Cryptococcal Infection of the Central Nervous System

Symposium on Infections of the Central Nervous System

Cryptococcal Infection of the Central Nervous System lames James R. Sabetta, M.D.,* M.D., * and Vincent T. Andriole, M.D.t

Cryptococcus neoformans is a relatively common cause of central nervous system infection. The clinical manifestations of cryptococcal meningitis and meningoencephalitis are best understood after study of the organism and its interaction with the immune system of the host. C. neoformans is an encapsulated yeast that reproduces by budding. The cell is 4 to 6 f..Lm J.Lm in diameter, with the capsule 1 to 30 J.Lm f..Lm wide. The organism grows well on chocolate agar, Sabouraud's medium, and other fungal media, with smooth, yellow-tan colonies appearing within 4 to 7 days of inoculation. Although most nonpathogenic species of Cryptococcus do not grow at 37°C, C. neoformans does. Other features include the lack of formation of pseudomycelia on rice-Tween and cornmeal agar, the ability to use creatinine as a nitrogen source, and the production of meningitis and hydrocephalus in mice within 3 weeks of injection. C. neoformans is a saprophyte distributed throughout the world. It can be isolated from the soil and organic debris of a variety of locations; pigeon habitats harbored the organism in 50 per cent of specimens in one study in the southeastern United States, with other sources positive in less than 10 per cent of cases. 22 Although the organism grows to high concentrations in pigeon feces, the birds are not clinically infected. 56 No toxins are known to be produced by C. neoformans. Indeed, the organism usually evokes minimal inflammatory response in tissue. The carbohydrate capsule of the organism is its major virulence factor identified to date. Nonencapsulated mutants are not pathogenic for mice,14 and the presence of a large capsule has been shown to decrease the ingestion of 27 Cryptococcal polysacthe organism by polymorphonuclear leukocytes. 27 charide, itself, in the concentrations seen clinically, does not interfere with phagocytosis. 27, 58 Although anticryptococcal antibody can develop in patients with cryptococcosis, the exact role of such antibody in host defense is not known. It

**Fellow, Fellow,

Infectious Disease Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut tProfessor of Medicine and Chief, Infectious Disease Section, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut

Medical Clinics of North America-Vol. America-Vo!' 69, No. 2, March 1985

333

334 334

JAMES

R.

SABETTA AND VINCENT

T.

ANDRIOLE

would not appear to be of primary importance, as only one half of patients with cryptococcal meningitis have such antibody upon recovery.25 Also, in vitro studies have shown that anticryptococcal antibody does not appear to increase ingestion of C. neoformans by either polymorphonuclear leukocytes or monocytes. 27 In contrast, a heat-labile factor, possibly comple27 Indeed, using neutrophils to opsonization.27 ment, appears needed for opsonization. study the opsonization of cryptococci, Diamond et aP6 a1. 26 observed that the alternate complement pathway played a key role in opsonization, with the classical pathway allowing for optimal kinetics. Also, complement depledocumented, 58 perhaps contributing tion during cryptococcemia has been documented,58 to the decreased survival seen with that complication of cryptococcal infection. Finally, the lack of complement on the surfaces of cryptococci recovered from infected cerebrospinal fluid (CSF) may contribute to the organism's survival in the central nervous system. 26 Other local factors may account for the predilection of cryptococci for the central nervous system. Whereas normal serum has a heat-stable, fungistatic anticryptococcal factor and saliva a heat-stable, fungicidal one, the CSF has no such inhibitor and, indeed, is a good nutritional medium for C. neoformans, since it contains glucose, thiamine, and other small-molecular-weight substances of importance. 49 Cell-mediated immunity would appear to be the major defense pathway against infection due to C. neoformans. This is best supported by the predisposition to cryptococcal infection seen in patients with conditions associated with altered cell-mediated immunity, such as lymphoma, leukemia, sarcoidosis, and corticosteroid therapy. Such serious coexisting conditions are usually present in one half of the patients in the published series of cryptococcal meningitis, with the range being 29 to 55 per 64 Morecent centll55,. 23, 23. 70, 70. 79, 79. 84, 84. 90 90 and in nearly all patients with cryptococcemia. 64 over, defects in cell-mediated immunity have been identified in patients with cryptococcal infection with no known underlying diseases. In studying such patients after recovery from cryptococcosis, Schimpff et al. 73 found a decrease in lymphocyte migration inhibition using cryptococcocin and heat-killed C. neoformans as stimuli. Also, compared with control subjects, patients with past or ongoing cryptococcal infection have a decrease in delayed-type hypersensitivity to fungal skin test antigens, but a normal lymphocyte transformation response to cryptococcocin, implying a defect 39. 73 Finally, there in the effector arm of lymphocyte-directed immunity. 39, has been at least one case report of cryptococcal meningitis in a brother and sister, the infections separated by 8 years and with anergy in one patient tested 24 months after cure, suggesting a familial defect in cell-me54 diated immunity in the two patients. 54 It is unclear at present whether or not hormonal factors have a role in 27 to 30 30 per host defense against C. neoformans. Women account for only 27 cent of patients with cryptococcosis, 15. 15, 25 but the higher incidence in men may be due to occupational exposure. In any case, cryptococci are susceptible in vitro to diethylstilbestrol and estradiol. 60 Cryptococcal meningitis has developed during pregnancy or immediately post partum in some patients,77 but it is not possible to conclude from the reports to date whether pregnancy protects against, predisposes to, or has no effect on cryptococcosis.

