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Chronic meningitis is defined as a symptom complex of insidious onset that is characterized by headache, fever, and mental status changes in association with cerebrospinal fluid (CSF) pleocytosis. The CSF protein is usually elevated, and the CSF glucose is often low. This syndrome may be caused by viral, bacterial, fungal, or parasitic agents. Noninfectious causes include malignancy, sarcoidosis, Behçet’s syndrome, and vasculitis.
Tuberculosis remains the most common cause of the chronic meningitis syndrome; it is a treatable disease even in the immunosuppressed patient. Hence, the diagnosis must be made and, at times, empiric therapy may be initiated. The diagnosis of tuberculous meningitis continues to be a difficult one. The disease is usually the result of breakdown of a long-standing granuloma. In about half of all patients, this breakdown is associated with some underlying condition, such as sarcoidosis, AIDS, malnutrition, or steroid therapy.
Clinical manifestations of tuberculous meningitis generally are similar to those of other chronic meningitides. A miliary picture on chest x-ray films and inappropriate antidiuretic hormone secretion are the only features useful to distinguish between tuberculous and cryptococcal meningitis. In one study, symptoms of tuberculous meningitis included fever (99°F to 103°F), lethargy, and headache. Duration of symptoms on presentation ranges from 2 days to 6 months. Hospitalization is often precipitated by complaints of headache. Meningeal signs are present in more than half of all cases. Peripheral WBC counts range from low normal to very elevated (>20,000/mm3).
Tuberculous meningitis is often a disease of the inner-city population in the United States. Mortality and morbidity in this group are high. The disease was similar in HIV-positive and HIV-negative patients in two different studies.
Klein et al. reviewed the CSF findings in 21 patients. All but one had a lymphocytic pleocytosis. In 16 of 21, CSF protein levels were above 50 mg/dL; 10 had CSF glucose levels of 40 mg/dL or less. Positivity on acid-fast smear varies dramatically among studies, from a low of 10% to a high of 90%. Prevention of mortality from the disease depends on rapid initiation of therapy; hence, better diagnostic methods are critical.
Several attempts have been made recently to develop rapid, sensitive, specific methods. Ribera et al. have studied the activity of adenosine deaminase in the CSF of patients with tuberculous meningitis. This biologic activity of this enzyme is detected in T lymphocytes, and increased plasma levels of the enzyme have been observed in infectious diseases related to cell-mediated immune response. At levels greater than 9 U/L, the test was found to be sensitive and specific. Levels appeared to correlate with disease activity, and persistently high levels predicted complications. Kadival et al. have used a radioimmunoassay for detecting Mycobacterium antigen. Antigen could be detected in 25 of 38 patients with tuberculous meningitis, versus none of 56 patients with nontuberculous meningitis. Assay results become negative after therapy. Krambovitis et al. used a latex agglutination immunoassay, which was also sensitive and specific (one false-positive occurred in a patient with Haemophilus influenzae meningitis). Other enzyme-linked immunosorbent assay (ELISA) techniques have also been described. Tuberculostearic acid, a structural component of Mycobacterium tuberculosis, can be identified by gas chromatography and was shown to be sensitive and specific in one small study.
The outcome of tuberculous meningitis depends on neurologic status at presentation, time to initiation of therapy, and underlying disease. Three drugs are usually recommended: isoniazid, rifampin, and ethambutol or pyrazinamide. Response occurs after about 1 month, and treatment is continued for 1 year. When empiric therapy is being used, rifampin has broad antimicrobial activity, and clinical response does not necessarily prove tuberculosis as a diagnosis. The use of corticosteroids in tuberculous meningitis remains controversial. Corticosteroids decrease the risk for herniation and may improve the CSF profile; however, survival does not appear to be affected.
The presentation of cryptococcal meningitis is very similar to that of tuberculosis. The disease has become much more common in the AIDS era and may be the first manifestation of AIDS. In addition, lymphoma, systemic lupus erythematosus, sarcoidosis, and renal transplantation are important predisposing conditions. Between 20% and 50% of patients with cryptococcal meningitis have no underlying illness. Cultures of specimens from sputum, bone marrow, or skin lesions may be useful in some patients. Spinal fluid findings, as in tuberculous meningitis, usually show a CSF pleocytosis. An India ink preparation yields positive results in 50% of cases; cryptococcal antigen can be detected in 80% to 90% of cases by a rapid, simple latex fixation test. Computed tomography may be necessary to identify cryptococcomas or to rule out hydrocephalus. The poor prognostic signs in cryptococcal meningitis have been well defined: (a) high opening CSF pressure, (b) low CSF glucose, (c) fewer than 20 WBCs in CSF, (d) high titers of cryptococcal antigen and positive India ink stain, and (e) concomitant disease, such as lymphoma.
