Professional Documents
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I. Background
A.Terminology. Aseptic meningitis refers to subarachnoid inflammation from any cause other than pyogenic
bacteria or fungi. The differential includes viruses, other microorganisms, and non-infectious causes. Since
most cases are caused by viruses, the terms "aseptic" and "viral" meningitis are often used synonymously.
Non-Viral Infections
partially treated bacterial meningitis
parameningeal infection
mastoiditis
sinusitis
brain abscess
spirochetal infections
syphilis
leptospirosis
Lyme disease
fungal
cryptococcal meningitis
coccidioidomycosis
histoplasmosis
tuberculous meningitis
toxoplasmosis
Rocky Mountain Spotted Fever
Mycoplasma pneumoniae
Bartonella henselae (cat scratch disease)
amebic meningoencephalitis
Non-Infectious Etiology
brain tumor
carcinomatous meningitis
chemical meningitis
intrathecal drugs and radiographic dyes
lead poisoning
benign intracranial hypertension
Unknown Etiology
Kawasaki disease
1. Meningitis may occur as part of a broader range of clinical manifestations caused by some viruses
(Table 1 ).
2. The differential diagnosis where aseptic meningitis is the sole or dominant manifestation is more limited
(Table 2).
a. Prior to the discovery of the non-polio enteroviruses (circa 1950), most cases were considered to be "non-
paralytic" poliomyelitis.
b. Large studies conducted from 1955 to 1962 among patients of all ages (1-3), found multiple agents
caused aseptic meningitis. Mumps virus and poliovirus infections are now controlled by
immunization in the U.S.
Unknown Etiology
Mollaret's syndrome
C. A prospective study conducted at three Baltimore hospitals from 1986 to 1990 showed > 90% of viruses
isolated from children under 2 y/o are coxsackie B viruses and echoviruses; coxsackie A viruses appear to
cause < 3% of cases (4).
II. Epidemiology
A.Seasonality. Aseptic meningitis disease activity corresponds to the seasonal pattern observed with all
enterovirus infections, i.e., a marked summer-fall predominance. Disease occurs at a lower incidence at other
times of the year.
B. Rates of Disease
1. Based on continuous surveillance in Olmsted County, MN the overall population-based rate of physician-
diagnosed aseptic meningitis was 17.8 per 100,000 person-years from 1976 through 1981 (5). This rate
compares closely with the 17.8 cases per 100,000 persons under 20 years of age discharged from Maryland
hospitals from 1979 through 1983 (Unpublished Data, Hospital Services Cost Review Commission, State of
Maryland, 1984) and is similar to a two-year survey in Israel which found a rate of 21.6 per 100,000 person-
years (6).
2. The age-specific incidence has varied somewhat among different reported outbreaks (7-14), but most data
indicate that aseptic meningitis is predominantly a disease of infants less than a year of age. A declining
number of cases are recognized among persons within increasingly older age groups (7,10). These data are
likely to contain some case-ascertainment bias; i.e., febrile infants are more likely to have lumbar punctures
than older children and adults.
A. Clinical Presentation
1. In the older child and adult aseptic meningitis presents with fever to 400 C, headache, meningismus, nausea
and vomiting (10). Other signs of enterovirus infection, i.e., rash, are present in a minority of cases. Altered
mentation, seizures, and focal neurological signs are unusual and suggest a diagnosis of
meningoencephalitis.
2. In infants less than a year of age the characteristic symptoms and signs of meningitis are difficult to elicit by
history and exam. The most common symptoms are fever and irritability (15). In practice, aseptic meningitis
is often diagnosed during the clinical evaluation of febrile infants without an apparent source of fever.
B. Laboratory Diagnosis
b. The CSF WBC differential may initially demonstrate a predominance of polys. The differential invariably
shifts to < 50% polys within 24 hours of onset of illness which is useful diagnostically (18,19).
c. The CSF glucose is generally normal or slightly low; values less than 40 mg/dl are documented (16,17).
