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Cryptococcal Endophthalmitis: Case Report and Review John R. C. Crump, Susan G. Elner, Victor M. Elner, and Carol A. Kauffman

From the Division of Infectious Diseases, Department of Internal Medicine, and Departments of Ophthalmology and Pathology, University of Michigan Medical School, and the Department of Veterans Affairs Medical Center, Ann Arbor, Michigan

Cryptococcus neoformans is an opportunistic fungus with a predilection for infecting the meninges. Ocular sequelae of cryptococcal infections of the CNS usually include cranial nerve palsies or papilledema secondary to increased intracranial pressure. Intraocular cryptococcosis occurs less frequently, and over the last 23 years, only 27 cases have been reported, including the case presented here. Intraocular infection was most often manifested by chorioretinal lesions and vitritis. Underlying diseases were detected in only 11 (41%) of the 27 patients. Of note, ocular lesions preceded symptomatic meningitis in six (27%) of 22 patients with CNS involvement. For seven patients, the diagnosis was made by histologic examination of specimens of aqueous or vitreous humor; for another eight patients, the diagnosis was made after enucleation or at autopsy. Ocular involvement frequently led to severe visual loss; return of vision to normal was unusual. Early recognition and treatment may improve outcome for these patients.

Cryptococcus neoformans is a budding yeast with a large polysaccharide capsule. It is widespread in the environment, especially in areas burdened with bird excreta, and has a worldwide distribution [1]. The spectrum of disease caused by C. neoformans ranges from asymptomatic pulmonary lesions to meningoencephalitis to fungemia with disseminated infection [2]. Before the advent of AIDS, cases of C. neoformans infection occurred as frequently in patients with apparently normal immune systems as in those with evidence of immunodeficiency [2-4]. In recent years, in the wake of the AIDS epidemic, cryptococcal infections have become much more common, occurring in 5% of all patients with AIDS [5]. The last large review of cryptococcal endophthalmitis was by Hiles and Font in 1968 [6]. Other than the case that they reported, the cases reviewed in that paper all occurred before amphotericin B was available (ca. 1960) and thus present the natural history of the infection without effective therapy. Our review includes all cases of cryptococcal endophthalmitis, in which adequate clinical data were available, reported in the English-language literature since the availability of effective antifungal therapy. Case Report An 84-year-old woman initially presented with a 1-week history of decreased vision in her right eye without associated pain or redness. Five years previously she had undergone

Received 24 September 1991; revised 26 December 1991. Reprints or correspondence: Dr. Carol A. Kauffman, Veterans Affairs Medical Center, 2215 Fuller Road, Ann Arbor, Michigan 48105. Clinical Infectious Diseases 1992;14:1069-73 © 1992 by The University of Chicago. All rights reserved. 1058-4838/92/1405-0009$02.00

uncomplicated cataract extractions at which time intraocular lenses were placed in both eyes. She had a history of hypertension, mild congestive heart failure, and angina pectoris and was taking furosemide, enalapril, and nitroglycerin. Physical examination revealed an elderly woman with a blood pressure of 170/110 mm Hg and a pulse of 100/min. Results of pulmonary, cardiovascular, abdominal, and integumentary examinations were within normal limits. A small, firm right cervical lymph node was noted. Neurological examination revealed an alert woman with a decreased attention span and poor short-term recall. Ocular examination revealed a visual acuity of counting fingers at 2 feet in the right eye and 20/40 in the left eye. An afferent pupillary defect was present in the right eye. Extraocular movements were normal. Examination of the ocular anterior segment demonstrated a normal left eye with an intraocular lens in good position. The fundus was unremarkable except for the suggestion of an occasional flat, grayish choroidal nodule. The right eye had keratitic precipitates on the inferior cornea, moderate inflammatory cells in the anterior chamber, pronounced clumps of cellular debris in the anterior vitreous, and an intraocular lens in position. The majority of retinal vessels were studded with gray-white cellular debris, and an elevated mass of white, blood-tinged debris appeared to extrude from the face of the optic disk and extend into the surrounding retina and vitreous (figure 1). Initial laboratory evaluation disclosed a white blood cell count of 6.4 X 10 6 /L and a hemoglobin level of 106 g/L; urinalysis revealed occasional white blood cells. A chest roentgenogram did not reveal any evidence of active lung disease. The patient received a periocular steroid injection on the right to reduce inflammation. One week later, results of the ocular examination were unchanged, and vitreous fluid from her right eye was collected via needle aspiration for cytologi-

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Table 1. Underlying conditions in 27 patients with cryptococcal ocular infection. Underlying condition Immunosuppressiont Hematologic malignancy AIDS Collagen vascular disease Ocular trauma Chronic alcoholism Diabetes mellitus Chronic active hepatitis None

No. (%) of patients* 5 (18) 3(11) 3(11) 2 (7) 2 (7) 1 (4) 1 (4) 1 (4) 14 (52)

* Several patients had more than one underlying disease. t Patients receiving immunosuppressive therapy had malignancy (two), collagen vascular disease (two), and chronic active hepatitis (one).

