% in the United States.¹ Similar dramatic decreases have occurred in other developed countries. Immunization has also had a big impact on the incidence of meningitis from S. pneumoniae in the United States and other developed countries. At present, the primary cause of bacterial meningitis in the United States is N. meningitides.² Other important causes of bacterial meningitis in children include Mycobacterium tuberculosis and Borrelia burgdorferi, the causative agent of Lyme disease.

Viral meningitis is fairly common. Enteroviruses are the most frequent cause. Meningoencephalitis can be caused by enteroviruses, arboviruses (including West Nile virus), and herpes viruses. Herpes simplex virus type 1 (HSV-1) infection occurs sporadically and causes a severe meningoencephalitis in children and adults. Herpes simplex virus type 2 (HSV-2) develops in neonates born to infected mothers. Varicella-zoster virus can cause CNS infections including acute cerebellar ataxia. Many other viruses can cause CNS infections, including cytomegalovirus, Ebstein-Barr virus, mumps virus, adenovirus, influenza virus, parainfluenza virus, rubeola virus, rubella virus, and rabies virus.

Fungal meningitis can occur in both normal and immunocompromised hosts. Important causes include Cryptococcus neoformans, Coccidioides immitis, and Candida albicans.

Parasite infections can cause eosinophilic meningitis, defined as meningitis with at least 10 eosinophils/mm³ of cerebrospinal fluid (CSF).³ The most frequent cause of eosinophilic meningitis throughout the world is helminth infection.

Bacterial meningitis in children usually results from bacteremia, arising from organisms colonizing the nasopharynx. Less commonly, meningitis is caused by direct spread of bacteria from a contiguous site of infection, such as sinusitis, or from penetration of the CSF space from trauma, dermal sinus tracts, or open neural tube defects. Viral respiratory infections can increase the likelihood of meningitis if the nasopharynx is colonized by bacteria.

Meningitis starts with breakdown of the blood–brain barrier. Then organisms enter the subarachnoid space. Once there, they can multiply quickly because the CSF has low levels of complement, antibodies, and other host defenses. Bacterial cell wall components and toxins produce an inflammatory response that increases vascular permeability and attracts leukocytes. The inflammatory response is responsible for much of the damage that ensues. Viral pathogens also produce damage by direct tissue destruction as well inflammation.

HISTORY

Infants ≤30 days old are at risk for meningitis due to an immature immune response. Symptoms in this age group are variable and nonspecific and include both fever and hypothermia. Neonates can present with a history of lethargy, poor feeding, fussiness, bulging fontanelle, vomiting, diarrhea, seizures, grunting, or respiratory distress. Elements in the birth history that increase the likelihood of bacterial meningitis include prematurity, low birth weight, delivery complications, maternal infection, and maternal colonization with group B streptococci or herpes simplex. Some neonates present with few symptoms early in the course of their illness, so maintain a high degree of suspicion for early meningitis when confronted with a potentially sick newborn.

SIGNS AND SYMPTOMS

Bacterial Meningitis

Certain signs and symptoms are especially helpful for diagnosing bacterial meningitis in infants and children. Caregiver reports of bulging fontanelle (likelihood ratio [LR] 8, 95% CI 2.4–26), or neck stiffness (LR 7.7, 95% CI 3.2–19), or seizures (outside of the febrile seizure range of 6 months to 6 years; LR 4.4, 95% CI 3.0–6.4), or reduced feeds (LR 2, 95% CI 1.2–3.4) are concerning for meningitis.⁴ Children with meningitis can present with the rapid onset of shock and altered mental status or with more gradual symptoms including fever, headaches, photophobia, upper respiratory symptoms, GI symptoms, irritability, and rash.

The World Health Organization's Pocket Book of Hospital Care for Children reported the performance of signs and symptoms for bacterial meningitis in infants and children and did not find any single clinical feature distinctive enough to make a "robust diagnosis of bacterial meningitis."⁵ However, the combination of fever, seizures, meningeal signs, and altered consciousness was consistently associated with bacterial meningitis.⁶

Viral Meningitis

Infants with viral meningitis typically present with irritability and decreased activity. Headache and fever are the usual complaints in children. Other symptoms include photophobia, rashes, nausea, vomiting, and pain in the neck, back, and legs. Most children with West Nile virus will be asymptomatic or have mild illness. Severe neurologic illness from West Nile virus is more common in adults than in children.⁷ Arboviruses can cause viral meningitis, encephalitis or acute flaccid paralysis.

