Introduction

Background
Despite advances in antimicrobial and general supportive therapies, central nervous system (CNS) infections remain a significant cause of morbidity and mortality in children. As classical signs and symptoms often are not present, especially in the younger children, diagnosing CNS infections is a challenge to the emergency department. Also, even for children who have had prompt diagnosis and treatment, a high frequency of neurologic sequelae remains. This often leads to legal action. The emergency clinician is faced with the daunting task of separating out those few children with CNS infections from the vast majority of children who come to the ED with less serious infections.

Pathophysiology
To develop bacterial meningitis, the invading organism must gain access to the subarachnoid space. This is usually via hematogenous spread from the upper respiratory tract where the initial colonization has occurred. Less frequently, there is direct spread from a contiguous focus (eg, sinusitis, mastoiditis, otitis media) or through an injury, such as a skull fracture. The most common causative organisms in the first month of life are Escherichia coli and group B streptococci. Listeria monocytogenes infection also occurs in patients in this age range and accounts for 5-10% of cases. Neisseria meningitidis infections occurring in the first month of life have been reported. From 30-60 days, group B streptococcal infection occurs frequently, and the gram-negative enterics decline in frequency. Streptococcus pneumoniae, Haemophilus influenzae, and N meningitidis occur rarely in this age group. In those older than 2 months, S pneumoniae and N meningitidis currently cause the majority of the cases of bacterial meningitis. H influenzae may still occur, especially in children who have not received the Hib vaccine. The most common causative organisms (eg, N meningitidis, S pneumoniae, H influenzae) contain a polysaccharide capsule that allows them to colonize the nasopharynx of healthy children without any systemic or local reaction. A concurrent viral infection may facilitate the penetration of the nasopharyngeal epithelium by the bacteria. Once in the bloodstream, the polysaccharide capsule allows the bacteria to resist opsonization by the classical complement pathway and, thus, inhibit phagocytosis. Unusual bacteria occasionally cause meningitis. Pasteurella multocida is known to cause skin infections from cat or dog bites. A recent case described a 7-week-old infant with P multocida meningitis after exposure to dog saliva with no wound, emphasizing the need to protect young children from this pathogen. This infection, while rare, is associated with significant morbidity and mortality. Salmonella meningitis should be suspected in any child with this organism grown at any other site in an unwell child or one younger than 6 months. Mothers known to be infected with Salmonella during pregnancy may put their child at risk. As therapy is different for Salmonella meningitis, while rare, it must be considered in the above situations. The bacteremic phase allows penetration of the cerebrospinal fluid (CSF) through the choroid plexus. The CSF is poorly equipped to control infection because type-specific antibodies do not penetrate the blood brain barrier well and complement components are absent or in low concentrations. The cell walls of both gram-positive and gram-negative bacteria contain potent triggers of the inflammatory response. In the gram-positive bacteria, teichoic acid is considered the major pathogenic component. In gramnegative bacteria, lipopolysaccharide or endotoxin is the major pathogenic component. These components are

