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Epidemiology, Clinical Manifestations, and Diagnosis of Cryptococcus Neoformans Meningoencephalitis in Patients With HIV - UpToDate
Epidemiology, Clinical Manifestations, and Diagnosis of Cryptococcus Neoformans Meningoencephalitis in Patients With HIV - UpToDate
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2021. | This topic last updated: Jul 15, 2020.
INTRODUCTION
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Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV - UpToDate 7/24/21, 12(38 PM
therapy for cryptococcal meningoencephalitis in patients with HIV" and "Microbiology and
epidemiology of Cryptococcus neoformans infection" and "Clinical manifestations and
diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-seronegative patients"
and "Cryptococcus neoformans: Treatment of meningoencephalitis and disseminated
infection in HIV seronegative patients" and "Cryptococcus neoformans infection outside the
central nervous system" and "Cryptococcus gattii infection: Microbiology, epidemiology, and
pathogenesis" and "Cryptococcus gattii infection: Clinical features and diagnosis" and
"Cryptococcus gattii infection: Treatment".)
EPIDEMIOLOGY
The vast majority (90 percent) of cases of cryptococcal meningoencephalitis are seen among
patients with AIDS and a CD4 count <100 cells/microL. Patients who present with
cryptococcosis can be antiretroviral therapy (ART) naïve or can be prescribed ART but have
drug resistance or poor adherence to their prescribed regimen.
Early diagnosis and treatment may help reduce cryptococcal meningitis-related mortality.
One way to diagnose cryptococcal infection early in the course of disease is through the
detection of serum cryptococcal antigen (CrAg), which can be detected at least three weeks
prior to the onset of neurologic symptoms. The prevalence of antigenemia has been found to
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Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV - UpToDate 7/24/21, 12(38 PM
vary depending upon the geographical area. As an example, in the United States, the
prevalence of cryptococcal antigenemia among patients with a CD4 count <100 cells/microL
was reported to be approximately 3 percent, whereas in Uganda the prevalence among such
patients was 8.2 percent [9,10]. A detailed discussion of the use of CrAg screening and early
therapy to preemptively manage meningoencephalitis is found elsewhere. (See
"Cryptococcus neoformans meningoencephalitis in patients with HIV: Treatment and
prevention", section on 'Screening and treatment of early infection'.)
CLINICAL MANIFESTATIONS
Other symptoms suggesting disseminated disease include cough, dyspnea, and skin rash
[11]. Visual and hearing loss can also occur [12,13].
Physical examination — The initial physical examination may be notable for lethargy or
confusion in association with fever. In one report, 24 percent of patients had altered
mentation on presentation, and 6 percent presented with focal neurologic deficits, such as
cranial neuropathies [2]. Other manifestations of disseminated disease may be evident,
including tachypnea and skin lesions resembling molluscum contagiosum ( picture 1) [11].
Increased diastolic hypertension may be reflective of increased intracranial pressure.
DIAGNOSIS
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Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV - UpToDate 7/24/21, 12(38 PM
headache. Initial evaluation includes a careful history, neurologic exam, and serum
cryptococcal antigen (CrAg). Evaluation should also include a lumbar puncture (LP) to assess
for increased intracranial pressure and culture of cerebrospinal fluid (CSF) to confirm the
diagnosis in those with symptoms and/or a positive serum CrAg. (See 'Importance of
neuroimaging' below and 'Lumbar puncture' below.)
Imaging can detect the presence of mass lesions, increased intracranial pressure, and/or
hydrocephalus, all of which impact treatment decisions.
● Imaging may suggest possible increased ICP with or without mass/space occupying
lesions in patients with cryptococcal meningoencephalitis. While LP and removal of CSF
may be beneficial for both diagnostic and therapeutic purposes, the risks and benefits of
the procedure must be discussed with the patient and/or health care proxy given the
very small, but possible chance of cerebral herniation in the setting of raised intracranial
pressure. Consultation with neurology and/or neurosurgery can be obtained to help
guide this discussion. A more detailed discussion on the risks of lumbar punctures is
found elsewhere. (See "Lumbar puncture: Technique, indications, contraindications, and
complications in adults", section on 'Cerebral herniation'.)
