Infections of the central nervous system (CNS) in children continue to pose a diagnostic and therapeutic challenge to clinicians. Because of the plethora of bacterial, viral, fungal, and protozoan agents capable of infecting the CNS, it is not possible to discuss them all within the context of this chapter. As such, this chapter focuses on agents most likely to be encountered by hospitalists in the course of their activities.

Simply defined, meningitis is an inflammation of the membranes (i.e. arachnoid, dura, and pia mater) surrounding the brain and spinal cord. Encephalitis involves an inflammatory process of the cerebrum. Although it is common to discuss each as separate entities, in many cases, particularly with viral infections of the CNS, they occur together as meningoencephalitis.

BACTERIAL MENINGITIS

Over the last three decades the number of cases of bacterial meningitis in the United States has steadily declined from 10,000 to 20,000 cases per year to approximately 4100 cases annually from 2003 to 2007.^1,2 In large part as a result of the development of conjugate vaccines against Haemophilus influenzae type B (Hib) and Streptococcus pneumoniae, Neisseria meningitidis has become the leading cause of bacterial meningitis in children.³ Before the introduction of conjugate vaccines for the prevention of childhood infections caused by Hib, this agent was the principal cause of bacterial meningitis in the United States, as well as invasive bacterial infections.⁴ Inclusion of Hib conjugate vaccines in the routine immunization schedule of children has resulted in the virtual disappearance of invasive Hib disease in children younger than 5 years⁵ and a fall in the incidence of Hib meningitis from 2.9 to 0.2 cases per 100,000 population. Coincident with this decline has been a shift in the median age of all patients with meningitis from 15 months to 41.9 years.^1,4

As a result of the licensure of the 7-valent and 13-valent (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F) pneumococcal conjugate vaccines in 2000 and 2010, respectively, a significant decrease in the reported cases of S. pneumoniae invasive disease has been observed.⁶ In one report, the incidence of invasive pneumococcal disease decreased by 50% the year following introduction of the 13-valent pneumococcal conjugate vaccine.⁷

The possible causes of bacterial meningitis are numerous (Table 98-1) and depend on such factors as age, immunization status, and underlying clinical condition (e.g. inherited or acquired immunodeficiency states, ventriculoperitoneal shunts, cochlear implants, cerebrospinal fluid [CSF] leaks). Immunocompromised hosts deserve special consideration when meningitis is suspected. Opportunistic infections caused by Cryptococcus neoformans, Toxoplasma, tuberculosis, and fungi (e.g. Aspergillus species) must be considered.

Despite a significant reduction in the incidence of early-onset Streptococcus agalactiae (group B Streptococcus) disease in the neonatal period through the use of intrapartum prophylactic antibiotics, group B Streptococcus continues to contribute to the burden of disease in this age group.^1,8 Group B Streptococcus, primarily subtype III strains, remains a significant cause of late-onset disease in the form of meningitis in neonates.⁹ Coliform bacteria, in particular, Kl antigen–possessing Escherichia coli, constitute the second largest group of causes of neonatal meningitis.¹⁰ Other gram-negative enteric bacilli such as Klebsiella, Enterobacter, and Salmonella may also cause sporadic cases of meningitis. Listeria monocytogenes occurs only rarely and may be associated with zoonotic outbreaks and maternal food contamination.^11-13 Other unusual yet notable causes of neonatal meningitis include Cronobacter sakazakii^14,15 and Citrobacter koseri.¹⁶

Worldwide and in the areas of the United States with poor vaccination coverage, S. pneumoniae, Neisseria meningitidis, and Hib are the most common pathogens in infants and young children.⁹ As mentioned, the routine use of conjugated Hib vaccines has resulted in virtual disappearance of this organism as a pathogen of children in most of the United States. These vaccines, however, have not had an impact on sporadic cases of nontypeable H. influenzae-related meningitis or those caused by strains of H. influenzae other than type B.

