on 20-Oct-2022 (Thu)

The onset of symptoms of acute meningitis typically is abrupt with progression over hours, but some patients become ill over several days, especially when early symptoms are not appreciated. (See "Clinical features and diagnosis of acute bacterial meningitis in adults".)

However, a small number of patients with acute meningitis may develop recurrent attacks between intervals of good health. (See "Approach to the adult with recurrent infections", section on 'Meningitis'.)

Chronic meningitis is arbitrarily defined as meningitis lasting for four weeks or more and is a complex entity with both infectious and noninfectious causes [1-7].

Patients with chronic meningitis usually have a subacute onset of symptoms including fever, headache, and vomiting. The symptoms can remain static, fluctuate, and/or slowly worsen. The symptoms and clinical course of chronic meningitis vary widely from patient to patient.

LIMITATIONS OF THE LITERATURE — Because of its rarity and the diversity of causes, the literature on chronic meningitis consists largely of case reports and a small number of retrospective case series from single centers. Selection, publication, and ascertainment biases greatly limit the utility of this literature for assessing the relative proportions of patients with any given etiologic diagnosis and for assessing the natural history of individual patients with chronic meningitis

Most of these case series describe patients from referral centers or geographic areas where selection bias was likely because of unique patient populations or because of local referral patterns. For example, one case series summarizing the clinical features of 83 patients with chronic meningitis collected over a 16-year period in a referral hospital in New Zealand reported that 40 percent of patients had tuberculous (TB) meningitis and that an additional 17 percent of patients responded to empiric antituberculous therapy [9]. However, most of the patients with TB described in this report were Maori people or Pacific Islanders.

An array of infectious agents can present as chronic meningitis, but a nearly identical syndrome can result from a number of inflammatory, malignant, or other noninfectious diseases (table 1) [5,6,12,13]. Despite extensive testing, an etiologic diagnosis may not be determined in up to one-third of all patients.

The initial evaluation of patients with chronic meningitis is often complex and difficult. In some cases, the diagnosis is first suspected and later confirmed because of subtle historical or epidemiologic clues or because of associated clinical findings that at first glance may seem to be incidental. For example, the presence of iritis or uveitis or the finding of localized cutaneous lesions may provide a crucial clue to the presence of diseases, such as sarcoidosis, Behçet syndrome, granulomatosis with polyangiitis, uveo-meningitis syndromes, or a systemic fungal infection that initially manifested as chronic meningitis. Similarly, the simultaneous presence of deafness and optic neuritis and uveitis are strong clues to a diagnosis of Vogt-Koyanagi-Harada syndrome

Similarly, patients with viral or postinfectious encephalitis (also known as acute disseminated encephalomyelitis) and a small percentage of patients with partially treated bacterial meningitis may have symptoms lasting for more than a month and thus may be erroneously considered to have chronic meningitis. (See "Viral encephalitis in adults", section on 'Viral versus postinfectious encephalitis'.)

The clinical symptoms of patients with chronic meningitis rarely point to a specific etiologic diagnosis. However, occasionally, a historical or epidemiologic clue can lead to the discovery of an otherwise obscure diagnosis (table 2).

Patients with coccidioidomycosis may acquire their infection after short stays in airports in endemic areas, and such information may be missed unless a meticulous history is obtained. Thus, all patients with chronic meningitis should be questioned about travel or residence in geographic areas known to be endemic for coccidioidomycosis, histoplasmosis, paracoccidioidomycosis, blastomycosis, schistosomiasis, trypanosomiasis, Angiostrongylus cantonensis infection, or cysticercosis.

A past history of a positive tuberculin skin test or an interferon-gamma release assay, current or prior treatment with a tumor necrosis factor-alpha inhibitor, or of a known exposure to tuberculosis (TB) may be enough justification to institute empiric therapy for tuberculous meningitis or to pursue this diagnosis further with special cultures or testing based upon polymerase chain reaction (PCR) technology, especially if preexisting infection with HIV is present. (See "Central nervous system tuberculosis: An overview".)

The immune status of all patients with chronic meningitis should be assessed by both history and laboratory testing. Patients should be questioned about risk factors for both HIV and human T-lymphotropic virus I and II (eg, a history of injection drug use, sexual promiscuity) and about possible or known exposure to syphilis.