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patients with HIV who are not receiving ART [14,15]; however, they can occur with
unmasking cryptococcosis in the setting of an immune reconstitution inflammatory
syndrome [10] and in patients with C. gattii infection. (See "Clinical management and
monitoring during antifungal therapy for cryptococcal meningoencephalitis in patients
with HIV", section on 'Immune reconstitution inflammatory syndrome' and
"Cryptococcus gattii infection: Clinical features and diagnosis".)
Lumbar puncture — A lumbar puncture (LP) is required to obtain CSF for confirmatory
testing to make the diagnosis of cryptococcal meningoencephalitis. The CSF profile classically
demonstrates a low white blood cell count in the CSF (eg, <50 cells/microL) with a
mononuclear predominance [16]. The CSF protein may be slightly elevated, while the glucose
concentrations are commonly low or normal [13]. Approximately 25 to 30 percent of patients
with culture-proven cryptococcal meningoencephalitis have a normal CSF profile [17,18].
An LP is also important for determining the patient's intracranial pressure (ICP), which can be
associated with significant morbidity and mortality [2,13]. The management of increased ICP
is discussed elsewhere. (See "Clinical management and monitoring during antifungal therapy
for cryptococcal meningoencephalitis in patients with HIV", section on 'Monitoring of
intracranial pressure'.)
Cryptococcal culture — CSF should be sent for cryptococcal culture; cream-colored mucoid
colonies are seen on agar plates generally within three to seven days.
India ink staining — Since the burden of organisms is usually high in patients with AIDS, an
India ink preparation of the CSF may demonstrate typical round encapsulated yeast
organisms consistent with Cryptococcus in 60 percent of patients [19]. However, India ink can
miss low burden infections; in one report, the sensitivity of India ink was only 42 percent
when the culture burden was <1000 colony forming units (CFU)/mL [19].
The advantage of the India ink preparation is that a diagnosis of cryptococcal infection can
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Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV - UpToDate 7/24/21, 12(38 PM
be made rapidly while confirmatory testing is being performed (eg, CSF culture or antigen).
India ink stains should be reviewed by a microbiologist who is familiar with the physical
characteristics of the organism.
Regardless of India ink results, a CrAg test should also be performed to confirm the
diagnosis. The antigen titer measurement can also provide an estimate of fungal burden and
prognosis. (See 'Prognostic factors' below.)
Cryptococcal antigen (CrAg) — CrAg can be detected in serum and CSF through
immunodiagnostic techniques, such as latex agglutination or sandwich enzyme-linked
immunosorbent assay (ELISA). The lateral flow assay (LFA) is an alternative approach to
detecting cryptococcal antigen. It is a simple dipstick test that is inexpensive to perform and
can be used on blood, serum, CSF, or plasma samples. The LFA compares favorably with the
latex agglutination and ELISA, and is used in both resource-limited and resource-available
areas [19,20]. In resource-limited settings, the LFA improves access to diagnostic testing and
time to diagnosis. The analytical sensitivity of LFA is approximately fourfold higher than latex
agglutination, thus CrAg titers by LFA and latex agglutination are not comparable.
Spinal fluid — A positive CrAg in the CSF strongly supports the diagnosis of cryptococcal
meningoencephalitis and is sufficient evidence to initiate treatment in patients with
symptoms and/or risk factors that are consistent with infection. Results of the CrAg test can
be obtained immediately after the LP is performed; thus, a positive CrAg test can suggest the
presence of infection well before the cultures become positive.
The CrAg is very sensitive and specific in the CSF and has been commonly detected by latex
agglutination. In a study of four latex agglutination assays and one enzyme linked
immunoassay, all performed well with sensitivities ranging from 93 to 100 percent and
specificities from 93 to 98 percent [21]. With latex agglutination, diagnostic false-positive
tests can result from infection due to the fungus Trichosporon asahii (formerly T. beigelii) or
bacteria of the Stomatococcus and Capnocytophaga genera [22-24]. These positive results are
usually present with low titers. False-positive CSF cryptococcal antigen results have been
reported rarely following exposure of samples to disinfectants or soap, or after samples were
placed into an anaerobic transport vial [25-27]. (See "Infections due to Trichosporon species
and Blastoschizomyces capitatus (Saprochaete capitata)".)
