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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 |
|
|
| Laboratory features |
|
|
|
|
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:
Patients with cryptococcal meningitis may present concomtantly with pulmonary, skin, or other localized manifestations of disseminated cryptococcosis [1242]. Even if CNS involvement is not clinically apparent, a lumbar puncture should be performed.
Neurologic sequela:
After an episode of cryptococcal meningitis, an important proportion of patients are left with permanent neurologic deficits. They include visual loss, decreased mental capacity, hearing loss, permanent cranial nerve palsies, and hydrocephalus. Severe visual loss without endophthalmitis occur either due to direct invasion of the optic nerve by cryptococci or related to the effect of increased intracranial pressure [1907]. In the classic study by Diamond and Bennett, of the 62 cured patients the rates of sequela were as follow:
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% |
A series of well characterized CT-detectable abnormalities have been described in about 50% of cases of cryptococcal meningitis. Imaging of the brain is a critical management step for multiple reasons. First, cryptococcal meningitis-related hydrocephalus may require surgical shunting for pressure relief and should be diagnosed and treated early. Second, focal lesions require an imaging follow up to determine if special therapeutic options are required. And finally, there is always the possibility of a second simultaneous process among AIDS-patients. Such concomitant diseases include Toxoplasma gondii encephalitis, CNS lynphoma, infections cause by Nocardia spp., and others [155]. These condition will not only require specific therapy but also may be the cause of increased intracranial pressure.
- 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
Cryptococcal meningitis is a serious condition with a rate of relapse ranging between 15 to 30% in HIV-negative and no less than 50% in AIDS patients [390]. Prior to the AIDS epidemic, three studies described a series of findings that were statistically related with poor prognosis [222, 588, 597]. The following table summarized their findings:
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; AmphocilTM or AmphotecTM), Amphotericin B Lipid Complex (ABLC; AbelcetTM), and Liposomal Amphotericin B (L-AMB; AmbisomeTM). Although much more expensive, these formulations have the well-recognized advantage of reduced nephrotoxicity when compare with amphotericin B deoxycholate (FungizoneTM).
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 AmbisomeTM (4 mg/kg/day) with amphotericin B (0.7mg/kg/day). Clinical response was similar in both groups, however, patients on AmbisomeTM not only had significantly less nephrotoxicity but faster cleareance of CSF [1311]. Accordingly, IDSA-MSG guidelines considere AmbisomeTM 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 |
|
| Fluconazole |
200-400 mg po qd |
| Itraconazole |
200 mg po bid |
| Amphotericin B |
1 mg/kg/day IV 1-3 days/wk |
1 Flucytosine
- Other agents
In vitro data have shown that posaconazole is a fungicidal and effective anticryptococcal agent with a promising role for the treatment of cryptococcal meningitis [797, 2466]. The potential role of voriconazole is also yet to be determined but preliminary data are also encouraging [1785]. Liposomal nystatin is another new antifungal agent still in Phase III clincial trial that may have a role in the treatment of cryptococcal diseases [385]. In contrast, caspofungin has no activity against Cryptococcus neoformans [195, 759].
Treatment of cryptococcal meningitis in patients with HIV-AIDS
In the pre-HAART era, the outcome of patients with cryptococcal meningitis was particularly poor. A media survival time of 5 months was described by Clark et al. in a review of 65 cases [450]. More than half of these patients died during the first 2 weeks of therapy. Prognostic factors for this population have been already discussed.
Until recently, it was recommended that AIDS patients be placed on a lifelong maintenance antifungal regimen, with fluconazole (200-400 mg/day), itraconazole (200 mg BID) or amphotericin B (1 mg/kg IV 1-3 times/week) [1836, 1992]. However, new highly active antiretroviral therapies (HAART) have had a major impact on the occurrence of opportunistic infections and cryptococcal meningitis does not seems to be an exception [1661, 1707, 1954]. A draft of the new version of USPHS/IDSA Guidelines for the prevention of opportunistic infection in persons infected with HIV considers the possibility of interrupting mantainance therapy in asymptomatic patients with sustained increased > 6 months of CD4+ lymphocytes. Data on this approach are still limited and close followup should be maintained if this approach is pursued.
On the other hand, it is important to have in mind, the so called "immune reconstitution syndrome" associated with HAART. This syndrome, in the case of cryptococcosis, can cause isolated or multiple indolent abscesses involving regional lymph nodes, neck, head, and chest. The diagnosis may be difficult as cultures are usually negative. However, in this case a biopsy to perform histopathologic study as well as serum cryptococcal antigen allow to establish the diagnosis [1425].
