Meningitis, which is an inflammation of the brain and spinal-cord membranes (meninges), is generally caused by microorganisms or other irritants in the cerebrospinal fluid (CSF).¹ Chronic meningitis is defined as meningeal inflammation that persists for more than 4 weeks, whereas acute meningitis lasts for less than 4 weeks.² Recurrent meningitis involves the occurrence of multiple acute episodes, each of which is less than 4 weeks in duration.^1,3,4 Chronic meningitis affects about 10% of patients diagnosed with meningitis.³ Some individuals with chronic meningitis seek medical attention before the symptoms or signs have been present for 4 weeks, so it is important to differentiate these patients from those who are recovering from acute or recurrent meningitis. Chronic meningitis may not be well known to pharmacists, although published cases date to the early 1970s.⁵ This article will concentrate on the causes and treatment of chronic meningitis.

There are numerous causes of chronic meningitis, including infectious, inflammatory, neoplastic, and toxic exposures. Infectious causes are bacteria, mycobacteria, fungi, viruses, and parasites. Noninfectious causes include, but are not limited to, sarcoidosis, Behçet's disease (BD), Wegener's granulomatosis (WG), systemic lupus erythematosus (SLE), medications, and neoplasms.^1,6,7 In up to one-third of patients with chronic meningitis, no cause is found.⁸

DIAGNOSIS

The approach to diagnosis includes many factors, such as symptoms; medical, medication, and exposure history; physical examination; CSF profile; and other tests (e.g., blood testing, cultures, neuroimaging, chest radiograph).¹ Symptoms are nonspecific and may include headache, fever, neck pain, ataxia, lethargy, nausea, and alterations of alertness and cognitive function. The classic triad of fever, headache, and neck stiffness occurs in about 85% of patients diagnosed with acute bacterial meningitis, but in only about 10% of patients with chronic meningitis.³ Patients with acute meningitis typically present abruptly with severe symptoms, whereas patients with chronic meningitis typically present more gradually with symptoms that may fluctuate, worsen, or remain static.^1,6,7 The duration of symptoms in chronic meningitis generally ranges from 17 months to 43 months.¹

Lumbar puncture is important in the diagnosis of chronic meningitis, although CSF findings are nonspecific. Lymphocyte counts are elevated in more than 90% of cases; elevated neutrophil counts occur in fewer than 10% of cases. Glucose levels may be normal or decreased. Protein levels usually are increased. Culture results are helpful, but usually are not available in a timely manner. CSF neutrophils are elevated in 90% of acute meningitis cases, and lymphocytes are elevated in only about 10% of cases.³ Typical CSF findings in patients with and without meningitis are given in TABLE 1.^9,10

CT and MRI can exclude conditions such as abscesses, tumors, and nonmeningeal infections.⁶ In a small number of patients, meningeal biopsies are helpful for diagnosing chronic meningitis.⁷

ETIOLOGY AND MANAGEMENT

Treatment of chronic meningitis requires a comprehensive workup. Empiric therapy for a presumed cause should be initiated if a patient appears ill or is deteriorating. If a patient is stable and there is no presumptive cause, specific treatment should wait until initial test results are known. Symptom treatment and supportive therapy should be implemented, and the presence of complications, such as seizures or hydrocephalus, warrants appropriate therapy.¹

Infectious Causes

Bacterial: Neisseria meningitides and Streptococcus pneumoniae account for 37% to 93% of acute bacterial meningitis cases, whereas the most common cause of chronic meningitis is Mycobacterium tuberculosis (40%-60%).³ In all cases of chronic meningitis, an HIV test should be performed, since many of the infectious causes are more common in HIV-infected individuals and the treatment course may vary in HIV-positive patients.¹⁰

M tuberculosis, the source of tuberculosis (TB), can cause tuberculous meningitis (TBM). TBM most commonly affects people from developing countries, alcoholics, and people with HIV/AIDS.^6,7,11 Presentation is usually nonspecific, involving headache, fever, malaise, lethargy, and confusion. A tuberculin skin test may be negative. TBM usually evolves over 1 to 2 weeks, and active pulmonary TB may be absent at the time it presents. CSF findings include increased opening pressure, lymphocytosis, increased protein levels, decreased glucose levels, and a positive culture for tubercle bacilli (culture results are usually delayed for weeks). Positive acid-fast bacilli on CSF smear may occur in some of the higher-grade infections.^6,7

