Find information on medical topics, symptoms, drugs, procedures, news and more, written for the health care professional.

* This is a professional Version *

Subacute and Chronic Meningitis

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 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.

Major Infectious Causes of Subacute or Chronic Meningitis

Organisms

Circumstances

Bacteria

Mycobacteria: ( Mycobacterium tuberculosis, rarely other mycobacteria)

Spirochetes: Lyme disease, syphilis, rarely leptospirosis

For Lyme disease, East Coast, upper Midwest, California, Oregon

Brucella sp

Associated with livestock

Unusual in the US or other developed countries

Ehrlichia sp

Fungi

Cryptococcus neoformans

C. gattii

Predominantly northern Pacific coast

May have more 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, but infection associated with rose thorns or brush

Parasites

Toxoplasma gondii

Viruses

Retroviruses: HIV, HTLV-1

In patients with known HIV or risk factors

Enteroviruses

In patients with a congenital immunodeficiency syndrome

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:

  • Hydrocephalus due to obstruction of the foramina of Luschka and Magendi or the aqueduct of Sylvius

  • Vasculitis, sometimes causing arterial or venous occlusion and stroke

  • Cranial nerve deficits, particularly of cranial nerves II, VII, and VIII

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 Table: CSF Findings in Meningitis). Occasionally, the first CSF abnormality is extremely low glucose.

Detecting the causative organism is often difficult because

  • CSF acid-fast staining is ≤ 30% sensitive.

  • CSF mycobacterial cultures are only about 70% sensitive and require up to 6 wk.

  • CSF PCR is about 50 to 70% sensitive.

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 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

  • 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, 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 Table: Some Noninfectious Causes of Meningitis) cause chronic meningitis.Noninfectious causes include

  • Cancer

  • Autoimmune rheumatic disorders including SLE, RA, and Sjőgren syndrome

  • Intracranial arteritis

  • Neurosarcoidosis

  • Behçet syndrome

  • Chronic idiopathic meningitis:

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

  • Aerobic and anaerobic bacterial culture

  • Mycobacterial and fungal culture

  • Cryptococcal antigen testing

  • Antigen or serologic testing

  • Special stains (eg, acid-fast staining, India ink)

  • Cytology

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

  • Consider risk factors (eg, time spent in endemic areas, HIV infection or risk factors for it, immunocompromise, autoimmune rheumatic disorders) to help identify likely causes.

  • Carefully checking for a systemic infection or disorder may provide the diagnosis.

  • Many samples may be needed for CSF analysis because CSF may contain few of the causative organisms; sometimes diagnosis requires cisternal or ventricular puncture and/or biopsy.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • No US brand name
  • RIFADIN, RIMACTANE
  • LANIAZID
  • OZURDEX
  • MYAMBUTOL
  • RAYOS
  • ROCEPHIN
  • CLAFORAN
  • DIFLUCAN
  • ANCOBON
  • MEDROL
  • VFEND

* This is a professional Version *