CNS Cryptococcosis in HIV

Updated: Jan 08, 2020
  • Author: Felicia J Gliksman, DO, MPH; Chief Editor: Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM  more...
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Cryptococcosis is the most common fungal infection of the central nervous system and may present as a space-occupying lesion, meningitis, or meningoencephalitis. In addition, cryptococcosis is the most common fungal disease in HIV-infected persons, and it is the AIDS-defining illness for 60–70% of HIV-infected patients.



Cryptococcus neoformans spreads hematogenously to the CNS from pulmonary foci, which may be subclinical. No pneumonitis is found in more than 85% of patients with cryptococcal CNS disease. In addition to invading the lung and CNS, cryptococci also invade the skin, bone, and genitourinary tract, but meninges appear to be the preferred site. The reasons are not clear, but several suggestions have been made. For one, cryptococcal capsule antigens may have limited ability to induce an inflammatory response in the cerebrospinal fluid. Furthermore, the alternative pathway of complement is absent in the CSF. By contrast, CSF is a good growth medium for the organism in culture, possibly because of trophic properties of dopamine and other neurotransmitters in the CSF and the absence of cryptococcus-toxic proteins.

Cryptococcal disease usually develops only when CD4+ lymphocyte counts fall below 100 cells/μL. At this stage, macrophage function also is impaired.

Immune reconstitution inflammatory syndrome occurs in some patients after treatment with highly active antiretroviral therapy (HAART). This syndrome is a paradoxical deterioration in the clinical status despite satisfactory control of viral replication and improvement of CD4+ counts as a result of an exuberant inflammatory response toward previously diagnosed or latent opportunistic pathogens.



Cryptococcus is ubiquitous in the environment. Among HIV-infected patients in the United States, the annual incidence of cryptococcosis is 2–7 cases per 1000, with up to 89% occurring as a CNS manifestation. [1] It is the fourth most common cause of opportunistic infections (after Pneumocystis jiroveci, cytomegalovirus [CMV], and mycobacteria), and CNS manifestations (66–89%) are by far more common than manifestations in other organs. Its incidence has declined recently because of widespread use of antifungal and antiretroviral agents. [2]  In the United States, the prevalence of cryptococcal antigenemia is 2.9% in HIV-infected patients with CD4 counts < 100cells/μl and 4.3% in those with CD4 counts < 50cells/μl. [3]

Worldwide, approximately 1 million cases of HIV-associated cryptococcol meningitis occur annually and disease accounts for more than 600,000 deaths. In developed countries, the widespread use of highly active antiretroviral therapy (HAART) has lowered the incidence of cryptococcosis, but the incidence and mortality of the disease remain extremely high in areas with uncontrolled HIV disease and limited access to HAART or health care. [4]

Of patients with AIDS in the United States, cryptococcal meningitis occurs more commonly in African Americans than in whites. [2] However, a case-controlled study did not find an association between cryptococcal infection and race, suggesting that race may just be a surrogate for the presence of other conditions or exposures.

CNS cryptococcosis is rare in children with AIDS.



Cryptococcus neoformans is a round or oval yeast, 4–6 mm in diameter, surrounded by a 30-mm-thick capsule. Based on the polysaccharide wall serology, use of nutrients, and DNA sequence, it is subclassified into C neoformans neoformans and C neoformans gattii. Most HIV-associated cryptococcal infections are caused by Cryptococcusneoformans, serotype A (found worldwide), but occasionally Cryptococcus gattii is the cause (found in Australia, subtropical regions, and the Pacific Northwest).



CNS cryptococcosis is fatal unless treated. Several studies report acute mortality rates of 6–14%. A minority of patients die within the first 6 weeks after diagnosis, despite treatment. Those who survive usually live for longer than 18 months. In addition, the rate of relapse after treatment is high (30–50%).

Predictors of poor prognosis are controversial, but reportedly they have included the following:

  • High CSF cryptococcal antigen titer (>1:1024)

  • Minimal CSF pleocytosis

  • Altered mental status at presentation

  • Positive India Ink preparation

  • Hyponatremia

  • Positive cultures from extrameningeal sites


Clinical Presentation

Disease onset is usually insidious, which may be why the time from symptom onset to diagnosis is, on average, 30 days or more. The delay also may be due to the waxing-and-waning course and the nonspecificity of symptoms.