Lyme disease is a rare cause of chronic meningitis, but patients should be asked about a past history of skin lesions typical or suggestive of erythema migrans or travel to or contact with ticks in an endemic area for Borrelia burgdorferi infection.

A careful review of all recent medications including the use of immunosuppressive drugs, immunoglobulin therapy, and nonsteroidal anti-inflammatory agents should be undertaken.

Patients should be questioned about contact with animals, including cats and wild game, or meat processing.

The presence or absence of systemic symptoms suggesting a vasculitic disorder, such as granulomatosis with polyangiitis, systemic lupus erythematosus, or Behçet syndrome, should be sought. For example, a history of iritis, recurrent genital or oral ulcers, or of nasal inflammation may lead to a diagnosis of Behçet syndrome

The presence of systemic symptoms such as weight loss, unexplained cough, or night sweats may be difficult to assess, since such symptoms can occur as a consequence of chronic meningitis or be related to an underlying malignancy that is the primary cause of the inflammatory reaction in the central nervous system (CNS)

A history of invasive spinal procedures, such as glucocorticoid injections for spinal pain, can be an important diagnostic clue to the presence of fungal meningitis due to contaminated glucocorticoids. (See "Central nervous system infections due to dematiaceous fungi (cerebral phaeohyphomycosis)", section on 'Outbreaks'.)

Careful questioning about the onset of symptoms is important, as it can help to determine if symptoms are intermittent (ie, more compatible with recurrent meningitis) or continuous.

The decision regarding which laboratory tests to perform should be based upon the clinical features of each individual patient and the probability that a specific disease is present. For example, routine evaluation of patients with chronic meningitis usually includes a tuberculin skin test, a chest radiograph, and serologic testing for syphilis as well as testing for the presence of HIV infection. However, tests for other infectious diseases such as Lyme disease, brucellosis, cysticercosis, trypanosomiasis, and/or schistosomiasis are only necessary in patients in whom there is reasonable pretest probability that the disease or condition is present

Antigen testing of the CSF for the presence of C. neoformans and a Venereal Disease Research Laboratory test for syphilis should be performed on all patients with chronic meningitis. The sensitivity and specificity of testing for cryptococcal meningitis is extremely high [5]; however, capsule-deficient strains of C. neoformans can rarely cause a false-negative antigen test [15].

Most patients with chronic meningitis have a predominance of lymphocytes, although a small percentage of patients have a predominance of neutrophils [16]. The differential diagnosis of chronic meningitis with a neutrophil predominance includes nocardiosis, brucellosis, and the endemic mycoses (table 4).

Nontuberculous mycobacteria can also cause chronic meningitis associated with a predominantly neutrophilic response in some cases and with a lymphocytic response in others

Occasionally, gram-positive rods may be visualized in the CSF of patients with chronic meningitis due to nontuberculous mycobacteria [ 17].

A sample of CSF should be submitted for cultures using media appropriate for growth of aerobic bacteria, mycobacteria, and fungi. If routine cultures are negative, it is sometimes useful to send 10 to 20 mL of CSF to the microbiology laboratory with instructions to culture the entire sample on appropriate media.

Polymerase chain reaction (PCR) testing of a sample of CSF using primers specific for Mycobacterium tuberculosis may be useful in some cases, and is discussed in detail elsewhere. (See "Tuberculous meningitis: Clinical manifestations and diagnosis", section on 'Nucleic acid amplification tests'.)

If brucellosis is suspected on the basis of epidemiologic clues such as exposure to unpasteurized milk or milk products, blood and CSF should be cultured using media incubated in a high concentration of carbon dioxide for three weeks, and serum should be tested for the presence of anti-Brucella antibodies.

Whipple's disease has been rarely associated with chronic meningitis and, in such cases, PCR testing of CSF has been diagnostic [ 18].

