Subacute and Chronic Meningitis

Mycobacterium tuberculosis Tuberculosis (TB) Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more 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 high-resource 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:

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

Occasionally, the first CSF abnormality is extremely low glucose.

Detecting the causative organism is often difficult because

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 is 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 for TB Tuberculosis is a chronic, progressive mycobacterial infection, often with an asymptomatic latent period following initial infection. Tuberculosis most commonly affects the lungs. Symptoms include... read more 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.

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... read more 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

CSF findings typically include

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

Doses for ceftriaxone are

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 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

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 Cryptococcosis Cryptococcosis is a pulmonary or disseminated infection acquired by inhalation of soil contaminated with the encapsulated yeasts Cryptococcus neoformans or C. gattii. Symptoms... read more is the most common cause of chronic meningitis in the Western hemisphere and the most common opportunistic infection in patients with AIDS Immune system Human immunodeficiency virus (HIV) infection results from 1 of 2 similar retroviruses (HIV-1 and HIV-2) that destroy CD4+ lymphocytes and impair cell-mediated immunity, increasing risk of certain... read more . Common causes of cryptococcal meningitis in the US are

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

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.

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 Overview of Vasculitis Vasculitis is inflammation of blood vessels, often with ischemia, necrosis, and organ inflammation. Vasculitis can affect any blood vessel—arteries, arterioles, veins, venules, or capillaries... read more and stroke Overview of Stroke Strokes are a heterogeneous group of disorders involving sudden, focal interruption of cerebral blood flow that causes neurologic deficit. Strokes can be Ischemic (80%), typically resulting... read more . 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

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.

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. Cranial nerve deficits are common. 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

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.

Meningitis is common among HIV-infected patients. Most CSF abnormalities result from HIV, which invades the CNS early in 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, Toxoplasma gondii, and Coccidioides immitis in endemic areas. CNS lymphoma can also cause symptoms and signs similar to those of meningitis in patients with HIV infection.

Regardless of the cause, parenchymal lesions may develop.

In patients with cancer, tumor cells may spread to the meninges. Spread most commonly occurs in patients with lung or breast cancer and melanoma but can occur in many other cancers. Carcinomatous meningitis is usually a late complication of cancer and should be considered if any patient with cancer has a change in mental status, hydrocephalus, or clinical signs referable to cranial or spinal nerve roots.

Similar leptomeningeal involvement can also occur in patients with leukemias or lymphomas, including primary CNS lymphoma.

CSF changes may be nonspecific (pleocytosis, low glucose, elevated protein); detection of malignant cells may require multiple lumbar punctures. MRI with gadolinium is used to detect metastatic deposits on nerve roots or other structures.

Treatment is directed against the underlying tumor, but prognosis is poor; the cancer usually recurs within 6 months.

Rarely, other infectious organisms and some noninfectious disorders (see table ) cause chronic meningitis. Noninfectious causes include

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.