Herpes simplex virus can cause devastating infection in neonates. Infection can present in three ways: (1) as disseminated disease with involvement of the CNS in 60% to 75% of cases; (2) as primary CNS disease; or (3) as disease localized to the skin, eyes, and/or mouth. About two thirds of infants with disseminated or CNS disease will have skin lesions, but these may not be present at the time of diagnosis. Neonatal herpes infections, including herpes simplex meningitis, can occur at up to 6 weeks of age.⁸ Herpes infection can be transmitted through an infected maternal genital tract but may also be transmitted from a nongenital maternal infection, for example, if a mother with oral herpes kisses the baby. Herpes simplex encephalitis (HSV-1) beyond the neonatal period presents with fever, altered mental status, seizures, and focal neurologic findings. It occurs sporadically.

PHYSICAL EXAMINATION

Neonates and infants <90 days old may have fever, normal temperature, or hypothermia. A normal temperature does exclude meningitis. Toxic appearance, lethargy, mottling, bulging fontanelle, abnormal cry, grunting, respiratory distress, and increased or decreased tone are all supportive of the diagnosis, but these signs can be absent. Jaundice or rash may occasionally be seen. Infants in the first months of life are unlikely to have a stiff neck. Fever in neonates (rectal temperature of 100.5°F or higher) should always prompt suspicion for meningitis. In the absence of fever, a clinician should be concerned about infants who are ill appearing, have the signs or symptoms listed earlier, or are just not "acting right" according to their caregivers.

Older infants (>90 days old) with meningitis may also have fever, hypothermia, toxic appearance, lethargy, mottling, bulging fontanelle, abnormal cry, grunting, and respiratory distress at presentation. Children (>36 months of age) may have fever and nuchal rigidity. The Kernig sign (with the patient lying supine and the hip flexed at 90 degrees, the patient cannot extend the knee fully without pain) and Brudzinski sign (with the patient lying supine, there is involuntary flexion of the legs with passive neck flexion) may be present. Children may have altered mental status, shock, focal neurologic signs, or signs of increased intracranial pressure. Rash or another focal sign of infection may be present. Consider bacterial meningitis in the child with seizures, outside the range of 6 months to 6 years.

DIFFERENTIAL DIAGNOSIS

In neonates, the most common causes of meningitis in the United States are group B Streptococcus, E. coli, and L. monocytogenes. Other organisms that cause meningitis include S. pneumoniae, other streptococci, nontypeable H. influenzae, Staphylococcus species, Klebsiella, Enterobacter, Pseudomonas, Treponema pallidum, and M. tuberculosis.⁹ Neonates can develop meningitis from primary viral infection with HSV or enteroviruses. The differential diagnosis of neonatal sepsis and meningitis includes infection from fungi (Candida) and protozoa (malaria crosses the placenta, and maternal malaria can infect the neonate). Noninfectious illnesses that can appear similar to sepsis and meningitis include cardiac disease, necrotizing enterocolitis, congenital adrenal hyperplasia, inborn errors of metabolism, and intracranial hemorrhage.

In older infants and children, the usual dilemma is differentiating acute viral and bacterial meningitis. The typical bacterial causes are N. meningitides, S. pneumoniae, and H. influenzae type b. Less common organisms include M. tuberculosis, Nocardia species, T. pallidum, and B. burgdorferi.² Fungal infections and parasitic infections can produce infection of the CNS. Infections around the brain and spinal cord may appear similar to meningitis. Collagen vascular disease, malignancy, and certain drugs and toxins should also be included in the differential diagnosis.

LABORATORY TESTING

All children suspected of having meningitis should undergo a lumbar puncture when they are clinically stable. Although establishing a diagnosis is important, patients who are unsTable but suspected of having bacterial meningitis should receive antibiotics as quickly as possible (see Table 117-1). Defer lumbar puncture until the child is stabilized and can tolerate the procedure. Positioning an infant or child for lumbar puncture before stabilization can result in hypoxia and hypotension. There are a few contraindications to lumbar puncture in children besides hypoxia and clinical instability. These include focal neurologic findings, thrombocytopenia, local infection at the lumbar site, and vertebral abnormalities. See chapter 116, Fever and Serious Bacterial Illness in Infants and Children, for details of pediatric lumbar puncture.

