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Subacute and Chronic Meningitis


John E. Greenlee

, MD, University of Utah Health

Last full review/revision Dec 2020| Content last modified Dec 2020
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Subacute meningitis develops over days to a few weeks. Chronic meningitis lasts ≥ 4 weeks. Possible causes include fungi, Mycobacterium tuberculosis, rickettsiae, spirochetes, Toxoplasma gondii, HIV, enteroviruses, and disorders such as autoimmune rheumatic disorders (eg, systemic lupus erythematosus [SLE], rheumatoid arthritis [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 cerebrospinal fluid (CSF) that is typically obtained via repeated lumbar punctures, sometimes using next-generation sequencing (if available), and sometimes biopsy or ventricular or cisternal puncture. Treatment is directed at the cause.

Chronic meningitis may last > 10 years. 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.


Tuberculous meningitis

M. tuberculosis Tuberculosis (TB) Tuberculosis (TB) is a chronic, progressive mycobacterial infection, often with a period of latency following initial infection. TB most commonly affects the lungs. Symptoms include productive... read more Tuberculosis (TB) 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 central nervous system (CNS) during primary or reactivated infection. In developed countries, meningitis usually results from reactivated infection. Reactivation may occur in patients treated with immunosuppressants such as tumor necrosis factor (TNF)-alpha antagonists (eg. infliximab, adalimumab, golimumab, certolizumab, etanercept).

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 Magendie or the aqueduct of Sylvius

  • Vasculitis, sometimes causing arterial or venous occlusion and stroke

  • Cranial nerve deficits, particularly of the 2nd, 7th, and 8th cranial nerves

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, cerebrospinal fluid (CSF) findings include

  • Mixed pleocytosis with lymphocytic predominance

  • Low glucose

  • Elevated protein

Occasionally, the first CSF abnormality is extremely low glucose.

Detecting the causative organism is often difficult because

  • CSF acid-fast staining is < 20% sensitive, even using immunofluorescence techniques.

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

  • CSF PCR is about 50 to 70% sensitive.

An automated rapid nucleic acid amplification test called Xpert MTB/RIF has been recommended by the World Health Organization (WHO) for the diagnosis of tuberculous meningitis. This test detects M. tuberculosis DNA and resistance to rifampicin in CSF specimens. Skin testing with controls for anergy or QuantiFERON®-TB Gold testing can document prior exposure to M. tuberculosis; however, results may be negative, particularly in older or immunosuppressed patients. Chest x-rays may show evidence of prior or ongoing infection in 40 to 50% of cases, and chest CT may be positive in up to two thirds of cases.

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 the anti-tuberculosis drugs First-line drugs Tuberculosis (TB) is a chronic, progressive mycobacterial infection, often with a period of latency following initial infection. TB most commonly affects the lungs. Symptoms include productive... read more First-line drugs isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months followed by isoniazid and rifampin for 6 to 7 months. Corticosteroids (prednisone or dexamethasone) may be added if patients present with stupor, coma, or neurologic deficits.

Meningitis due to spirochetes

Lyme disease Lyme Disease Lyme disease is a tick-transmitted infection caused by the spirochete Borrelia species. Early symptoms include an erythema migrans rash, which may be followed weeks to months later by neurologic... read more Lyme Disease is a chronic spirochetal infection caused by Borrelia burgdorferi in the US and by B. afzelii and B. garinii in Europe. Lyme 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, false-positive rates may be unacceptably high.

Treatment of Lyme meningitis is with cefotaxime or ceftriaxone given over 14 days. Doses for cefotaxime are

  • Children: 150 to 200 mg/kg/day IV in 3 to 4 divided doses (eg, 50 mg 3 to 4 times a day)

  • Adults: 2 g IV every 8 hours

Doses for ceftriaxone are

  • Children: 50 to 75 mg/kg/day IV (2 g maximum) once a day

  • Adults: 2 g IV once a day

Clinicians should remember that concomitant anaplasmosis or babesiosis is possible in patients with severe disease.

Syphilitic meningitis

Syphilitic meningitis is less common; it is usually a feature of meningovascular syphilis Late or tertiary syphilis Syphilis is caused by the spirochete Treponema pallidum and is characterized by 3 sequential clinical, symptomatic stages separated by periods of asymptomatic latent infection. Common manifestations... read more Late or tertiary 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

  • 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. Magnetic resonance 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 every 4 hours (eg, 2 to 4 million units every 4 hours) for 10 to 14 days.

Cryptococcal meningitis

Cryptococcal meningitis Cryptococcosis Cryptococcosis is a pulmonary or disseminated infection acquired by inhalation of soil contaminated with the encapsulated yeasts Cryptococcus neoformans or C. gattii. Symptoms are those of pneumonia... read more Cryptococcosis is the most common cause of chronic meningitis in the Western hemisphere and the most common opportunistic infection in patients with AIDS. 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 of cryptococcal meningitis. 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. Cryptococcal meningitis may develop and persist over months or years.

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. Occasionally, diagnosis is extremely difficult and may require examination of multiple large (20 to 30 mL) amounts of CSF over a period of time. Tests for cryptococcal antigen and fungal culture should be done each time.

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 US (in 2002) resulted in 5 cases of meningitis. The most recent outbreak (in late 2012 and 2013) resulted in 753 cases of meningitis, stroke, myelitis, or other fungal infection-related complications and in 61 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 and 2013; a few cases were caused by Aspergillus or Cladosporium species.

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 symptom, followed by altered cognition, nausea or vomiting, or fever. Symptoms may be delayed by as much as 6 months 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 polymerase chain reaction (PCR) test, available through the Centers for Disease Control and Prevention (CDC); 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 species 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 sodium levels should be measured periodically during the 2 to 3 weeks after initiation of treatment.

Prognosis is guarded, and appropriate treatment does not guarantee survival.

Other fungal meningitides

Coccidioides, Histoplasma, Blastomyces, Sporothrix, and Candida species may all cause chronic meningitis similar to that caused by C. neoformans. Coccidioides species are confined to the American Southwest (predominantly southern Utah, New Mexico, Arizona, and California). Histoplasma and Blastomyces species 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 species 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.

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.

Other causes of chronic meningitis

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 of Subacute and Chronic Meningitis

  • CSF analysis

Clinical findings in patients with subacute or chronic meningitis 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 of subacute or chronic meningitis 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 available, next-generation (metagenomic) sequencing can be used to rapidly sequence large stretches of nucleic acids and thus identify otherwise undetectable pathogens in CSF.

If clinicians suspect tuberculous meningitis, they can use an automated test called Xpert MTB/RIF, which has been recommended by the WHO for the diagnosis of tuberculous meningitis. This test can detect the DNA of Mycobacterium tuberculosis in CSF specimens. Skin testing with controls for anergy or QuantiFERON®-TB Gold testing can document prior exposure to M. tuberculosis; however, results may be negative, particularly in older or immunosuppressed patients. Chest x-rays may show evidence of prior or ongoing infection in 40 to 50% of cases, and chest CT may be positive in up to two thirds of cases.

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 of Subacute and Chronic Meningitis

  • Treatment of the cause

Treatment of subacute or chronic meningitis 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.

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