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The lateral flow assay (LFA) has become the primary approach for detecting CrAg worldwide.
The LFA is easier to use and less expensive than latex agglutination. In addition, the LFA
appears to perform equally well as or better than other tests. As an example, in a study of
832 HIV-infected individuals from sub-Saharan Africa, LFA was shown to have >99 percent
sensitivity and specificity among persons with suspected meningoencephalitis [19]. In this
study, LFA had the best test performance when compared with latex agglutination, culture,
or India ink microscopy.
Serum/plasma — Serum/plasma testing can have a role in diagnosing patients with both
symptomatic and asymptomatic disease.
CrAg titers generally correlate with initial organism burden and prognosis. However,
following titers are not helpful in management of acute disease in patients with HIV
since changes in titer do not precisely correlate with clinical response [29]. Also, the
slope of decline is not helpful in predicting those patients who may relapse [30]. (See
"Clinical management and monitoring during antifungal therapy for cryptococcal
meningoencephalitis in patients with HIV", section on 'Laboratory monitoring for fungal
infection'.)
Cryptococcal PCR — Multiplex polymerase chain reaction (PCR) systems for CNS infections
(eg, BioFire FilmArray), which screen for the presence of C. neoformans and C. gattii, are
increasingly being used in clinical practice. In one study from Africa, this test detected
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Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV - UpToDate 7/24/21, 12(38 PM
Cryptococcus in the CSF of patients diagnosed with a first episode of cryptococcal infection
with >90 percent sensitivity and excellent specificity. PCR was particularly help to distinguish
persistent culture-positive relapse from paradoxical immune reconstitution inflammatory
syndrome (IRIS) [31]. (See "Clinical management and monitoring during antifungal therapy
for cryptococcal meningoencephalitis in patients with HIV", section on 'Immune
reconstitution inflammatory syndrome'.)
However, clinicians should be cautioned that PCR sensitivity decreases to less than 50
percent with low fungal burdens (<100 CFU/mL CSF) [31]. In addition, this test is expensive
and is not commonly used in low and middle income countries. More studies are needed to
better understand the sensitivity and specificity of this test for cryptococcal infections, as well
as the clinical value in patients without HIV [32].
The prostate gland is recognized as an extraneural site from which Cryptococcus can reside,
leading to relapse with systemic dissemination after discontinuation of treatment. Detection
of Cryptococcus on urine culture can be improved with prostatic massage. Prior to the era of
potent antiretroviral therapy (ART), persistent prostatic sequestration of Cryptococcus was
described in patients who were treated for six weeks with amphotericin B with or without
flucytosine, with subsequent relapse after treatment discontinuation [33].
Prompt LP with measurement of CSF opening pressure and rapid CSF CrAg assays (or India
ink testing if CrAg is not available) remains the preferred diagnostic approach. However,
obtaining a diagnosis can be challenging in some settings because of limited access to LP
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and/or neuroimaging. When this occurs, the risks and benefits favor performing LP without
prior neuroimaging, rather than in high-income country settings where the prevalence of
cryptococcal meningoencephalitis is lower.
● If testing for CrAg is positive, treatment with antifungal therapy should be initiated. (See
"Cryptococcus neoformans meningoencephalitis in patients with HIV: Treatment and
prevention".)
● If rapid serum or plasma CrAg is negative or not available, empiric therapy should
generally not be administered. Instead, the patient should undergo further diagnostic
evaluation, in an appropriate setting, as soon as possible.
A preemptive strategy involving serum CrAg screening and antifungal therapy may reduce
the risk of developing cryptococcal meningoencephalitis in asymptomatic patients who are at
high risk for developing disease, and may allow earlier therapy for those with CNS
involvement. A detailed discussion on the prevention of cryptococcal disease is found
elsewhere. (See "Cryptococcus neoformans meningoencephalitis in patients with HIV:
Treatment and prevention", section on 'Screening and treatment of early infection'.)