released in the CSF during bacterial growth and especially with the lysis of bacterial cells. Antibiotic therapy causes a significant release of the mediators of the inflammatory response. The mediators of the inflammatory response include cytokines (tumor necrosis factor, interleukin 1, 6, 8, 10), platelet activating factor, nitric oxide, prostaglandins, and leukotrienes. These mediators cause disruption of the blood brain barrier, vasodilation, neuronal toxicity, meningeal inflammation, platelet aggregation, and activation of leukocytes. The capillary endothelial cell is the main site of injury in bacterial meningitis; thus, it is a vasculitis, which results in destruction of vascular integrity. The ultimate consequences are damage to the blood brain barrier, brain edema, impaired cerebral blood flow, and neuronal injury. Because of the damage done by the body's response to the infection, various anti-inflammatory agents have been used in an attempt to decrease the morbidity and mortality of bacterial meningitis. Only dexamethasone occasionally has been proven effective. Viral meningitis or aseptic meningitis is the most common infection of the CNS. It most frequently occurs in children younger than 1 year. Enterovirus is the most common causative agent and is a frequent cause of febrile illnesses in children. Other viral pathogens include paramyxoviruses, herpes, influenza, rubella, and adenovirus. Meningitis may occur in up to half of children younger than 3 months with enteroviral infection. Enteroviral infection can occur any time during the year but is associated with epidemics in the summer and fall. Viral infection causes an inflammatory response but to a lesser degree than bacterial infection. Damage from viral meningitis may be due to an associated encephalitis and increased intracranial pressure. Fungal meningitis is rare but may occur in immunocompromised patients; children with cancer, previous neurosurgery, or cranial trauma; or premature infants with low birth rates. Most cases are in children who are receiving antibiotic therapy and, thus, usually are inpatients. The etiology of aseptic meningitis caused by drugs is not well understood. This form of meningitis is infrequent in the pediatric population. Encephalitis is a similar disease of the central nervous system. This disease is an inflammation of brain parenchyma. Often, a viral agent is responsible. Viral entry occurs through hematogenous or neuronal routes. The more common form of encephalitis is transmitted by bites of mosquitoes and ticks, infected with the virus. The virus comes from the Togavirus, Flavivirus, and Bunyavirus families. The more common types of encephalitis in the United States are La Crosse virus, eastern equine encephalitis virus, and St Louis virus. Often, these causes of encephalitis cause similar signs and symptoms. Confirmation and differentiation come from laboratory testing. However, its utility is limited to a number of identifiable pathogens. West Nile virus is becoming a leading cause of encephalitis, caused by the arbovirus from the Flaviviridae family. Mosquitoes, spreading virus between its natural hosts, migrating birds, transmit it. Mosquitoes bite humans, who become infected with the virus. However, human hosts are dead-end hosts for the virus. Most humans do not develop the disease. Approximately 1 symptomatic infection develops for every 120-160 asymptomatic ones. The young and old are at risk of developing symptomatic disease.

It has become a greater public health issue, given that spread occurs with migratory birds. The first cases were identified in New York City in 1999, with additional cases being identified in the following years across the United States. Encephalitis can be transmitted by other means. Herpetic encephalitis and rabies are two examples, where transmission occurs by direct contact and mammalian bites, respectively. In the case of herpetic encephalitis, there is evidence of virus reactivation and subsequent intraneuronal transmission, leading to encephalitis.

Frequency
United States

The advent of vaccine has changed the incidence of disease. The incidence of disease caused by H influenzae, S pneumoniae, and N meningitidis has decreased. The advent of universal Hib vaccination in developed countries has lead to the reduction of more than 99% of invasive disease. The vaccine is directed against the H influenzae type b strain. This protection continues even when Hib is coadministered with other vaccines. Just as important, the vaccine continues to confer immunity into later childhood. A similar effect occurs with the advent of pneumonococcal vaccine. This is true for the pneumococcal polysaccharide vaccines conjugated to various proteins. Given at ages 2, 4, and 6 months, this vaccine has reduced invasive disease more than 90%. Age groups most affected are those younger than age 2 years and those aged 2-5 years. This was proven in a surveillance study in Louisville, Kentucky.1 Nearly half of those with pneumococcal disease are caused by nonvaccine serotypes.2,3 However, vaccine for Neisseria has not been efficacious in younger children. This is due to poor immunogenic response. Current recommendation targets immunization for children older than age 2 years and high-risk patients with asplenic and terminal complement deficiencies. In addition, young adults living in close quarters, such as dormitories or military barracks, will benefit. The incidence of neonatal meningitis has shown no significant change in the last 25 years. Viral meningitis is the most common form of aseptic meningitis and, since the introduction of mumps vaccine, is caused by enteroviruses in up to 85% of cases. Incidence of encephalitis is more difficult to estimate because of difficulty in establishing the diagnosis. One report estimates an incidence of 1 in 500-1000 in the first 6 months of life.
International