CRYPTOCOCCAL INFECTION OF TIlE THE NERVOUS SYSTEM

335

PATHOGENESIS OF INFECTION

C.. neoformans is acquired by inhalation of the organism Infection with C from environmental sources, with no human-to-human transmission documented. Most patients with intact immunity are able to contain the infection in the lung or at the hilar nodes. This is evident from cases of asymptomatic pulmonary cryptococcal lesions,16, 48, 48, 53 from the incidental finding of subpleural cryptococcal nodules at autopsy in patients dying of other diseases,44, 57, 82 and from the reports of cryptococcal granulomas of hilar 72 Indeed, most nodes in association with subpleural cryptococcal lesions. 72 patients with intact immunity will contain primary pulmonary cryptococcal infection in the same manner as they would primary tuberculosis; moreover, such patients usually do well without any antifungal therapy. 29, 43, 53 An occasional patient with primary pulmonary cryptococcosis and no known abnormality of immunity will, however, develop disseminated disease, as will nearly all immunocolnpromised immunocompromised hosts. 53 Most patients with disseminated disease will have meningeal involvement, but also susceptible are the skin,71 skin,?1 bone,38 prostate,47 prostate,4' kidneys,68 eyes,63, 88 liver, 67, 67, 69 69 spleen,2 87 , 89 The endocardium is rarely infected, adrenals,2,2, 12 and lymph nodes. nodes,87, adrenals, 64 As most patients with cryptococeven in the presence of cryptococcemia. 64 cal meningitis have no comcomitant pulmonary involvement, it is likely that they have reactivation of primary disease, analogous to secondary, extrapulmonary tuberculosis, and often occurring in the setting of an acquired deficiency of cell-mediated immunity. The pathologic findings seen with cryptococcal infection of the central nervous system include a basilar, chronic meningitis as well as lesions throughout the brain consisting of clusters of organisms with little inflammatory response. Such lesions can become large enough to be seen macroscopically and are then called cryptococcomas (or torulomas). On histopathologic examination, cryptococci are seen with periodic acid-Schiff (PAS), Gridley, Gomori's methenamine silver, and mucicarmine stains. CLINICAL MANIFESTATIONS Cryptococcal meningitis affects persons of all ages, although most are 15 As noted above, in most series, 70 per cent 01d,15 usually 30 to 60 years old. of patients are men,15, 25 and 50 per cent have serious underlying conditions such as lymphoma, leukemia, sarcoidosis, or corticosteroid therapy. therapy.I15,5, 23, 70, 79,84,90 Patients with diabetes mellitus, hepatic cirrhosis, and pregnancy have developed cryptococcal meningitis, but it is uncertain infection, if these conditions truly predispose to infection. The most common symptoms and signs associated with cryptococcal meningitis are headache, fever, nausea, vomiting, mental status changes (confusion, irritability, impaired memory, behavioral changes, somnolence, psychosis), and neck stiffness. Less common are visual disturbances (blurred vision, retrobulbar pain, diplopia, photophobia), cranial nerve palsies, papilledema, cerebellar signs, seizures, and aphasia. The exact frequencies at which these manifestations are found are given in Table 1, which has been compiled from several series. series,15, 15, 23, 23, 70 It is important to

336 336

JAMES

Table 1. SIGN OR SYMPTOM

Headache Fever Nausea, vomiting Mental status changes Meningeal signs Visual disturbances Cranial nerve palsies Papilledema Ataxia Seizures Aphasia No signs or symptoms

T. ANDRIOLE R. SABETTA AND VINCENT T.

Meningitis!5ls , 23.70 Signs and Symptoms in Cryptococcal Meningitis 23, 70 NUMBER AFFECTED/ NUMBER EXAMINED

PER CENT AFFECTED

84/97 58/97 51197 51/97 50/97 48/97 32/97 18/57 16/57 25/97 4/26 7/71 7171 7171 7/71

87 60 53 52 50 33 32 28 26 15 10 10

note that some patients with cryptococcal meningitis are asymptomust be examined whenever C, matic;15, 46, 55, 70, 83 for this reason, the eSF CSF lllust C. neoformans is isolated from any site. As noted above, in addition to causing a chronic basilar meningitis, C. neoformans can produce lesions throughout the brain consisting of clusters inflammation, These cryptococcomas can be microof organisms with little inflammation. macroscopic, Tiny accumulations of cryptococci within the optic scopic or macroscopic. 36 patients nerve have been noted to cause optic atrophy, as seen in 33 of 36 63 Although they can produce series,63 with cryptococcal meningitis in one series. symptoms of an expanding intracranial lesion,76 macroscopic cryptococcomas can be asymptomatic,31 thus making a head eT CT scan necessary in any patient with cryptococcosis. Rarely, toruloma can develop in the spinal cord, spinal epidural or subdural space, 18, 76 or even the ventricles. 59, 86 Interestingly, patients with macroscopic cryptococcoma reported in the literature generally have not had malignancies of the reticulendothelial system,31, system.31, 76 The onset of cryptococcal meningitis is usually insidious but can be acute in the severely immunosuppressed patient. Untreated, the disease is invariably fatal. fataL 15, 62 Of 178 cases of central nervous system cryptococcosi~ cryptococcosi~ I8 Although year,IS reviewed in 1951, 86 per cent of patients died within 1 year. there have been many reports of patients who have had untreated cryptococcal meningitis for several years, including Beeson's case of 16 years' duration,3 it appears that even these patients eventually die of active infecuntreated, 3, 17 tion if untreated.