Onset is rarely fulminant. Lung involvement is found in fewer than one third of patients with CNS cryptococcosis. Occasionally, evidence of unsuspected CNS cryptococcosis is detected on cerebrospinal fluid analysis done for other reasons. In almost half of patients, cryptococcosis in the CNS or elsewhere is the AIDS-defining illness.

Signs and symptoms at onset may be nonspecific and include the following:

  • Headache (73–81%)

  • Fever (62–88%)

  • Malaise (38–76%)

  • Nausea and vomiting (8–42%)

  • Stiff neck (22–44%)

  • Visual disturbances (30%)

  • Altered mental status with somnolence (18–28%)

  • Photophobia (19%)

  • Papilledema (10%)

  • Cranial neuropathies, including nystagmus and amblyopia (6%)

Occasionally, patients may experience focal neurologic symptoms or seizures. Focal signs may indicate that the infectious meningeal process has reached superficial layers of the cortex and cerebellum, or they may point to cryptococcomas (ie, cryptococcal abscesses), most commonly in the basal ganglia and cerebellum (see the images below).

Magnetic resonance imaging showing a cryptococcoma Magnetic resonance imaging showing a cryptococcoma in the medulla.
Coronal section of brain showing a cryptococcoma i Coronal section of brain showing a cryptococcoma in the basal ganglia.

Mental status changes include confusion, psychomotor retardation, irritability, agitation, personality changes, and psychosis. Nuchal rigidity may be absent because of minimal inflammation. Altered mental status is a common symptom in C neoformans–infected HIV patients. [5, 6]

Cortical atrophy tends to be the exclusive attribute of C neoformans infection and more common in HIV-positive cases. [7, 6]

Hydrocephalus must be suspected with new-onset impaired consciousness, motor signs, nausea, vomiting, or visual impairment. This usually occurs late in the course of cryptococcosis.

Bilateral visual loss also can result from arachnoiditis at the level of the optic nerves or cryptococcal invasion of the optic nerve. Conditions of visual impairment and gradual blindness in C gattii was also observed by Lalloo et al. [7] Occasionally, symptoms and signs of a radiculomyelopathy predominate because of spinal cord involvement. Patients may have radicular pain, stiffness or spasticity, limb weakness, sphincter disturbances, loss of sensation, and weakness.


CSF Analysis

Measurement of opening pressure is an important aspect of lumbar puncture. Opening pressure is elevated to greater than 25cm H20 in approximately 60–80% of patients. [8, 9]  CSF analysis may yield normal (ie, reference) results in 25% of patients and may be minimally abnormal in as many as 50%; therefore, identifying the organism via India Ink and serology is crucial.

CSF fluid appearance can be clear or turbid. Protein levels exceed 45 mg/dL in one third to two thirds of cases, ranging from normal to 300 mg/100 dL. The glucose level is usually normal and is less than 60% of the serum level in only 17–65%.

Mononuclear pleocytosis (>20 cells/μL) occurs in 13–31% of cases. Numbers vary between reports, but in one study, 55% of patients had fewer than 10 mononuclear cells/μL.

Close to 100% of CSF culture results are positive for Cryptococcus neoformans, whereas 55% of blood culture results are positive. India ink stain is positive in 60–80% of infected patients but many labs in the United States no longer perform this test. 

Testing for CSF and serum cryptococcal antigen (CrAg) may be diagnostic with a sensitivity of 94.1% and 93.6%, respectively; a negative test should not be used as a rationale to discontinue treatment. CrAg may be present weeks to months before symptom onset [10] and a positive serum CrAg warrants a lumbar puncture to assess for meningeal infection. Antigen is detected via latex agglutination, enzyme immunoassays, and lateral flow assay. Testing for CrAg in the serum is a useful initial screening tool in HIV-infected patients. [11]  A positive titer is sufficient to initiate therapy while cultures are pending in the appropriate clinical setting.


