Meningitis in HIV

Meningitis in HIV

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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. 

Although the incidence of cryptococcal meningoencephalitis has declined in patients who have access to antiretroviral therapy (ART), cryptococcal disease remains a leading cause of mortality in the developing world where access to ART is limited. 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. [1]

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.

Surprisingly, a study from China published in 2012 found a lower mortality in HIV-infected patients than in HIV-uninfected patients with cryptococcal meningitis. [2] 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).

CSF reveals the following at this stage:

Elevated protein and mononuclear pleocytosis

Normal glucose level

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.

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. [3] 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. 

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. 

Drugs of choice include ganciclovir for CMV ventriculoencephalitis and amphotericin B for cryptococcal meningitis. [4, 5, 6]

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. [7] Patients in both arms of the study also received flucytosine, 25 mg/kg 4 times daily. [7]

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. [8]

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. 

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

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.

Overview

What forms of meningitis are associated with HIV?

What causes HIV-associated meningitis?

What is the prevalence of HIV-associated meningitis?

What is the prognosis of HIV-associated meningitis?

Which factors increase the risk of mortality from HIV-associated meningitis?

Which clinical history findings are characteristic of HIV-associated meningitis?

Which physical findings are characteristic of HIV-associated meningitis?

What are the signs and symptoms of cryptococcal meningitis in patients with HIV infection?

How is meningitis due to cytomegalovirus differentiated from aseptic HIV-associated meningitis?

Which conditions are included in the differential diagnoses of HIV-associated meningitis?

How is immune reconstitution inflammatory syndrome (IRIS) differentiated from HIV-associated meningitis?

What is the role of CSF analysis in the workup of HIV-associated meningitis?

Which CSF analysis findings are characteristic of cryptogenic meningitis in patients with HIV infection?

Which CSF analysis findings are characteristic of cytomegalovirus ventriculoencephalitis in patients with HIV infection?

Which CSF analysis findings are characteristic of cryptococcal meningitis in patients with HIV infection?

What is the role of brain imaging in the workup of HIV-associated meningitis?

How is HIV-associated meningitis treated?

What is the prevalence of recurrence of HIV-associated meningitis?

What is included in the long-term monitoring of HIV-associated meningitis?

Jarvis JN, Harrison TS. HIV-associated cryptococcal meningitis. AIDS. 2007 Oct 18. 21 (16):2119-29. [Medline].

Liao CH, Chi CY, Wang YJ, et al. Different presentations and outcomes between HIV-infected and HIV-uninfected patients with Cryptococcal meningitis. J Microbiol Immunol Infect. 2012 Aug. 45(4):296-304. [Medline].

Roy M, Chiller T. Preventing deaths from cryptococcal meningitis: from bench to bedside. Expert Rev Anti Infect Ther. 2011 Sep. 9(9):715-7. [Medline].

Hamill RJ, Sobel JD, El-Sadr W, Johnson PC, Graybill JR, Javaly K, et al. Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety. Clin Infect Dis. 2010 Jul 15. 51(2):225-32. [Medline].

Milefchik E, Leal MA, Haubrich R, Bozzette SA, Tilles JG, Leedom JM, et al. Fluconazole alone or combined with flucytosine for the treatment of AIDS-associated cryptococcal meningitis. Med Mycol. 2008 Jun. 46(4):393-5. [Medline].

[Guideline] Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010 Feb 1. 50(3):291-322. [Medline].

Bicanic T, Wood R, Meintjes G, Rebe K, Brouwer A, Loyse A, et al. High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. Clin Infect Dis. 2008 Jul 1. 47(1):123-30. [Medline].

Longley N, Muzoora C, Taseera K, Mwesigye J, Rwebembera J, Chakera A, et al. Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. Clin Infect Dis. 2008 Dec 15. 47(12):1556-61. [Medline].

Gulshan Uppal, MD Private Practice at Freeman Hospital

Gulshan Uppal, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Florian P Thomas, MD, PhD, MA, MS Chair, Neuroscience Institute and Department of Neurology, Director, Multiple Sclerosis Center and Hereditary Neuropathy Centers, Hackensack University Medical Center; Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine at Seton Hall University; Professor Emeritus, Department of Neurology, St Louis University School of Medicine; Editor-in-Chief, Journal of Spinal Cord Medicine

Florian P Thomas, MD, PhD, MA, MS is a member of the following medical societies: Academy of Spinal Cord Injury Professionals, American Academy of Neurology, American Neurological Association, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society, Sigma Xi

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM Adjunct Associate Professor of Neurology, University of Missouri-Columbia School of Medicine; Medical Director of St Mary’s Stroke Program, SSM Neurosciences Institute, SSM Health

Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Headache Society

Disclosure: Nothing to disclose.

Meningitis in HIV

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