LABORATORY MANIFESTATIONS AND DIAGNOSIS eSF in patients with cryptococcal infection of the Examination of the CSF central nervous system generally suggests a chronic, lymphocytic meningitis, The opening pressure is elevated in 65 per cent of patients,15 the gitis. CSF protein level increased in 90 per cent, 15, 23,70,79 23, 70, 79 and the CSF eSF eSF glucose level is depressed in 75 per cent. 15. IS, 23, 23, 70, 79 It has been found that 97 per

337

CRYPTOCOCCAL INFECTION OF THE NERVOUS SYSTEM

cent of patients have abnormal CSF cell counts, 15, 70 with most patients having less than 150 leukocytes, 15, 23, 25 with over one half of the cells lymphocytes, Unfortunately, none of these findings can provide a precise diphocytes. agnosis. agnosis, Cryptococci can be demonstrated by an India ink preparation of the CSF in 60 per cent of patients (the range is 40 to 79 per cent -in in various series 44,, 9, 15,23,37,70). 15, 23, 37, 70). This test is very easy to perform, but care should be taken not to confuse lymphocytes with fungal organisms. A definitive diagnosis of cryptococcal meningitis can be made, of course, by isolating the organism from the CSF. The number of patients with positive CSF cultures in most series is over 90 per cent, 15, 23, 70 but this figure no doubt is inflated owing to the criteria used for study inclusion. Indeed, even in such series, only 75 per cent of patients have an initial CSF culture that is positive. 70 This has been the experience at Yale, where of 25 cases of cryppositive.7° tococcal to coccal meningitis seen over the last 28 years, only 18 patients (72 per observations), cent) had initially positive CSF cultures (unpublished observations). Serologic methods to aid in the diagnosis of cryptococcal meningitis have been in use for years. years, The indirect fluorescent test for anticryptococcal antibody is of low sensitivity and specificity, with antibody found in the sera of 40 per cent of patients with cryptococcal meningitis,25, 52 and rarely CSF.52 subjects, 9 in in the CSF. 52 False positive results are seen in normal control subjects,9 infections,9,9, .52 patients with other fungal infections, 52 and in patients skin-tested with cryptococcocin. 99 Moreover, as patients with cryptococcal meningitis rarely, if ever, have a rise in antibody titer,9, 52 the test is seldom helpful. The most useful serologic test for cryptococcosis is the latex agglutination test for cryptococcal antigen. This test detects as little as 25 to 60 ng fluid,s, 51, 66 and can be positive when of cryptococcal antigen per ml of body fluid,5, CSF cultures and India ink preparations are negative. 78 Occasionally, the latex test is positive before a eSF CSF pleocytosis occurs. 78 As the titer of antigen declines with clinical improvement,25, 66 the test is useful to follow. follow, The eSF CSF of patients with cryptococcal meningitis is positive by latex agglutination in over 90 per cent of cases (range of 71 to 100 per cent44,, 11,23,35,51,52,66,80); 11, 23, 35, 51, 52, 66, 80); the serum of such patients is positive in 50 per cent 1l , 52, 66). of cases (range of 18 to 71 per centll 66), Both nonspecific factors and rheumatoid factor can cause false positive reactions in the serum and CSF. Many nonspecific reactions can be eliminated by heating the serum samCSF samples at 100 100°C 56°C for 3 minutes and the eSF ples at 56°e e for 10 minutes,37 now standard procedures in most laboratories. Approximately 1.5 per cent of all CSF and 2.5 per cent of all sera will agglutinate latex particles coated with normal as well as anticryptococcal rabbit globulin, implying rheumatoid-like factor interference. 28, 81 In general, a sample should be considered truly positive only if the agglutination of immune-globulincoated particles is at least fourfold that of nonimmune-globulin-coated par66 However, even with this criterion, 0.4 per cent of samples will be ticles,66 ticles. falsely positive. 51 If necessary, rheumatoid factor activity can be removed 45 pronase,81 pronase, 81 by pretreatment of the sample with 0.003 M dithiothreitol,36, dithiothreitol, 36, 45 or 0.1 M EDTA with boiling,30 boiling. 3o The complement-fixation test for cryptococcal antigen is 100 per cent specific but has a sensitivity of only 32 per cent in CSF and 36 per cent in sera,6 making it less useful clinically than is the latex test. An enzyme0

