Subacute or chronic meningitis is characterized by a gradual onset, often without any predisposing factor. These syndromes run their course over weeks, months or years. The clinical signs include headache, fever, stiff neck, and altered consciousness. Lower cranial nerve palsies may accompany basilar meningitis.
Of the treatable conditions, crytococcosis and syphilis can be easily diagnosed on the basis of serology and antigen detection. Lyme disease (Borrelia burgdorferi) with nervous system involvement usually presents as a chronic meningitis and should be suspected if a combination of facial nerve palsy (often bilateral) and aseptic meningitis is present. Later in the course of the disease it may cause an encephalomyelitis, although several patterns of peripheral neuropathies, radiculopathy, and myositis have also been described. The characteristic skin lesion erythema chronicum migrans is often accompanied by secondary annular skin lesions. Other symptoms may include myalgias, arthral-gias, dysesthesias, or abdominal pain. The causative spirochete, Borrelia burgdorferi, is transmitted by the bite of an infected Ixodes tick. Infection can spread hematogenously to, heart, nervous system, joints, and other organs (reviewed in ref. 5).
Fungal meningitis occurs primarily in individuals with immunosuppression. Crypto-coccus neoformans is the most common cause of meningitis in patients with human immunodeficiency virus (HIV) infection and in transplant patients. Other fungal infections that may occur in individuals with defects in cell-mediated immunity may include Coccidioides immites and histoplasmosis. Patients with granulocytopenia or a functional abnormality of granulocytes as is seen in diabetes mellitus are at risk of developing infections due to Candida, Aspergillus fumigatus, and Zygomycetes organisms (mucormycosis). Candida infections may also occur through central lines and in patients on broad-spectrum antibiotic therapy.
Tuberculous meningitis in HIV-infected patients is very similar to that in non-HIV-infected patients, except that the HIV-infected patients are more likely to have symptoms suggestive of extrameningeal tuberculosis. CNS tuberculosis can occur in the absence of pulmonary tuberculosis (6).
Treponema pallidum is a spirochete that causes syphilis. It is now recognized that CNS disease can occur through all stages of the infection. Although several well-characterized CNS syndromes have been described with T. pallidum they can be broadly classified into meningeal involvement (asymptomatic, subacute meningitis, meningo-vascular syphilis) that occurs early and is still common and parenchymal involvement (general paresis, tabes dorsalis, and gumma), which occurs several years after the primary infection and is rare. In contrast to the preantibiotic era, neurosyphilis today is identified in young patients most often with HIV coinfection, and early symptomatic syndromes and asymptomatic neurosyphilis are identified more frequently than late neurosyphilis syndromes (7,8).
Fungal meningitis is commonly present in a state of immunosuppression which is also often associated with thrombocytopenia; hence platelet counts should be per formed prior to performing a lumbar puncture. If the platelet count is <50,000/mm3, platelet transfusion is necessary. Neuroimaging (CT or MRI scan), preferably with contrast, should also be performed in these patients, as fungal meningitis is often associated with intracranial mass lesions. Fungi are typically difficult to isolate and culture from the CSF, because the infection occurs primarily in the basilar cisterns, and fungi are seldom present in the lumbar thecal sac where the lumbar puncture is performed. Hence large volumes (40-50 mL) of CSF are typically necessary for fungal cultures, and to improve the chances of finding the organism, the CSF from the later tubes should be used and it should be centrifuged and the pellet used for cultures and smears. If repeated cultures are negative and it remains essential to establish a diagnosis, a cis-ternal puncture may be considered. Biopsy of the basilar meninges may also be performed, but it carries a high morbidity rate. Biopsy of the cortical meninges is typically negative and hence not useful. For cryptococcus, antigen detection by latex agglutination is the most sensitive and specific test available. However, in HIV-infected patients, cryptococci may be detected by India ink in nearly 80% patients (9).
In tuberculous meningitis, similar to other chronic meningitides, a lymphocytic pleocy-tosis is commonly seen in the CSF. However, early in the course of the illness (2-3 d) polymorphonuclear cells may be present which are replaced by lymphocytes (10). Similarly, following initiation of antituberculous therapy polymorphonuclear cells may reappear in the CSF (11). Because tuberculous meningitis is also a basilar meningitis, similar guidelines should be followed with regards to collection and processing of CSF as discussed previously. In addition, in some patients with tuberculous meningitis, owing to the large amount of protein present, a cobweb-like clot may appear on the surface of the fluid if kept undisturbed for a few hours. Tubercle bacilli get trapped in this proteinaceous material and can be identified by a acid-fast bacilli (AFB) smear. Alternatively, by adding 95% alcohol to the CSF the proteins can be precipitated and then examined. Smears are positive in approx 10-30% patients with tuberculous meningitis. Cultures require 3-6 wk and are positive in approx 75% patients. Polymerase chain reaction for M. tuberculosis may help establish the diagnosis early.
Two types of serological tests are available for diagnosing syphilis, broadly called tryponemal and nontreponemal tests. The tryponemal tests detect specific antibodies against Tryponema pallidum antigens and include the fluorescent treponemal antibody absorption test (FTA-ABS) and the microhemagglutination-T pallidum test (MHA-TP). The nontreponemal tests detect antibodies against lipid antigens on the membrane of T. pallidum and include the Veneral Disease Research Laboratory test (VDRL) and the rapid plasma reagin test (RPR). The treponemal tests become positive earlier in the course of infection and are more specific than the nontreponemal tests. A large number of conditions have been described in which false-positive syphilis serology may occur (12). Most studies use a newly reactive positive CSF VDRL as a criteria for diagnosis of asymptomatic neurosyphilis. In two large prospective studies of CNS syphilis, CSF findings of patients with and without HIV infection were compared (13). The frequency of isolation of T. pallidum was similar in both instances, the only difference being the presence of a slightly greater lympho-cytosis in the HIV-infected patients.
