Dr. Fungus - Mycoses (CNS Cryptococcosis)

This page updated:
1/27/2007 9:23:00 AM

DoctorFungus - All Rights Reserved © 2007 Copyright
& Privacy Policy

Site built and designed for doctorfungus by Webillustrated

You are here: Mycoses >

Navigate this section from here:

CNS Cryptococcosis

Even though the route of entry of Cryptococcus neoformans to the body is the respiratory tract, CNS infection is by far the most frequent manifestation of cryptococcosis. The majority of affected individuals present with a clinical picture of meningitis. However, Cryptococcus neoformans is also able to produce a variety of other CNS lesions including cryptococcomas, subdural effusions, and spinal cord lesions [936, 1070, 1310, 2132]. Although we and the literature in general refer to the meningeal syndrome ascryptococcal meningitis (CM), the correct histopathologic term for this condition would be meningoencephalitis because most cases show involvement of both the meninges and the underlying brain parenchyma [390]. It has been postulated that Cryptococcus neoformans's neurotropism is related to the activity of an enzyme, phenoloxidase, and its ability to produce melanin from certain cathecholamine precursors [1917].

NOTE: A general discussion of this topic is available on the introductory cryptococcosis page

During the pre-AIDS era, few data existed on the incidence of cryptococcal meningitis because there was no obligation to report cryptoccal infections. It has been estimated that no more than 300 patients were seen with this condition in the United States each year [498, 1357]. CNS disease was always the most commonly noted disease form, regardless of underlying risk factors.
Among immunosupressed non-AIDS patients, CNS disease has also represented the most frequent clinical presentation of cryptococcal infection. Kaplan et al. reviewed the autopsies of 23 cases of cryptococcosis occurring from 1956 to 1972 at one of the larger cancer center in the United States (Memorial Sloan-Kettering Cancer Center). Eighty-seven percent of these cases had evidence of CNS infection [1151]. A restrospective review of the literature by Husain et al. showed that from 178 cases of cryptococal infections in organ transplant recipients, 115 (72%) had CNS infections [1088].
After the beginning of the AIDS epidemic, a dramatic increase in the frequency of cryptococcal infections occurred and was mostly related to meningeal infections [498, 2076]. As an example, C. neoformans became the most common cause of culture-positive meningitis in adults in New York City [498]. The following table summarize data from several of most comprehensive reports of cryptococcosis in AIDS. In total, about 77% of cases on this population presented with CNS disease:

Cryptococcosis in patients infected with HIV

Series
[1242] [2500] [441] [450]
N 27 34 106 63
Proportion of patients with meningitis 67 % 76 % 84 % 81 %

A recent comprehensive surveillance for cryptococcosis by Hajjeh et al. revealed that 89% of HIV-positive patients with this infection presented with meningitis or fungemia [968]. Cryptococcal meningitis was the AIDS-defining illness in 5 to 7% of patients with AIDS before the introduction of protease inhibitors [91, 450]. Also, around 7% of patients requiring hospitalization presented with cryptococcal meningitis at the beginning of the AIDS epidemic [441]. It was estimated that during the same period cryptococcosis decreased the survival of AIDS patients by 2 years, regardless of the absolute number of CD4 lymphocytes [1067]. Current trends may have changed due to the marked improvement of quality and length of life produced by highly-active antiretroviral thearpy (HAART) [1707]

Risk factors

The classical risk factors for cryptococcocosis are usually also present in cases of cryptococcal meningitis.