Treatment for TBM is longer than that for pulmonary TB, which is treated for about 6 months. Therapy consists of rifampin 10 mg/kg/day orally, isoniazid 5 mg/kg/day orally (with pyridoxine), pyrazinamide 15 to 30 mg/kg/day orally, and either ethambutol 15 to 20 mg/kg/day orally or streptomycin 15 mg/kg/day intramuscularly for 2 months, followed by 10 months of rifampin and isoniazid.^6,7,12 The treatment course may be extended to 1 to 2 years if the patient is neurologically compromised or immunosuppressed.¹³ Isoniazid and rifampin have excellent penetration into the CSF. Pyrazinamide and ethambutol penetrate sufficiently, especially with inflamed meninges; streptomycin penetrates poorly, but still demonstrates benefit in clinical studies.^6,7

The most common side effects of TB drugs include peripheral neuropathy (isoniazid), flulike illness (rifampin), nausea/vomiting/malaise (pyrazinamide), and visual disturbances (ethambutol). All of the agents may cause rash and hepatotoxicity.¹² Moxifloxacin 400 mg/day orally may be used if there are concerns about resistance. The regimen may need to be altered if resistance is present. Corticosteroids and neurosurgery also are treatment options.^6,7 A randomized trial of dexamethasone plus anti-TB drugs versus anti-TB drugs alone showed a decrease in mortality in the steroid group, with no effect on residual morbidity.¹⁴ Household contacts should be tested and treated for latent TB as appropriate.^6,7

Neurosyphilis (most often presenting as meningitis) can be caused by Treponema pallidum, the source of syphilis. It can occur in both immunocompetent and immunocompromised (especially HIV/AIDS) individuals. Neurosyphilis usually evolves within months of inoculation, but frequently is asymptomatic. Fever often is absent, but headache and confusion may be evident. Typical CSF findings include lymphocytosis, increased protein levels, normal glucose levels, and positive serologic tests for syphilis.^6,7,13 Penicillin G is the drug of choice for the treatment of neurosyphilis; if an allergy to penicillin exists, desensitization should be strongly considered. Aggressive dosing (24 million units/day IV) often is required to eradicate the organism. With initiation of penicillin G, a release of endotoxin may occur, resulting in skin rash and an inflammatory response known as the Jarisch-Herxheimer reaction.¹⁵

Borrelia burgdorferi, which is responsible for Lyme disease, also can cause neuroborreliosis (which may present as meningitis). Neuroborreliosis is most often the result of exposure to an ixodid tick. Neuroborreliosis usually presents after the characteristic Lyme disease rash disappears. CSF findings include lymphocytosis, increased protein levels, normal glucose levels, and positive serologic tests for B burgdorferi. The main symptoms of neuroborreliosis are peripheral and cranial neuropathies, and treatment is ceftriaxone 2 g/day IV or penicillin G 20 million units/day IV for 10 to 14 days. Doxycycline 100 mg/day IV may be used in patients who are allergic to penicillins or cephalosporins. Symptoms usually resolve slowly over weeks to months.^6,7

Other bacteria that can cause chronic meningitis are Leptospira (through exposure to animal fluids or infected water), Brucella (through exposure to cattle or unpasteurized milk), and Nocardia asteroides (found in the soil; can cause infection in immunocompromised patients).⁶

Fungal: The most common fungal cause of chronic meningitis is Cryptococcus neoformans (an encapsulated yeast), occurring most often in patients with HIV/AIDS.⁶ Other fungal sources are Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis, Aspergillus fumigatus, Candida albicans, and Sporothrix schenckii. Fungal meningitis usually occurs in immunocompromised individuals, and presentation depends on the fungus involved. Cryptococcal meningitis usually presents as headache, fever, and lethargy. Other symptoms are visual impairment, cranial neuropathies, ataxia, seizures, and altered cognition. Findings usually include lymphocytosis, decreased glucose levels, increased protein levels, positive culture tests, and a greatly elevated opening pressure upon lumbar puncture.^1,6,7

