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Subacute and Chronic Meningitis

By John E. Greenlee, MD

Last full review/revision November 2015 by John E. Greenlee, MD

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 of 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. Rarely, chronic meningitis has a protracted benign
course, then resolves spontaneously.

Subacute and chronic meningitis may result from a wide variety of organisms and conditions.

Major Infectious Causes of Subacute or Chronic Meningitis

Organisms Circumstances

Organisms Circumstances


Mycobacteria: ( Mycobacterium —
tuberculosis, rarely other mycobacteria)

Spirochetes: Lyme disease, syphilis, For Lyme disease, East Coast, upper Midwest,
rarely leptospirosis California, Oregon
Associated with livestock
Brucella sp
Unusual in the US or other developed countries

Ehrlichia sp —
Associated with exposure to urine of rats,
Leptospira sp mice, and other animals

Unusual in Western countries


Cryptococcus neoformans —

CSF findings include  Mixed pleocytosis with lymphocytic predominance  Low glucose . control of these bacteria depends largely on T cell-mediated immunity (see Tuberculosis (TB)). tuberculosis causes a basilar meningitis that results in 3 complications:  Hydrocephalus due to obstruction of the foramina of Luschka and Magendi or the aqueduct of Sylvius  Vasculitis. Meningeal symptoms usually develop over days to a few weeks but may develop much more rapidly or gradually. meningitis usually results from reactivated infection. HTLV-1 In patients with known HIV or risk factors Enteroviruses In patients with a congenital immunodeficiency syndrome Tuberculous meningitis M. sometimes causing arterial or venous occlusion and stroke  Cranial nerve deficits. but infection associated with rose thorns or brush Parasites Toxoplasma gondii — Viruses Retroviruses: HIV. M. Inflammation of the basilar meninges. Characteristically. shown by contrast-enhanced CT or MRI. gattii Appears to have a widespread distribution Coccidioides immitis Southwestern US Histoplasma capsulatum Central and Eastern US Blastomyces sp Predominantly Central and Eastern US Sporothrix sp (unusual) No geographic distribution. These bacteria may infect the CNS during primary or reactivated infection. Characteristically. In developed countries. Predominantly northern Pacific coast C. VII. thus. suggests the diagnosis. tuberculosis are aerobic bacteria that replicate in host cells. and VIII Diagnosis of tuberculous meningitis may be difficult. There may be no evidence of systemic tuberculosis. particularly of cranial nerves II.

Corticosteroids (prednisone or dexamethasone) may be added if patients present with stupor. rifampin. the first CSF abnormality is extremely low glucose. it begins more slowly than acute viral meningitis. Currently. tuberculosis DNA and resistance to rifampicin in CSF specimens. or neurologic deficits. Meningitis due to spirochetes Lyme disease is a chronic spirochetal infection caused by Borrelia burgdorferi in the US and by B. California. and ethambutol for 2 mo followed by isoniazid and rifampin for 6 to 7 mo (see Tuberculosis (TB) : First-line drugs). This test detects M. garinii in Europe. Detecting the causative organism is often difficult because  CSF acid-fast staining is ≤ 30% sensitive. usually. The disease is spread by Ixodes ticks. coma. The meningitis may be acute or chronic. Up to 8% of children and some adults who contract Lyme disease develop meningitis.  CSF mycobacterial cultures are only about 70% sensitive and require up to 6 wk. Because tuberculous meningitis has a rapid and destructive course and because diagnostic tests are limited. the WHO recommends treatment with isoniazid. The states include mid-Atlantic and northeastern coastal states. this infection should be treated based on clinical suspicion. Clues to the diagnosis include  Time spent in wooded areas and travel to an endemic area (including in Europe)  History of erythema migrans or other symptoms of Lyme disease  Unilateral or bilateral facial palsy (common in Lyme disease but rare in most viral meningitides)  Papilledema (well-described in children with Lyme disease but rare in viral meningitis) CSF findings typically include  Lymphocytic pleocytosis  Moderately elevated protein  Normal glucose . In the US. and Washington. An automated rapid nucleic acid amplification test called Xpert MTB/RIF has been recommended by the WHO for the diagnosis of tuberculous meningitis. afzelii and B.  Elevated protein (see Table: CSF Findings in Meningitis) Occasionally. Wisconsin. 12 states account for 95% of cases. pyrazinamide.  CSF PCR is about 50 to 70% sensitive. Oregon. usually the deer tick in the US.

