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

Bacteria
Mycobacteria: ( Mycobacterium
tuberculosis, rarely other mycobacteria)

Spirochetes: Lyme disease, syphilis,

rarely leptospirosis

For Lyme disease, East Coast, upper Midwest,

California, Oregon
Associated with livestock

Brucella sp
Unusual in the US or other developed countries
Ehrlichia sp
Leptospira sp

Associated with exposure to urine of rats,

mice, and other animals
Unusual in Western countries

Fungi
Cryptococcus neoformans

Predominantly northern Pacific coast

C. 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, 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 (see Tuberculosis (TB)). 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

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.

An automated rapid nucleic acid amplification test called Xpert MTB/RIF has been
recommended by the WHO for the diagnosis of tuberculous meningitis. This test detects M.
tuberculosis DNA and resistance to rifampicin in CSF specimens.
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) : First-line
drugs). 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

Normal glucose

Diagnosis of Lyme disease is based on serologic tests with enzyme-linked immunosorbent

assay (ELISA), followed by Western blot analysis to confirm. In some laboratories, falsepositive rates may be unacceptably high.
Treatment of Lyme meningitis 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 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 of syphilitic meningitis 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 with syphilitic meningitis 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 (see
Cryptococcosis). Common causes of cryptococcal meningitis in the US are

Cryptococcus neoformans var. neoformans (serotype D strains)

C. neoformans var. grubii (serotype A strains)

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, at times with
protracted relapses and remissions.
CSF findings typically include

Lymphocytic pleocytosis

Elevated protein

Low glucose

However, cellular response may be minimal or absent in patients with advanced AIDS or
another severe immunocompromised state.
Diagnosis of cryptococcal meningitis 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.
Symptoms may be delayed by as much as 6 mo after the epidural injection. Signs of
meningeal irritation are absent in about one third of patients.
Typical CSF findings include

Neutrophilic pleocytosis
Elevated protein

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

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 Sjgren syndrome

Intracranial arteritis

Neurosarcoidosis

Behet 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

CSF analysis

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 of the cause

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.