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HIV-1 Associated CNS Conditions Meningitis

Author: Niranjan N Singh, MD, DNB, Assistant Professor of Neurology, University of


Missouri Columbia
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
Contributor Information and Disclosures
Updated: Feb 23, 2010

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Overview

Differential Diagnoses & Workup

Treatment & Medication

Follow-up

References

Keywords
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Introduction
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.

Pathophysiology
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.

Frequency
United States
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 HIVseropositive 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.

Clinical
History
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

Physical

Examination can reveal nuchal rigidity, fever, and cranial neuropathies.


In rare cases, the patient is somnolent or confused.

Treatment
Medical Care
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.

Consultations
Coordination of care with the primary care physician and an infectious disease specialist is
recommended.

Medication
The goal of pharmacotherapy is to reduce morbidity and prevent complications.

Antiviral agents
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.

Ganciclovir (Cytovene, Vitrasert)


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.

Dosing
Interactions

Contraindications

Precautions

Adult

Induction: 5 mg/kg IV bid for 14 d


Maintenance: 5 mg/kg/d IV for 5-7 d, then 500 mg PO q4h or 1 g PO tid for life
Pediatric

Not established for congenital/neonatal infection

Dosing
Interactions

Contraindications

Precautions

Concomitant administration of cytotoxic drugs (eg, dapsone, vinblastine, doxorubicin,


pentamidine, flucytosine, vincristine, amphotericin B, trimethoprim/sulfamethoxazole
combinations, other nucleoside analogs) may result in additive toxicity in bone marrow,
spermatogonium, and germinal layers of skin and GI mucosa (coadminister only if potential
benefits outweigh risks); coadministration with imipenem-cilastatin may cause generalized
seizures (use only if potential benefits outweigh risks); serum creatinine may increase after use
of cyclosporine or amphotericin B; probenecid reduces renal clearance; bioavailability may
increase when didanosine administered simultaneously or 2 h before; zidovudine may decrease
bioavailability, whereas ganciclovir increases bioavailability of zidovudine

Dosing
Interactions

Contraindications

Precautions

Documented hypersensitivity; thrombocytopenia (platelets <25 x 109/L); neutropenia (ANC


<500/L)

Dosing
Interactions

Contraindications

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Clinical toxic effects include granulocytopenia, anemia, and thrombocytopenia; oral form (vs IV
form) associated with increased rate of CMV retinitis progression, use oral form only when
benefits outweigh risks (eg, advanced HIV disease); half-life and plasma or serum concentrations
may be increased due to reduced renal clearance; dosages > 6 mg/kg IV may result in increased
toxicity; rapid infusions may result in increased toxicity; reconstituted solutions of IV form have
high pH (pH 11); phlebitis or pain may occur at site of IV infusion despite further dilution in IV
fluids; administration should be accompanied by adequate hydration; photosensitization
(photoallergy or phototoxicity) may occur

Foscarnet (Foscavir)
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.

Dosing
Interactions

Contraindications

Precautions

Adult

60 mg/kg IV tid for 14 d, then 90-120 mg/kg IV qd for life


Pediatric

<12 years: Not established


>12 years: Administer as in adults

Dosing
Interactions

Contraindications

Precautions

Avoid use in combination with potentially nephrotoxic drugs (eg, aminoglycosides, amphotericin
B, IV pentamidine) unless potential benefits outweigh risks; coadministration with IV
pentamidine may cause hypocalcemia

Dosing
Interactions

Contraindications

Precautions

Documented hypersensitivity

Dosing
Interactions

Contraindications

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may
use if benefits outweigh risk to fetus
Precautions

May cause decline in renal function; for correct dosing, obtain 24-h urine with CrCl at baseline
and thereafter (discontinue if CrCl <0.4 mL/min/kg); hydration may reduce nephrotoxicity;
carefully monitor electrolytes (eg, Ca, Mg); assess for electrolyte and mineral abnormalities if
mild perioral numbness, paresthesias, or seizures occur; granulocytopenia and anemia may occur
(monitor CBC regularly); infuse into veins with adequate blood flow to avoid local irritation; to
avoid toxicity, do not administer by rapid or bolus IV injection

Antifungal agents
These agents treat systemic fungal infections, such as cryptococcal meningitis.

Amphotericin B, conventional (Amphocin, Fungizone)


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.

Dosing
Interactions

Contraindications

Precautions

Adult

0.7-1 mg/kg/d IV; total cumulative dose is 3 g


Combination therapy: 0.7-1 mg/kg/d amphotericin B IV and 100 mg/kg/d flucytosine PO for 2
wk
Pediatric

Not established; recommended dose 0.5 mg/kg/d IV

Dosing
Interactions

Contraindications

Precautions

Antineoplastic agents may enhance potential of amphotericin B for renal toxicity, bronchospasm,
and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of
renal toxicity increased with cyclosporine

Dosing
Interactions

Contraindications

Precautions

Documented hypersensitivity

Dosing
Interactions

Contraindications

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may
use if benefits outweigh risk to fetus

Precautions

Monitor renal function, serum electrolyte (eg, Mg, K) concentrations, liver functions, CBC, and
hemoglobin; resume at lowest level (eg, 0.25 mg/kg) if interrupted for <7 d; hypoxemia, acute
dyspnea, and interstitial infiltrates may occur in neutropenic patients receiving leukocyte
transfusions (separate amphotericin infusion from transfusion in time)

Flucytosine (Ancobon)
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.

Dosing
Interactions

Contraindications

Precautions

Adult

100 mg/kg PO qd for 2 wk


Combination therapy: 0.7-1 mg/kg/d amphotericin B IV and 100 mg/kg/d flucytosine PO for 2
wk
Pediatric

Not established; suggested dose 200 mg/kg IV qd

Dosing
Interactions

Contraindications

Precautions

Toxicity may be increased by amphotericin B; may be inactivated by cytosine

Dosing
Interactions

Contraindications

Precautions

Documented hypersensitivity

Dosing
Interactions

Contraindications

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may
use if benefits outweigh risk to fetus
Precautions

Caution in bone marrow suppression; adjust dose in renal impairment

Fluconazole (Diflucan)
Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome
P-450 and sterol C-14 alpha-demethylation.
Achieves responses similar to amphotericin but has higher rate of early mortality.

Dosing
Interactions

Contraindications

Precautions

Adult

400 mg PO qd for 10 wk, then 200 mg PO qd for life


Pediatric

2-3 mg/kg PO qd

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