The most frequent presenting complaints in patients with cryptococcal meningitis include:

Fever
Headache
Changes in level of consciousness (somnolence, confusion, stupor or coma)
Dizziness
Visual disturbances
Seizures
Unsteady gait
Irritability
Nausea and/or vomiting

On the physical exam it is often possible to find nuchal rigidigy and other meningeal signs. Papilledema is a relatively common finding that correlates strongly with intracranial pressures > 350 mm H₂O [893]. Cranial nerve palsies can also occur. In this case, patients may present with diplopia, reduced visual acuity, facial weakness, and/or numbness. Not infrequently ankle clonus, extensor plantar response, and hyperrelexia are present. Ataxia, sensory changes, aphasia, and other neurologic findings can also be found. [2168]. Dementia may be seen and is sometimes the only initial clinical clue [2154]. In the normal host, these findings usually develop in an subacute to chronic fashion lasting over a period of 2 to 4 weeks or even longer. Overall, this is the pattern of "chronic meningitis" for which there are several diagnostic possibilities, including tuberculous and coccidiodomycosis meningitis [2168].

Immunosuppressed individuals (patients with cancer, AIDS or under corticosteroid therapy) usually have a more acute course, although some still present with few or no symptoms [1798]. Among AIDS patients the clinical picture varies broadly, with some patients having none of the classic complaints [450]. In the series by Chuck et al., only 76% and 65% of AIDS patients with documented meningeal cryptococcosis had headache and fever respectively [441]. Therefore, any AIDS patient with unexplained fever, progressive dementia, or confusion should have a work-up to rule out cryptococcal meningitis. Cryptococcal meningitis is rare until the CD4+ T-cell fall bellow 50 cells/mm³ [893]. As AIDS progresses, either because of lack of adequate therapy or resistance to antiretroviral therapy, the severity and permanent nature of AIDS-associated immunosuppression make this infection particularly difficult to permanently eradicate. The natural history in patients with advanced HIV infection is one of remission and then relapse.

Cryptococcosis in severely immunocompromised hosts (AIDS patients, organ transplant recipients, and patients treated with high doses of corticosteroids)

Clinical features

Concurrent infection of CNS and other sites (lungs, skin, urinary tract, and/or others)

High rates of relapse

Laboratory features

Blood and urine culture frequently positive

India ink test heavily positive

High cryptococcal-antigen titers

Taken from [390]

Interestingly, clinical differences have been described depending in the infecting variety of Cryptococcus neoformans [2132]. When C. neoformans var. gattii is the causal agent, papilledema, pulmonary involvement, hydrocephalus, and multiple enhacing lesions (cryptococcomas) on imaging studies are more frequent [426, 1314].

Non-neurological manifestations:

pulmonary

1242

Neurologic sequela:

hydrocephalus

1907

Neurological sequela related to cryptococcal meningitis

Sequelae	Rates
Decrease mental function ("chronic brain syndrome")	31%
Residual visual loss	8%
Residual motor impairment	5%
Residual cranial palsies	3%

From [588]

Diagnostic criteria:

CSF culture. Microbiologic confirmation of Cryptococcus neoformans in the cerebrospinal fluid is the strongest proof of cryptococcal meningitis [869, 1715]. From 149 HIV-negative patients with cryptococcal meningitis, 89% were culture-proven [1715]. When the underlying condition is AIDS, the rates of positive CSF cultures rise to 95-100% [1242, 2500].
CSF India ink preparation. India ink is probably the most important screening test to rule out cryptococcal meningitis. The encapsulated cells of this yeast can be easily distinguished when using the black colloidal medium of this preparation. According to Casadevall and Perfect, the test will be positive when about 10³ to 10⁴ CFU/ml are present in a CSF sample. AIDS patients have larger concentrations of yeast ranging between 10⁵ to 10⁷ CFU/ml [390]. The diagnosis of cryptococcal meningitis can be established with this test in about half of the cases of cryptococcal meningitis in HIV-negative cases and up to 80% of patients with AIDS [390, 1715]. False-positive test have been described when leukocytes, fat droplets, tissue cells or myelin globules are confused with the yeast. Centrifuging the CSF to 500 rpm for about 10 minutes can improve the sensitivity of this test [390].

