Niranjan N Singh, MD, DNB,
Assistant Professor of Neurology, University
of Missouri Columbia
Nothing to disclose.
Coauthor(s)
Florian P Thomas, MD, MA, PhD,
Drmed,,
Director, Spinal Cord Injury Service, St
Louis Veterans Affairs Medical Center; Director, National MS
Society Multiple Sclerosis Center; Director, Neuropathy
Association Center of Excellence, Professor, Department of
Neurology and Psychiatry, Associate Professor, Institute for
Molecular Virology, and Department of Molecular Microbiology
and Immunology, St Louis University
Nothing to disclose.
Specialty Editor(s)
Francisco Talavera, PharmD, PhD,
Senior Pharmacy Editor,
eMedicine
eMedicine Salary Employment
Richard J Caselli, MD,
Professor, Department of Neurology, Mayo
Medical School, Rochester, MN; Chair, Department of
Neurology, Mayo Clinic of Scottsdale
Nothing to disclose.
Ronald A Greenfield, MD,
Professor, Department of Internal Medicine,
Section of Infectious Diseases, University of Oklahoma
College of Medicine
Pfizer Honoraria Speaking
and
teaching; Gilead Honoraria Speaking
and teaching; Ortho
McNeil Honoraria Speaking and
teaching; Wyeth Honoraria Speaking
and
teaching; Abbott Honoraria Speaking
and
teaching; Astellas Honoraria Speaking
and teaching; Cubist Speaking and
teaching
Background
Different forms of meningitis are associated with HIV infection. They may be classified according to the etiologic agent as cryptococcal, tuberculous, syphilitic, or Listeria species; others are lymphomatous or aseptic.
Meningitis is multifactorial in patients with HIV/AIDS. Besides specific pathogens, autoimmune processes and HIV itself have been implicated.
Although HIV-seropositive individuals are at increased risk 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. An early form of aseptic, HIV-associated meningitis develops within days to weeks after HIV infection. It appears as a mononucleosis-like illness and is rarely associated with encephalitis. Meningitides due to cryptococcosis, coccidioidomycosis, histoplasmosis, or other fungal infection are AIDS-defining events and occur typically with very low CD4+ lymphocyte counts.
Chronic meningitis or episodes of acute meningitis for which no cause is found can occur anytime during the disease course.
An asymptomatic form is found in one third of patients in whom CSF is examined for other reasons (eg, headache).
Cytomegaloviral (CMV) infection usually presents as an encephaloventriculitis with possible meningeal involvement.
Medications as causes are often overlooked including nonsteroidal anti-inflammatory drugs (NSAIDs), trimethoprim/sulfamethoxazole, and intravenous immunoglobulin (IVIG).
In patients receiving highly active anti-retroviral therapy (HAART) and 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. Symptoms that are consistent with an infectious and/or inflammatory condition appear while the patient is on antiretroviral therapy and the symptoms 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.
Cryptococcal meningitis is the most common opportunistic infection of the CNS, 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.
Rarer CNS infections are due to Listeria monocytogenes, coccidioidomycosis, histoplasmosis, syphilis, and tuberculosis. CNS syphilis may occur earlier and more frequently in HIV-seropositive individuals than in HIV-seronegative individuals.
Bacterial meningitis often occurs in conjunction with sepsis due to the same organism.
In rare cases, metastatic CNS lymphoma can appear as meningitis.
Mortality/Morbidity
Mortality rates and morbidity vary by the etiology of meningitis. A previously reported mortality rate of 20% for cryptococcal meningitis, for example, may now be as low as 6% owing to more aggressive therapy. Higher mortality rates correlate with poor mental status, high CSF opening pressure at presentation, positive India ink test, extra-CNS manifestations, and higher fungal burdens.
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.
One meta-analysis showed that stiff neck occurred in 50% of cases of non-AIDS meningitis; four studies shoed rates of 22%, 31%, 37%, and 44% for AIDS meningitis. Similarly, the frequency of papilledema was 28% in that same study of non-AIDS meningitis, whereas frequencies of 6% and 8% were reported in 2 studies of AIDS meningitis.
Characteristics of HIV-seropositive patients with meningitis are the following:
Patients present with malaise, fever, stiff neck, photophobia, and headache.