338

JAMES

R. SABETTA AND VINCENT T. ANDRIOLE

linked immunosorbent assay (ELISA) that can detect as little as 6.25 ng per ml of cryptococcal antigen has been developed. It appears clinically remains small. 75 sensitive and specific, but the number of patients tested relllains Despite the value of the India ink stain, CSF culture, and the latex agglutination test for cryptococcal antigen, a few patients with cryptococcal meningitis still escape diagnosis. At times, a presumptive diagnosis must be made, based on the presence of lymphocytic meningitis and an extraneural culture positive for C. neoformans. The urine is particularly useful to culture in suspected cases, since it harbors cryptococci in approximately .1.0 The blood, bone 35 per cent of patients with cryptococcal meningitis .15 marrow, sputum, and skin are less frequently positive. 15. 15, 64 Another useful aid in the diagnosis of cryptococcal meningitis is CSF cytologic examination, which can delllonstrate demonstrate cryptococci not only with the mucicarmine, PAS, and Grocott stains but also with the routine Papanicolaou stain. 88 Finally, in a few documented cases, cultures of the CSF obtained by cisternal tap revealed cryptococci, whereas cultures of large volumes of CSF, India ink preparations and tests for cryptococcal antigen had failed. 7,7. 34 The differential diagnosis of cryptococcal meningitis includes all causes of chronic meningitis but usually involves the other fungal meningitides, lymphoma or carcinoma of the meninges, and tuberculous meningitis. As most of the lymphocytes seen in the CSF in cryptococcal meningitis are T cells,21,74 74 determination of lymphocyte subsets was used to differentiate cells,21, between lymphomatous meningitis and infection in one case of a malignancy with B-cell markers. 21 Tuberculous meningitis may be hard to distinguish from cryptococcal meningitis, although patients with the former condition are more likely to have an abnormal mental status, nuchal rigidity, 8o However, a positive an abnormal chest radiograph, and hyponatremia. 80 so PPD is not more likely in patients with tuberculous meningitis. 80

THERAPY 1.5, 62 62 AmphoterCryptococcal meningitis is invariably fatal if untreated. 15, 1,33 and remains the 1950SI,33 icin B has been used for treatment since the 1950S most important therapeutic agent against cryptococcosis. Three reports describe the results of treatment of cryptococcal meningitis with amphoteri1. 5 mg per kg daily or every cin B given intravenously in doses up to 1 to 1.5 other day .15, 70, 70, 79 79 Correcting for duplicate case reports in these studies, overall 52 per cent of patients were cured after a first course of therapy, 12 per cent relapsed but were cured with retreatment, 25 per cent died of cryptococcal meningitis, and 10 per cent died of other diseases or were still on therapy at the time of reporting. 15, IS. 70, 70. 79 Thus, 64 per cent of patients with cryptococcal meningitis are cured with standard doses of amphotericin B. Alone, 5-fluorocytosine is inadequate therapy for cryptococcal meningitis. Only 30 per cent of patients can be cured,IO cured,lo and there are a number of relapses and failures due to the development of drug resistance during treatment. 10, 85, 91 Finally, there is significant marrow toxicity associated 10. 50 including fatal marrow aplasia. aplasia, 13, 50 with this agent, 10,

CRYPTOCOCCAL INFECTION OF THE NERVOUS SYSTEM

339 339

Utz et al. 84 used low-dose amphotericin B (20 mg per day, given intravenously) combined with 150 mg per kg per day of 5-fluorocytosine to treat 15 patients with cryptococcal meningitis. Of this group, 53 per cent of patients were cured, 20 per cent died with active disease, and 27 per cent died of other causes; there were no relapses. This prompted a large prospective study comparing combination therapy consisting of amphotericin B (0.3 mg per kg per day) and 5-fluorocytosine (150 mg per kg per day) to single therapy with amphotericin B (0.4 mg per kg per day for 42 days, then 0.8 mg per kg every other day for 28 days).4 Sixteen of 24 patients (67 per cent) were cured or improved on combination therapy, compared with 11 of 27 (41 per cent) on single therapy, allowing the authors to propose combination therapy as the regimen of choice in treatment of crypto coccal meningitis. It should be noted, however, that seven patients, who tococcal were unable to adhere to the combination protocol because of 5-fluorocytosine toxicity and were subsequently cured or improved with amphotericin B therapy alone, were excluded from analysis. Moreover, the 26 per cent cure rate (7 out of 27) seen with the unconventionally low doses of amphotericin B used in the single-agent group does not at all compare to the cure rates of 47 to 58 per cent achieved by others l5, 70, 79 with initial therapy with conventional doses of amphotericin B, and certainly not with the 61 to 67 per cent cure rate with repeated courses of amphotericin B.15, 70, 79 There is no conclusive evidence that in the treatment of cryptococcal meningitis the combination of 5-fluorocytosine and amphotericin B is any more efficacious than amphotericin B used alone in standard doses (0.6 to 1 mg per kg per day). The optimal duration of amphotericin B therapy for cryptococcal meningitis has not been definitively established. In general, therapy has been continued for at least 6 weeks. In addition, four CSF samples obtained at weekly intervals should reveal declining antigen titers and should be sterile on culture. At the present, other agents cannot be recommended for the therapy of cryptococcal meningitis. Miconazole has been used in isolated cases of cryptococcal infection,40, 61 but its efficacy in cryptococcal meningitis has not been defined. Based on one case report,65 ketoconazole would not appear to be efficacious. However, given some evidence for synergy with amphotericin B in the murine model of disseminated cryptococcosis,41 further studies are needed to define a potential future role for ketoconazole in combination therapy. Transfer factor appears to have led to improvement in some patients with cryptococcal infection,20, 42 but the experience with this agent is limited. Interestingly, in China, garlic has been used to treat cryptococcal meningitis, with 70 per cent of the patients claimed to be cured or improved. 32 Intrathecal therapy with amphotericin B for cryptococcal meningitis has generally been reserved for very ill patients or for those who relapse after a course of intravenous therapy. Thus, it is not surprising that in several reports, the proportion of patients who died of infection was higher in the group given adjunctive intrathecal amphotericin B than in those treated with intravenous drug therapy alone. 15, IS, 70 In one series in which 62 patients were cured, the addition of intrathecal therapy appeared to be