CT and MRI

CT scan is acceptable as a screening study, but MRI, with and without contrast, is the preferred imaging modality. CT scan findings may be nonspecific or normal. Cryptococcal pseudocysts may appear as nonenhancing, hypodense lesions on CT scan.

With MRI, T1-weighted images may show low-intensity lesions in the basal ganglia, which are hyperintense on T2-weighted images and may enhance with gadolinium.

Twenty to thirty percent of patients show meningeal enhancement, parenchymal solid mass lesion without hemorrhage (granuloma), atrophy, cerebral edema, or hydrocephalus (see the image below). Commonly, in patients with increased intracranial pressure, the ventricles are small. If the imaging studies show a cryptococcal mass lesion (ie, cryptococcoma), toxoplasmosis and lymphoma must be considered in the differential diagnosis; brain biopsy may be indicated.

This image shows meningeal enhancement in a patien This image shows meningeal enhancement in a patient with cryptococcal meningitis.

Histologic Findings

The meninges are opaque, and a capsular material may fill the subarachnoid space. Mixed meningeal infiltrates consisting of lymphocytes, eosinophils, plasma cells, multinucleated giant cells (containing phagocytized organisms), and neutrophils may surround clusters of organisms and sometimes form granulomas, but often the inflammatory response is scant.

Cryptococci extend along Virchow-Robin spaces into the brain. Parenchymal tubercles consisting of pseudocysts filled with organisms without significant inflammatory response, capsule formation, or gliosis are observed most often in the basal ganglia and cortical gray matter, but they may also be found elsewhere.


Primary Treatment

If left untreated, cryptococcal CNS infections are fatal. Treatment involves the phases of induction, consolidation, and maintenence therapy. Treatment with amphotericin B, flucytosine, fluconazole, and other antifungal agents greatly improves the prognosis, but a mortality rate of 6%, despite therapy, has been reported.

Per the Infectious Diseases Society of America (IDSA), for induction therapy of cryptococcal meningitis in HIV-infected patients, the following regimen is preferred:

  1. Liposomal amphotericin B 3–4 mg/kg IV daily PLUS flucytosine 25mg/kg PO in 4 divided doses at 6 hour intervals OR
  2. Amphotericin B deoxycholate 0.7–1.0 mg/kg IV daily PLUS flucytosine 25mg/kg PO in 4 divided doses at 6 hour intervals, for at least 2 weeks. [12]  

Flucytosine should be adjusted in renal impairment. Serum flucytosine levels should be monitored 2 hours post-dose, after 3–5 doses. The drug concentration should be between 25–100 mg/L. Patients on amphotericin B should be monitored for dose-dependent nephrotoxicity and electrolyte disturbance.

Consolidation therapy can begin 2 weeks after successful induction therapy, which occurs with clinical improvement and negative CSF culture. The IDSA preferred regimen is fluconazole 400mg PO or IV once daily for at least 8 weeks, followed by 200mg daily for chronic maintenence. Alternatively, one can use itraconazole 200mg PO twice daily for chronic maintenence. Maintenence should be continued for at least one year and discontinued when CD4 ≥ 100 cells/mmfor at least 3 months and on ART. Maintenence should be restarted if CD 4< 100 cell/mm3. 

Liposomal amphotericin B may lead to quicker improvement with less renal toxicity. Flucytosine may be given intravenously in severe cases and in patients without oral intake. [12]

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

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. [10]

When flucytosine is unavailable, amphotericin B in combination with fluconazole (800-1200 mg/day). or voriconazole (300 mg twice daily) is an effective alternative in patients not receiving interacting medications. [11]

A double-blind, placebo-controlled phase II study suggested that adjunctive recombinant interferon-gamma 1b (rIFN- gamma 1b) may induce more rapid early sterilization of CSF in patients with HIV-associated Cryptococcus meningitis. [3] Patients in the treatment arm of this study received 100 or 200 µg 3 times weekly for 10 weeks, plus standard antifungal therapy. IDSA guidelines suggest considering adjunctive rIFN- gamma 1b (100 µg/m2 3 times weekly for 10 weeks) along with standard antifungal therapy, in cases of refractory infection. For patients weighing less than 50 kg, consider giving 50 µg/m2. [12]