Figure 1. Photograph of the fundus of the right eye that demonstrates inflammatory debris extruding from the optic disk and extending into the surrounding vitreous and retina. Small areas of hemorrhage are present within the inflammatory exudate. Many of the retinal vessels are also encased or beaded with inflammatory debris.

cal examination. No neoplastic or inflammatory cells were found. Biopsy of the cervical lymph node showed reactive hyperplasia. Two weeks after initial presentation, the patient underwent closed vitrectomy in her right eye. Cytological examination of the vitreous fluid revealed encapsulated, budding yeasts typical of C. neoformans (figure 2). She was admitted to the hospital, and after further questioning of the patient and her family, it was found that she had had low-grade fevers, night sweats, and lethargy for at least 6 weeks. Analysis of CSF disclosed the following values: white

blood cell count, 79 X 10 6/L, with 82% neutrophils, 7% lymphocytes, and 11% histiocytes; glucose level, 1.39 mmol/L; and protein level, 0.93 g/L. An India ink stain preparation of CSF showed encapsulated, budding yeast, and results of the latex agglutination test for cryptococcal antigen were positive at a titer of 1:128. Results of a test for cryptococcal antigen in serum were negative. Cultures of blood, CSF, urine, and vitreous specimens yielded C. neoformans. The patient was treated with fluconazole (200 mg daily), and her fever, malaise, anorexia, headache, and mental status changes resolved. Cultures of CSF became negative in week 2 of therapy. By week 10, the titer of cryptococcal antigen in the CSF had fallen (1:32) as had the white blood cell count (15 X 10 6/L); the India ink stain preparation of CSF remained positive, and CSF cultures continued to show no growth. Vision did not return to her right eye, and her course was complicated by intraocular hypertension and rubeosis iridis. Fluconazole therapy was continued for 5 months. Five months after fluconazole therapy was stopped, the titer of cryptococcal antigen in the CSF was 1:2, and the white blood cell count in the CSF was 1 X 10 6 /L; the India ink stain preparation of CSF was persistently positive. One month later, the patient experienced a relapse of cryptococcal meningitis and died with disseminated cryptococcosis. Results

Figure 2. Cytospin preparation of vitreous aspirate from the eye in figure 1. Alcian blue staining demonstrates multiple organisms surrounded by mucopolysaccharide capsules intermixed with inflammatory cells (stain, hematoxylin and alcian blue; original magnification, X 1,000).

Patient characteristics. Since 1968, 27 cases of cryptococcal endophthalmitis, including our case, have been reported in the English-language literature [6-30]. The mean age of the patients was 42.4 years (range, 13-84 years); 18 were men and nine were women. Underlying diseases. An underlying illness that potentially predisposed the patient to cryptococcosis was present in only 11 patients (41%) (table 1). Another two patients had direct inoculation of the organism into the eye—one sustained an injury from farmyard debris [21] and the other

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Table 2. Method of diagnosis of cryptococcal ocular infection. Method of diagnosis Culture of specimen from nonocular site Vitreous aspiration or biopsy Enucleation Autopsy Aqueous aspiration or biopsy Latex agglutination test for cryptococcal antigen

No. (%) of patients 11 (41) 5 (18) 4 (15) 4 (15) 2(7) 1 (4)