340

JAMES

R.

SABETTA AND VINCENT

T.

ANDRIOLE

contributory in 3 of 18 patients in whom it was used. 25 Moreover, as complications due to intrathecal amphotericin B are seen in 60 per cent of patients,79 its use is recommended only for refractory cases. The same recommendation can be made for intraventricular amphotericin B administered through a subcutaneous reservoir, a procedure associated with multiple complications,24 including infection of the catheter tip. 74 Although medical therapy has been used alone to successfully treat cryptococcomas,19, some patients with cryptococcomas, 19, 31 the therapy required was very extensive, with patients worsening on conventional doses of amphotericin B. Thus, unless torulomas are small and numerous or inaccessible to drainage, surgery should be used as an adjunct to medical therapy. 76

PROGNOSIS For the individual patient with cryptococcal meningitis, the most important factor predictive of survival is the absence of major underlying, predisposing illness. 25, 70, 79 In a study of III patients with cryptococcal meningitis at the National Institutes of Health, the reviewers noted that in addition to the presence of lymphoreticular malignancy and corticosteroid therapy, initial parameters predictive of death from active' active infection were a positive India ink preparation, an elevated CSF opening pressure, hypoglycorrhachia, less than 20 white blood cells per mm 33 of CSF, cryptococci cultured from more than one extraneural site, absent cryptococcal antibody, and a CSF or serum cryptococcal antigen titer greater than or 25 Predictive of relapse were an initial CSF white blood cell 1:32.25 equal to 1:32. count below 20 cells per mm 3, positive extraneural cultures, absent cryptococcal to coccal antibody, a low CSF glucose level after 4 or more weeks of therapy, a post-treatment CSF or serum antigen titer of 1:8 or higher, no decrease in CSF or serum antigen during therapy, and a daily corticosteroid dose of 20 mg or more of prednisone after completion of therapy. 25 2S , 79 but have been reIn general, relapses occur within 12 months 25 il'nporported to occur up to 29 months after completion of therapy. 70 Of importance, 15 to 20 per cent of patients cured of infection will have positive CSF India ink smears with negative cultures for months to years after termination of therapy. 25, 70 Although nearly all such patients do not relapse, 25, 70 particularly careful follow-up examination of the CSF is warrelapse,25, ranted beyond the usual 1 to 2 years in this setting. Although the cure rate in treated cryptococcal meningitis approaches 70 per cent, only 50 to 60 per cent of the patients cured are neurologically normal, 23, 25, 70 with the remainder suffering visual loss, cranial nerve palsies, significant motor dysfunction, and impairment of mental status. Hopefully, a more thorough understanding of this illness can allow for more prompt diagnosis and treatment.

REFERENCES in man. 1. Andriole, V. T., and Kravetz, H. N.: The use of amphotericin B.. B.in 180:269, 1962.

J.