Less common findings are confusion, somnolence, and personality changes.
The time course is variable. Patients with aseptic meningitis, a diagnosis of exclusion, have a good prognosis and do not require any specific treatment.
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. Sometimes Cryptococcus neoformans is incidentally found in the CSF.
CMV ventriculoencephalitis often causes death within weeks to months. It usually results in a change in mental status evolving over several weeks and can be misdiagnosed as HIV-associated dementia
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
Elevated protein and mononuclear pleocytosis
Normal glucose level
CMV encephaloventriculitis
Often, polymorphonuclear pleocytosis
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 1 study of patients with AIDS, 26% had normal findings; 40% had high protein levels, low glucose levels, and pleocytosis; and 55% had < 10 lymphocytes per cubic millimeter.
One caveat: High CSF opening pressure is present in about two thirds of patients and is a poor prognostic sign.
CSF may have a clear or turbid appearance.
Protein and glucose levels may be high or normal.
Variable mononuclear pleocytosis is observed. The WBC count may be >20 x 109/L.
Cultures are the criterion standard, but weeks and several specimens may be needed to obtain a positive result.
Results of the India ink test is 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. The initial diagnostic sensitivity of cryptococcal CSF antigen is 94.1%, followed by the serum antigen 93.6%; however, this tool is unreliable in assessing point of discontinuation of antifungal therapy, at least among patients who are HIV positive.
Findings may be nonspecific because of concurrent nonmeningitic neurological complications of HIV (eg, atrophy in cases of AIDS dementia/HIV encephalopathy).
Ependymal enhancement is seen with CMV encephaloventriculitis.
Drugs of choice include ganciclovir for CMV encephaloventriculitis and amphotericin B for cryptococcal meningitis.
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 assessing the fungicidal effect of amphotericin 1 mg plus flucytosine versus amphotericin 0.7 mg plus flucytosine, higher dose amphotericin B was rapidly fungicidal compared with standard dose; side effects were comparable.[1] Similarly, fluconazole at 1200 mg/d was more fungicidal than 800 mg oral daily, with tolerable side effect profile.[2]
Treatment should be administered in consultation with an infectious disease specialist.
Ganciclovir or foscarnet is recommended for CMV encephaloventriculitis. In patients who develop this condition during treatment with either of these 2 drugs for CMV infection in another organ or have received either drug before, a ganciclovir-foscarnet combination is recommended.
Clinical Context:
Synthetic guanine derivative active against CMV. Acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpesviruses in vitro and in vivo. Levels of ganciclovir triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly because of preferential phosphorylation of ganciclovir in virus-infected cells. In patients who with progression of CMV retinitis while receiving maintenance treatment with either form, induction regimen should be readministered.
Clinical Context:
Organic analog of inorganic pyrophosphate that inhibits replication of known herpesviruses, including CMV, HSV-1, and HSV-2. Inhibits viral replication at pyrophosphate-binding site on virus-specific DNA polymerases. Poor clinical response or persistent viral excretion during therapy may be due to viral resistance.
Patients who can tolerate foscarnet well may benefit from early maintenance treatment at 120 mg/kg/d. Individualize dosing to renal function.
Clinical Context:
Produced by strain of Streptomyces nodosus; can be fungistatic or fungicidal. Binds to sterols, such as ergosterol, in the fungal cell membrane, causing intracellular components to leak and subsequent fungal cell death.
Clinical Context:
Converted to fluorouracil after penetrating fungal cells, inhibiting RNA and protein synthesis. Active against Candida and Cryptococcus species and generally used in combination with amphotericin B.
Initially treat patients with amphotericin B (0.7-1 mg/kg/d) with flucytosine for 2 weeks followed by fluconazole 400 mg PO qd for 10 weeks. The symptomatic intracranial hypertension should be treated with repeated lumbar punctures.
Patients with mild disease, pancytopenia, renal insufficiency, or abnormalities in electrolyte (K, Mg) may be treated with fluconazole 200 mg BID for 8-10 weeks.
Secondary prevention continues with fluconazole 200 mg qd.
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 encephaloventriculitis also may recur. As for cryptococcal meningitis, relapse within 1 year is most likely in patients who do not receive maintenance therapy.