Before the advent of conjugated pneumococcal vaccines, children younger than 2 years were overwhelmingly the group at highest risk for bacterial meningitis from this organism. Use of the 13-valent conjugated pneumococcal vaccine has dramatically reduced the incidence of invasive disease, including meningitis, in this age group.⁷

An association between the use of cochlear implants and pneumococcal meningitis has been established.^17,18 The rate of pneumococcal meningitis in children in whom cochlear implants with positioners were used was 214 cases per 100,000 person-years 24 to 47 months after surgery.¹⁷

The age distribution of cases of meningococcal meningitis and disease in the United States is biphasic, with infants younger than 1 year exhibiting the highest incidence of the disease. A second, smaller and broader peak is observed in children and adolescents aged 11 to 19 years.¹⁹ More than half of cases in infants younger than 1 year are due to serogroup B, whereas in individuals older than 11 years, three quarters are the due to serogroups C, Y or, less likely, W-135. These latter three serogroups are included in the tetravalent (serogroups A, C, Y, W-135) conjugated meningococcal vaccine. Although initially approved for administration as a single dose vaccine, data obtained in an efficacy study conducted from 2006 to 2010 demonstrated progressive waning of immunity, prompting the recommendation for a two-dose series.²⁰

BRAIN ABSCESS

Brain abscess is a relatively rare CNS infection. However, nearly 25% of all brain abscesses occur in individuals younger than 15 years.²¹ In a recent pediatric study, the median age at presentation was 10 years with a bimodal distribution at 18 months and 11 years.²² In 90% of cases, a predisposing factor was identified. The most common source of infection of the brain comes from the middle ear, paranasal sinuses, or teeth. Children with congenital cardiac defects associated with right-to-left shunts are also at risk for the development of brain abscess.

The location of the brain abscess is related to the underlying condition of its genesis. Additionally, the location and predisposing condition may suggest the possible bacterial cause of the abscess. Dental and sinus infections may result in frontal lobe abscesses. Mastoiditis or chronic ear infections result in abscesses located in the temporal lobe or cerebellum. Abscesses from hematogenous spread secondary to endocarditis may occur throughout the parenchyma of the brain. Finally, abscesses arising from penetrating head trauma or that are postoperative in nature tend to be located adjacent to the site of the cranial breech.

The most commonly involved microorganisms in the etiology of brain abscesses in children are aerobic and anaerobic streptococci (60%–70%), gram-negative anaerobic bacilli (20%–40%), Enterobacteriaceae (20%–30%), Staphylococcus aureus (10%–15%), and fungi (1%–5%).²³ In approximately a third of cases, the brain abscess is polymicrobial in origin and includes both aerobic and anaerobic organisms. In as many as 30% of cases no organism is found.

HERPESVIRIDAE ENCEPHALITIS

In the United States, the herpes simplex viruses (HSVs) are the most common cause of sporadic, fatal encephalitis.^24,25 These viruses are distributed worldwide, with no seasonal variation in the incidence of infection. Acquisition occurs solely by human-to-human transmission.

Non-neonatal HSV encephalitis is estimated to occur in approximately 1 in 250,000 to 500,000 individuals per year.²⁶ Virtually all cases are the result of HSV type 1. In approximately 50% of cases of non-neonatal HSV encephalitis, the CNS infection appears to occur coincident with the primary infection. In the remainder, it is the result of reactivation of previous infection.^27,28

The estimated incidence of neonatal herpes is approximately 1 in 3200 deliveries, which results in approximately 1500 cases of neonatal HSV infection annually.²⁴ Approximately 75% of cases of neonatal HSV infection are the result of HSV type 2. A third of all neonates with HSV infection are categorized as having CNS disease (see Chapter 98).²⁹