As useful as it can be for diagnostic purposes, the India ink test is NOT a good guide to response. Accordingly, Diamond and Bennett demonstrated that, as long as the same sample is culture-negative, persistently positive India ink preparations did not correlate with poor outcome [588]. Indeed, India Ink preparations remained positive for as long as 8 years in one of their successfully treated patients.
Cryptococcal Antigen: a very useful test for diagnosis of patients with cryptococcal meningitis is the determination of cryptococcal-antigen titers in the CSF. Initial titer correlate with the burden of yeast in the CSF. This test have been consistently positive in over 90% of cases of cryptococcal meningitis among HIV-positive patients.

Cryptococcal antigen in the CSF of HIV-patients with CM

Sequelae
[1242] [2500] [441] [450]
N 16 26 88 40
Proportion of patients with meningitis 100% 92% 91% 92.5%

While the crytococcal antigen test is very helpful, it is important to also keep in mind that both false-positive and false-negative results may occur.

Importantly, cryptococcal-antigen titers are not recommended for follow-up and treatment decisions because the kinetics of the antigen clearance both in CSF and serum are unpredictable [390].

Serum cryptococcal antigens are also very likely to be positive among patients with CNS cryptocococcosis, particularly when compared with patients with disseminated non-neural cryptococcosis [1242]. However, serum cryptococcal antigen do not cross the blood-brain barrier, therefore, blood levels have no influence on CSF titers.
CSF changes consistent with cryptococcal meningitis. The inflammatory response cause by Cryptococcus neoformans provokes the appearance of leukocytes in the CSF (50 to 500 cell/microliter). Although mononuclear cells are commonly predominant, neutrophilic pleocytosis either at the initial tap or through the course of the whole illness occur in up to 25% of cases [2168]. The level of pleocytosis is typically much lower in AIDS patients [390]. Interestingly, if the cell count is done by using a Coulter counter, both the yeast and the white blood cells will be included, thus falsely elevating the CSF white cell count [229]. Mildly increased CSF protein levels (< 500 mg/dl) related to the host inflammatory response and to the presence of anticryptococcal antibodies are usually found [1276]. High levels of CSF protein may be indicative of block of the CSF circulation. At least one fourth of patients with cryptococcal meningitis have decreased glucose [390]. The persistance of a low glucose level (hypoglycorrahchia) is considered a poor prognostic finding [588].

All the previously mentioned CSF findings can be identical to those seen with tubercoulous meningitis. Not only that, but as mentioned before, clinical manifestations are very similar, particularly when the disease presents in normal hosts [2168]. Therefore, when dealing with a case like this, it is neccesary to look for one of the discussed confirmatory tests. Sometimes a biopsy specimen could be the clue to confirm the diagnosis of intracranial cryptococcosis

Other diagnostic evidence:

Elevated intracranial opening pressure. CSF opening pressures are frequently high in patients with cryptococcal meningitis, ranging from about 190 to 310 mm H₂O [1822]. This finding is more frequent for AIDS patients in whom up to 60% of cases may have pressures > 250 mm H₂O and 30% pressures > 350 mm H₂O [570, 893]. Interestingly, these high levels of intracranial pressure at the initial tap do not always correlate with the expected clinical signs and symptoms, therefore it is recommended to measure opening pressures in all patients and not only in those with clear-cut manifestations [893]. As we will discuss, this parameter is considered a poor prognostic finding not only at the beginning of the diagnosis but during the follow-up period.

Computed tomography of the head.