For diagnosis of Lyme disease, positive or equivocal results on an enzyme-linked immunosorbent assay (ELISA), immunofluorescent assay (IFA), or immunodot assay requires supplemental testing with a Western blot assay. A negative result on the West-
em blot or ELISA indicates that there is no serologic evidence of infection by B. burgdorferi (14).
Once polymerase chain reaction (PCR) techniques become available for clinical use, they will revolutionize the diagnosis of chronic meningitis, owing to their extreme sensitivity and rapidity with which the diagnosis can be established (15,16).
For all types of fungal meningitis, intravenous amphotericin B is the treatment of choice. The major side effect of amphotericin B is renal impairment; hence renal functions should be monitored every other day for the first month and then weekly for the duration of therapy. Addition of flucytosine allows a dose reduction of amphotericin B and hence decreases the chance of developing nephrotoxicity. However, at serum concentrations >100 ^g/mL bone marrow suppression may occur and therefore drug levels should be monitored regularly. The risk of bone marrow suppression should be carefully weighed in patients with acquired immunodeficiency syndrome (AIDS) who may be on other drugs with similar side effects. In patients with AIDS and fungal meningitis, maintenance therapy with fluconazole is necessary for life (17).
Treatment requires the use of intravenous and intrathecal amphotericin B administered preferably by an Ommaya reservoir. It is recommended that treatment be continued for at least 1 yr after the CSF returns to normal. Intrathecal steroids may be used to decrease drug related inflammatory reaction.
In non-AIDS patients a clinical trial that compared fluconazole to amphotericin B showed that treatment with fluconazole required 36% fewer days of hospitalization (18). In non-AIDS patients, a negative or low cryptococcal antigen titer suggests that the infection is adequately treated. However, in patients with AIDS, CSF cryptococcal antigen may remain positive despite adequate treatment owing to release of antigen from dead cells or slow clearing of the antigen from the CSF. Hence the clinical status is the best indicator for response to therapy and repeated CSF evaluations are not needed. Serum cryptococcal antigen titers are useful in patients on maintenance therapy. A rising titer indicates a relapse and requires confirmation with cultures. Prognostic factors in AIDS patients includes the titer of cryptococcal antigen in CSF, serum albumin level, and CD4 cell count, which together with dose of amphotericin B, have the strongest association with failure to achieve negative CSF cultures by d 14 (19).
Initiation of empiric chemotherapy should not await the results of CSF cultures (20). Isoniazid and pyrazinamide have excellent penetration of the blood-CSF and blood-brain barriers even under noninflamed conditions and hence form the backbone of all antituberculosis therapy. Treatment of tuberculous meningitis in non-AIDS patients should be initiated with isoniazid, rifampicin, and pyrazinamide. Pyridoxine is given to prevent isoniazid-induced peripheral neuropathy. If antimicrobial resistance is suspected, ethambutol may also be added. Once a clinical response is noted, pyrazi-namide and ethambutol may be discontinued (usually after 2 mo of treatment). Isoniazid and rifampicin should be continued for 9-12 mo. In patients with HIV infection it is recommended that treatment be initiated with four drugs: isoniazid; rifampicin; the third drug, which should be either ethambutol or pyrazinamide; to and the fourth drug, which should be streptomycin, rifabutin, or clofazimine. The recommended dosage for isoniazid is two to three times that of non-AIDS patients (i.e., 10-15 mg/kg/d). Hence these patients should be carefully monitored for the development of peripheral neuropathy. Ethambutol causes a dose-related optic neuropathy, while rifampicin, pyrazinamide, and isoniazid can be hepatotoxic. The American Academy of Pediatrics (21) recommends the use of isoniazid, rifampicin, pyrazinamide, and streptomycin for 2 mo followed by isoniazid and rifampicin for another 2 mo. They recommend that liver function be monitored for the first several months. The Academy also recommends that the use of corticosteroids be considered in this patient population. Dexamethasone (0.3-0.5 mg/kg/d) is to be given during the first week of therapy followed by prednisone staring at 2 mg/kg/d and gradually tapered over 3-4 wk. The steroids decrease cerebral edema and the inflammatory reaction (22).
Penicillin is the drug of choice for neurosyphilis treatment. However, the total dose, the most appropriate formulation, and the duration of therapy remain a subject of debate. The CDC recommends intravenous crystalline penicillin G, 12-24 million units daily in divided dosages at 4-h intervals for 10-14 d. Lower dosages do not provide adequate CSF levels of the drug. An alternative regimen is the use of procaine penicillin, 2.4 million units given intramuscularly daily, plus probenecid, 500 mg orally, four times daily for 10-14 d (23). The interactions of HIV and syphilis are still not completely understood. However, patients with syphilis and HIV infection are at increased risk for treatment failure, so that higher dosages of penicillin given for 10-14 d offer no clear advantage over standard regimens (24). Careful observation coupled with a low threshold for repeat CSF evaluation remains the recommended management strategy for these patients (25). In patients allergic to penicillin, tetracy-clines, chloramphenicol and ceftriaxone have been suggested based on case reports. Erythromycin frequently results in treatment failure.
Intravenous ceftriaxone or cefotaxime are the treatment of choice for nervous system involvement with Lyme disease due to their good CSF penetration and long halflife (26,27). However controlled trials have shown that intravenous penicillin (28) and doxycycline may be just as effective (29,30). Courses of therapy ranging from 10 to 21 d are supported by the available evidence, although the optimal duration of therapy is unknown (31). Recently a vaccine has become available for human use for individuals at high risk (32).
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