Maintenance Therapy

Maintenance therapy should be continued with fluconazole 200 mg/day for at least one year. Amphotericin B (1 mg/kg/wk) is less effective than fluconazole, but it is an alternative for patients who experience relapse on fluconazole or for those who cannot tolerate it. Itraconazole 200 mg/day can be an alternative to fluconazole, but it is less effective. There is limited data for use of the newer triazoles, voriconazole, and posaconazole as most data is reported for refractory cases, with success rate in 50%. [14, 15]

Lifelong secondary prevention may be required. Relapses occur if secondary prevention is stopped or becomes ineffectual. Relapse rates without prevention range from 15–27%; and from 0–7% with antifungal prophylaxis.

Discontinuing secondary antifungal prophylaxis may be considered in selected patients who have responded well to highly active antiretroviral therapy (HAART), with 12–18 months of successful suppression of HIV viral replication. This remains controversial.

Criteria for discontinuing antifungal suppressive therapy during HAART, according to IDSA guidelines, are maintenance of a CD4+ cell count above 100 cells/µL and an undetectable or very low HIV RNA level for 3 months or longer (minimum of 12 months of antifungal therapy). [12] The guidelines advise considering reinstitution of maintenance therapy if the CD4+ cell count falls below 100 cells/µL.

Patients with cryptococcal disease who initiate HAART are at risk for cryptococcal immune reconstitution inflammatory syndrome (IRIS). Boulware et al found that in HAART-naive patients with AIDS and prior cryptococcal meningitis who developed IRIS after starting HAART, the cerebrospinal fluid tended to show less inflammation, with decreased CSF leukocytes (25 cells/mL or fewer), protein (50 mg/dL or less), interferon-gamma, interleukin-6, interleukin-8, and tumor necrosis factor-alpha, compared with patients who did not develop IRIS. [16]


Treatment of Relapse

Patients who experience relapse should be restarted on induction-phase therapy. The susceptibility of the relapse isolate should be determined. A minimum inhibitory concentration (MIC) with a dilution difference of 3 or higher from the original isolate suggests development of direct drug resistance. Otherwise, an isolate with an MIC of 16 µg/mL or more for fluconazole or 32 µg/mL or more for flucytosine may be considered resistant, and alternative agents should be considered. [12]

Consider salvage consolidation therapy with fluconazole (800–1200 mg/day orally), voriconazole (200–400 mg twice daily orally), or posaconazole (200 mg orally 4 times daily or 400 mg orally twice daily) for 10–12 weeks. If there are compliance issues and a susceptible isolate, prior suppressive doses of fluconazole may be reinstituted. [12]


Treatment of Increased Intracranial Pressure

Opening pressure is elevated to greater than 25cm H20 in 60–80% of patients with AIDS and cryptococcal CNS infection. [8, 9]  This is probably due to obstruction of the basal meninges or impaired CSF absorption. Since increased intracranial pressure is a prognostic factor whose correction leads to symptomatic improvement, this must be managed aggressively.

In the absence of obstructive hydrocephalus or risk of herniation, increased pressure (>25cm H2 O) can be relieved by serial lumbar punctures. For those who cannot tolerate repeated lumbar punctures, a lumbar drain or ventriculostomy should be considered. A lumbar-peritoneal shunt or ventriculoperitoneal shunt may be indicated as well. Decreasing intracranial pressure can rapidly improve headache, nausea, and vomiting. Mannitol and corticosteroids have no proven benefit and are not recommended. [12]  Acetazolamide should not be used for treatment of increased intracranial pressure as it may cause hyperchloremic acidosis. [17]


Treatment of Complications

In the presence of cryptococcal immune reconstitution inflammatory syndrome (IRIS) ART and antifungal therapy should be continued.

Seizures should be treated with standard therapy. Drugs that are less likely to affect bioavailability of highly active antiretroviral therapy (HAART) agents or anticryptococcal therapy are preferred.

Cognitive impairment may improve with successful anticryptococcal therapy. On a case-by-case basis, the presence of a cryptococcoma may lead to consideration of surgical intervention.

Rare visual loss due to local arachnoiditis or cryptococcal invasion of the nerves can be approached by nerve sheath decompression.