Amphotericin is the drug of choice for cryptococcal meningitis. In the absence of bone marrow suppression, flucytosine is usually added. Treatment is generally continued for 4 weeks in patients with mild disease. Those patients with underlying disease, fewer than 10 WBCs in CSF, antigen titer above 1:32, or positive India ink stain should receive 6 weeks of treatment. Flucytosine is generally avoided in the AIDS patient. In some patients refractory to parenteral therapy, intraventricular amphotericin therapy with an Ommaya reservoir has been successful. In AIDS patients, initial treatment is with amphotericin; relapses are prevented with long-term fluconazole therapy. Treatment with fluconazole in acute disease has also been successful.
Coccidioidomycosis is another common cause of chronic meningitis syndrome. A careful travel history may be an important clue to the disease. Residents of southern California, Nevada, Utah, Arizona, New Mexico, Texas, Mexico, and Central America are at risk for the disease by inhaling arthrospores of Coccidioides immitis. Visitors to these areas may also contract the disease. Two thirds of patients who contract the disease have no risk factors. However, disseminated disease and meningitis are more likely to develop in blacks, Filipinos, and pregnant women after pulmonary infection. The symptoms of coccidioidomycosis meningitis cannot be distinguished from those of chronic meningitis with other causes, but evaluation for lesions of skin, bone, and lung may provide critical information. CSF parameters are nonspecific. In some patients, a polymorphonuclear leukocyte predominance in CSF may be noted. CSF cultures are often negative.
Culture plates must be handled with care because they are infectious to laboratory personnel. Detection of complement-fixing antibody in the CSF is specific and 75% to 90% sensitive for diagnosis. Systemic and local amphotericin therapy is recommended. IV amphotericin should be continued to a total dose of 3 to 4 g. Most experts recommend an Ommaya reservoir for intraventricular therapy rather than repeated intrathecal injection, which often results in arachnoiditis.
Blastomyces dermatitidis can also cause chronic meningitis. Meningitis occurs in about one third of patients with disseminated disease. Diagnosis is usually made by concomitant culture of sputum, skin lesions, bone or joint fluid, and prostatic secretions. The organism is rarely cultured from CSF, and serologic tests are not reliable for extrapulmonary infection.
The presentation of histoplasmosis meningitis is similar to that of B. dermatitidis meningitis, and culture of other sites is often required for diagnosis. Half the patients have positive CSF cultures; 90% have CSF antibody. IV amphotericin is recommended for meningitis associated with histoplasmosis or blastomycosis. Intraventricular therapy is used for relapse.
Actinomycosis can be associated with many central nervous system (CNS) lesions, including brain abscess, meningitis, subdural empyema, and epidural abscess. Brain abscesses present with focal neurologic findings, and many patients have evidence of dental infection, mastoiditis, sinusitis, or skin infection. Actinomycosis may involve the meninges alone, producing a basilar meningitis that is indolent and manifested solely by a lymphocytic pleocytosis. In such cases, the disease is frequently misdiagnosed as tuberculous meningitis. Actinomyces organisms are fastidious, gram-positive, filamentous bacteria. They often grow slowly and have anaerobic or microaerophilic growth requirements. High-dose penicillin remains the drug of choice.
Nocardia asteroides infection may also present as chronic meningitis without brain abscess, but this is unusual. Sulfonamides are the antimicrobials of choice.
Several spirochetes are neurotrophic and can cause a chronic meningitis syndrome. Syphilitic meningitis usually occurs within 2 years of acute infection. Fever is often absent, and headache may be the sole complaint. A CSF pleocytosis with high protein and low sugar may mimic the findings of other chronic meningitides. The diagnosis is suggested by a positive result on treponemal tests and CSF Venereal Disease Research Laboratory (VDRL) tests. Many investigators have reported a change in the clinical spectrum of neurosyphilis recently. Patients may complain of vague chronic symptoms, including headache. They tend not to have classic tertiary signs, such as tabes dorsalis or pupillary changes.
The CNS effects of Lyme disease are receiving increasing attention. Borrelia burgdorferi can cause chronic meningitis as a second stage of Lyme disease, months after tick exposure and initial infection. Bell’s palsy and radiculopathic syndromes are most common. Meningitis patients present often without fever but with headache, photophobia, and stiff neck, and they may present with long-standing symptoms. A CSF pleocytosis is found. Protein is elevated, and about 15% of patients have low CSF sugar. Results of a CSF VDRL test may be false-positive, but treponemal tests will be negative. Local CSF antibody production occurs, but serologic tests appear to lack sensitivity and specificity. Tests to detect spirochetal DNA in host material may be useful in the future. Recommended treatment includes high-dose penicillin or ceftriaxone.