A. M. A.,

CRYPTOCOCCAL INFECTION OF THE NERVOUS SYSTEM

341

2. Baker, R. D., and Haugen, R. K.: Tissue changes and tissue diagnosis in cryptococcosis. Am. J. Clin. PathoI., Pathol., 25:14, 1955. years· duration. Arch. Intern. 3. Beeson, P. B.: Cryptococcal meningitis of nearly sixteen years' Med., 89:797, 1952. 4. Bennett, J. E., Dismukes, W. E., Duma, R. J., et al.: A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N. Engl. J. Med., 301:126, 1979. 5. Bennett, ]. J. E., and Bailey, J. W.: Control for rheumatoid factor in the latex test for Pathol., 56:360, 1971. cryptococcosis. Am. J. Clin. PathoI., crypto coccal polysac6. Bennett, J. E., Hasenclever, H. F., and Tynes, B. S.: Detection of cryptococcal charide in sera and spinal fluid: Value in diagnosis and prognosis. Trans. Assoc. Am. Physicians, 77:145, 1964. crypto coccal meningitis. J. A. M. A., 236:2517, 7. Berger, M. P., and Paz, J.: Diagnosis of cryptococcal 1976. 8. Bernard, P. C., G., Szyfelbein, W. M., Weiss, D., et al.: Diagnosis of cryptococcal cryptococcal meningitis by cytologic methods: An old technique revisited. Neurology, 30:102, 1980. 9. Bindschadler, D. D., and Bennett, J. E.: Serology of human cryptococcosis. Ann. Intern. Med., 69:45, 1968. 10. Block, E. R., and Bennett, J. E.: Clinical and pharmacological studies with 5-fluorocytosine (5-FC). Clin. Res., 20:525, 1972. Gordon, M. A., and Elmdorf, D. F.: Detection ofC. of C. neoformans antigen 11. Bloomfield, N., Cordon, in body fluids by latex particle agglutination. Proc. Soc. Exp. BioI. Med., 114:64, 1963. 12. Bowman, H. E., and Ritchey, J. 0.: Cryptococcosis (torulosis) involving brain, adrenal, U rol., 71:373, 71 :373, 1954. and prostate. J. UroI., 13. Bryan, C. S., and McFarland, J. A.: Cryptococcal meningitis: Fatal marrow aplasia from combined therapy. J. A. M. A., 239:1068, 1978. I. Nonencapsulated mutants. J. Bacte14. Bulmer, C. S., and Sans, M. D.: C. neoformans. 1. riol., 94:1475, 1967. Ailing, D. W., Spickard, A., et al.: Diagnostic and prognostic value of 15. Butler, W. T., AIling, clinical and laboratory findings in cryptococcal meningitis. N. EngI. Engl. J. Med., 270:59, 1964. G. D.: Primary pulmonary cryptococcosis. Am. Rev. Respir. Dis., 94:236, 16. Campbell, C. 1966. 17. Campbell, C. G. D., Carrier, R. D., and Busey, J. F.: Survival in untreated cryptococcal meningitis. Neurology, 31:1154, 1981. 18. Carton, C. A., and Mount, L. A.: Neurosurgical aspects of cryptococcosis. J. Neurosurg., 8:143, 1951. 19. Coleman, D. L., and Andriole, V. T.: An unusual pontine mass lesion. Yale J. BioI. Med., 55:51-58, 1982. 20. Conrad, R., and Lerner, W.: The use of transfer factor in a patient with chronic cryptococcal meningitis. Clin. Res., 21 :596, 1973. Gormus, B. J., Yarchoan, R., et aI.: al.: Cryptococcal meningitis with false 21. Davies, S. F., Cormus, positive cytology in the CSF. J. A. M. A., 239:2369, 1978. 22. Denton, J. F., and DiSalvo, A. F.: The prevalence of Cryptococcus neoformans in various natural habitats. Sabouradia, 6:213, 1968. 23. DeWytt, DeWytt, C. N., Dickson, P. L., and Holt, C. G. W.: Cryptococcal meningitis: A review of 32 years' experience. J. Neurol. Sci., 53:283, 1982. 24. Diamond, R. D., and Bennett, J. E.: A subcutaneous reservoir for intrathecal therapy of fungal meningitis. N. Engl. J. Med., 288:186, 1973. 25. Diamond, R. D., and Bennett, J. E.: Prognostic factors in cryptococcal meningitis: A III cases. Ann. Intern. Med., 80:176, 1974. study in 111 26. Diamond, R. D., May, J. E., Kane, M. A., et al.: The role of the classical and alternate complement pathways in host defenses against Cryptococcus neoformans infection. J. Immunol., 112:2260, 1974. ImmunoI., rypto27. Diamond, R. D., Root, R. K., and Bennett, J. E.: Factors influencing killing of C Cry ptococcus neoformans by human leukocytes in vitro. J. Infect. Dis., 125:367, 1972. 28. Dolan, C. T.: Specificity of the latex cryptococcal antigen test. Am. J. Clin. Pathol., 58:358, 1972. al.: Cryptococcosis, with emphasis on 29. Duperval, R., Hermans, P. E., Brewer, N. S., et aI.:

342 30. 31. 32. 33.

34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54.

JAMES

R.

SABETTA AND VINCENT

T.