In a survey by the Hib and Pneumococcal Working Group, the incidence of meningitis in 2000 varied from regions across the world. The overall incidence of pneumococcal meningitis was 17 cases per 100,000, with the highest incidence in Africa at 38 cases per 100,000 and the lowest incidence in Europe at 6 cases per 100,000. The overall death rate was 10 cases per 100,000. The highest death rate was 28 cases per 100,000 in Africa, and the lowest death rates were 3 cases per 100,000 in Europe and Western Pacific regions.4 A similar trend was identified for Hib meningitis. The overall incidence of Hib meningitis in 2000 was 31 cases per 100,000. The African region had the highest rate at 46 cases per 100,000, and Europe had the lowest rate at 13 cases per 100,000. The death rate was 13 cases per 100,000. The highest death rate was 31 cases per 100,000 in Africa, and the lowest death rate was 4 cases per 100,000 in Europe.5

Mortality/Morbidity

Morbidity and mortality rates depend on the infectious agent, age of the child, general health, and prompt diagnosis and treatment. Despite improvement in antibiotic and supportive therapy, a significant mortality and morbidity rate remains.

The overall mortality for bacterial meningitis is 5-10% and varies with causative organism and age. Neonatal meningitis has a mortality rate of 15-20%. In older children, the mortality rate is 3-10%. Meningitis from S pneumoniae has the highest mortality rate (26.3-30%); H influenzae type B has a 7.7-10.3% mortality rate; N meningitidis has the lowest mortality rate of the most common organisms, at 3.5-10.3%.

Up to 30% of children have neurological sequelae. This varies by organism, with S pneumoniae having the highest rate of complications. One study indicates that the complication rate from S pneumoniae meningitis did not vary if the infection was from a penicillin sensitive or resistant strain. This study showed that dexamethasone did not improve outcomes.6

Some studies have shown the incidence of profound bilateral hearing loss, up to 4% in all bacterial meningitis cases.7 Sensorineural hearing loss is one of the most frequent problems. Children at greatest risk for hearing loss include those with evidence of increased intracranial pressure, abnormal findings on CT scan, male sex, low glucose levels in CSF, infection by S pneumoniae, and nuchal rigidity.

As many of the children affected are very young and cognitive and motor skills are immature, some of the sequelae may not be recognized for years. A recent study followed children who recovered from meningitis for 5-10 years. They found 1 in 4 school-aged meningitis survivors had either serious and disabling sequelae or a functionally important behavior disorder or neuropsychiatric or auditory dysfunction that impaired their performance in school.

Viral meningoencephalitis: Enteroviral infection usually has few complications. Herpes simplex and arbovirus infections, in addition to viral infections in AIDS patients, can result in severe neurological disease. Tuberculous meningitis: Morbidity and mortality rates are related to the stage of the disease. Stage I has a 30% significant morbidity, stage II 56%, and stage III 94%.

Race

Bacterial meningitis more frequently occurs in black and Hispanic children. This is thought to be related to socioeconomic rather than racial factors.

Sex
Prevalence of bacterial meningitis is higher in males. A recent report from Finland showed males more often had mumps and varicella encephalitis, whereas females had adenoviral and Mycoplasma encephalitis more often.

Age
For both meningitis and encephalitis, the greatest occurrence is in children younger than 4 years with a peak incidence in those aged 3-8 months.

Clinical

History
Bacterial meningitis

The younger the child, the less likely he or she is to exhibit the classic symptoms of fever, headache, and meningeal signs. Meningitis in the neonatal period is associated with maternal infection or pyrexia at delivery. The child younger than 3 months may have very nonspecific symptoms, including hyperthermia or hypothermia, change in sleeping or eating habits, irritability or lethargy, vomiting, high-pitched cry, or seizures.