Other spirochetal diseases, including leptospirosis and relapsing fever, may present with meningitis in addition to other systemic symptoms. These meningitides are usually self-limited.
Other bacteria can cause a chronic meningitis syndrome. Brucellosis usually presents with night sweats, lymphadenopathy, and hepatosplenomegaly. CNS involvement is rare, but when it does occur, a chronic meningitis syndrome is common. Culture from blood or CSF requires special media and longer incubation (2 to 4 weeks). Blood or CSF agglutination titers may be needed for diagnosis. Tetracycline with rifampin or streptomycin is recommended for treatment. Listeria monocytogenes and Neisseria meningitidis infections, which are more likely to produce an acute meningitis, can also present as a more protracted, insidious disease. An underlying immunodeficiency state may be present in these cases.
Viral infections usually cause meningoencephalitis or aseptic meningitis, with CSF pleocytosis and normal CSF sugar in most cases. Chronic meningitis caused by echovirus or coxsackievirus occurs in patients with agammaglobulinemia or multiple myeloma. HIV infection itself or with concomitant progressive multifocal leukoencephalopathy may cause mental status abnormalities and a chronic CSF pleocytosis.
Noninfectious disease processes may mimic a chronic infectious meningitis syndrome. Metastatic carcinoma from an unsuspected primary carcinoma in the breast or lung can cause a chronic meningitis syndrome, as can lymphoma and melanoma. In many cases, back pain, radicular pain, and cranial nerve abnormalities will also be present. Most patients have a CSF pleocytosis. Cytology is positive for malignant cells in 50% to 80% of patients. CSF lactate dehydrogenase has recently been shown to be a useful test. Findings on computed tomography and magnetic resonance imaging will usually be positive.
Sarcoidosis presents with neurologic findings in 48% of patients. Cranial nerve abnormalities, peripheral neuropathy, and focal cerebral and intraspinal lesions are most common. Aseptic meningitis rarely occurs without other manifestations of sarcoidosis. In one study, CSF pleocytosis was noted in 43% of patients, and hypoglycorrhachia in only 10%. When this disease is suspected, careful examination of optic and other cranial nerves, as well as evaluation of other systems, is crucial. Diagnosis is usually made outside the CNS, such as by biopsy of lymph node, liver, or parotid or other salivary gland. Specific CNS markers for sarcoid have not yet been developed.
Behçet’s disease usually is recognized by the triad of oral or genital ulcers, skin lesions, and uveitis. Meningoencephalitis develops in 25% of patients, often in association with flare-up of other symptoms. CSF pleocytosis is present, with elevated protein and normal sugar. (S.L.B.)
Anderson NE, Willoughby EW. Chronic meningitis without predisposing illness: a review of 83 cases. Q J Med 1987;63:283.
Tuberculosis is still the most common cause of chronic meningitis.
Bouza E, et al. Coccidioidal meningitis. An analysis of 31 cases and review of the literature. Medicine (Baltimore) 1981;3:139.
Complement-fixing antibody is an important test in coccidioidal meningitis. Intra-thecal administration of amphotericin is more effective than IV administration.
Bouza E, et al. Brucellar meningitis. Rev Infect Dis 1987;9:810.
Review of the neurologic manifestations of systemic brucellosis.
Bozzette SA, et al. A placebo-controlled trial of maintenance therapy with fluconazole after treatment of cryptococcal meningitis in the acquired immunodeficiency syndrome. N Engl J Med 1991;324:580.
Randomized, controlled trial shows that fluconazole prevents the relapse of cryptococcal meningitis in AIDS patients.
Buggy BP. Nocardia asteroides meningitis without brain abscess. Rev Infect Dis 1987; 9:228.
Case reports of N. asteroides meningitis without brain abscess or focal findings.
Butler WT, et al. Diagnostic and prognostic value of clinical and laboratory findings in cryptococcal meningitis. A follow-up study of 40 patients. N Engl J Med 1964;270:59.
Variability in both clinical symptoms and CSF parameters in patients with cryptococcal meningitis.
Daniel TM. New approaches to the rapid diagnosis of tuberculous meningitis. J Infect Dis 1987;155:599.
Reviews new developments in the diagnosis of tuberculous meningitis, including biochemical, antigen, and antibody methods.