received a corneal transplant from a donor who was subsequently found to have disseminated cryptococcosis [26]. Two patients had prior cataract extractions ([6] and this patient), only one of whom had intraocular lens implants (this patient). Four patients had significant exposure to bird (primarily pigeon) feces temporally related to their illness [9, 10, 20, 25]. Ocular symptoms. Symptomatic eye disease was seen in 24 (89%) of the patients; for the other three, asymptomatic ocular involvement was found in the course of the workup for extraocular cryptococcal disease [7, 18, 25]. The most common symptom was a decrease in visual acuity, which occurred in 17 patients ([6, 8, 9, 11-15, 19, 22, 23, 27-30] and this patient). In five patients, the visual loss occurred suddenly [11, 27, 29, 30]. Pain was noted in three patients [10, 19, 24], floaters were noted in three [17, 19, 28], and photophobia in one [10]. Twelve of 24 patients had bilateral eye involvement, with eight patients experiencing symptomatic involvement of both eyes simultaneously [11-13, 17, 23, 29, 30]. Two patients had involvement in one eye followed by later symptoms in the other [6, 22], one had resolution of symptoms in one eye with progression in the other [8], and one had asymptomatic bilateral involvement [25]. Ocular findings. The most common finding was choroidal infection manifested by choroiditis with or without associated retinitis [8, 9, 11-16, 18-23, 28-30]. Retinovitreal masses and anterior uveitis were less commonly seen ([11, 16, 18, 24] and this patient). Vitritis was commonly associated with chorioretinal disease. Retinal detachment was seen during the course of the infection in four patients [8, 16, 18, 24]. Ocular histopathologic findings were noted in enucleation or autopsy specimens from nine patients [6-8, 10, 16, 17, 21, 23, 27]. The inflammatory response ranged from sparse perivascular infiltration with lymphocytes [7, 23] to panophthalmitis with acute and chronic inflammatory cells [27]. Granulomatous reactions were seen in three specimens [6, 8, 16]. Associated extraocular cryptococcal infection. In all, 25 (93%) of 27 patients had extraocular manifestations of cryptococcal infection. Cryptococcosis involved the CNS in 22 (81%) of the 27 patients ([6, 8-10, 12-15, 17-25, 28-30]

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and this patient), and in only one was this involvement asymptomatic [14]. Eye disease preceded CNS disease in six (27%) of these 22 patients ([10, 14, 20, 21, 24] and this patient). Three patients had no involvement of the CNS but had other systemic diseases-cutaneous in one [7] and pulmonary in two [11, 27]. In two patients, ophthalmologic disease was the sole manifestation of cryptococcal infection; one had infection secondary to corneal transplantation [26], and the other had chronic, recurrent uveitis [ 16]. Diagnosis. For 15 patients, Cryptococcus organisms were identified in the eye by cytological or histopathologic examination of aqueous or vitreous aspirates ([6, 13, 14, 18, 19, 26] and this patient) or enucleation specimens [8, 16, 21, 27] or at autopsy [7, 10, 17, 23] (table 2). Culture results supported the diagnosis for all seven patients from whom aspirate/biopsy specimens were taken, and culture of one enucleation specimen was positive for Cryptococcus organisms. None of the autopsy specimens were cultured. For 11 other patients (41%), the diagnosis was based on the results of culture or histopathologic examination of fluids and tissue specimens other than those from the eye [9, 11, 12, 20, 22, 24, 25, 28-30], and for one patient, the diagnosis was based solely on positive results of a latex agglutination test for antigens of C. neoformans in serum and CSF [15]. Treatment and outcome. Twenty-four of 27 patients received antifungal treatment; two died before therapy could be started [7, 17], and one with isolated ophthalmic disease was cured with enucleation alone [16]. Of the 24 patients given antifungal drugs, 13 received both amphotericin B and flucytosine [8-11, 14, 19, 20, 22, 26-29], nine received amphotericin B as a single agent [6, 12, 13, 18, 21, 23-25, 30], one received flucytosine only [15], and one (our patient) received fluconazole. Intraocular amphotericin B (0.3 to 7.0 p,g) was used as adjunctive therapy for five patients [6, 13, 14, 18, 19]. A poor outcome (as defined by failure of vision to return to baseline, performance of enucleation, or death) was seen in 21 (84%) of 25 patients for whom outcome was clearly stated. Only four patients had return of vision back to baseline (table 3). Five patients underwent enucleation because of persistence of pain or inflammation or the need for examination of tissue [6, 8, 16, 21, 27]. Six patients, five of whom

Table 3. Outcome in 27 patients with cryptococcal ocular infection. Outcome Vision decreased Died Enucleated eye Improved vision Unknown

No. (%) of patients 10 (37) 6 (22) 5 (18) 4 (15) 2(7)

