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Subacute meningitis develops over days to a few weeks. Chronic meningitis lasts ≥ 4 wk. Possible causes include fungi, Mycobacterium tuberculosis, rickettsiae, spirochetes, Toxoplasma gondii, HIV, enteroviruses, and disorders such as autoimmune rheumatic disorders (eg, SLE, RA) and cancer. Symptoms and signs are similar to those of other meningitides but more indolent. Cranial nerve palsies and infarction (due to vasculitis) may occur. Diagnosis requires analysis a large volume of CSF (typically obtained via repeated lumbar punctures) and sometimes biopsy or ventricular or cisternal puncture. Treatment is directed at the cause.
Chronic meningitis may last > 25 yr. Subacute and chronic meningitis may result from a wide variety of organisms and conditions. Rarely, chronic meningitis has a protracted benign course, then resolves spontaneously.
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Table 10
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Major Infectious Causes of Subacute or Chronic Meningitis |
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Organisms
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Circumstances
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Bacteria
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Mycobacteria: (Mycobacterium tuberculosis, rarely other mycobacteria)
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—
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Spirochetes: Lyme disease, syphilis, rarely leptospirosis
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For Lyme disease, East Coast, upper Midwest, California, Oregon
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Brucella sp
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Associated with livestock
Unusual in the US or other developed countries
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Ehrlichia sp
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—
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Fungi
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Cryptococcus neoformans
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—
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C. gattii
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Predominantly northern Pacific coast
May have more widespread distribution
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Coccidioides immitis
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Southwestern US
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Histoplasma capsulatum
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Central and Eastern US
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Blastomyces sp
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Predominantly Central and Eastern US
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Sporothrix sp (unusual)
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No geographic distribution, but infection associated with rose thorns or brush
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Parasites
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Toxoplasma gondii
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—
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Viruses
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Retroviruses: HIV, HTLV-1
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In patients with known HIV or risk factors
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Enteroviruses
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In patients with a congenital immunodeficiency syndrome
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Tuberculous meningitis:
M. tuberculosis are aerobic bacteria that replicate in host cells; thus, control of these bacteria depends largely on T cell-mediated immunity. These bacteria may infect the CNS during primary or reactivated infection. In developed countries, meningitis usually results from reactivated infection. Meningeal symptoms usually develop over days to a few weeks but may develop much more rapidly or gradually. Characteristically, M. tuberculosis causes a basilar meningitis that results in 3 complications:
Diagnosis of tuberculous meningitis may be difficult. There may be no evidence of systemic tuberculosis. Inflammation of the basilar meninges, shown by contrast-enhanced CT or MRI, suggests the diagnosis. Characteristically, CSF findings include mixed pleocytosis with lymphocytic predominance, low glucose, and elevated protein (see Meningitis: CSF Findings in Meningitis ). Occasionally, the first CSF abnormality is extremely low glucose.
Detecting the causative organism is often difficult because
Serum interferon-γ assays can detect prior tuberculosis but do not necessarily confirm M. tuberculosis as the cause of meningitis.
Because tuberculous meningitis has a rapid and destructive course and because diagnostic tests are limited, this infection should be treated based on clinical suspicion. Currently, the WHO recommends treatment with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 mo followed by isoniazid and rifampin for 6 to 7 mo (see Mycobacteria: Tuberculosis (TB)). Corticosteroids (prednisone or dexamethasone) may be added if patients present with stupor, coma, or neurologic deficits.
Meningitis due to spirochetes:
Lyme disease is a chronic spirochetal infection caused by Borrelia burgdorferi in the US and by B. afzelii and B. garinii in Europe. The disease is spread by Ixodes ticks, usually the deer tick in the US. In the US, 12 states account for 95% of cases. The states include mid-Atlantic and northeastern coastal states, Wisconsin, California, Oregon, and Washington. Up to 8% of children and some adults who contract Lyme disease develop meningitis. The meningitis may be acute or chronic; usually, it begins more slowly than acute viral meningitis.