In healthy children, the nonsimplex members of the Herpesviridae family (varicella-zoster virus, human herpesvirus 6, cytomegalovirus, and Epstein-Barr virus) infrequently cause meningitis and encephalitis.³⁰ Varicella-zoster virus and human herpesvirus 6 have been shown to be rare causes of meningoencephalitis and encephalitis in immunocompetent children.^30,31 Neurologic complications^30,31 occur in ≤1% of healthy children infected with varicella-zoster virus. Cerebellar ataxia is the most common (1 in 4000) neurologic complication after primary varicella-zoster virus infection. Varicella-zoster virus encephalitis is a serious complication with an incidence of 1 to 2 per 10,000 cases of varicella in healthy persons and is seen more frequently in infants and adults.^30,31

ENTEROVIRAL AND PARECHOVIRAL MENINGITIS AND ENCEPHALITIS

The genera enterovirus (EV) and parechovirus are members of the Picornaviridae family of viruses. The genus Enterovirus was originally organized into five species: the polioviruses, echoviruses, group A and group B coxsackieviruses, and numbered EVs. More recently, the genus has been reorganized into four species: Enteroviruses 1–4, totaling over 100 serotypes.³² Humans are the only natural hosts for EVs. The principal mode of human-to-human transmission is fecal–oral. Respiratory transmission and self-inoculation are important routes of transmission for some EVs. Vertical transmission may also occur. EV infections occur predominantly during the summer and early fall. With the eradication of wild-type poliovirus transmission from the Americas, the predominant CNS syndromes associated with EV infection are now meningitis and encephalitis.

The parechoviruses (HPeVs) are a relatively newly recognized genus of viruses associated with human infection.³² The genus is currently comprised of 16 members. They share the same natural host, modes of transmission, seasonality, and CNS syndromes as the EV.³³

The EVs are the preeminent cause of viral meningitis in the United States.³⁴ Conservative estimates of the annual number of cases of EV meningitis range from 30,000 to 75,000. The highest incidence of disease occurs in infants younger than 1 year and children 5 to 10 years of age.³⁴ The echoviruses and group B coxsackieviruses are the principal EVs associated with meningitis. EVs are reported to be responsible for 10% to 20% of identifiable cases of viral encephalitis.³⁵ The group A coxsackieviruses are the predominant EV subgroup associated with encephalitis.

The HPeVs have been found in 2.4% to 7.4% of archival CSF samples that were negative for EV.³³ Of the 16 HPeV serotypes, HPeV type 3 (HPeV-3) is the major cause of CNS disease. The majority of cases of HPeV-3 meningitis occur in children <2 years of age. Parechovirus-related encephalitis has almost exclusively been reported in neonates and young infants. HPeV-1 and -3 have been associated with encephalitis, with HPeV-3 the dominant serotype. The majority of cases of meningitis and encephalitis occur in males.

ARBOVIRAL ENCEPHALITIS

The arboviruses represent a heterogeneous group of viruses from distinct viral families linked by a common mode of transmission to humans: the bite of an insect or arthropod.³⁶ Arboviral infections occur during the summer months and coincide with periods of increased activity of their insect and arthropod vectors. The primary arboviral encephalitides in the United States are La Crosse encephalitis, West Nile virus (WNV) encephalitis, and St. Louis encephalitis. Less common forms include Eastern and Powassan encephalitides. No cases of Western equine encephalitis have been reported in the United States since 2000. The majority of human arboviral infections result in subclinical disease or febrile syndromes that do not involve the CNS. When the CNS is involved, meningitis, encephalitis, or meningoencephalitis commonly result.³⁷

LA CROSSE ENCEPHALITIS

The cause of La Crosse encephalitis is an RNA virus of the same name. Most cases occur from July to early October. Cases of La Crosse encephalitis are predominantly reported from the northern Midwestern states and West Virginia. In areas endemic for La Crosse virus, the annual incidence of the disease is approximately 20 to 30 cases per 100,000 in individuals younger than 15 years.³⁸ Only 0.3% to 4% of La Crosse virus infections result in symptomatic disease.³⁸ Nearly all cases of La Crosse encephalitis occur in individuals 14 years or younger.^38-41 Males account for the majority of cases.^38,39,42,43