Dismukes WE, et al. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for 4 as compared with 6 weeks. N Engl J Med 1987;317:334.
Patients with cryptococcal meningitis who have underlying disease should be treated for 6 weeks with amphotericin and flucytosine.
Dooley DP, et al. Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 1997;25:872.
Corticosteroids seem to improve neurologic outcomes and decrease mortality.
Dube MP, Holton PD, Larsen RA. Tuberculous meningitis in patients with and without human immunodeficiency virus infection. Am J Med 1992;93:520.
HIV infection had little impact on the findings and on hospital mortality of patients with tuberculous meningitis. Intracerebral mass lesions were more common in AIDS patients.
Finkel MF. Lyme disease and its neurologic complications. Arch Neurol 1988;45:99.
Patients with CNS Lyme disease may present with long-standing headache and CSF pleocytosis. CSF IgG and IgM levels should be obtained when CNS Lyme disease is suspected.
French GL, et al. Diagnosis of tuberculous meningitis by detection of the tuberculostearic acid in cerebrospinal fluid. Lancet 1987;1:117.
Tuberculostearic acid, a structural component of M. tuberculosis, can be detected in CSF by gas chromatography.
Haas EJ, et al. Tuberculous meningitis in an urban general hospital. Arch Intern Med 1977;137:1518.
Acid-fast smears of CSF were positive in only 6 of 19 cases.
Harvey RI, Chandrasekar PH. Chronic meningitis caused by Listeria in a patient infected with human immunodeficiency virus. J Infect Dis 1988;157:1091.
L. monocytogenes may cause a picture of chronic meningitis in the immunosuppressed patient.
Kadival GV, et al. Radioimmunoassay for detecting Mycobacterium tuberculosis antigen in cerebrospinal fluid of patients with tuberculous meningitis. J Infect Dis 1987; 155:608.
M. tuberculosis antigen can be detected in CSF by radioimmunoassay early in the course of disease.
Kennedy DH, Fallon RJ. Tuberculous meningitis. JAMA 1979;241:264.
Mortality in tuberculous meningitis is strongly associated with delay in diagnosis.
Klein NC, Damsker B, Hirschman SZ. Mycobacterial meningitis. Retrospective analysis from 1970 to 1983. Am J Med 1985;79:29.
Reviews CNS presentation in 21 patients with mycobacterial meningitis. CSF findings are variable and may include predominance of polymorphonuclear leukocytes, normal protein, and normal sugar.
Kovacs JA, et al. Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med 1985;103:533.
In AIDS patients with cryptococcal meningitis, CSF WBC count, sugar, and protein were frequently normal. Relapse was very common.
Krambovitis E, et al. Rapid diagnosis of tuberculous meningitis by latex particle agglutination. Lancet 1984;2:1229.
Results of this test were positive in 17 of 18 patients with tuberculous meningitis. Results in control CSF samples from patients with other meningitides and neurologic diseases were negative in 133 of 134 cases.
Kravitz GR, et al. Chronic blastomycetic meningitis. Am J Med 1981;71:501.
CSF cultures are rarely positive in blastomycosis meningitis, and serologic tests are not specific.
Lecour H, Miranda M. Human leptospirosis. A review of 50 cases. Infection 1989;17:8.
Meningitis usually occurs concurrently with other symptoms in leptospirosis.
Lukehart SA, et al. Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Ann Intern Med 1988;109:855.
Discusses implications of CNS syphilis in patients with AIDS.
McKinney RE, Katz SL, Wilfert CM. Chronic enteroviral meningoencephalitis in agammaglobulinemic patients. Rev Infect Dis 1987;9:334.
Echovirus causes a culture-proven chronic meningitis in patients with agammaglobulinemia.
Meyers BR, Hirschman SZ. Unusual presentations of tuberculous meningitis. Mt Sinai J Med 1974;41:407.
Describes presentation of tuberculous meningitis. Fifty percent of patients have predisposing underlying disease.
Moosa MY, Coovadia YM. Cryptococcal meningitis in Durban, South Africa: a comparison of clinical features, laboratory findings, and outcome for human immunodefiency virus-positive and -negative patients. Clin Infect Dis 1997;24:131.
Headache, fever, stiff neck, and neurologic findings were more common in HIV-infected patients.
Ogawa SK, et al. Tuberculous meningitis in an urban medical center. Medicine (Baltimore) 1987;66:371.
Detailed discussion of symptomatology. Fever is almost invariably present in tuberculous meningitis.