Another cryptococcal species. neoformans usually develops in immunocompromised patients but occasionally develops in patients without apparent underlying disease. neoformans can be in soil. Meningitis due to C. CSF findings may include pleocytosis (usually lymphocytic). Clinicians should remember that concomitant anaplasmosis or babesiosis is possible in patients with severe disease. The meningitis may be acute or chronic. and low glucose. it may cause meningitis in people with a normal immune status. 2 to 4 million units q 4 h) for 10 to 14 days. C. neoformans var. retinitis. MR angiography and cerebral angiography may accurately differentiate between parenchymal disease and arteritis.Diagnosis of Lyme disease is based on serologic tests with enzyme-linked immunosorbent assay (ELISA). at times with protracted relapses and remissions. false- positive rates may be unacceptably high. cranial nerve deficits (especially of the 7th cranial nerve). grubii causes 90% of cases. Doses for cefotaxime are 150 to 200 mg/kg/day IV in 3 to 4 divided doses (eg. gattii. Patients with syphilitic meningitis are treated with aqueous penicillin 12 to 24 million units IV/day given in divided doses q 4 h (eg. Common causes of cryptococcal meningitis in the US are  Cryptococcus neoformans var. In some laboratories. it is usually a feature of meningovascular syphilis. Cryptococci cause a basilar meningitis with hydrocephalus and cranial nerve deficits. Diagnosis of syphilitic meningitis is based on serum and CSF serologic tests. These abnormalities may be more pronounced in patients with AIDS. vasculitis is less common. and pigeon or other bird excreta. neoformans (serotype D strains)  C. followed by fluorescent treponemal antibody absorption (FTA-ABS) testing to confirm. Syphilitic meningitis is less common. It may be accompanied by complications such as cerebrovascular arteritis (possibly causing thrombosis with ischemia or infarction). 50 mg tid to qid) for children and 2 g IV q 8 h for adults. neoformans var. or myelitis. C. followed by Western blot analysis to confirm. 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. 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 (see Cryptococcosis). elevated protein. Treatment of Lyme meningitis is with cefotaxime or ceftriaxone given over 14 days. CSF findings typically include  Lymphocytic pleocytosis . Meningeal symptoms usually begin insidiously. grubii (serotype A strains) C. has caused meningitis in the Pacific region and Washington state. trees.

Signs of meningeal irritation are absent in about one third of patients. the diagnosis can be based on culture. Fungal meningitis that develops after epidural methylprednisolone injection Occasionally. The most recent outbreak (in 2012) resulted in 414 cases of meningitis. stroke. . diagnostic yield with these tests is 80 to 90%. Headache is the most common presenting symptoms. may also be used. resulting in vasculitis and stroke. followed by altered cognition. or fever. available through the Centers for Disease Control and Prevention. The first outbreak in the United States (in 2002) resulted in 5 cases of meningitis. Typical CSF findings include  Neutrophilic pleocytosis  Elevated protein  Frequently low glucose The most sensitive test for Exserohilum meningitis is a PCR test. often with infection at the base of the brain. outbreaks of fungal meningitis have occurred in patients given spinal epidural injections of methylprednisolone. In each case. Symptoms may be delayed by as much as 6 mo after the epidural injection. Diagnosis of cryptococcal meningitis is based on cryptococcal antigen tests and fungal culture. neoformans meningitis but do not have AIDS are traditionally treated with the synergistic combination of 5-fluorocytosine and amphotericin B. in a few cases. or other fungal infection-related complications and in 31 deaths. a few cases were caused by Aspergillus or Cladosporium sp.  Elevated protein  Low glucose However. Patients with cryptococcal meningitis and AIDS are treated with amphotericin B plus flucytosine (if tolerated) followed by fluconazole. myelitis. which has a sensitivity of 50%. the drug had been prepared by a compounding pharmacy. Aspergillus meningitis may be suspected if galactomannan levels in CSF are elevated. Outbreaks have also occurred in Sri Lanka (7 cases) and Minnesota (1 case). nausea or vomiting. Patients who have C. India ink preparation. Most cases were caused by Exophiala dermatitidis in 2002 and by Exserohilum rostratum in 2012. blood vessels may be affected. The meningitis tends to develop insidiously. cellular response may be minimal or absent in patients with advanced AIDS or another severe immunocompromised state. and there were significant violations of sterile technique during drug preparation. diagnosis is based on culture.