Treatment involves amphotericin B (AMB) IV combined with flucytosine orally. Guidelines recommend AMB deoxycholate (AMBD) 0.7 to 1 mg/kg/day with flucytosine 100 mg/kg/day for 2 weeks, followed by fluconazole 400 mg/day orally for at least 10 weeks.¹⁶ There is some published experience with various forms of lipid-based AMB, but the data are much weaker than for AMBD, so lipid-based AMB is usually recommended only for patients who have or are likely to develop nephrotoxicity with AMBD.¹⁶ Long-term fluconazole (usually 400 mg/day orally) may be used for secondary prophylaxis after response to initial treatment.⁷

A case series of 114 patients diagnosed with chronic meningitis in Thailand found C neoformans to be the most common causative agent (54%).¹⁷ Seventy-nine percent of patients with C neoformans were HIV-positive. The second most common cause of chronic meningitis in this case series was M tuberculosis (37%).¹⁷

A case report published in 2005 discussed the difficulty of diagnosing chronic meningitis in a patient who had capsule-deficient C neoformans.¹⁸ It is important to consider this possibility when antigen tests are negative but strong suspicion of chronic meningitis exists.

Viral: There are many viral causes of meningitis, among them HIV, cytomegalovirus, zoster, herpes simplex virus, enteroviruses, and Epstein-Barr virus. Lymphocytosis, increased protein levels, and normal glucose levels usually are found. Therapies for herpesviruses (IV acyclovir) and HIV (highly active antiretroviral therapy) are used, but there are no antiviral therapies specifically for chronic meningitis. Vaccines help prevent meningitis caused by polio and zoster viruses.^1,6,7

Parasitic: Parasitic causes of chronic meningitis include Taenia solium, Angiostrongylus cantonensis, Toxoplasma gondii, and Acanthamoeba species.^6,7 The larval form of T solium, a pork tapeworm, is responsible for cysticercosis, a disease that can affect subcutaneous, muscle, or central nervous system (CNS) tissue. Cysticercosis is the most common parasitic infection of the CNS. It is most common in Latin America, Asia, Africa, and parts of Europe. It can be asymptomatic, but sometimes symptoms such as severe headache, seizures, vision changes, and ischemic cerebrovascular disease may occur.¹⁹ CSF findings usually include elevated protein levels, normal glucose levels, and eosinophilia.^19,20

About half of patients who develop cysticercosis present with meningitis. A case report published in 2006 described a patient who had worked in Madagascar (where she occasionally ate raw pork) for a year in the 1970s and was diagnosed with chronic cysticercal meningitis 30 years after skin manifestations that responded clinically to treatment.¹⁹ The patient had a complete clinical recovery from meningitis after treatment with albendazole 400 mg twice daily orally for 15 days, then 400 mg/day orally for 15 days (dose decreased owing to gastrointestinal [GI] side effects) and prednisone 60 mg/day orally for 3 days.¹⁹

Noninfectious Causes

Several autoimmune diseases have been rarely associated with chronic meningitis. The causative mechanism is unclear.

Sarcoidosis is a chronic, multisystem, granulomatous disorder of unknown etiology that is characterized pathologically by the presence of noncaseating granulomas (nodular inflammatory lesions) in the lungs, skin, joints, eyes, and--rarely--CNS. Sarcoidosis typically affects young adults. Meningeal involvement may be either acute aseptic meningitis or chronic meningitis. Meningeal mass lesions also may develop. Patients with sarcoidosis who present with symptoms of meningitis should be evaluated and treated promptly because the disease usually is caused by opportunistic organisms, such as cryptococci. CSF findings in noninfectious meningitis usually are lymphocytosis or monocytosis, decreased or normal glucose levels, and increased protein levels. Sarcoidosis usually responds to a course of oral corticosteroids. Methotrexate may be added to shorten the time to complete resolution.^6,7