Meningismus and a bulging fontanel may be observed but are not needed for diagnosis. A child who is quiet at rest but who cries when moved or comforted may have meningeal irritation (paradoxical irritability). After age 3 months, the child may display symptoms more often associated with bacterial meningitis, with fever, vomiting, irritability, lethargy, or any change in behavior. After age 2-3 years, children may complain of headache, stiff neck, and photophobia. The clinical course may be brief and fulminant with rapid progression of symptoms or may follow a more gradual course with several days of upper respiratory infection progressing to more severe symptoms. The fulminant course is more often associated with N meningitidis infection.

Viral meningitis

In areas with widespread vaccination of children, enteroviruses are the most common causes of viral meningitis. The onset is variable and may have several days of fever, anorexia, and general malaise. It also may present as a rather abrupt onset of fever, nausea, vomiting, and headache.

Additional symptoms are shared with enteroviral infections, such as pharyngitis, conjunctivitis, and myositis. Other causes of viral meningitis also may be associated with encephalitis. Arboviral infections frequently have associated encephalitis and seizures. Adenoviral, mumps, and varicella-zoster infections tend to be more severe than enteroviral infections, and often evidence of encephalitis is present. In areas with low vaccination rates, mumps virus is often the most frequent cause of meningitis.

Fungal meningitis occurs in immunocompromised patients and has a variable presentation. Aseptic meningitis may be caused by drugs, usually nonsteroidal anti-inflammatory drugs (NSAIDs), IVIG, and antibiotics. A recent report was of a pediatric patient with a trimethoprim-sulfamethoxazole induced meningitis. Symptoms were similar to those of viral meningitis. Symptoms may occur within minutes of ingestion of the drug. Encephalitis Diagnosis for the causative viral agent is aided by historical facts. Information such as season of year, travel, activities, and exposure to animals helps with diagnosis.

A distinction between viral encephalitis and postinfectious encephalomyelitis is important because management and prognosis are different. With postinfectious encephalomyelitis, the usual presentation is a nonspecific respiratory viral syndrome.

Physical
Physical examination findings are widely variable based on age and infecting organism. It is important to remember that the younger the child, the less specific the symptoms. In the young infant findings that definitely point to meningitis are rare. The infant may be febrile or hypothermic. Bulging of the fontanel, diastasis of the sutures, and nuchal rigidity point to meningitis but are usually late findings. As the child grows older, the physical examination becomes more reliable.

Meningeal signs (eg, headache, nuchal rigidity, positive Kernig and Brudzinski signs) should be sought, and their presence or absence recorded. Focal neurological signs may be present in up to 15% of patients and are associated with a worse prognosis. Seizures occur in up to 30% of children with bacterial meningitis. Obtundation and coma occur in 15-20% of patients and are more frequent with pneumococcal meningitis. Encephalitis may present like meningitis or the symptoms of the systemic viral infection may predominate.

Encephalitis Physical findings for encephalitis are fever, headache, and decreased neurological function. Decreased neurological functions include altered mental status, focal neurological function, and seizure activities. These findings can help identify the virus type and prognosis.

In West Nile virus, the signs and symptoms are nonspecific and include fever, malaise, periocular pain, lymphadenopathy, and myalgia. West Nile virus has some unique physical findings including fine, maculopapular, erythematous rash; proximal muscle weakness; and flaccid paralysis. This rash is commonly found in children.

Critically ill patients have neurological dysfunction, such as altered mental status and cranial nerve dysfunction, as the major physical finding.

Causes
Risk factors for bacterial meningitis Age Low family income Attendance at day care Head trauma Splenectomy

Chronic disease Children with facial cellulitis, periorbital cellulitis, sinusitis, and septic arthritis have an increased risk of meningitis. Maternal infection and pyrexia at the time of delivery are associated with neonatal meningitis.

Use of the Hib and p neumococcal vaccine decreases the likelihood of infection from these agents. Viral meningoencephalitis Immunizations for measles, mumps, and rubella decrease the risk of infection from those agents. It is unclear why some patients with systemic viral illnesses develop meningitis or encephalitis.

Fungal meningitis occurs in immunocompromised patients.