DIFFERENTIAL DIAGNOSIS
The differential diagnosis in the advanced AIDS patient with fever and headache includes
toxoplasmosis, tuberculosis meningitis, lymphoma, syphilis, and progressive multifocal
leukoencephalopathy. Patients with toxoplasmosis may also have focal findings, such as
specific hand weakness, while patients with cryptococcal meningoencephalitis usually have
cranial neuropathies, particularly cranial nerve VI. Patients with tuberculous meningitis may
also have other clues to the diagnosis, such as cough, hemoptysis, and an abnormal chest x-
ray. Patients with secondary syphilis with aseptic meningitis usually have normal mentation
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Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV - UpToDate 7/24/21, 12(38 PM
and a disseminated maculopapular rash. Those with central nervous system (CNS) lymphoma
may have focal neurologic deficits with abnormal neuroimaging reflecting an intracranial
tumor. (See "Toxoplasmosis in patients with HIV" and "Progressive multifocal
leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis".)
PROGNOSTIC FACTORS
The prognosis for patients with AIDS-associated central nervous system (CNS) cryptococcosis
has improved dramatically with antifungal treatment coupled with potent antiretroviral
therapy (ART), which leads to effective viral suppression and immunologic recovery [35,36].
However, early treatment with ART during the first two weeks of induction antifungal therapy
for CNS cryptococcosis should be avoided since higher mortality occurred in comparison
with delayed ART [37]. The treatment of cryptococcal meningoencephalitis and the timing of
ART initiation are discussed elsewhere. (See "Cryptococcus neoformans meningoencephalitis
in patients with HIV: Treatment and prevention" and "Clinical management and monitoring
during antifungal therapy for cryptococcal meningoencephalitis in patients with HIV".)
Acute mortality from cryptococcal meningoencephalitis with underlying HIV infection ranges
from 6 to 16 percent in high-income countries [16,35,38-40]. The significant clinical and
laboratory predictors of death during the initial few weeks of treatment include [38]:
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Cryptococcosis" and
"Society guideline links: Opportunistic infections in HIV-infected adults and adolescents".)
● Symptoms typically begin indolently over a period of one to two weeks. The most
common symptoms are fever, malaise, and headache. Other neurologic findings (eg,
cranial neuropathies), may also be present. Symptoms suggesting disseminated disease
include cough, dyspnea, and skin rash. (See 'Clinical manifestations' above.)
● 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. (See 'Importance of neuroimaging' above.)
● The significant clinical and laboratory predictors of death during initial induction therapy
include an abnormal mental status, a CSF antigen titer of >1:1024 by latex agglutination
or >1:4000 by lateral flow assay (LFA), and a pleocytosis of <20 CSF white blood
cells/microL. (See 'Prognostic factors' above.)
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REFERENCES
2. Cox GM, Perfect JR. Cryptococcus neoformans var neoformans and gattii and Trichospor
on species. In: Topley and Wilson's Microbiology and Microbial Infections, 9th Ed, Edwar
d LA (Ed), Arnold Press, London 1997.
3. Lee SC, Dickson DW, Casadevall A. Pathology of cryptococcal meningoencephalitis:
analysis of 27 patients with pathogenetic implications. Hum Pathol 1996; 27:839.
4. Park BJ, Wannemuehler KA, Marston BJ, et al. Estimation of the current global burden of
cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009; 23:525.
7. Rajasingham R, Smith RM, Park BJ, et al. Global burden of disease of HIV-associated
cryptococcal meningitis: an updated analysis. Lancet Infect Dis 2017; 17:873.
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11. Murakawa GJ, Kerschmann R, Berger T. Cutaneous Cryptococcus infection and AIDS.
Report of 12 cases and review of the literature. Arch Dermatol 1996; 132:545.
12. Rex JH, Larsen RA, Dismukes WE, et al. Catastrophic visual loss due to Cryptococcus
neoformans meningitis. Medicine (Baltimore) 1993; 72:207.
13. Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial
pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study
Group and AIDS Cooperative Treatment Groups. Clin Infect Dis 2000; 30:47.
18. Garlipp CR, Rossi CL, Bottini PV. Cerebrospinal fluid profiles in acquired
immunodeficiency syndrome with and without neurocryptococcosis. Rev Inst Med Trop
Sao Paulo 1997; 39:323.
19. Boulware DR, Rolfes MA, Rajasingham R, et al. Multisite validation of cryptococcal
antigen lateral flow assay and quantification by laser thermal contrast. Emerg Infect Dis
2014; 20:45.