Clues to the diagnosis include
CSF findings typically include lymphocytic pleocytosis, moderately elevated protein, and normal glucose. Diagnosis is based on serologic tests with enzyme-linked immunosorbent assay (ELISA), followed by Western blot analysis to confirm. In some laboratories, false-positive rates may be unacceptably high. Treatment is with cefotaxime or ceftriaxone given over 14 days. Doses for cefotaxime are 150 to 200 mg/kg/day IV in 3 to 4 divided doses (eg, 50 mg tid to qid) for children and 2 g IV q 8 h for adults. Doses for ceftriaxone are 50 to 75 mg/kg/day IV (2 g maximum) once/day for children and 2 g IV once/day for adults. Clinicians should remember that concomitant anaplasmosis or babesiosis is possible in patients with severe disease.
Syphilitic meningitis is less common; it is usually a feature of meningovascular (secondary) syphilis. The meningitis may be acute or chronic. It may be accompanied by complications such as cerebrovascular arteritis (possibly causing thrombosis with ischemia or infarction), retinitis, cranial nerve deficits (especially of the 7th cranial nerve), or myelitis. CSF findings may include pleocytosis (usually lymphocytic), elevated protein, and low glucose. These abnormalities may be more pronounced in patients with AIDS. Diagnosis is based on serum and CSF serologic tests, followed by fluorescent treponemal antibody absorption (FTA-ABS) testing to confirm. MR angiography and cerebral angiography may accurately differentiate between parenchymal disease and arteritis. Patients are treated with aqueous penicillin 12 to 24 million units IV/day given in divided doses q 4 h (eg, 2 to 4 million units q 4 h) for 10 to 14 days.
Cryptococcal meningitis:
Cryptococcal meningitis is the most common cause of chronic meningitis in the Western hemisphere and the most common opportunistic infection in patients with AIDS. Cryptococcus neoformans var. neoformans (serotype D strains) and C. neoformans var. grubii (serotype A strains) are common causes of cryptococcal meningitis in the US; C. neoformans var. grubii causes 90% of cases. C. neoformans can be in soil, trees, and pigeon or other bird excreta. Meningitis due to C. neoformans usually develops in immunocompromised patients but occasionally develops in patients without apparent underlying disease. Another cryptococcal species, C. gattii, has caused meningitis in the Pacific region and Washington state; it may cause meningitis in people with a normal immune status.
Cryptococci cause a basilar meningitis with hydrocephalus and cranial nerve deficits; vasculitis is less common. Meningeal symptoms usually begin insidiously, with protracted relapses and remissions. CSF findings typically include lymphocytic pleocytosis, elevated protein, and low glucose. However, cellular response may be minimal or absent in patients with advanced AIDS or another severe immunocompromised state.
Diagnosis is based on cryptococcal antigen tests and fungal culture; diagnostic yield with these tests is 80 to 90%. India ink preparation, which has a sensitivity of 50%, may also be used.
Patients who have C. neoformans meningitis but do not have AIDS are traditionally treated with the synergistic combination of 5-fluorocytosine and amphotericin B. Patients with cryptococcal meningitis and AIDS are treated with amphotericin B plus flucytosine (if tolerated) followed by fluconazole.
Fungal meningitis that develops after epidural methylprednisolone injection:
Occasionally, outbreaks of fungal meningitis have occurred in patients given spinal epidural injections of methylprednisolone. In each case, the drug had been prepared by a compounding pharmacy, and there were significant violations of sterile technique during drug preparation. The first outbreak in the United States (in 2002) resulted in 5 cases of meningitis. The most recent outbreak (in 2012) resulted in 414 cases of meningitis, stroke, myelitis, or other fungal infection-related complications and in 31 deaths. Outbreaks have also occurred in Sri Lanka (7 cases) and Minnesota (1 case). Most cases were caused by Exophiala dermatitidis in 2002 and by Exserohilum rostratum in 2012; a few cases were caused by Aspergillus or Cladosporium sp.
The meningitis tends to develop insidiously, often with infection at the base of the brain; blood vessels may be affected, resulting in vasculitis and stroke. Headache is the most common presenting symptoms, followed by altered cognition, nausea or vomiting, or fever. Signs of meningeal irritation are absent in about one third of patients. Typical CSF findings include neutrophilic pleocytosis, elevated protein, and frequently low glucose.