CT Findings in Cryptococcal Meningitis

Findings	Frequency	References
Non-AIDS patients
Normal	50%	[474]
Hydrocephalus	25%
Gyral enchancement	15%
Focal masses single or multiple (enhancing and non-enhancing)	15 - 25%
AIDS patients
Normal	50%	[1828]
Diffuse cortical atrophy	34%
Hydrocephalus	9%
Focal masses	11%

hydrocephalus

special therapeutic options

Toxoplasma gondii

Nocardia

155

Cultures from extraneural sites such as blood, skin, pleural fluid, urine, sputum, prostate or stool. This finding is particularly frequent among AIDS patients [1242]. This should be considered in two ways. On one hand, some cases with neurologic symptoms and negative CSF culture may have an extraneural cryptococcal infection that, once documented by culturing the appropriate sample, may clarify the etiology of the CNS syndrome. AIDS patients with cryptococcal meningitis are indeed more inclined to be in this group [390]. On the other hand, patients presenting primarily with an extraneural cryptococcal infection should be tapped to define the extent (if any) of CNS involvement.

Prognostic factors

Prognostic factors in Non-AIDS patients with cryptococcal meningitis

Pre-treatment indicators of poor prognosis	References
Underlying diseases
Lymphoreticular malignancies	[588]
Corticosteroid therapy	[588]
Clinical findings
Abnormal mental status	[597]
High opening pressure	[588]
Laboratory
CSF findings
Low glucose levels throughout the course of therapy	[588]
Low WBC (<20/mm³)	[588, 597]
Initial India ink positive	[588]
High titers of cryptococcal Ag (> 1:32)	[222, 588]
Extra-CNS culture positive sites (specially blood cultures, but also urine, stool, sputum or other extraneural sites)	[588]

At the post-treatment evaluation, factors such as the duration of time with a positive India ink smear and/or CSF findings were not related to poor outcome on the long term (relapse) [588]. One patient on Diamond's series had a India Ink preparation positive for 8 years. Several patients who responded satisfactorily to therapy had abnormal protein CSF for periods as long as 5 years [588]. Low-grade CSF pleocytosis (10 to 50 cells/mm³) for as long as 6 months is also a possible finding that does not always predict failure [390].

For AIDS patients with cryptococcal meningitis, prognostic factors have been established as well.

Prognostic factors for AIDS patients with cryptococcal meningitis

Poor prognostic indicator	References
Underlying diseases
Intravenous drug abuse	[2287]
Clinical findings
Age > 30 years	[515]
Abnormal mental status	[1994]
High opening pressure (>350 mm H₂O)	[893]
Laboratory
CSF findings
Low CSF glucose	[515]
Positive culture at 2 weeks	[2287]
High titers of cryptococcal Ag (> 1:32)	[1994, 2451]
Positive blood and urine culture	[2451]

Interestingly, the level of CD₄ counts has not been found to be related to the outcome. However, cryptococcal meningitis is rare before the CD4+ T-cell fall bellow 50 cells/mm³. In the study by Graybill et. al, the mean CD₄ count for the four groups studied range between 18 and 21 cell/mm³ [893].

A good summary of the previously discussed risk factors, is Casadevall's risk assesment evaluation [390].

Risk categories for patients with cryptococcal meningitis according with Casadevall and Perfect

[390]

• High risk

Underlying disease

AIDS or neoplasia

CSF indicators of high burden of yeast:

India ink test >10⁶ CFU/ml
Cryptococcal antigen titers > 1:1024

Poor inflammatory response:

CSF leukocyte count < 20 cell/µl

Altered mental status:

stupor or coma

Increased intracranial pressure

• Low risk

Non-AIDS; no neoplasic disease

CSF results:

Culture positive only

Good inflammatory response:

CSF leukocyte count > 20 cell/µl

Normal mental status: lucid

In conclusion, the immune status of the host is probably the most crucial factor for this disease.

Special resource: You may also want to refer to theInfectious Disease Society of America-Mycoses Study Group (IDSA-MSG) Practice Guidelines for this disease. It is available at the IDSA website.