BD is a chronic multisystem inflammatory disorder that primarily causes vasculitis. It can involve the skin and mucous membranes, eyes, joints, lungs, GI tract, vascular system, and CNS. The classic triad is oral ulcerations, genital ulcerations, and eye lesions. BD affects mostly young adults in the region extending from the Mediterranean Sea to Japan. Neurologic involvement is rare, but has a poor prognosis. CSF findings include lymphocytosis, increased protein levels, and normal glucose levels.^6,7 Meningitis in BD can be acute, chronic, or recurrent and is treated with corticosteroids.^6,7,21

WG is a severe, necrotizing, granulomatous systemic vasculitis associated with the cytoplasmic form of the antineutrophil cytoplasmic antibody. It mostly involves the respiratory tract and kidneys, but may also affect the eyes and CNS. Chronic meningitis, a rare complication of WG, is treated with high-dose corticosteroids and cyclophosphamide.^7,22

A chronic inflammatory disease of unknown origin that often affects young women, SLE can involve the skin, joints, kidneys, lungs, nervous system, serous membranes, or other organs. It is characterized by the production of a number of antinuclear antibodies. Aseptic meningitis can occur in people with SLE as a result of the lupus, from the medications (i.e., nonsteroidal anti-inflammatory drugs [NSAIDs], azathioprine) used for specific symptoms, or from opportunistic infections that develop in individuals receiving chronic immunosuppressive therapy. CSF findings typically include lymphocytosis, increased protein levels, and variable glucose levels.^6,7,23 Treatment should be aimed at the specific etiology involved, and any drugs suspected of causing the meningitis should be withdrawn.²⁴

Rarely, chronic meningitis is caused by medications. The most common medications associated with aseptic meningitis are NSAIDs (including cyclooxygenase-2 inhibitors), antibiotics (especially trimethoprim/sulfamethoxazole), IV immunoglobulins, and OKT3 antibodies (monoclonal antibodies targeting T₃ receptors). Patients with SLE and connective-tissue disease appear to be predisposed to drug-induced aseptic meningitis (DIAM) associated with NSAIDs. Patients with autoimmune diseases have a high likelihood of DIAM from antibiotics. The pathogenesis of DIAM is not known, although it has been proposed that DIAM is an immunologic hypersensitivity reaction. Symptoms include fever, headache, meningeal signs, nausea, vomiting, and lethargy. Lymphocytosis or neutrophilia, increased or normal protein levels, and decreased or normal glucose levels may be found; eosinophilia also may exist. Any medication believed to be the cause of meningitis should be stopped. Rapid recovery (within 5 days) once the medication is stopped is typical for DIAM. Reexposure could strengthen the evidence for causality, but usually is not in the patient's best interest.^6,7,25-27

Neoplastic meningitis may be the first sign in 5% to 10% of patients diagnosed with cancer. Many tumors can cause meningitis, but small-cell lung cancer and melanoma are the most likely tumors to spread to the meninges. CSF findings include elevated opening pressure, increased protein levels, decreased or normal glucose levels, and mononuclear or mixed pleocytosis (increase in number of cells). Symptoms usually include intractable headache, changes in mental activity, cranial neuropathy, neurologic dysfunction, and neck stiffness.^6,7,28

ROLE OF THE PHARMACIST

Pharmacists should encourage patients to give their physicians detailed histories of travel, ingested medications, and exposures to help identify the etiology of chronic meningitis. Pharmacists consulting with chronic meningitis patients in the hospital or the community should discuss the importance of being compliant with the treatment regimen in order to prevent resistance, recurrence, or treatment failure.

CONCLUSION

Chronic meningitis is an inflammation of the meninges that lasts for more than 4 weeks. It has infectious (bacterial, viral, fungal, and parasitic) and noninfectious sources (granulomatous and inflammatory diseases, drugs, and neoplasms). CSF findings are nonspecific, but usually well defined for each cause. Treatment of infectious sources usually involves antimicrobials. Therapy for chronic meningitis due to granulomatous or inflammatory diseases usually involves corticosteroids. Pharmacists can play a role in helping identify drug-induced causes of chronic meningitis.

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