Children with focal neurologic signs should undergo a head CT scan prior to lumbar puncture and should receive antibiotics promptly without waiting for the results of the scan or lumbar puncture. CSF abnormalities of meningitis, such as neutrophilic pleocytosis, low glucose, and high protein, will persist for days despite antibiotic treatment. Bacteria are generally not evident on Gram stain after antibiotics have penetrated the CSF (time intervals for clearance of bacteria in the CSF range from 15 minutes to several hours; see later section, "The Child Pretreated with Antibiotics").

Spinal fluid should be sent for cell count, protein, glucose, Gram stain, and culture. In the event of a traumatic tap, send fluid for culture and use clinical judgment in the interpretation of other results. Decision rules correcting the WBC count based on the number of red cells may not be reliable.

The CSF of patients with bacterial meningitis tends to have lower glucose, higher protein, higher WBC counts, and a more frequent predominance of neutrophils relative to the CSF of patients with viral meningitis, but there is considerable overlap between the two groups.^12,13,14 Data for the development of the Bacterial Meningitis Score were collected on children from 20 U.S. EDs from 2001 to 2004, and any one of the following risk factors was associated with bacterial meningitis: CSF protein >80 micrograms/L; positive CSF Gram stain; peripheral absolute neutrophil count ≥10,000 cells/μL; CSF absolute neutrophil count ≥1000 cells/μL; or a seizure before or after presentation.¹⁵ The Bacterial Meningitis Score predicted a very low risk of bacterial meningitis for those children with none of the above risk factors (sensitivity, 98.3%; negative predictive value, 99.9%). Two children, both <2 months old, had bacterial meningitis despite a negative Bacterial Meningitis Score. The overall worldwide generalizability of the score, or its stability in view of a country's vaccination practices, is not known. The biomarkers of erythrocyte sedimentation rate, C-reactive protein, interleukin-6, and procalcitonin do not perform robustly enough to serve as proxies for lumbar puncture and examination and culture of CSF.

Polymerase chain reaction is especially helpful in diagnosing viral meningitis. Polymerase chain reaction is available for HSV, Epstein-Barr virus, enterovirus, and cytomegalovirus, as well as others. Polymerase chain reaction is useful for the diagnosis of meningitis due to tuberculosis and is sensitive for acute neurosyphilis as well.¹⁶

Latex agglutination testing has been proposed for the rapid diagnosis of bacterial meningitis, particularly when the patient has already received antibiotics. However, testing is only available for certain bacteria. Furthermore, sensitivity varies depending on the organism. A negative test does not rule out bacterial meningitis. Although latex agglutination testing may be helpful in certain situations, it is not recommended for routine use.^17,18 Counterimmunoelectrophoresis can also be used for identifying bacterial causes of meningitis. It requires special equipment and is cumbersome to perform.¹⁹ Counterimmunoelectrophoresis has relatively poor specificity, creating a number of false positives.

ANTIBIOTICS

Antibiotics may have difficulty penetrating the blood–brain barrier. Therefore, doses used to treat meningitis are frequently higher than the doses used for other pediatric infections (Table 117-1).

For neonates, presumptive therapy for meningitis is generally ampicillin and cefotaxime or gentamicin. For older infants and children, Table 117-1 lists empiric treatment that will cover the three major bacterial causes of meningitis in the United States (N. meningitides, S. pneumoniae, and H. influenzae type b).

Patients with viral meningitis and meningoencephalitis generally receive supportive treatment, although acyclovir should be used when HSV infection is suspected. Lyme disease, tuberculous meningitis, fungal meningitis, and parasitic infections of the CNS all require specific therapy.

STEROIDS

Much of the damage caused by bacterial meningitis results from the inflammatory response in the CNS. In particular, labyrinthitis can result from bacterial meningitis, producing sensorineural hearing loss. For that reason, dexamethasone therapy to reduce CNS inflammation has been studied as a possible adjunct to antibiotic therapy.