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had underlying diseases, died ([7, 10, 17, 23, 30] and this patient). The number of patients who failed to respond to therapy was no different among those receiving single-drug therapy and those receiving two drugs. Likewise, those patients receiving intraocular amphotericin B had no improvement in outcome when compared with those not treated with an intraocular drug; only one of these patients had improvement of vision [19]. For six patients, ocular involvement was noted a few days to 6 weeks after the institution of antifungal therapy [11, 12, 25, 29, 30]. The four patients for whom eye involvement was documented a few days after the start of antifungal therapy manifested decreasing visual acuity [11, 29, 30]; the other two had changes found on ophthalmologic examination but had only minimal or no symptoms [12, 25]. Four patients received systemic corticosteroids as initial therapy; a brief favorable response was seen in two [10, 20], while progressive visual loss was noted in the other two [13, 24]. Discussion This review describes 27 cases of cryptococcal endophthalmitis reported since 1968. Although papilledema and cranial nerve palsies secondary to increased intracranial pressure are seen commonly in patients with cryptococcal meningitis, intraocular cryptococcal infection is uncommon. In a significant number of patients, ocular infection either was the only site of cryptococcal disease or preceded clinically apparent meningitis. Thus, recognition of ocular involvement with C. neoformans may lead to earlier diagnosis and treatment of cryptococcosis, as in our patient. The diagnosis should be considered in intraocular inflammatory conditions with choroidal or retinovitreal infiltration. The diagnosis of cryptococcal ocular infection can be established by obtaining samples of aqueous or vitreous humor for histologic and microbiological examination. This method appears to be both rapid and sensitive when special care is taken to look for a fungus. Papanicolaou's stain or alcian blue stain, used in the present case, shows budding yeast with capsules in cytological preparations. Definitive histologic identification of C. neoformans requires use of the mucicarmine stain, which is specific for this organism [1]. There was evidence of infection at other sites in the majority of cases of ocular cryptococcal infection. Results of cultures of blood and urine or tests for cryptococcal antigen in serum were positive in the majority of the cases. Thus, patients with ocular cryptococcal infection are similar to many patients with cryptococcal meningitis in that disseminated infection in association with positive cultures of extraneural specimens is common [31]. Performing a lumbar puncture produced a high diagnostic yield, especially for those patients with systemic or neurological symptoms in addition to ocular symptoms. In over one-half of the cases, there was no underlying con-

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dition that predisposed the patient to infection with C. neoformans. Whether these patients had isolated T cell defects specific to Cryptococcus organisms was not addressed. It has been shown that subtle defects in cell-mediated immunity, demonstrated by abnormalities in reactivity to skin tests for cryptococcin and T lymphocyte transformation in response to cryptococcal antigens, occur in some patients recovering from cryptococcal infection [32]. The AIDS epidemic has brought about an increase in the number of cryptococcal infections. It stands to reason that intraocular cryptococcal infection will be seen with increasing frequency given the increasing number of cases of cryptococcosis in patients with AIDS. In these patients, ocular involvement with C. neoformans could be confused with other opportunistic pathogens infecting the eye. However, the primary choroidal involvement, which is the most typical presentation of cryptococcal endophthalmitis, may help to distinguish it from that due to cytomegalovirus, Toxoplasma gondii, or herpes simplex virus infections, which primarily infect the retina rather than the choroid. Patients with AIDS who present with cryptococcosis and chorioretinal lesions should be assessed for the possibility of intraocular cryptococcal infection before empirical therapy with ganciclovir is used for treatment of possible cytomegalovirus retinitis. In the cases reviewed, the outcome of intraocular cryptococcosis was dismal. Most patients were left with permanent visual impairment; the mortality rate was 22%, which is in keeping with mortality rates noted in several large series of cases of cryptococcal meningitis [2-4]. In this small number of patients, the outcome did not depend on the type of treatment received, but five of six patients who died of cryptococcosis had underlying diseases. Of the three human immunodeficiency virus–positive patients described, two responded favorably to therapy with resolution of choroiditis [29]. However, only one patient regained near-normal vision, and the other had permanent impairment secondary to optic atrophy. Standard therapy for cryptococcal meningitis has been amphotericin B and flucytosine. Even with this therapy, therapeutic failures or relapses occur in —33% of cases [33]. Fluconazole, a new triazole antifungal drug, has activity against C. neoformans and has been shown to be beneficial in treating cryptococcal meningitis in patients with AIDS [34]. It is not clear which regimen is most effective for patients who do not have AIDS. The most effective therapy for intraocular cryptococcal infection is not known. More data are available regarding treatment of intraocular infection with Candida organisms [35, 36], but the applicability to cryptococcal ocular infection is not assured since the pathogenesis of experimental ocular infection with these two fungi in the rabbit appears to differ [37]. Success with amphotericin B may be limited by its poor intravitreal penetration and potential for toxicity [35, 38] . Flucytosine has excellent penetration into the vitreous, but