Intracraneal hypertension
The pathophysiology of cryptococcal meningits involves variable levels of basilar meningeal inflammation that interfere with CSF resorption. In addition, once therapy is given, important amounts of osmotic materials (mannitol and polysaccharides antigen) may be released into the CSF by dying yeasts. Patients with particulary high burden of yeast may then develop a syndrome of intracranial hypertension. Lumbar pressures are then > 350 mm H2O and CT or NMR scans are normal. Communicating hydrocephalus can then occur. This finding is associated with papilledema, pathological reflexes, impaired hearing and delayed CSF mycological clearance at two weeks [894]. Other clinical signs include decrease sensorium, sudden visual and/or hearing loss, new cranial neuropathies, and even sudden death [390].
A large fungal burden is particularly characteristic of cryptococcal meningitis in AIDS patients and this probably cause further interruption of the passage of CSF accross the arachnoid villi [390, 894]. Among 221 AIDS patients with cryptococcal meningitis, 60% had pressures higher than 250 mm H20 [894].
Therapy
Several procedures have been used to reduce the high levels of intracranial pressure and the sequelae they cause in some of the patients affected by this entity.
Serial lumbar punctures
Based on the results of an observational study, Graybill and collaborators recomend that patients with opening pressures > 250 mm H2O have serial lumbar punctures [894]. This procedure may not only help because of the removal of fluid but also with the removal of fungal polysaccharide. Prospective trials have not evaluated this practice because of the small number of cases [893]. Although certain authors have stressed the risk of herniation with this technique, performing such taps helps identify patients that may require lumbar drains or ventriculoperitoneal shunting [105]. This may be especially required for patients with continous high pressure after 4-7 days of daily CSF drainage during appropriate antifungal therapy. These patients can die from intracranial herniation if their problem is not properly managed [893].
Medical treatments
The administration of agents like acetazolamide, mannitol, or corticosteroids have been attempted with the purpose of decreases secretion of the CSF or cause an osmotic gradient by making the plasma hypertonic [893, 1136]. There are no data to support the advantange of any of these alternatives to the previously discussed option of mechanical decompression. And, anecdotally, the initiation of steroids has sometimes been associated with worsening of clinical status, perhaps due to further suppression of host immune response.
Placement of ventricular shunts
Neurosurgical shunting is sometimes require for the treatment of persistent hydrocephalus not responding to previously discussed mesures. Both ventriculoperitoneal and ventriculoatrial shunts have been used [1096, 1722]. In the classic study by Diamond and Bennett, 10 out of 111 cases (9%) developed hydrocephalus and required shunt placement [588]. A common mistaken belief is that shunting will increase the risk of dissemination or can interfere with cure. This procedure can be done any time after antifungal therapy has been started and negative CSF culture are not required to place a shunt [390].
Cryptococcal brain abscesses or "Cryptococcomas"
The majority of cases of cryptococcal meningitis show also underlying brain parenchyma involvement [390]. In addition, certain cases of intracerebral cryptococcal massess without meningitis have also been described [781]. Focal cryptococcal lesions can be single or multiple and affect not only the brain parenchyma but the spinal cord an its roots [1747]. Three distinct types of focal lesions have been described [76, 1987]:
- Cryptococcal intracerebral abscesses or so called "Cryptococcomas" are firm lesions with a defined fibrous capsule, and variable degrees of pyogenic to granulomatous inflammatory reaction that may have a central mass of cryptococci [781, 1310]. This type of lesion can be identified with CT or MRI in around 11% of patients with AIDS and up to 25% of normal hosts [390].
- Gelatinous pseudocysts or "soap bubbles". These lesions are collections of highly encapsulated yeast surrounded by a minimal or none immunological response [1987]. They are both radiological and histologically similar to dilated perivascular spaces although larger (> 3 mm) [1070]. On CT scanning these lesions are isodense or hypodense and do not enhance with contrast injection [1828]. Their appeareance on MRI as hypertense on T2 imaging, hypotense on T1 and do not enhance with gadolinium [1467].
- A third and unusual type are septated lesions which have been described within the intraventricular spaces around the chorid plexus [1677].
Most cases will respond to medical treatment. However, IDSA-MSG recommend considering surgery when parenchymal lesions are larger than 3 cm. [781, 1993]. This should be considered in the context of clinical data, because it has been more recently shown images that intracranial lesions on CT or MRI may persist for as long as 5 years in patients succesfully treated [1070].
When assesing these patients it is important to remember that AIDS patients and other immunosupressed individuals may have concomitant conditions that mimic cryptococcomas (e.g., CNS Toxoplasmosis, CNS Lymphoma) [155].
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India Ink of CSF with C. neoformans
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Mucicarmine stain of brain infected with C. neoformans
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