Data supporting the benefits of dexamethasone treatment have not been robust in children. Dexamethasone does appear to reduce the likelihood of hearing loss in children with meningitis due to H. influenzae type b. Reviews have not shown a consistent benefit of steroid treatment for other bacterial causes of infection, including S. pneumoniae.^11,20

The American Academy of Pediatrics states that dexamethasone may be considered for treatment of infants and children with meningitis due to H. influenzae type b²¹ but does not recommend steroid use in other bacterial forms of meningitis. If it is used for bacterial meningitis, dexamethasone needs to be given before or with the first dose of antibiotics to be most effective. The dose of dexamethasone is 0.15 milligrams/kg IV every 6 hours. Steroids such as prednisolone are recommended for parasitic eosinophilic meningitis.²²

The opportunity for giving steroids for bacterial meningitis in the ED is very limited. The diagnosis of H. influenzae type b meningitis is not clinical but depends on the Gram stain and other analyses—studies that return after the time frame for steroid administration. Thus, the ED circumstances for administering dexamethasone for meningitis are rare.

In children with bacterial meningitis, the risks of dexamethasone therapy have been minor. A small number of patients have had GI bleeding. Recurrence of fever after dexamethasone has been stopped has also been seen. Theoretically, dexamethasone could decrease the concentration of vancomycin in the CSF, but there are no specific vancomycin dosing changes when dexamethasone is given.²³

Mortality from bacterial meningitis has been reduced to <10% with antibiotics and supportive care.² However, survivors can experience sensorineural hearing loss, visual impairment, seizures, hydrocephalus, cognitive impairment, learning disabilities, and emotional problems.²⁴ Factors predicting hearing loss include S. pneumoniae as the etiologic agent and low glucose levels in CSF. Factors predicting mortality include coma, seizures, shock, respiratory distress, neutropenia, and a high protein level in CSF. Factors predicting adverse neurologic consequences in general include coma, seizures, fever for at least 7 days, and a low WBC count in CSF. Additional, although less robust, predictors include symptoms for more than 48 hours, male gender, fever, and absence of petechiae.²⁵

In the ED, physicians may see respiratory compromise, shock, seizures, hypoglycemia, and hyponatremia in children with meningitis. Hypoglycemia results from sepsis and physiologic stress and is treated with administration of dextrose. Hyponatremia most commonly results from the syndrome of inappropriate antidiuretic hormone secretion due to brain inflammation. If syndrome of inappropriate antidiuretic hormone secretion is suspected, initiate fluid restriction to 75% of maintenance requirements after treating shock and dehydration. Low sodium can also be due to home therapy: oral rehydration with hypotonic liquids. Seizures can be due to brain inflammation, hypoglycemia, or hyponatremia, so correct glucose and sodium before administering antiepileptic medications.

Children with meningitis can also develop subdural effusions, empyemas, and strokes during treatment for bacterial meningitis, but these are not usually present at the time of ED presentation.

Viral meningitis and meningoencephalitis can range from mild illness to a fulminating course leading to death or permanent neurologic disability. Some lasting effects can be subtle, such as learning disorders. Fungal meningitis can cause death or severe disability, particularly in immunocompromised hosts. Eosinophilic meningitis from helminth infection is generally self-limited and does not require antifungal therapy.

In almost all circumstances, admit children with suspected bacterial or viral meningitis for definitive diagnosis, treatment, and supportive care. After discharge, children need long-term monitoring for neurodevelopmental problems and hearing loss.

THE CHILD WITH A VENTRICULOPERITONEAL SHUNT

One of the most common causes of shunt failure in patients with shunted hydrocephalus is shunt infection. Most infections occur soon after shunt placement. The predominant organism is Staphylococcus epidermis, suggesting that the infecting organism is likely introduced at the time of surgery. Other infecting agents include Staphylococcus aureus, gram-negative rods, Enterococcus faecalis, and Propionibacterium species. Predictors of shunt infection include premature birth, use of a neuroendoscope during shunt placement, and replacement of an infected shunt.²⁶ Only about 10% of shunt infections occur more than 1 year after shunt surgery. Patients with late infections frequently develop peritonitis, often from appendicitis.²⁷ Shunt infections can present with symptoms of increased intracranial pressure, fever, redness or swelling along the shunt, or abdominal pain. Treatment should include vancomycin and a third-generation cephalosporin. Add an aminoglycoside if the Gram stain shows gram-negative rods.

THE UNVACCINATED CHILD

Widespread immunization against Hib and S. pneumoniae has drastically reduced the rate of serious bacterial illness or meningitis from these two organisms. Children who are not immunized benefit from herd immunity. Nevertheless, when unvaccinated neonates or children develop fever, consider meningitis. Prior to the age of 18 months, children are less likely to develop meningismus, and it is difficult to exclude meningitis on clinical grounds alone. The septic-appearing infant or child with no immunizations should be managed conservatively with a lumbar puncture to exclude meningitis.

