Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
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.
Organisms Circumstances
Organisms Circumstances
Bacteria
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
Fungi
Cryptococcus neoformans
Predominantly northern Pacific coast
C. gattii
Appears to have a widespread distribution
Parasites
Toxoplasma gondii
Viruses
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:
Cranial nerve deficits, particularly of cranial nerves II, VII, and VIII
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.
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.
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)
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, false-
positive 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.
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
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.
Lymphocytic pleocytosis
Elevated protein
Low glucose
However, cellular response may be minimal or absent in patients with advanced AIDS or
another severe immunocompromised state.
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.
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.
Neutrophilic pleocytosis
Elevated protein
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.
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.
Lymphocytic pleocytosis
Elevated protein
Low glucose
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.
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
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.
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.
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
Cytology
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.