WEST NILE NEUROINVASIVE SYNDROMES

West Nile virus, the etiologic agent of West Nile fever and West Nile neuroinvasive syndromes, is a virus found worldwide that made its American debut in 1999.⁴⁴ Currently, WNV has superseded all autochthonous North American arboviruses as the single most important cause of arboviral CNS disease in the United States. The states with the highest average median incidences of pediatric WNV disease are South Dakota, Wyoming, New Mexico, and Nebraska.⁴⁵

ST. LOUIS ENCEPHALITIS

St. Louis encephalitis virus is widely distributed in the United States. Until the introduction of WNV to North America in 1999, St. Louis encephalitis virus was the single major cause of epidemic encephalitis in the United States.⁴⁶

BACTERIAL MENINGITIS

The clinical presentation of bacterial meningitis is varied and influenced greatly by the age of the patient. A history of antecedent upper respiratory tract infection may be reported in up to 75% of children with meningitis.^47,48 The presence of fever is noted in more than 85% of patients; however, fever is rarely the sole complaint, the exception being neonates and very young infants, whose presentation may consist of only fever without an identifiable focus of infection. As such, these infants present a particular diagnostic challenge to the clinician because they often exhibit only nonspecific signs such as irritability, somnolence, and low-grade fever.^9,49

CNS findings such as headache, photophobia, and neck or back pain are more common in older children and adolescents. In infants, a full fontanelle may be present. Seizures are noted in 20% to 30% of children before or within 3 days after the diagnosis and tend to be more frequently associated with meningitis secondary to S. pneumoniae and H. influenzae.⁴⁹ The seizures may be partial, generalized with focal predominance, or partial with secondary generalization.⁵⁰

Findings on physical examination include alterations in level of consciousness that can range from irritability to somnolence and lethargy, to coma. Up to 10% of patients at any age are comatose at the time of admission.^49,51 Findings of nuchal rigidity or presence of the Brudzinski and Kernig signs are indicators of meningeal irritation; however, they have low sensitivity so their absence does not exclude the diagnosis of meningitis.

Skin findings such as petechiae and purpura are commonly associated with meningococcal meningitis, but they can be seen in association with S. pneumoniae and H. influenzae infections as well. It is important to keep in mind that the development of petechiae or purpura may be preceded by a maculopapular rash (see Chapter 58).

Focal neurologic abnormalities serve as indicators of compromised cerebral blood flow or increased intracranial pressure (ICP). Cranial nerve palsies, nystagmus, aphasia, hemiparesis, ataxia, hearing loss, and visual field defects may be present. Papilledema is a relatively late finding and not commonly associated with the acute phase of bacterial meningitis.⁴⁹ Patients may present with evidence of hemodynamic instability or shock. Approximately 15% of children with pneumococcal meningitis present in shock.^52,53

BRAIN ABSCESS

Factors influencing the clinical presentation of brain abscesses in children are the size and location of the abscess as well as the age and immune status of the child. As is the case with bacterial meningitis, the presentation of brain abscess in infants and children can be nonspecific. The classic triad of fever, headache, and focal neurologic deficits occurs in less than 30% of all cases. In children who are able to report headache, it is the most common symptom. Fever may be seen in half to three-quarters of cases. Vomiting, seizures, and focal neurologic deficits occur in a third to half of all cases. Focal neurologic signs reflect the location of the abscess. Lethargy, stupor, and coma are seen late in the course of the illness. Papilledema is seen in less than a quarter of cases.