Antifungal therapy

Treating cryptococcal meningitis is a challenge both for the physician and the patient. The course of therapy cannot be predetermined but rather a continuous follow-up of CSF paramenters is needed. This is particulary important when managing immunosuppressed individuals in whom a resolution of the underlying immunedeficiency is not possible. Treatment is classically divided into three periods: induction, consolidation, and mantainance. Induction refers to the first two weeks of therapy. This is followed for a course of consolidation therapy that is usually given for 6 to 10 weeks. Long-term mantainance therapy is always required among AIDS-patients with CD4 counts less than 200 cells/ml. Ideally, follow-up CSF cultures should be performed at 6-week to 6-month intervals [588]. Non-AIDS patients should be followed for 1 year after therapy has been completed [390].

Amphotericin B

Cryptococcal meningitis was consistently a fatal condition before the introduction of amphotericin B [222]. Initial experience with this agent reduced mortaliy to around 30% [2032]. Afterwards, the first prospective comparative trial comparing this agent alone or in combination with flucytosine was done. In this trial, a favorable response rate of 41% was achieved when using 0.4mg/kg/day (alone) for 10 weeks with a mortality rate of 31% [222]. Later on, Saag and colleagues compared amphotericin B with fluconazole in AIDS patients with cryptococcal meningitis [1994]. A similar rate of success of 40% was obtained with a 10-week-long regimen of 0.4mg/kg/day.

Although the combination of amphotericin B with flucytosine has proven to be superior, IDSA-MSG guidelines consider the use of this agent alone as "an acceptable alternative" [1993, 1994]. For this regimen a dose of 0.7 to 1 mg/kg/day is recommended for 6 to 10 weeks [1993]. If used only for the induction period, the same dose is given for 2 weeks, follow as we will discussed by fluconazole.
Intrathecal amphotericin B

Amphotericin B levels in the CSF are low [801], and consequently intraventricular administration has been attempted in cases of severe cryptococcal meningitis with satisfactory results [1822]. However, a series of side effects can be expected when using this procedure. The irritative effect of amphotericin B can lead to headache, vomiting, site pain, parhesthesias and a more or less severe arachnoiditis [801]. If an the Ommaya reservoir is placed to give this therapeutic regimen, the risk of bacterial superimposed infections is certainly increased [390]. Finally, because of the lack of comparative trials with this treatment and the variety of doses used on the previously quoted studies, it is not possible to recommend a specific regimen. Considering the availability of other antifungal agents that achieve good concentrations in the CSF, this therapeutic option is now little used and should be reserved for severe cases that fail to responsd to conventional treatments [390, 1993].
Lipid-associated forms of amphotericin B

New pharmacologic preparations deliver amphotericin B molecules in a diversity of lipid vehicles that include Amphotericin B Colloidal Dispersion (ABCD; Amphocil^TM or Amphotec^TM), Amphotericin B Lipid Complex (ABLC; Abelcet^TM), and Liposomal Amphotericin B (L-AMB; Ambisome^TM). Although much more expensive, these formulations have the well-recognized advantage of reduced nephrotoxicity when compare with amphotericin B deoxycholate (Fungizone^TM). Also, in theory, more amphotericin B can be deliver to a single patient. However, an animal model of cryptococcal meningitis showed that when comparing equal amounts of drug (1 mg/kg/day) the fungicidal activity of regular amphotericin B was superior to ABLC [1761]. Thus, higher doses of the lipid-based formulations must be used. Clinical data for the treatment of cryptococcal meningitis is limited with to a small trial comparing Ambisome^TM (4 mg/kg/day) with amphotericin B (0.7mg/kg/day). Clinical response was similar in both groups, however, patients on Ambisome^TM not only had significantly less nephrotoxicity but faster cleareance of CSF [1311]. Accordingly, IDSA-MSG guidelines considere Ambisome^TM at 4 mg/kg/day as the best option among these agents [1993].
Amphotericin B plus flucytosine

