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Aseptic Meningitis

Steven Wilson, M.D.

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. Table 1. Causes of Aseptic Meningitis other than Enteroviruses. Viral Diseases with Systemic Manifestations mumps herpes simplex varicella-zoster adenoviruses Epstein-Barr virus parvovirus (erythema infectiosum) lymphocytic choriomeningitis virus 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 B. Etiology of Viral Meningitis 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 "nonparalytic" 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. Table 2. Etiology of Aseptic Meningitis Presenting with Predominately CNS Symptoms and Signs. Viral Diseases Limited to Central Nervous System enteroviruses mumps arboviruses lymphocytic choriomeningitis virus (LCM) 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 physiciandiagnosed 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 personyears (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. III. Clinical and Laboratory Features 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 1. The peripheral WBC and differential are usually non-specific. 2. CSF examination (Table 3).

a. The CSF white cell count usually ranges from 10 to 500 cells, but WBC > 2000 have been reported in as many as 18E/'0 of cases in one series (16). Virus may occasionally be isolated from the CSF of symptomatic infants with CSF WBC counts (15,17). 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.

C. Differential Diagnosis (22) 1. Bacterial meningitis and partially treated meningitis 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. 4. Spirochetal meningitis is most likely to occur in older children and adults a. syphilis b. leptospirosis c. Lyme disease IV. Complications and Prognosis A. Acute Complications 1. Complete recovery is the rule, most infants and children recover completely within 3-7 days of onset. a. Focal or generalized meningoencephalitis may accompany meningitis (24,25). (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. 2. a. Possible mechanism(s) of CNS complications in enterovirus meningitis 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). B. Long Term Sequelae 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. Farmer, et al (31), followed 1 5 infants who had coxsackie B5 virus meningitis during an outbreak in a newborn nursery. At age 6 years, two children had spasticity and delayed development, compared with none of 15 retrospectively selected control children. 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. 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.

b.

c.

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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). C. Chronic Meningitis in Immunocompromised Patients 1. Patients with agammaglobulinemia are susceptible to persistent or recurrent meningoencephalitis with enteroviruses. A variety of CNS manifestations are seen, including weakness, lethargy, headache, cognitive and intellectual decline, hearing loss, ataxia, seizures, and sensory abnormalities (36). a. Chronic myositis, hepatitis, and skin rash are sometimes noted.

b.

Administration of intraventricular IVIG may suppress or eradicate infection in some patients. There is now considerable interest in antiviral treatment of these patients

2. Other patients with near or total absence of B cell function (i.e., bone marrow transplant patients) may also develop persistent enterovirus infections. V.Management of Aseptic Meningitis A.Admission. Admission to hospital is not necessary for all cases. Admission for the following patients: 1. 2. 3. Infants under 6 months Cases with complicated neurological findings, ie, seizures, obtundation 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. 4. Persistent or complicated cases a. b. c. d. repeat lumbar puncture CSF AFB stain culture CSF for bacteria, mycobacteria, fungi CSF and serum studies including: VDRL, cryptococcal antigen, leptospira antibody, Lyme disease antibody

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-. 10. Wilfert CM, Lauer BA, Cohen M, Cohen M, Costenbader ML, Myers E. An epidemic of echovirus 18 meningitis. J Infect Dis 1975;131:75-78. 11. Bowen GS, Fisher MC, DeForest A, et al. Epidemic of meningitis and febrile illness in neonates caused by ECHO type 11 virus in Philadelphia. Ped Infect Dis J 1983;2:359-363. 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.