The CSF protein is normal or slightly increased over the normal values for age.
3. Virology
a. Cell culture virus isolation rates from the CSF have varied from 20% to 90% in various reports. Viruses
are less often isolated from CSF than from the GI tract (Table 4). Enteroviruses are often isolated from the
oropharynx for 1-2 weeks after onset of symptoms, and from the feces for 3-8 weeks.
b. The use of the polymerase chain reaction (PCR) to detect enterovirus RNA in CSF is likely to be more
rapid and more sensitive than cell culture (20). Sawyer, et al, found that PCR detected enteroviral RNA in
97% of culture positive CSF specimens, and in 66% of of culture negative CSF specimens from aseptic
meningitis patients (21 ).
c. In general, antibody determination is of little value in the diagnosis of aseptic meningitis because of the
large number of different enterovirus serotypes.
a. The most important task of the physician managing a suspected case of aseptic meningitis is to rule out
more serious, treatable causes of meningitis. This may be the most difficult when the patient has
previously received antibiotics that could potentially mask the diagnostic CSF findings of bacterial
meningitis.
( 1 ) Studies of large numbers of children with H. influenza bacterial meningitis suggest that prior antibiotic
treatment slightly but significantly reduces the rate of positive gram stain and culture results, the
percentage of CSF PMN, and the CSF protein concentration (23). However, virtually all patients with
partially treated bacterial meningitis will have one or more CSF values that suggest bacterial disease.
2. Parameningeal bacterial infections may present with an "aseptic" CSF pleocytosis. The differential should
include: otitis media, mastoiditis, sinusitis, subdural empyema, brain abscess, and epidural abscess.
3. Tuberculous meningitis and cryptococcal meningitis may initially be confused with viral meningitis.
Persistence of CNS symptoms for more that 3-5 days, or progressive neurological dysfunction should
provoke a workup for these pathogens.
A. Acute Complications
1. Complete recovery is the rule, most infants and children recover completely within 3-7 days of onset.
(1) 12% of patients with aseptic meningitis developed signs of encephalitis during the acute illness
(26). Specific signs included seizures (3.4%), weakness (1.0%), and coma (3.7%). Most patients
were teenagers and young adults. Virtually all the complications were associated with
coxsackieviruses and echoviruses.
( 2 ) In a Baltimore study of aseptic meningitis among children < 2 years of age, the acute illness was
complicated by either complex seizures, physical evidence of increased intracranial pressure, or
coma in 25 (9%) cases (15). However, these complications were not associated with adverse long
term neurological sequelae.
a. IADH syndrome is reported in from 9% (27) to 64% (28) of children with viral meningitis. The clinical
significance of this observation is probably minimal.
b. Inflammatory. mediators. Interleukin-1-beta is found in the CSF of patients with viral
meningitis, but in lower concentrations than found in bacterial meningitis (29).
1. The study of Lepow, et al (26), found a high degree of subjective complaints (fatigue, irritability, limb pain),
peripheral neurological abnormalities (limb tightness, muscle weakness) remaining 1-24 months after the
acute illness. Some patients may have had poliomyelitis.
2. Several small studies have suggested that aseptic meningitis occurring at a very young age may be
associated with significant neurological sequelae.
a. Sells, et al (30), studied 19 children (at 2-8 years of age) who had a history of viral meningitis occurring
from 1 to 64 months of age. The 13 children who had meningitis when under 12 months of age had
significantly lower IQ's than the matched control children. Three (16%) of the children had severe
neurologic abnormalities.
c. Wilfert, et al (32), reported nine children who were tested at 9 to 58 months of age after documented
enterovirus meningitis at 0-3 months of age. The mean IQ's of the cases did not differ from that of
control infants born at the same institution, but the cases scored significantly lower on the Peabody
Picture Vocabulary Test, a measurement of receptive language. No appreciable neurological sequelae
were noted.
d. Gonzalez-del-Rey, et al, (33) reported a 3 year prospective study of 16 infants with viral meningitis under
3 months of age, and 13 controls from well child clinics matched for sex, race, and socioeconomic
status. No difference was noted between cases and controls in developmental tests, but the cases
scored significantly lower in several tests of receptive and verbal language development.
