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Background

Pediatric aseptic meningitis is an inflammation of the meninges caused mainly by nonbacterial organisms, specific
agents, or other disease processes. Aseptic meningitis (including viral meningitis) is the most common infection of the
central nervous system (CNS) in the pediatric population, occurring most frequently in children younger than 1 year.
Despite advances in antimicrobial and general supportive therapies, CNS infections remain a significant cause of
morbidity and mortality in children.

Because the classic signs and symptoms are often absent, especially in younger children, diagnosing pediatric CNS
infections is a challenge to the emergency department (ED). Even when such infections are promptly diagnosed and
treated, neurologic sequelae are not uncommon. Clinicians are faced with the daunting task of distinguishing the
relatively few children who actually have CNS infections from the vastly more numerous children who come to the ED
with less serious infections.

Patophysiology

Organisms colonize and penetrate the nasopharyngeal or oropharyngeal mucosa, survive and multiply in the blood
stream, evade host immunologic mechanisms, and spread through the blood-brain barrier. Infection cannot occur until
colonization of the host has taken place (usually in the upper respiratory tract). The mechanisms by which circulating
viruses penetrate the blood-brain barrier and seed the cerebrospinal fluid (CSF) to cause meningitis are unclear. [1]

Viral infection causes an inflammatory response but to a lesser degree than bacterial infection does. Damage from
viral meningitis may be due to an associated encephalitis and increased intracranial pressure (ICP).

The pathophysiology of aseptic meningitis caused by drugs is not well understood. This form of meningitis is
infrequent in the pediatric population.

Etiology

Although many agents and conditions are known to be associated with pediatric aseptic meningitis, often a specific
cause is not identified, because a complete diagnostic investigation is not always completed. Viruses are the most
common cause, and enteroviruses (EVs) are the most frequently detected viruses. The use of molecular diagnostic
techniques (eg, polymerase chain reaction [PCR] assay) has significantly increased diagnostic accuracy.

Viruses
EV is a frequent cause of febrile illnesses in children. Other viral pathogens include paramyxovirus, herpesvirus,
influenza virus, rubella virus, and adenovirus. Meningitis may occur in as many as 50% of children younger than 3
months with EV infection. EV infection can occur at any time during the year but is associated with epidemics in the
summer and fall.

Viruses associated with aseptic meningitis include the following:

EV 71, EV 70, EV 75[2, 3, 4, 5, 6, 7]


Polioviruses types 1, 2, and 3
Coxsackievirus type A (23 serotypes) and type B (6 serotypes)
Echoviruses (31 serotypes; see the image below)[8, 9, 10]
Human parechoviruses (HPeV) (6 serotypes; HPeV types 1 and 2 were previously classified as echovirus
types 22 and 23 within the genus Enterovirus)
Arbovirus (eastern, western, and Venezuelan equine encephalitis viruses; Powassan virus; California group
viruses [primarily LaCrosse virus]; St. Louis encephalitis virus; West Nile virus; and Colorado tick fever)
Mumps virus
Herpes simplex virus (HSV) types 1 and 2
Cytomegalovirus (CMV)
Epstein-Barr virus (EBV)
Human herpesvirus type 6 (HHV6) and type 7 (HHV7)
Varicella-zoster virus (VZV)
Adenovirus types 3 and 7
Human immunodeficiency virus (HIV)
Lymphocytic choriomeningitis (associated with contact with guinea pigs, hamsters, and pet mice)
Rhinovirus
Measles virus
Rubella virus
Influenza A and B viruses, including H1N1[11, 12]
Parainfluenza virus
Parvovirus B19
Rotavirus
Coronavirus
Variola virus
Flavavirus[13] Skin lesions due to echovirus type 9 on neck and chest of young girl. Echoviruses belong to genus

Enterovirus and are associated with illnesses including aseptic meningitis, nonspecific rashes, encephalitis, and myositis.
Viral vaccines
Viral vaccines related to aseptic meningitis include the following:

Mumps vaccine[14]
Measles-mumps-rubella (MMR) vaccine
Polio vaccine
Rabies vaccine
Yellow fever vaccine[15]
Nonpyogenic bacteria
Certain bacterial infections may give rise to aseptic meningitis (eg, partially treated bacterial meningitis or brain
abscess). Nonpyogenic bacteria associated with aseptic meningitis include the following:

Mycobacterium tuberculosis
Leptospira
Treponema pallidum
Borrelia (relapsing fever, Lyme disease)
Nocardia
Bartonella
Atypical mycobacteria
Brucella
Other organisms
Atypical organisms associated with aseptic meningitis include the following:

Chlamydia
Rickettsia
Mycoplasma
Parasites associated with aseptic meningitis include the following:

Roundworms
Tapeworms
Flukes
Amoebae
Toxoplasma
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 occur in children who are
inpatients receiving antibiotic therapy. Fungi associated with aseptic meningitis include the following:

Candida
Histoplasma
Cryptococcus
Additional organisms associated with aseptic meningitis include the following:

Blastomyces dermatitidis
Coccidioides immitis
Alternaria species
Aspergillus species
Cephalosporium species
Cladosporium trichoides
Drechslera hawaiiensis
Paracoccidioides brasiliensis
Petriellidium boydii
Sporotrichum schenckii
Ustilago species
Zygomycetes species
Diseases and other conditions or events
Diseases associated with aseptic meningitis include the following:

Leukemia
Behet disease
Systemic lupus erythematosus (SLE)
Sarcoidosis
Sj gren syndrome[16]
Dermoid and epidermoid cysts[17]
CNS tumor
Kawasaki disease[18]
Recurrent benign endothelioleukocytic aseptic meningitis (Mollaret meningitis) [19]
Neonatal-onset multisystem inflammatory disorder (one of the cryopyrin-associated periodic syndromes
[CAPS])[20]
Other conditions or events associated with aseptic meningitis include the following:

Immunoglobulin replacement therapy


Heavy metal poisoning
Intrathecal agents
Foreign bodies (eg, shunt or reservoir)
Drugs

Epydemiology

United States Statistics


The incidence of aseptic meningitis in the United States has been estimated to be approximately 75,000 cases per
year. Before the introduction of the MMR vaccine program, the mumps virus was the most common cause, accounting
for 5-11 of 100,000 cases of meningitis; it now accounts for approximately 0.3 of 100,000 cases, and EV has become
the most common cause. In a North American study from 1998-1999, most cases occurred between July and October.
[21]

International Statistics
In a university clinic in Mainz, Germany, from 1986-1989, 12 (10.3%) of 117 cases of acute aseptic meningitis were
due to the mumps virus, 3 (7.7%) were due toBorrelia burgdorferi, 3 (2.6%) were due to tick-borne encephalitis, and 2
(1.7%) were due to (HSV).[22] Ninety-one (77.8%) cases were due to other causes. Sixty-four percent of cases occurred
in the spring and summer.

In a tertiary care childrens hospital in Athens, Greece, 506 cases of aseptic or viral meningitis were reviewed from
1994 through 2002; the estimated annual incidence was 17 cases per 100,000 children younger than 14 years. [23] Most
cases occurred during summer (38%) and autumn (24%), and 47 of 96 patients (48.9%) had positive results for
enteroviral RNA on CSF polymerase chain reaction (PCR) assay of cerebrospinal fluid (CSF).

The Austrian reference laboratory for poliomyelitis received 1,388 stool specimens for EV typing from patients with
acute flaccid paralysis or aseptic meningitis between 1999 and 2007; 201 samples from 181 cases were positive for
nonpoliomyelitis EV.[24] The mean patient age was 5-6 years, with 90% of cases in children younger than 14 years.
Aseptic meningitis was identified in 65.6% of the cases. Echovirus 30 was the most frequent viral cause of aseptic
meningitis, due to an epidemic in 2000, followed by coxsackievirus B types 1-6 and EV 71.

Age-related demographics
Aseptic meningitis is more common in children than in adults. In the Mainz study, 69% of the patients were aged 5
years or older,[22] and in the Athens study, the median age was 5 years (range, 1 month to 14 years). [23] However, in a
Korean study, a higher incidence was reported in individuals younger than 1 year (10% of total affected) and in
individuals aged 4-7 years (44.1%).[25]

Sex-related demographics
Until comparatively recently, no sex predilection had been reported for EV infection, although reactivation of HSV-2
infection occurs mostly in adults (with a female-to-male ratio of 6:1). In the Mainz study, 66% of the patients were
male.[22]

A Korean study of 2201 children reported a male-to-female ratio of 2:1. [25] In Japan, an outbreak of aseptic meningitis
caused by echovirus type 30 in 54 patients showed a male-to-female ratio of 2.2:1. [26] The Athens study also showed a
higher prevalence in males, with a male-to-female ratio of 1.8:1. [23]

Race-related demographics
In a South African study, the median age of white children with aseptic meningitis (64 months) was significantly greater
than that of nonwhite children (45 months) and that of black children (26 months). [27]

Prognosis
Full recovery is usual after uncomplicated viral aseptic meningitis. Most cases resolve within 7-10 days.

Recurrence is possible (known as Mollaret, or benign recurrent meningitis). Associated viruses include Epstein-Barr
virus (EBV), coxsackieviruses B5 and B2, echoviruses 9 and 7, herpes simplex virus (HSV)-1 and HSV-2, and human
immunodeficiency virus (HIV).

Overall mortality and morbidity for aseptic meningitis are unclear. In a Taiwanese study of EV 71 infections, 78 of 408
hospitalized children died.[7] Of children with rhombencephalitis due to EV infection, 14% died.

Subsequent studies suggested better outcomes. In both a Canadian study of 802 patients (1998-99) [21] and a Korean
study of 2201 children (1987-2003),[25] no deaths were reported. In the Athens study of 506 children, no serious
complications or deaths were reported.[23]

Patient Education
For more information, visit the Meningitis Foundation of America Web site. TheMeningitis Research Foundation offers
useful material for nonexperts, parents, and health care professionals.

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