20. Jarvis JN, Percival A, Bauman S, et al. Evaluation of a novel point-of-care cryptococcal
antigen test on serum, plasma, and urine from patients with HIV-associated
cryptococcal meningitis. Clin Infect Dis 2011; 53:1019.
21. Tanner DC, Weinstein MP, Fedorciw B, et al. Comparison of commercial kits for detection
of cryptococcal antigen. J Clin Microbiol 1994; 32:1680.
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23. McManus EJ, Jones JM. Detection of a Trichosporon beigelii antigen cross-reactive with
Cryptococcus neoformans capsular polysaccharide in serum from a patient with
disseminated Trichosporon infection. J Clin Microbiol 1985; 21:681.
24. Westerink MA, Amsterdam D, Petell RJ, et al. Septicemia due to DF-2. Cause of a false-
positive cryptococcal latex agglutination result. Am J Med 1987; 83:155.
25. Blevins LB, Fenn J, Segal H, et al. False-positive cryptococcal antigen latex agglutination
caused by disinfectants and soaps. J Clin Microbiol 1995; 33:1674.
26. Boom WH, Piper DJ, Ruoff KL, Ferraro MJ. New cause for false-positive results with the
cryptococcal antigen test by latex agglutination. J Clin Microbiol 1985; 22:856.
27. Wilson DA, Sholtis M, Parshall S, et al. False-positive cryptococcal antigen test associated
with use of BBL Port-a-Cul transport vials. J Clin Microbiol 2011; 49:702.
30. Aberg JA, Watson J, Segal M, Chang LW. Clinical utility of monitoring serum cryptococcal
antigen (sCRAG) titers in patients with AIDS-related cryptococcal disease. HIV Clin Trials
2000; 1:1.
31. Rhein J, Bahr NC, Hemmert AC, et al. Diagnostic performance of a multiplex PCR assay
for meningitis in an HIV-infected population in Uganda. Diagn Microbiol Infect Dis 2016;
84:268.
32. Leber AL, Everhart K, Balada-Llasat JM, et al. Multicenter Evaluation of BioFire FilmArray
Meningitis/Encephalitis Panel for Detection of Bacteria, Viruses, and Yeast in
Cerebrospinal Fluid Specimens. J Clin Microbiol 2016; 54:2251.
33. Larsen RA, Bozzette S, McCutchan JA, et al. Persistent Cryptococcus neoformans
infection of the prostate after successful treatment of meningitis. California
Collaborative Treatment Group. Ann Intern Med 1989; 111:125.
34. The World Health Organization. Guidelines for the diagnosis, prevention and manageme
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36. Lanoy E, Guiguet M, Bentata M, et al. Survival after neuroAIDS: association with
antiretroviral CNS Penetration-Effectiveness score. Neurology 2011; 76:644.
37. Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis
of cryptococcal meningitis. N Engl J Med 2014; 370:2487.
38. Saag MS, Powderly WG, Cloud GA, et al. Comparison of amphotericin B with fluconazole
in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses
Study Group and the AIDS Clinical Trials Group. N Engl J Med 1992; 326:83.
39. Robinson PA, Bauer M, Leal MA, et al. Early mycological treatment failure in AIDS-
associated cryptococcal meningitis. Clin Infect Dis 1999; 28:82.
40. Bratton EW, El Husseini N, Chastain CA, et al. Comparison and temporal trends of three
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transplant. PLoS One 2012; 7:e43582.
Topic 3757 Version 26.0
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Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV - UpToDate 7/24/21, 12(38 PM
GRAPHICS
Disseminated cryptococcosis
Multiple umbilicated papules are present on the face of this patient with
cryptococcosis. The lesions resemble molluscum contagiosum.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights reserved.
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Contributor Disclosures
Gary M Cox, MD Nothing to disclose John R Perfect, MD Grant/Research/Clinical Trial Support: Merck
[Antifungal agents]; Astellas [Antifungal agents]; Pfizer [Antifungal agents]. Consultant/Advisory Boards:
Merck [Antifungal agents]; Astellas [Antifungal agents]. John A Bartlett, MD Nothing to disclose Milana
Bogorodskaya, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
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