Meningitis in HIV

Like other infections, HIV infection increases risk of meningitis, a serious condition with possible deleterious outcomes. HIV-associated meningitis can be due to a variety of etiologic agents, with a selected few listed below: 

• Cryptococcal

• Tuberculous

• Meningococcal

• Aseptic

Up to 43% of HIV-associated meningitis cases do not have identifiable etiology. This figure is lower compared to non-HIV infected individuals, in whom up to 69% have meningitis of unknown cause. ^[1]

Among the known causes, Cryptococcus neoformans, a fungus, is the most common etiology in HIV-associated meningitis, mainly in patients with AIDS and a CD4 count < 100 cells/microL. Cryptococcal meningitis is one of the AIDS-defining illnesses. 

Other causes of AIDS-defining meningitis include:

• Histoplasma

• Coccidioides

• Mycobacterium tuberculosis or other Mycobacterium species

• Cytomegalovirus

In addition to these specific causes of meningitis, evidence suggests that AIDS patients are also more likely than the general population to develop community-acquired bacterial or viral meningitides.

It is worth noting that in addition to specific pathogens, autoimmune processes and HIV itself have been implicated in the development of HIV-associated meningitis.

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

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

A non-infectious etiology of meningitis in HIV is lymphoma.

In the United States, the most common known cause of HIV-associated meningitis is cryptococcal meningitis, affecting 30% of patients with HIV-associated meningitis. The second most common cause is bacterial, accounting for 12%, among which Streptococcus pneumoniae is the most commonly identified causative organism. Of note, 43% of patients with HIV-associated meningitis do not have identifiable etiology. ^[1]  In an Uganda cohort, cryptococcal meningitis remains the most common etiologic agent, accounting for more than 60% of patients with HIV-associated meningitis, followed by tuberculous meningitis, which accounted for about 5%; about 6.4% of cases have an unidentified etiology. ^[2]

Globally, the burden of cryptococcal meningitis remains high despite recent advances in HIV detection and treatment, with an estimated 223,100 incidence cases in 2014. ^[3]  A low CD4 cell count is the main predictor of risk of cryptococcal meningoencephalitis; the vast majority of cases occur among AIDS patients with a CD4 count < 100 cells/microL.

The prognosis in patients with HIV-associated meningitis depends on the etiology of meningitis, the stage of HIV infection, and the availability of treatments. Patients with aseptic meningitis, a diagnosis of exclusion, have a good prognosis and do not require any specific treatment. In sub-Saharan Africa, short-term mortality from HIV-associated meningitis is high. A systematic review calculated the numbers to be 44%, 46%, and 54% from cryptococcal meningitis, TB meningitis and pneumococcal meningitis, respectively. ^[4]  In developed countries, cryptococcal meningitis mortality ranges from 13% ^[1]  to 20%, ^[5]  owing to better resources and improved 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.

Surprisingly, a study from China published in 2012 found a lower mortality in HIV-infected patients than in HIV-uninfected patients with cryptococcal meningitis. ^[6] The reason for decreased mortality in the HIV-infected population was determined to be low intensity of inflammation and effective surgical cerebrospinal fluid drainage for increased intracranial pressure.

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

Cryptococcal antigen is present several weeks before overt signs of meningitis develop; therefore, its detection provides an opportunity to catch infection early, and, hence, screening persons with HIV for cryptococcal infection when they access health care can identify asymptomatic infected patients, allowing for prompt treatment and prevention of death. ^[7] This can be used as a point-of-care assay and serve as a cost-effective screening.

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.

The definitive diagnosis of cryptococcal meningoencephalitis is made by culture of the organism from the cerebrospinal fluid (CSF). A positive cryptococcal polysaccharide antigen in the CSF or serum strongly suggests the presence of infection well before the cultures become 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.

Radiographic imaging of the brain must be performed prior to lumbar puncture if there is a concern for increased intracranial pressure (ICP) and/or other space-occupying lesions. 

Treatments should be tailored to the etiologic agent.

To treat cryptococcal meningitis, the World Health Organization (WHO) recommends a shortened regimen consisting of a single 10-mg/kg dose of liposomal amphotericin B with 14 days of flucytosine and high-dose fluconazole, especially in resource-poor settings. ^[8]  This is based on new evidence from a randomized controlled study that found that a shortened duration of amphotericin B treatment produced significantly less side effects and was non-inferior compared to a prior recommended regimen with a more prolonged amphotericin course. ^[9]  

This induction treatment should be followed by consolidation and maintenance treatments with fluconazole to prevent recurrence until evidence of sustained ART-related immune reconstitution. Without maintenance therapy, 50%–70% of patients relapse within 1 year.

Because amphotericin B treatment is not available in many centers in developing countries, oral therapy is an important alternate option for induction treatment. 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. ^[10]

Secondary to the significant toxicity of the medications used, very close laboratory monitoring is needed for renal insufficiency, hematologic abnormalities, and electrolyte disturbances during therapy. 

To treat cytomegalovirus (CMV) meningitis, a combination therapy with ganciclovir and foscarnet should be used as the initial treatment until symptomatic improvement, followed by maintenance therapy until evidence of sustained ART-related immune reconstitution. ^[11]

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.

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.

Current recommendation for maintenance therapy for cytomegalovirus (CMV) meningitis is monotherapy with valganciclovir 900 mg/day.