3. More recent studies with larger numbers of cases and more appropriate controls have found no effect of viral
meningitis on cognitive development.
a. A study in Pittsburgh retrospectively comparing 33 children with aseptic meningitis with 31 sibling
controls found no difference in neurodevelopmental outcome (34).
b. The Baltimore study prospectively followed 140 infants who had aseptic meningitis when < 24 months old
and 140 matched controls, and performed a battery of quantitative neurological and standardized
developmental tests. Aseptic meningitis had no effect on subsequent test scores (35).
2. Other patients with near or total absence of B cell function (i.e., bone marrow transplant patients) may also
develop persistent enterovirus infections.
A.Admission. Admission to hospital is not necessary for all cases. Admission for the following patients:
3. Patients with any clinical or laboratory findings that would suggestive of bacterial disease
B. Management Options
1. Treat with appropriate systemic antibiotics until CSF and blood culture have remained negative for at least
72 hours.
2. Observe without antibiotic therapy. This option generally demands a repeat lumbar puncture within 8-24
hours of the initial tap.
3. When more widely available, the PCR assay may assist in immediate management decisions.
VI. References
1. Lennette EH, Magoffin R, Knouf EG. Viral central nervous system disease: An etiologic study conducted at the
Los Angelos County General Hospital. J Am Med Assn 1962;179:687.
2. Lepow ML, Carver DH, Wright HT, Woods WA, Robbins FC. A clinical, epidemiologic and laboratory
investigation of aseptic meningitis during the four-year period, 1955-1958. Observations concerning etiology and
epidemiology. N Eng J Med 1962;266:1181 I1187.
3. Meyer HM, Johnson RT, Crawford IP, et al. Central nervous system syndromes of viral etiology. A study of 713
cases. Am J Med 1960~79:334-337.
4. Bedin LE, Rorabaugh ML, Helddch F, Roberts K, Doran T, Modlin JF. Aseptic meningitis in infants less than two
years of age: diagnosis and etiology. J Infect Dis 1993;168:888-892.
5. Nicolosi A, Hauser WA, Beghi E, et al. Epidemiology of central nervous system infections in OImsted County,
Minnesota, 1950-1981. J Infect Dis 1986;154:399-408.
6. Softer D, Alter M, Kahana E, et al. Aseptic meningitis: frequency among Israeli ethnic groups. J Neurol 1977;
214:89-96. J Neurol 1977;214:89-96.
7. Marier R, Rodriguez W, Chloupek RJ, etal.Coxsackie virus B5 infection and aseptic meningitis in neonates and
children. Am J Dis Child 1975;129:321-325.
8. Sabin AB, Krumbiegel ER, Wigand R. ECHO type 9 virus disease. Am J Dis Child 1958;96:197-.
9. Torphy DE, Ray GC, Thompson RS, et al. An epidemic of aseptic meningitis due to echovirus type
30:Epidemiologic features and clinical and laboratory findings. Am J Pub Health 1970;60:1447-.
12. Niiller DG, Gabrielson MO, Bart K J, Opton EM, Horstmann DM. An epidemic of aseptic meningitis,
primarily among infants, caused by echovirus 11-prime. Pediatr 1968;41:77-90.
13. Peters ACB, Vielvoye G J, Versteeg J, Bots GTAM, Lindeman J. Echo 25 focal encephalitis and subacute
hemichorea. Neurol 1979;29:676-681.
14. Sumaya CV, Corman LI. Enteroviral meningitis in early infancy: significance in community outbreaks. Pediatric
Infectious Disease 1982;3:151-154.