Meningitis in HIV 

Different forms of meningitis are associated with HIV infection. They may be classified as follows, according to the etiologic agent:

• Cryptococcal
• Tuberculous
• Syphilitic
• Listeria species
• Lymphomatous
• Aseptic

Chronic meningitis or episodes of acute meningitis for which no cause is found can occur at any time during the course of AIDS. In addition, although individuals who are HIV seropositive are at increased risk for the development of certain types of meningitis, evidence suggests that they are also more likely than the general population to develop community-acquired bacterial or viral meningitides.

Meningitis is multifactorial in patients with HIV or AIDS. Besides specific pathogens, autoimmune processes and HIV itself have been implicated in the development of HIV-associated meningitis.

Aseptic meningitis may be caused by HIV-1 itself. An early form of aseptic, HIV-associated meningitis develops within days to weeks after HIV infection.

The appearance of meningitis due to cryptococcosis, coccidioidomycosis, histoplasmosis, or other fungal infections is an AIDS-defining event and occurs typically in patients with very low CD4⁺ lymphocyte counts.

Medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), trimethoprim-sulfamethoxazole, and intravenous immunoglobulin (IVIG) are often overlooked as possible causes of HIV-associated meningitis.

In the United States, cryptococcal meningitis is the most common HIV-associated opportunistic infection of the central nervous system, affecting 5-7% of patients with AIDS. The second most common type of meningitis is aseptic meningitis, which may be caused by HIV-1 itself.

The prognosis in patients with HIV-associated meningitis depends on the etiology of meningitis and the stage of HIV infection. Patients with aseptic meningitis, a diagnosis of exclusion, have a good prognosis and do not require any specific treatment. Cryptococcal meningitis once had a mortality of 20%, but this may now be as low as 6%, owing to more aggressive therapy.

Higher mortality rates correlate with the following:

• Poor mental status
• High cerebrospinal fluid opening pressure at presentation (present in about two thirds of patients)
• Positive CSF India ink test
• Extra-CNS manifestations
• Higher fungal burdens, in fungal meningitis
• Cytomegalovirus ventriculoencephalitis (often causes death within weeks to months)

In general, symptoms and signs typically associated with meningitis are less likely to occur in HIV-seropositive individuals than in the general population. This probably reflects the different organisms involved and the differences in immune responses.

Physical examination can reveal malaise, photophobia, headache, nuchal rigidity, fever, and cranial neuropathies. Less common findings are confusion, somnolence, and personality changes.

Cryptococcal meningitis can occur acutely, with severe headache, change in mental status, fever, nuchal rigidity, and focal signs, or with a subacute course of malaise and headache without stiff neck over several weeks.

Cytomegaloviral infection usually presents as ventriculoencephalitis, with possible meningeal involvement, while aseptic HIV-associated meningitis appears as a mononucleosis-like illness and in rare cases is associated with encephalitis.

The differential diagnosis of HIV-associated meningitis includes chronic paroxysmal hemicrania, meningococcal meningitis, migraine headache, neurosyphilis, and staphylococcal meningitis. Other problems to be considered include lymphomatous meningitis; bacterial meningitis, which often occurs in conjunction with sepsis; and cytomegalovirus ventriculoencephalitis, which usually results in a change in mental status that evolves over several weeks and can be misdiagnosed as HIV-associated dementia.

In patients receiving highly active antiretroviral therapy (HAART) who have a syndrome of relapsing-remitting meningitis with negative cultures and atypical signs and symptoms, consider immune reconstitution inflammatory syndrome (IRIS). This is regarded as an overactive response of a newly reconstituted immune system to infectious agents already present in the patient when the therapy is started.

In IRIS, patients who are on antiretroviral therapy develop symptoms that are consistent with an infectious or inflammatory condition and that cannot be explained by a new or a previous infection or by the side effects of the therapy. It has been proposed that IRIS is due to an imbalance of CD8⁺/CD4⁺ cells.

In rare cases, metastatic CNS lymphoma can appear as meningitis.

CSF analysis facilitates the diagnosis of specific HIV-related etiologies and the assessment of other non–HIV-associated causes. CSF findings include the following:

• Meningitis at seroconversion and cryptogenic meningitis
• Cytomegalovirus (CMV) ventriculoencephalitis
• Cryptococcal meningitis

Sometimes, Cryptococcus neoformans is incidentally found in the CSF.