ANDRIOLE AN:qRIOLE

72:13, the significance of isolation of C. neoformans from the respiratory tract. Chest, 72: 13, 1977. Eng, R R. H., and Person, A.: Serum cryptococcal antigen determination in the presence of rheumatoid factor. J. Clin. Microbiol., 14:700, 1981. Fujita, N. K., Reynard, M., Sapico, F. L., et al.: Cryptococcal intracerebral mass lesions: The role of computed tomography and nonsurgical management. Ann. Intern. Med., 94:382, 1981. Garlic in cryptococcal meningitis: A preliminary report of 21 cases. Chin. Med. J., 93(2):123, 1980. Gold, W., Stout, H. A., Pagano, J. F., et al.: Amphotericins A and B, antifungal antibiotics produced by a streptomycete. 1. In vitro studies. In Welch, H., and MartiIbanez, F. (eds.): New York, Antibiotics Annual. Medical Encyclopedia, Inc., 1956. Gonyea, E. F.: Cisternal panculture and cryptococcal meningitis. Arch. Neurol., 28:200, 1973. Goodman, J. S., Kaufman, L., and Koenig, M. G.: Diagnosis of cryptococcal crypto coccal meningitis: Value of immunologic detection of cryptococcal antigen. N. Engl. J. Med., 285:434, 1971. Gordon, M. A., and Lapa, E. W.: Elimination of rheumatoid factor in the latex test for cryptococcosis. Am. J. Clin. Pathol., 60:488, 1974. and prognosis of Gordon, M. A., and Vedder, D. K.: Serologic tests in the diagnosis "and cryptococcosis. J. J. A. M. A., 197:131, 1966. R, and Gilmer, W. S.: Skeletal cryptococcosis: Report of a case and review Gosling, H. R., of the literature. J. Bone. Joint Surg., 38A:660, 1956. Graybill, J. R., and Alford, R R. H.: Cell-mediated immunity in cryptococcosis. Cell. ImJ. R, munol., 14:12, 1974. Graybill, J. R., and Levine, H. B.: Successful treatment of cryptococcal meningitis with intraventricular miconazole. Arch. Intern. Med., 138:814, 1978. R., Williams, D. M., VanCutsen, E., et al.: Combination therapy of experiGraybill, J. R, mental histoplasmosis and cryptococcosis with amphotericin Band ketoconazole. Rev. Infect. Dis., 2:551, 1980. Spitier, L. E.: Disseminated cryptococcosis treated with Gross, P. A., Patel, C., and Spitler, transfer factor. J.A. M. A., 240:2460, 1978. Hammerman, K. J., Powell, K. E., Christianson, C. S., et al.: Pulmonary cryptococcosis: Clinical forms and treatment-CDC cooperative mycoses study. Am. Rev. Respir. Dis., 108:1116, 1973. Haugen, R R. K., and Baker, R R. D.: The pulmonary lesions in cryptococcosis with special reference to subpleural nodules. Am. J. Clin. Pathol., 24:1381, 1954. R. J., and Mackenzie, D. W. R: R.: False positive latex test for cryptococcal antigen in Hay, R J. Clin. Pathol., 35:244, 1982. cerebrospinal fluid. J. Hellman, R. N., Hinrichs, J., J., Sicard, G., et al.: Cryptococcal pyelonephritis and dissem141:128, inated cryptococcosis in a renal transplant recipient. Arch. Intern. Med., 141 :128, 1981. Cryptococcal prostatitis. Am. J. J. Clin. Pathol., 75:257, Hinchey, W. W., and Someren, A.: Cryptococcalprostatitis. 1981. Houk, V. N., and Moser, K. M.: Pulmonary cryptococcosis: Must all receive amphotericin B? Ann. Intern. Med., 63:583, 1965. J., and Bolande, R. P.: Humoral defense mechanisms in cryptococcosis: SubIngel, H. J., c. stances in normal human serum, saliva, and cerebrospinal fluid affecting growth of C. neoformans. J. Infect. Dis., 116:75, 1966. Kauffman, C. A., and Frame, P. T.: Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrob. Agents Chemother., 11:244, 1977. R. J., et al.: Detection of cryptococcal Kaufman, C. A., Bergman, A. G., Severance, R antigen: Comparison of two latex agglutination tests. Am. J. Clin. Pathol., 75:106, 1981. Kaufman, L., and Blumer, S.: Value and interpretation of serological tests for the diagnosis of cryptococcosis. Appl. Microbiol., 16:1907, 1968. Kerkering, T. M., Duma, R R. J., and Shadomy, S.: The evolution of pulmonary cryptococcosis. Ann. Intern. Med., 94:611, 1981. Krick, J. A.: Familial cryptococcal meningitis. J. Infect. Dis., 143:133, 1981.