HERPESVIRIDAE ENCEPHALITIS

Regardless of age, HSV infection of the brain results in necrotizing encephalitis. The virus demonstrates a particular predilection for the temporal lobes. In older patients, the signs and symptoms of HSV encephalitis are the result of the area or areas of the brain affected.^54,55 Symptoms include fever, altered consciousness, bizarre behavior, disorientation, and localized neurologic findings. In infants, clinical findings include seizures, which may be focal or generalized, irritability, lethargy, tremors, poor feeding, temperature instability, and a bulging fontanelle.

In cerebellar ataxia caused by varicella, the onset of ataxia is generally coincident with appearance of the exanthem. However, the ataxia may begin several days before the onset of the rash and up to 2 weeks after its appearance. Other symptoms include vomiting, nystagmus, headache, and nuchal rigidity. In contrast, the onset, which may be sudden or gradual, of varicella-zoster virus encephalitis occurs approximately 1 week after appearance of the rash and consists of headache, altered sensorium, and vomiting.³¹ Seizures occur in approximately a third to half of cases. Additional neurologic findings include abnormal plantar reflexes, hyporeflexia or hyperreflexia, hypotonia or hypertonia, hemiparesis, and sensory changes.

ENTEROVIRAL AND PARECHOVIRAL MENINGITIS AND ENCEPHALITIS

Enteroviral meningitis has an abrupt onset associated with fever. The fever may be biphasic: initially associated with nonspecific constitutional symptoms and then subsiding, and returning at the onset of neurologic symptoms. Infants exhibit nonspecific symptoms such as poor feeding, vomiting, exanthems, and respiratory tract findings. In older children and adolescents, symptoms may include anorexia, vomiting, headache, exanthems, myalgia, upper and lower respiratory tract symptoms, and abdominal pain.³⁴ In young infants, neurologic findings are minimal or absent and may consist of irritability, lethargy, a bulging fontanelle, and nuchal rigidity. In 10% of infants, acute CNS complication (seizures, increased ICP, and depressed mental state) may occur.^34,35 Headache is almost invariably present in older children and adolescents. Nuchal rigidity is mild and more frequently present in older toddlers, children, and adolescents. Photophobia is also a common finding in older patients.

In addition to the nonspecific symptoms described for meningitis, children with EV encephalitis have mental status changes that range from lethargy and mild disorientation to frank coma. Focal neurologic findings similar to those in HSV encephalitis may occur.³⁵ Infection with some strains of enterovirus 71 may result in severe brainstem encephalitis in children.⁵⁶

Parechoviral meningitis shares many of the characteristics of EV meningitis listed above. Males comprise the majority of cases.³³ Fever and irritability are the presenting findings in the majority of infants. A rash may be present in over half of cases. Gastrointestinal signs (i.e. emesis, diarrhea, distention) and respiratory symptoms (i.e. rhinorrhea, cough, tachypnea, apnea, wheezing) may be present. Notably absent are findings of increased intracranial pressure (bulging fontanelle) or meningeal irritation (nuchal stiffness, Kernig or Brudzinski signs).

In HPeV encephalitis, seizures are the predominant clinical finding. Fever, irritability, and rash are seen in the majority of cases. Apnea and hypotension may occur in up to half of cases.

ARBOVIRAL ENCEPHALITIDES

La Crosse Encephalitis

The incubation period for La Crosse encephalitis ranges from 5 to 15 days.³⁸ Typically, the onset of illness is characterized by a prodrome lasting 2 to 3 days that consists of fever, headache, malaise, and gastrointestinal symptoms.^39-43,57,58 Lethargy or an altered sensorium follow, and up to a third of children progress to coma. Seizures have been reported in 46% to 62% of children and may be generalized, focal, partial, partial complex, or status. Some patients have a sudden onset of fever and headache, followed 12 to 24 hours later by abrupt, prolonged, and difficult-to-control seizures.³⁹ Signs of meningeal irritation are reported in up to 60%, and focal neurologic findings occur in 16% to 25%. Clinical deterioration during the first 4 days of admission to the hospital is not uncommon.³⁸ Nearly 60% of hospitalized children require admission to the intensive care unit and a quarter require mechanical ventilation.