If routine tests fail to disclose a likely pathogen or a likely cause for the meningitis, at least 20 to 30 mL of CSF should also be sent for cytologic examination, flow cytometry, and immunoglobulin heavy-chain rearrangement studies by PCR

Serum antibody tests for fungal pathogens may not accurately detect the presence of a fungal pathogen in the CSF. Some patients with meningitis due to Histoplasma capsulatum, for example, do not have detectable antibody titers in the serum, yet antibodies against H. capsulatum or antigen can be detected in the CSF [19,20]

1,3-Beta-D-glucan, a cell wall component of many fungi, is detected by the beta-D-glucan assay. The serum beta-D-glucan assay may be positive in patients with a variety of invasive fungal infections, including invasive candidiasis. The beta-D-glucan assay using CSF might be a useful adjunct to CSF cultures in patients with chronic Candida meningitis [22].

Testing of serum for antibodies to Brucella, Ehrlichia/Anaplasma, Mycoplasma pneumoniae [25], and Toxoplasma gondii can rarely yield a diagnosis in a patient with chronic meningitis, but a single positive antibody test may not be diagnostic of active infection.

As an example, a study evaluating the utility of metagenomic sequencing of CSF specimens from 80 patients with chronic meningitis found that only 15 percent of these samples yielded any organisms, and in half of these cases the detected organism was considered to be inconsistent with the clinical presentation [28].

Although CSF obtained from the lumbar space is usually adequate to diagnose most causes of meningitis, obtaining spinal fluid from the ventricular space for the examination may be useful in rare cases (eg, patients with ventriculitis) [15,29].

Imaging studies — Magnetic resonance imaging (MRI) and computed tomography (CT) are useful in the evaluation of patients with chronic meningitis, but these imaging techniques lead to a specific diagnosis in a minority of patients. However, such imaging is important since it can exclude important abnormalities such as a parameningeal focus of infection, abscess, or a tumor.

Chest radiographs should be obtained in all patients with chronic meningitis. Such radiographs can lead to a diagnosis such as tuberculosis (TB), sarcoidosis, a systemic fungal infection, or a malignancy. Further imaging with a chest CT should be pursued if chest radiographs are negative and suspicion for one of these diagnoses is high.

In one case series involving 37 patients with chronic meningitis of unknown cause who eventually underwent a biopsy, a definitive diagnosis was made in 16 of 41 biopsies (39 percent) [11]. However, when a biopsy was performed in an area of meningeal enhancement on either MRI or CT, a diagnosis was obtained in 12 of 15 cases (80 percent). In contrast, surgical biopsy was diagnostic in only 2 of 22 cases (9 percent) in which the MRI showed no enhancing regions.

The findings in the preceding study are in contrast with earlier studies that failed to show a similarly high yield from meningeal biopsy.

Antituberculous therapy — If a diagnosis is not established by the above diagnostic modalities and if symptoms are severe or fail to improve after a period of observation, empiric therapy with antituberculous therapy may be useful (even if the tuberculin skin test is negative).

Concurrent steroid therapy should ideally be avoided during an empiric trial of antituberculous medication because it may obscure the evaluation of the clinical response. However, in patients with severe symptoms, concurrent steroid therapy is reasonable and appropriate. If no improvement occurs after four to six weeks of empiric antituberculous therapy and if all mycobacterial cultures remain negative, antituberculosis therapy can reasonably be discontinued.

Glucocorticoids — Empiric glucocorticoid therapy may be useful in selected patients who fail to improve during follow-up, despite the absence of carefully controlled studies demonstrating benefit in patients with chronic meningitis.

ntibacterial or antiviral therapy — Empiric antibacterial therapy is rarely indicated unless there are specific clues such as a neutrophilic pleocytosis or there is other evidence of prior clinically suspected but partially treated central nervous system (CNS) or parameningeal bacterial infection. Antiviral therapy is usually not useful unless the diagnosis of Mollaret's meningitis is thought to be possible or likely.

Prognosis — Despite numerous difficulties in establishing reliable data on prognosis, most patients with chronic meningitis in whom a diagnosis cannot be established after a thorough workup have a relatively good outcome. Symptoms either resolve or remain stable over follow-up periods, ranging from one to three years. Repeated diagnostic evaluations in this subgroup of patients will reveal a diagnosis in a minority of cases; the most likely diagnosis to be uncovered during follow-up is neoplasm.