The real question is what to do with the unimmunized child with a fever who is not toxic appearing and has no obvious source for fever on physical examination. In children who have not been immunized, obtain a WBC count and blood culture and give ceftriaxone if the WBC count is ≥15,000/mm³. Arrange 24-hour follow-up either in the ED or with the child's primary provider. See chapter 116, for further discussion.

THE CHILD PRETREATED WITH ANTIBIOTICS

Children who have signs or symptoms of meningitis but who have been pretreated with antibiotics present an important challenge. In one study, after receiving ≥50 milligrams/kg of a third-generation cephalosporin, sterilization of the CSF occurred as early as 15 minutes in meningococcal meningitis, about 4 hours in pneumococcal meningitis, and about 8 hours in group B streptococcal meningitis. Blood cultures obtained prior to antibiotic treatment were positive in 74% of cases.²⁸ Antibiotic pretreatment was examined in another study, which showed that CSF WBC count and absolute neutrophil count were unaffected by antibiotic administration, but patients had higher CSF glucose levels and lower protein levels after about 12 hours of antibiotic administration.²⁹ In the situation where a child has been pretreated, CSF assays with polymerase chain reaction, latex agglutination, or counterimmunoelectrophoresis may be helpful for the diagnosis of meningitis. In differentiating bacterial from viral meningitis, erythrocyte sedimentation rate and C-reactive protein have not performed well, but serum procalcitonin may be helpful. Using 0.5 nanograms/mL as the cut-off point (<0.5 for viral infection and >0.5 for bacterial infection), the sensitivity of procalcitonin is reported as 99% and specificity as 83%.³⁰

THE CHILD WITH CSF LEAK

Children with CSF rhinorrhea or otorrhea are most likely to develop meningitis from S. pneumoniae. The signs and symptoms of meningitis tend to be milder in this group than in children with pneumococcal meningitis from bacteremia. Therefore, this is a situation in which meningitis is still a possibility despite a somewhat well-appearing child. Recommended treatment is with a third-generation cephalosporin and vancomycin.³¹

THE CHILD WITH PENETRATING HEAD TRAUMA

Children who have experienced penetrating head trauma can get meningitis from S. aureus, coagulase-negative staphylococci such as S. epidermidis, and gram-negative rods. Initial therapy should consist of a combination of drugs including vancomycin; cefepime, ceftazidime, or meropenem; plus an aminoglycoside such as gentamicin or amikacin.³²

THE CHILD WITH A COCHLEAR IMPLANT

A cochlear implant increases the risk of meningitis in children. In most cases, the initial event is an acute episode of otitis media in the side with the implant, followed by the development of meningitis. In the first 2 months after cochlear implant surgery, treat otitis media with parenteral antibiotics. After 2 months, treat nontoxic children with otitis media with oral antibiotics.³³ S. pneumoniae is the most common cause of meningitis in children with implants. Obtain cultures of middle ear fluid and CSF in children with suspected meningitis.

Children with meningitis in the first 2 weeks after implantation are at risk of a greater range of pathogens than patients presenting later and should receive broad-spectrum antibiotics, such as meropenem and vancomycin. Children with symptoms of meningitis developing later than 2 weeks after implantation should receive the standard empiric treatment for meningitis (Table 117-1). Consult ear, nose, and throat specialists for imaging recommendations and possible surgical management.³³

THE CHILD WITH A FEBRILE SEIZURE

Children with meningitis can present with seizures. However, simple febrile seizures are more common. Simple febrile seizures occur in up to 5% of children between 6 and 60 months of age. About one third of children will experience a recurrence. The American Academy of Pediatrics defines simple febrile seizures as seizures that are generalized, last less than 15 minutes, and do not recur within 24 hours. Per the guidelines, a lumbar puncture should be performed if the child has an examination consistent with meningitis.³⁴ Children between 6 and 12 months of age should be considered for a lumbar puncture if they are missing immunizations against Hib or S. pneumoniae or if their immunization status is not known. Clinicians should be able to recognize meningitis clinically after 12 months of age. A lumbar puncture should also be considered in children pretreated with antibiotics because antibiotics can mask the development of meningitis. Routine blood work, imaging, and electroencephalogram are not recommended.³⁴