An asymptomatic form of meningitis is found in one third of patients in whom CSF is examined for other reasons (eg, headache).

Meningitis at seroconversion and cryptogenic meningitis

CSF reveals the following at this stage:

• Elevated protein and mononuclear pleocytosis
• Normal glucose level

Cytomegalovirus ventriculoencephalitis

The following CSF characteristics are seen with this condition:

• Polymorphonuclear pleocytosis (common)
• Low to normal glucose level
• Normal to high protein levels

Polymerase chain reaction (PCR) is more sensitive than culture in detecting CMV. In 2 studies, PCR had essentially 100% sensitivity in histologically proven CMV and was positive in 4 samples that had negative culture results.

Cryptococcal meningitis

In one study of patients with AIDS, 26% of patients with cryptococcal meningitis had normal CSF findings; 40% had high protein levels, low glucose levels, and pleocytosis; and 55% had fewer than 10 lymphocytes/mL.

The CSF may have a clear or turbid appearance in cryptococcal meningitis. Variable mononuclear pleocytosis is observed, and the white blood cell (WBC) count may be over 20 x 10⁹/L. A high CSF opening pressure is present in about two thirds of patients and is a poor prognostic sign.

CSF cultures are the criterion standard in diagnosing cryptococcal meningitis, but weeks and several specimens may be needed to obtain a positive result. Results of the India ink test are supportive of the diagnosis if positive, but they do not exclude the diagnosis if they are negative

Test results for serum and CSF cryptococcal antigen may be positive in cryptococcal meningitis. The initial diagnostic sensitivity of cryptococcal CSF antigen is 94.1%, followed by the serum antigen of 93.6%; however, this tool is unreliable in assessing point of discontinuation of antifungal therapy, at least among patients who are HIV positive.

Brain imaging

Findings on brain imaging may be nonspecific because of concurrent nonmeningitic neurologic complications of HIV, such as atrophy in cases of AIDS dementia/HIV encephalopathy.

Ependymal enhancement is seen with CMV ventriculoencephalitis.

Drugs of choice include ganciclovir for CMV ventriculoencephalitis and amphotericin B for cryptococcal meningitis.^{[1, 2, 3]}

In cases of cryptococcal meningitis, initially treat patients with amphotericin B (0.7-1 mg/kg/day) with flucytosine for 2 weeks, followed by fluconazole 400 mg orally daily for 10 weeks. High-dose amphotericin B with flucytosine and high-dose fluconazole with flucytosine have been tried in patients with cryptococcal meningitis with promising results.

In a randomized study that compared 1 mg/kg versus 0.7 mg/kg of amphotericin B in HIV-infected patients with cryptococcal meningitis, the higher dose was more rapidly fungicidal; side effects were comparable.^[4] Patients in both arms of the study also received flucytosine, 25 mg/kg 4 times daily.^[4]

Because amphotericin B treatment is not available in many centers in developing countries, oral therapy is an important alternative. Results of a randomized trial suggest that a 2-week course of high-dose fluconazole (1200 mg/day) combined with flucytosine (100 mg/kg/day) is the optimal oral therapy for cryptococcal meningitis. The combination proved more fungicidal than fluconazole alone and had a tolerable side-effect profile.^[5]

Treatment should be administered in consultation with an infectious disease specialist.

Recurrence

Cryptococcal meningitis may recur after treatment. Without maintenance therapy, 50-70% of patients relapse within 1 year.

The rate decreases to 2-7% in patients treated with long-term fluconazole.

CMV ventriculoencephalitis also may recur.

Follow-up care in patients with CMV meningitis includes the following drugs and dosages:

• Ganciclovir 500 mg PO q4h or 1 g PO tid for life
• Foscarnet 90-120 mg/kg IV daily for life

In cryptococcal meningitis, maintenance therapy should be continued with fluconazole 200 mg/day. Lifelong secondary prevention may be required. Consideration might be given to discontinuing secondary antifungal prophylaxis in selected patients who have responded well to highly active antiretroviral therapy (HAART), with 12-18 months of successful suppression of HIV viral replication.

Symptomatic increased intracranial pressure should be treated with repeated lumbar punctures.

Patients with mild disease, pancytopenia, renal insufficiency, or abnormalities in electrolytes (potassium, magnesium) may be treated with fluconazole 200 mg twice daily for 8-10 weeks.