The rationale for this combination is based on the pharmacologic characteristics of the second agent. Flucytosine is a very potent antifungal against C. neoformans that achieves excellent CSF concentrations (60-75% plasma levels). However, when used alone, drug resistance appears rapidly causing high rates of relapses and failures [219]. Consequently, the drug has been mainly evaluated in combination with amphotericin B. Indeed, the previously mentioned randomized trial proved that 0.3 mg/kg/day of amphotericin B in combination with 150 mg/kg/day of flucytosine for 6 weeks was better than 0.4 mg/kg/day of amphotericin B for 10 weeks. Success rates were 67% vs. 41%, respectively. CSF sterilization was achived in 100% for the combination group at 2 weeks. Still, flucytosine has serious sides effects, mainly bone marrow toxicity and gastrointestinal disturbances, that may complicate its use. This may become particularly problematic for AIDS patients with advanced disease [441]. However, according to the IDSA-MSG guidelines this combination should be considered the first treatment option for the induction and consolidation period boths for HIV-negative and HIV-positive patients.
Ketoconazole.

Even though ketoconazole has an excellent in vitro anti-cryptococcal activity, its CSF penetration is poor. In addition, clinical data on the use of this agent for cryptococcal meningitis ARE very limited. Casadevall and Perfect stress that if needed this agent should be restricted to non-meningeal cryptococcosis [390]. The IDSA-MSG guidelines do not include this agent [1993].
Fluconazole

Among the available azoles, fluconazole has the advantage of having excellent pharmacokinetic qualities that include both very good CSF penetration and excellent bioavailability when taken orally [316, 1758, 1759, 1930]. Therefore, despite being fungistatic, fluconazole has an important role not only as an alternative for the treament of cryptococcal meningitis but as the cornestone of maintainance therapy of AIDS patients [313, 1836]. Although this regimen has only been studied in patients with AIDS, IDSA-MSG guidelines recommend it both for HIV-negative and HIV-positive patients [1297, 1471, 1993]. In both settings, a dose of 400 mg/day should be administered for 10 weeks for consolidation therapy, while 200 mg/day is usually enough for the mantainance therapy of AIDS patients [313, 1836, 1992]. However, selected AIDS patients with advanced disease either because the lack or failure of HAART may required doses as high as 800 mg/day [236].

Itraconazole

Interestingly, the limited itraconazole CSF penetration does not limit the ability of this agent to have a curative effect on cryptococcal meningitis [576]. Its lipophilic properties seem to explain the accumulation of the drug in the host cells and tissue [390]. Indeed, a succesful rate as high as 65% have been achieved when using 200 mg twice/day [576]. However, a distintion should be made between the different formulations of this drug. Absorption of drug from the itraconazole capsule formulation is poor and gives erratic non-predictable serum levels. A new liquid formulation, the beta-cyclodextrin elixir, has a 30% better bioavailability. Recently, an intravenous presentation has been released to the market, however, no data on the use of these formulations for CNS cryptococcosis is available yet.

For AIDS patients, itraconazole has shown to be less effective than amphotericin B plus flucytosine as induction therapy of cryptococcal meningitis [526]. This drug has also been evaluated for maintenance theray of AIDS-related cryptococcal meningitis with discouraging results [1992].

Therapy of CNS Cryptococcosis for Patients infected with HIV

Agent	Dose
Induction: First 2 weeks
Amphotericin B plus 5-FC¹	AmB: 0.7-1mg/kg/day 5-FC: 100 mg/kg/day
Amphotericin B	AmB: 0.7-1mg/kg/day
Fluconazole	400-800 mg/day
Itraconazole	400-800 mg/day
Consolidation: 6 to 10 weeks
Amphotericin B plus 5-FC¹	AmB: 0.7-1mg/kg/day 5-FC: 100 mg/kg/day
Amphotericin B	AmB: 0.7-1mg/kg/day
Fluconazole	400-800 mg/day
Itraconazole	400-800 mg/day
Fluconazole plus 5-FC¹	Fluc: 400-800 mg/day 5-FC: 100 -150 mg/kg/day
Lipid formulations of AmB	3-6 mg/kg/day
Maintenance: Lifelong