O’Toole RD, et al. Dexamethasone in tuberculous meningitis. Ann Intern Med 1969; 70:39.
Decreased risk of herniation, improved CSF parameters, but no change in mortality is associated with use of steroids in tuberculous meningitis.
Pachner AR. Spirochetal diseases of the CNS. Neurol Clin 1986;4:207.
Excellent review of CNS syphilis, Lyme disease, leptospirosis, and relapsing fever.
Polsky B, Depman MR, Gold JWM. Intraventricular therapy of cryptococcal meningitis via a subcutaneous reservoir. Am J Med 1986;81:24.
Retrospective evaluation of intraventricular amphotericin in cryptococcal meningitis. Early intraventricular therapy may be beneficial for those with a poor prognosis.
Porkert MT, et al. Tuberculous meningitis at a large inner-city medical center. Am J Med Sci 1997;13:325.
Thirty-four patients with tuberculous meningitis were studied at a public hospital in Atlanta. Tuberculous meningitis is a devastating disease in inner-city residents with a delay in diagnosis and has a high mortality rate. Whether or not a patient was HIV-positive did not affect the clinical presentation.
Reik L. Disorders that mimic CNS infection. Neurol Clin 1986;4:223.
When granulomatous involvement of basal meninges is the predominant pathology, disease will look like tuberculous meningitis.
Ribera E, et al. Activity of adenosine deaminase in cerebrospinal fluid for the diagnosis and follow-up of tuberculous meningitis in adults. J Infect Dis 1987;155:603.
Adenosine deaminase levels are elevated in the CSF of patients with tuberculous meningitis. The test appears to be both sensitive and specific.
Richardson EP. Progressive multifocal leukoencephalopathy 30 years later. N Engl J Med 1988;318:315.
Progressive multifocal leukoencephalopathy may occur in as many as 38% of AIDS patients. Article provides a good overview of this disease.
Rosen MS, Lorber B, Myer AR. Chronic meningococcal meningitis. An association with C5 deficiency. Arch Intern Med 1988;148:1441.
N. meningitidis may cause chronic meningitis in patients with complement deficiency.
Simon RP. Neurosyphilis. Arch Neurol 1985;42:606.
Describes the many syndromes of neurosyphilis, including CSF parameters.
Smego RA, Jr. Actinomycosis of the central nervous system. Rev Infect Dis 1987;9:855.
Actinomycosis causes several types of CNS disease, particularly brain abscess. An isolated chronic meningitis picture can occur.
Southern PM, Sanford JP. Relapsing fever: a clinical and microbiological review. Medicine (Baltimore) 1969;48:129.
Relapsing fever is associated with CNS disease in 8% of tick-borne and 30% of louse-borne infections.
Steere AC. Lyme disease. N Engl J Med 1989;9:593.
Describes the clinical manifestations of stages 1 through 3 of Lyme disease.
Steere AC, Pachner AR, Malawista SE. Neurologic abnormalities of Lyme disease: successful treatment with high-dose intravenous penicillin. Ann Intern Med 1983;99:767.
Chronic meningeal symptoms caused by Lyme disease resolve with high-dose penicillin therapy.
Stern BJ, et al. Sarcoidosis and its neurological manifestations. Arch Neurol 1985; 42:909.
Sarcoidosis presents with neurologic symptoms in 48% of cases. However, an isolated chronic meningitis syndrome is unusual.
Stern JJ, et al. Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients. Am J Med 1988;85:477.
Fluconazole was useful in preventing cryptococcal meningitis relapse in AIDS patients.
Stockstill MT, Kauffman CA. Comparison of cryptococcal and tuberculous meningitis. Arch Neurol 1983;40:81.
The clinical pictures of tuberculous and cryptococcal meningitis are similar. A miliary pattern on chest x-ray films and inappropriate secretion of antidiuretic hormone support a diagnosis of tuberculous meningitis.
Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982;49:759.
Metastatic carcinoma, particularly from primary carcinoma of lung and breast, can cause chronic meningitis syndrome.
Wheat J, et al. Cerebrospinal fluid Histoplasma antibodies in central nervous system histoplasmosis. Arch Intern Med 1985;145:1237.
CSF antibodies in histoplasmosis meningitis are 90% sensitive. The disease is increasing in HIV-positive patients.
Yechoor VK, et al. Tuberculosis meningitis among adults with and without HIV infection. Experience in an urban public hospital. Arch Intern Med 1996;156:1710.
Tuberculous meningitis was found to be a relatively common disease in urban nonwhites. Underlying HIV disease did not affect clinical or laboratory features of the disease or response to therapy.


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