CRYPTOCOCCAL INFECTION OF THE NERVOUS SYSTEM

343

55. Liss, H. P., and Rimland, D.: Asymptomatic cryptococcal meningitis. Am. Rev. Respir. and Dis., 124:88, 1981. 56. Littman, M. L., and WaIter, J. E.: Cryptoccosis: Current status. Am. J. Med., 45:922, 1968. 57. Littman, M. L., and Zimmerman, L. E.: Cryptococcosis. New York, Grune and Stratton, Inc., 1956. 5S. Macher, A. M., Bennett, J. E., Gadek, J. E., et al.: Complement depletion in crypto58. coccal sepsis. J. Immunol., 120:1686, 1978. 59. Manganello, L. O. J., and Nicholas, P.: Intraventricular torula granuloma. J. Neurosurg., 12:306, 1955. 60. Mohr, J. A., Long, H., McKown, B. A., et al.: In vitro susceptibility ofC. of C. neoformans to steroids. Sabouradia, 10: 171, 1972. 10:171, 61. Morgans, M. E., Thomas, M. E. M., and Mackenzie, D. W. R.: Successful treatment of 2: 100, 1979. systemic cryptococcosis with miconazole. Br. Med. J., 2:100, 62. Mosberg, W. H., and Arnold, J. G.: Torulosis of the central nervous system: Review of the literature and report of five cases. Ann. Intern. Med., 32:1153, 1950. 63. Okun, E., and Butler, W. T.: Ophthalmologic complications of cryptococcal meningitis. Arch. Ophthalmol., 71 :52, 1964. 62:98,1983. 64. Perfect, J. R, R., Durack, D. T., and Gallis, H. A.: Cryptococcemia. Medicine, 62:98, 1983. 65. Perfect, J. R, R., Durack, D. T., Hamilton, J. D., et al.: Failure ofketoconazole in cryptococcal meningitis. J. A. M. A., 247:3349, 1982. cryptococcallatex 66. Prevost, E., and Newell, R.: Commercial cryptococcal latex kit: Clinical evaluation in a medical center hospital. J. Clin. Microbiol., 8:529, 1978. J., Benfield, J. R., Ripon, J. W., et al.: Cryptococcal hepatitis presenting as 67. Procknow, J. J., a surgical emergency. J. A. M. A., 191:269, 1965. Jr., Stacy, W. K., Toone, E. c., 68. Randall, R. E. Jr., C., et al.: Cryptococcal pyelonephritis. N. Engl. J. Med., 279:60, 1968. 69. Sabesin, S. M., Fallon, H. J., and Andriole, V. T.: Hepatic failure as a manifestation of 111:661, cryptococcosis. Arch. Intern. Med., 111 :661, 1963. 70. Sarosi, G. A., Parker, J. D., Doto, I. L., et al.: Amphotericin B in cryptococcal menin71 :1079, 1969. gitis: Long-term results of treatment. Ann. Intern. Med., 71:1079, 71. Sarosi, G. A., Silberfarb, P. M., and Tosh, F. E.: Cutaneous cryptococcosis: A sentinel of disseminated disease. Arch. Dermatol., 104:1, 1971. 72. Sayler, W. R, R., Sayler, D. C., Baker, R R. D.: Primary complex of Cryptococcus and pulmonary lymph nodes. 130:74, 1974. 73. Schimpff, Schimp£f, S. C. and Bennett, J. E.: Abnormalities in cell-mediated immunity in patients with C. neoformans infection. J. Allergy Clin. Immunol., 55:430, 1975. 74. Schonheyder, H., Thestrup-Pedersen, K., Esmar, V., et al.: Cryptococcal meningitis: Complications due to intrathecal treatment. Scand. J. Infect. Dis., 12:155, 1980. 75. Scott, E. N., Muchmore, H. G., and Felton, F. G.: Comparison of enzyme immunoassay and latex agglutination methods for detection of Cryptococcus neoformans antigen. Am. J. Clin. Pathol., 73:790, 1980. 76. Selby, R. C., and Lopes, N. M.: Torulomas (cryptococcal granulomata) of the central nervous system. J. Neurosurg., 38:40, 1973. 77. Silberfarb, P. M., Sarosi, G. A., and Tosh, F. E.: Cryptococcosis and pregnancy. Am. J. Obstet. Gynecol., 112:714, 1972. 78. Snow, S. M., and Dismukes, W. E.: Cryptococcal meningitis: Diagnostic value of cryptococcal antigen in cerebrospinal fluid. Arch. Intern. Med., 135:1155, 1975. 79. Spicard, A., Butler, W. T., Andriole, V., et al.: The improved prognosis of cryptococcal meningitis with amphotericin B therapy. Ann. Intern. Med., 58:66, 1963. 80. Stockstill, M. T., and Kaufman, C. A.: Comparison of cryptococcal and tuberculous meningitis. Arch. Neurol., 40:81, 1983. 81. Stockman, L., and Roberts, G. D.: Specificity of the latex test for cryptococcal antigen: A rapid, simple method for eliminating interference factors. J. Clin. Microbiol., 16:965, 1982. 82. Talerman, A., Bradley, J. M., and Woodland, B.: Cryptococcallymphadenitis. J. Med. Microbiol., 3:633, 1970. 83. Tarala, R R. A., and Smith, J. D.: Cryptococcosis treated by rapid infusion of amphotericin B. Br. Med. J., 2:28, 1980.

344

JAMES

R. SABETTA AND VINCENT T. ANDRIOLE

84. Utz, Utz. J. P., Garriques, I. 1. L., Sande, M. A., et al.: Therapy of cryptococcosis with a combination of flucytosine and amphotericin B. J. Infect. Dis., 132:368, 1975. 85. Utz, J. P., Shadomy, S., McGehee, R. F., et al.: 5-Fluorocytosine: Experience in patients with pulmonary and other forms of cryptococcosis. Am. Rev. Respir. Dis., 99:975, 1969. 86. Vijayan, N., Bhatt, G. R., and Dreyfus, P. M.: Intraventricular cryptococcal granuloma: A case report with review of the literature. Neurology, 21 :728, 1971. 87. Voyles, G. Q., and Beck, E. M.: Systemic infection due to Torula histolytica (C. hominis): Report of four cases and review of the literature. Arch. Intern. Med., 77:504, 1946. 88. Weiss, C., Perry, Perry,!. I. H., and Shevky, M. C.: Infection of the human eye with Cryptococcus neoformans (Torula histolytica). Arch. Ophthalmol., 39:739, 1948. 89. Zelman, S., O'Neil, R. H., and Plant, A.: Disseminated visceral torulosis without nervous system involvement, with clinical appearance of granulocytic leukemia. Am. J. Med., 11 :658, 1951. 90. Zimmerman, L. E., and Rappaport, H.: Occurrence of cryptococcosis in patients with malignant disease of the reticuloendothelial system. Am. J. Clin. Pathol., 24:1050, 1954. 91. Zylstra, W.: Cryptococcosis and 5-fluorocytosine [Comment]. Aust. N. Z. J. Med., 4:296, 1974. Infectious Disease Section Yale University School of Medicine 333 Cedar Street New Haven, Connecticut 06510