usually lymphocytic meningitis persists for months or even years.Meningitis due to Exophiala or Exserohilum sp is rare. and death does not result. Liver enzyme and Na levels should be measured periodically during the 2 to 3 wk after initiation of treatment. if patients with subacute meningeal symptoms reside in or travel to this region. In some patients. However. Coccidioidal meningitis tends to resist treatment and may require lifelong treatment with fluconazole. Coccidioides sp are confined to the American Southwest (predominantly southern Utah. Thus. New Mexico. voriconazole 6 mg/kg/day IV is recommended initially. and Candida sp may all cause chronic meningitis similar to that caused by C. and definitive treatment is not known. Histoplasma. but no organisms are identified. Other fungal meningitides Coccidioides. Other causes of chronic meningitis Rarely. chronic. Arizona. the meningitis . Sporothrix. Histoplasma and Blastomyces sp occur predominantly in the central and eastern US. Prognosis is guarded. Blastomyces. and Sjőgren syndrome  Intracranial arteritis  Neurosarcoidosis  Behçet syndrome  Chronic idiopathic meningitis: Chronic idiopathic meningitis Occasionally. clinicians should suspect the appropriate fungal causes. other infectious organisms and some noninfectious disorders (see Table: Some Noninfectious Causes of Meningitis) cause chronic meningitis. RA. Drug dosage should be adjusted based on blood levels of the drug. Treatment of the other fungal meningitides is usually with amphotericin B. Voriconazole and amphotericin B have also been used. and California). and appropriate treatment does not guarantee survival. CSF findings typically include  Lymphocytic pleocytosis  Elevated protein  Low glucose Candida sp may also cause polymorphonuclear pleocytosis. Noninfectious causes include  Cancer  Autoimmune rheumatic disorders including SLE. neoformans.

which invades the CNS early in the course of the infection. B. many other organisms can cause chronic meningitis in patients with HIV infection. acid-fast staining. biopsy) is indicated. Generally. neoformans (the most common). immunocompromise. Treponema pallidum. Diagnosis  CSF analysis Clinical findings are often nonspecific. recent time spent in endemic areas) and occasionally specific neurologic deficits (eg. Coccidioides immitis. such as C. Meningitis may then remit or follow a steady or fluctuating course. M. CSF contains only a few of the organisms. burgdorferi. particularly for cultures. CNS lymphoma can also cause findings similar to those of meningitis in these patients. diagnosis based on CSF findings may require multiple large samples over time. and other fungi. neoformans meningitis in HIV-infected patients or C. India ink)  Cytology If CSF findings do not provide a diagnosis and meningitis is causing morbidity or is progressive. particular cranial nerve deficits) suggest specific causes. organisms are recovered from ventricular or cisternal CSF when lumbar CSF is negative. Chronic meningitis in patients with HIV infection Meningitis is common among HIV-infected patients. Thus. Toxoplasma gondii. In many of the infections that cause chronic meningitis. sometimes risk factors (eg. immitis infections in patients living in the southwestern US. Most CSF abnormalities result from HIV.eventually remits spontaneously. tuberculosis. They include C. Typically. cisternal or ventricular puncture. However. Onset of meningitis and meningeal symptoms often coincides with seroconversion. empiric trials of antifungal drugs or corticosteroids have not been helpful. making identification of the cause difficult. more invasive testing (eg. a careful search for a systemic infection or disorder may suggest a cause for meningitis. CSF findings include lymphocytic pleocytosis. CSF analysis commonly includes  Aerobic and anaerobic bacterial culture  Mycobacterial and fungal culture  Cryptococcal antigen testing  Antigen or serologic testing  Special stains (eg. Also. . However. HIV infection or risk factors for it. Occasionally. Regardless of the cause. parenchymal lesions may develop.

immunocompromise. time spent in endemic areas. see above. blind meningeal biopsy has a very low yield. for other causes. see elsewhere in the manual). HIV infection or risk factors for it. and fungal meningitides.  Carefully checking for a systemic infection or disorder may provide the diagnosis.MRI or CT may be done to identify focal areas of inflammation for biopsy.  Many samples may be needed for CSF analysis because CSF may contain few of the causative organisms. spirochetal. . Key Points  Consider risk factors (eg. autoimmune rheumatic disorders) to help identify likely causes. Treatment  Treatment of the cause Treatment is directed at the cause (for mycobacterial. sometimes diagnosis requires cisternal or ventricular puncture and/or biopsy.