The most sensitive test for Exserohilum meningitis is a PCR test, available through the Centers for Disease Control and Prevention; in a few cases, the diagnosis can be based on culture. Aspergillus meningitis may be suspected if galactomannan levels in CSF are elevated; diagnosis is based on culture.
Meningitis due to Exophiala or Exserohilum sp is rare, and definitive treatment is not known. However, voriconazole 6 mg/kg/day IV is recommended initially. Drug dosage should be adjusted based on blood levels of the drug. Liver enzyme and Na levels should be measured periodically during the 2 to 3 wk after initiation of treatment. Prognosis is guarded, and appropriate treatment does not guarantee survival.
Other fungal meningitides:
Coccidioides, Histoplasma, Blastomyces, Sporothrix, and Candida sp may all cause chronic meningitis similar to that caused by C. neoformans. Coccidioides sp are confined to the American Southwest (predominantly southern Utah, New Mexico, Arizona, and California). Histoplasma and Blastomyces sp occur predominantly in the central and eastern US. Thus, if patients with subacute meningeal symptoms reside in or travel to this region, clinicians should suspect the appropriate fungal causes.
CSF findings typically include lymphocytic pleocytosis, elevated protein, and low glucose. Candida sp may also cause polymorphonuclear pleocytosis.
Coccidioidal meningitis tends to resist treatment and may require lifelong treatment with fluconazole.
Voriconazole and amphotericin B have also been used. Treatment of the other fungal meningitides is usually with amphotericin B.
Other causes of chronic meningitis:
Rarely, other infectious organisms and some noninfectious disorders (see Meningitis: Some Noninfectious Causes of Meningitis) cause chronic meningitis.Noninfectious causes include
Chronic idiopathic meningitis:
Occasionally, chronic, usually lymphocytic meningitis persists for months or even years, but no organisms are identified; and death does not result. In some patients, the meningitis eventually remits spontaneously. Generally, empiric trials of antifungal drugs or corticosteroids have not been helpful.
Chronic meningitis in patients with HIV infection:
Meningitis is common among HIV-infected patients. Most CSF abnormalities result from HIV, which invades the CNS early in the course of the infection. Onset of meningitis and meningeal symptoms often coincides with seroconversion. Meningitis may then remit or follow a steady or fluctuating course. However, many other organisms can cause chronic meningitis in patients with HIV infection. They include C. neoformans (the most common), M. tuberculosis, Treponema pallidum, B. burgdorferi, Toxoplasma gondii, Coccidioides immitis, and other fungi. CNS lymphoma can also cause findings similar to those of meningitis in these patients.
Regardless of the cause, parenchymal lesions may develop.
Diagnosis
Clinical findings are often nonspecific. However, a careful search for a systemic infection or disorder may suggest a cause for meningitis. Also, sometimes risk factors (eg, immunocompromise, HIV infection or risk factors for it, recent time spent in endemic areas) and occasionally specific neurologic deficits (eg, particular cranial nerve deficits) suggest specific causes, such as C. neoformans meningitis in HIV-infected patients or C. immitis infections in patients living in the southwestern US.
Typically, CSF findings include lymphocytic pleocytosis. In many of the infections that cause chronic meningitis, CSF contains only a few of the organisms, making identification of the cause difficult. Thus, diagnosis based on CSF findings may require multiple large samples over time, particularly for cultures. CSF analysis commonly includes
If CSF findings do not provide a diagnosis and meningitis is causing morbidity or is progressive, more invasive testing (eg, cisternal or ventricular puncture, biopsy) is indicated. Occasionally, organisms are recovered from ventricular or cisternal CSF when lumbar CSF is negative. MRI or CT may be done to identify focal areas of inflammation for biopsy; blind meningeal biopsy has a very low yield.
Treatment
Treatment is directed at the cause (for mycobacterial, spirochetal, and fungal meningitides, see above; for other causes, see elsewhere in the manual).
Key Points
Last full review/revision February 2013 by John E. Greenlee, MD
Content last modified March 2013
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