West Nile Neuroinvasive Syndromes

The majority of human WNV infections are subclinical. West Nile fever develops in approximately 20% of those infected.^59-61 Neuroinvasive forms of infection, which include encephalitis, meningitis, meningoencephalitis, and acute flaccid paralysis (AFP), develop in less than 1% of all infected individuals.^60,61 The overwhelming majority of reported cases of neuroinvasive disease have been in adults.⁶⁰ The single most significant risk factor for the development of neuroinvasive disease and an adverse outcome is increasing age.

From 1999 through 2007, only 5% of all WNV cases and 4% of neuroinvasive disease in the United States occurred among children <18 years of age. Of pediatric cases, 68% were in the form of West Nile fever, 30% neuroinvasive disease, and 2% were unclassified. The distribution of West Nile neuroinvasive disease was meningitis 47%, encephalitis or meningoencephalitis 37%, AFP 1%, and unspecified in 15%. The median age of all reported cases was 14 years (range 1 day to 17 years). Two neonates were infected in utero. Three children classified as neuroinvasive disease succumbed to the illness.⁴⁵

The incubation period of WNV infection is usually 2 to 6 days but can range from 2 to 14 days.^59,62 The symptoms of neuroinvasive WNV infection, primarily described in adults, include fever, headache, altered mental status, weakness, neck stiffness, seizures, gastrointestinal symptoms, and rash.^60,63 Patients with the AFP syndrome exhibit asymmetric weakness, hypotonia, and absent or diminished deep tendon reflexes, without pain or sensory loss in the affected limb or limbs.^64,65 Limited reports of the clinical presentations of WNV-associated encephalitis, meningoencephalitis, AFP, and meningitis in children do exist,^45,65-68 but overall the presentations are similar to those seen in adults.

St. Louis Encephalitis

The clinical presentation of St. Louis encephalitis virus infection is age dependent and varies from subclinical infection to fatal encephalitis.^37,69,71 The overwhelming majority of St. Louis encephalitis virus infections in humans are asymptomatic. The ratio of clinical to subclinical infection varies from 1:800 in children younger than 10 years to 1:85 in adults.⁷⁰

Three neurologic syndromes associated with St. Louis encephalitis virus infection have been described: encephalitis, aseptic meningitis, and febrile headache alone.³⁷ In infants, children, and adolescents, encephalitis, aseptic meningitis, and febrile headache occur in 56%, 38%, and 6% of cases, respectively.

The incubation period of St. Louis encephalitis ranges from 4 to 21 days.^37,71 The onset of neurologic illness may be heralded by nonspecific symptoms of malaise, fever, headache, somnolence, myalgias, abdominal and back pain, and occasionally conjunctivitis, photophobia, and upper respiratory tract symptoms.⁷² Fever is nearly universal. Headache is present in most children capable of reporting it. Nausea and vomiting occur in approximately three-quarters of children.^73,74 Abnormal neurologic signs and symptoms include seizures, altered sensorium, including coma, evidence of meningeal irritation, seizures, and cranial nerve palsies.^73-76

The differential diagnosis of bacterial and viral meningitis, brain abscess, and encephalitis encompasses a broad array of bacterial, viral, fungal and protozoal agents (Table 98-1). In addition, multiple noninfectious systemic illnesses and drugs can produce syndromes that mimic the previously mentioned conditions.

Evaluation of any patient with suspected meningitis or encephalitis requires CSF examination. Although routine neuroimaging of all patients before the performance of lumbar puncture is not required,^77,78 it should be performed in the settings of papilledema, altered mental status, focal neurologic findings, or suspicion of an intracranial mass lesion. Regardless of the decision to perform or delay the lumbar puncture, antibiotic therapy should not be delayed. If a decision is made to delay lumbar puncture, blood should be obtained for culture before the administration of antibiotics.