Pediatric Meningitis and Encephalitis

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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 gram-negative 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.

Epidemiology

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.

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.

History

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.

Causes

Laboratory Studies

Imaging Studies

Other Tests

Procedures

Prehospital Care

Emergency Department Care

Consultations

Medication Summary

The goals of pharmacotherapy are to eradicate the infection, reduce morbidity, and prevent complications.

Cefotaxime (Claforan)

Clinical Context:  Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms. Arrests bacterial cell wall synthesis, which, in turn, inhibits bacterial growth.

Ceftazidime (Fortaz)

Clinical Context:  Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin binding proteins.

Ampicillin (Omnipen, Principen)

Clinical Context:  Bactericidal activity against susceptible organisms. Alternative to amoxicillin when unable to take medication orally.

Ceftriaxone (Rocephin)

Clinical Context:  Third-generation cephalosporin with broad-spectrum, gram-negative activity; lower efficacy against gram-positive organisms; higher efficacy against resistant organisms. Arrests bacterial growth by binding to one or more penicillin binding proteins.

Gentamicin (Garamycin)

Clinical Context:  Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes.

Not the DOC. Consider if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms.

Dosing regimens are numerous. Adjust dose based on CrCl and changes in volume of distribution. May be given IV/IM.

Chloramphenicol (Chloromycetin)

Clinical Context:  Not used frequently since introduction of third-generation cephalosporins. Binds to 50 S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria.

Vancomycin (Vancocin)

Clinical Context:  Potent antibiotic directed against gram-positive organisms and active against Enterococcus species. Indicated for patients who cannot receive or have failed to respond to penicillins and cephalosporins or have infections with resistant staphylococci. For abdominal penetrating injuries, it is combined with an agent active against enteric flora and/or anaerobes.

To avoid toxicity, current recommendation is to assay vancomycin trough levels after third dose drawn 0.5 h prior to next dosing. Use CrCl to adjust dose in patients diagnosed with renal impairment.

Class Summary

IV antibiotics are required for bacterial meningitis. If the causative organism is unknown, antibiotics regimens can be based on the child's age.

Infants younger than 30 days, ampicillin and an aminoglycoside or a cephalosporin (cefotaxime) are recommended.

Children 30-60 days old, ampicillin and a cephalosporin (ceftriaxone or cefotaxime) can be used. Since S pneumoniae occasionally occurs in this age range, vancomycin should be considered instead of ampicillin.

In older children, a cephalosporin (eg, cefotaxime, ceftriaxone) or ampicillin plus chloramphenicol can be used.

Incidence of resistant S pneumoniae is increasing. If this is considered to be a potential pathogen, add vancomycin to the therapeutic regimen. Use of penicillin or ampicillin in the 3 months prior to illness is associated with increased risk of infection with resistant S pneumoniae.

Dexamethasone (Decadron)

Clinical Context:  Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.

Class Summary

Uncertainty exists as to the benefits of corticosteroids as adjuvant therapy for meningitis. In adults, corticosteroids, given prior to or along with the first dose of antibiotics, reduce morbidity and mortality by hearing loss, long-term neurological sequelae, and deaths. These findings were applicable to high-income countries.

From their recent meta-analysis, Mongelluzzo et al found no benefits of corticosteroids in children. The survival and time to hospital discharge were comparable between the corticosteroid treatment group and the nontreatment group. Even when comparing age and causative organism, these two groups did not differ in survival and hospital discharge. To date, the role of corticosteroids as an adjuvant therapy is of uncertain benefits.[19]

Rifampin (Rifadin)

Clinical Context:  Inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. Take on an empty stomach.

Acyclovir

Clinical Context:  Prodrug activated by phosphorylation by virus-specific thymidine kinase that inhibits viral replication. Herpes virus thymidine kinase (TK), but not host cells TK, uses acyclovir as a purine nucleoside, converting it into acyclovir monophosphate, a nucleotide analogue. Guanylate kinase converts the monophosphate form into diphosphate and triphosphate analogues that inhibit viral DNA replication.

Has affinity for viral thymidine kinase and once phosphorylated causes DNA chain termination when acted on by DNA polymerase. Inhibits activity of both HSV-1 and HSV-2.

Class Summary

Used prophylactically in contacts of children with H influenzae or N meningitidis, as described.

Further Inpatient Care

Further Outpatient Care

Inpatient & Outpatient Medications

Transfer

Deterrence/Prevention

Routine childhood immunizations have been shown to effectively decrease the incidence of certain types of meningitis and encephalitis. Routine vaccination with Haemophilus influenzae type b vaccine (ActHIB, Hiberix, Liquid PedvaxHIB) has greatly diminished the incidence of meningitis.[69] The meningococcal A C Y and W-135 vaccine (Menactra) is also used in children as young as 9 months old who are at high risk and as a routine vaccine in early adolescents. A Hib conjugate and meningococcal serogroups C&Y conjugate combination vaccine, MenHibrix, was approved by the FDA in June 2012 for use in infants. The combination vaccine is indicated in children aged 6 weeks to 18 months for active immunity against invasive disease. It is given as a 4-dose series usually at well-baby checkups.

Antibiotic prophylaxis is recommended for all household contacts in those households with at least 1 unvaccinated child younger than 48 months in patients with H influenzae meningitis. Prophylaxis should be started as soon as possible in all contacts in the household if any child is younger than 12 months. Careful observation of any contacts and immediate evaluation is warranted if a fever develops.

Prophylaxis is recommended for all persons in contact with oral secretions of patients with N meningitidis meningitis. This includes a health care worker who performed mouth-to-mouth resuscitation, intubation, or suctioning.

The use of rifampin, ceftriaxone, and ciprofloxacin has been effective prophylaxis. In a systematic review, ciprofloxacin and ceftriaxone are more effective up to 4 weeks of posttreatment against resistant strains of N meningitidis.

Complications

Prognosis

Author

Jeffrey Hom, MD, MPH, FACEP, FAAP, Assistant Professor, Department of Pediatrics/Emergency Services and Department of Emergency Medicine, New York University School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Robert Allan Felter, MD, FAAP, CPE, FACPE, Professor of Clinical Pediatrics, Department of Pediatrics, Georgetown University School of Medicine; Medical Director, Pediatric Emergency Medicine and Inpatient Services, Inova Loudoun Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Garry Wilkes, MBBS, FACEM, Director of Emergency Medicine, Calvary Hospital, Canberra, ACT; Adjunct Associate Professor, Edith Cowan University, Western Australia

Disclosure: Nothing to disclose.

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Grace M Young, MD, Associate Professor, Department of Pediatrics, University of Maryland Medical Center

Disclosure: Nothing to disclose.

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center

Disclosure: Nothing to disclose.

Chief Editor

Richard G Bachur, MD, Associate Professor of Pediatrics, Harvard Medical School; Associate Chief and Fellowship Director, Attending Physician, Division of Emergency Medicine, Children's Hospital of Boston

Disclosure: Nothing to disclose.

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