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the development of resistance by Candida and Cryptococcus organisms limits its use to that of adjunctive therapy only [39]. Fluconazole reaches levels in the eye and CSF that are 50% of the peak serum concentration [40, 41]. Data accumulated using the rabbit model show fluconazole to be inferior to amphotericin B in clearing eyes infected with Candida albicans [36]. However, preliminary data from studies of humans with candidal endophthalmitis who were treated with fluconazole is encouraging (C. A. Kauffman, S. F. Bradley, and A. K. Vine, unpublished data). Cryptococcal endophthalmitis is a rapidly progressive disease. Intraocular cryptococcosis occurs with concurrent CNS infection in the majority of cases, but it may be the first clinical manifestation of cryptococcal infection. Diagnosis can usually be made by performing histologic and microbiological studies on an aspirate or biopsy specimen of the vitreous humour. Evidence of extraocular cryptococcosis can also be sought in other body fluids and tissue specimens in many cases. Treatment has generally not affected the outcome of cryptococcal endophthalmitis; however, earlier diagnosis may allow improved outcome. References 1. Rippon JW. Cryptococcosis. In: Medical mycology. The Pathogenic fungi and the actinomycetes. 3rd ed. Philadelphia: WB Saunders, 1988:582-609. 2. Lewis JL, Rabinovich S. The wide spectrum of cryptococcal infections. Am J Med 1972;53:315-22. 3. Spickard A. Diagnosis and treatment of cryptococcal disease. South Med J 1973;66:26-31. 4. Perfect JR, Durack DT, Gallis HA. Cryptococcemia. Medicine (Baltimore) 1983;62:98-109. 5. Panther LA, Sande MA. Cryptococcal meningitis in AIDS. In: Sande MA, Volberding PA, eds. The medical management of AIDS. 2nd ed. Philadelphia: WB Saunders, 1990;265-79. 6. Hiles DA, Font RL. Bilateral intraocular cyptococcosis with unilateral spontaneous regression. Report of a case and review of the literature. Am J Ophthalmol 1968;65:98-108. 7. Avendario J, Tanishima T, Kuwabara T. Ocular cryptococcosis. Am J Ophthalmol 1978;86:110-3. 8. Shields JA, Wright DM, Augsburger JJ, Wolkowicz MI. Cryptococcal chorioretinitis. Am J Ophthalmol 1980;89:210-8. 9. Chapman-Smith JS. Cryptococcal chorioretinitis: a case report. Br J Ophthalmol 1977;61:411-3. 10. Schulman JA, Leveque C, Coats M, Lawrence L, Barber JC. Fatal disseminated cryptococcosis following intraocular involvement. Br J Ophthalmol 1988;72:171-5. 11. Bisseru B, Bajaj A, Carruthers RH, Chhabra HN. Pulmonary and bilateral retinochoroidal cryptococcosis. Br J Ophthalmol 1983;67:15761 12. Okun E, Butler WT. Ophthalmologic complications of cryptococcal meningitis. Arch Ophthalmol 1964;71:52-7. 13. Henderly DE, Liggett PE, Rao NA. Cryptococcal chorioretinitis and endophthalmitis. Retina 1987;7:75-9. 14. Hiss PW, Shields JA, Augsburger JJ. Solitary retinovitreal abscess as the initial manifestation of cryptococcosis. Ophthalmology 1988;95:162-5. 15. Condon PI, Terry SI, Falconer H. Cryptococcal eye disease. Doc Oph-

thalmol 1977;44:49-56.

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16. Vogiatzis KV, Makley TA, Werling K. Cryptococcosis in a phthisical eye. Ann Ophthalmol 1981;104:433-5. 17. Doft BH, Curtin VT. Combined ocular infection with cytomegalovirus and cryptococcus. Arch Ophthalmol 1982;100:1800-3. 18. Malton ML, Rinkoff JS, Doft BS, Kennerdell JS. Cryptococcal endophthalmitis and meningitis associated with acute psychosis and exudative retinal detachment. Am J Ophthalmol 1987;104:438-9. 19. O'Dowd GJ, Frable WJ. Cryptococcal endophthalmitis: diagnostic vitreous aspiration cytology. Am J Clin Pathol 1983;79:382-5. 20. Stone SP, Bendig J, Hakim J, Kinnear PE, Azadian BS, Clifford-Rose F. Cryptococcal meningitis presenting as uveitis. Br J Ophthalmol 1988;72:167-70. 21. Birkmann LW, Bennett DR. Meningoencephalitis following enucleation for cryptococcal endophthalmitis. Ann Neurol 1978;4:476-7. 22. Chapman-Smith JS, Parr DH, Say PJ. Ocular cryptococcosis in New Zealand. N Z Med J 1980;91:291-3. 23. Khodadoust AA, Payne JW. Cryptococcal (torular) retinitis: a clinicopathologic case report. Am J Ophthalmol 1969;67:745-50. 24. Grieco MH, Freilich DB, Louria DB. Diagnosis of cryptococcal uveitis with hypertonic media. Am J Ophthalmol 1971;72:171-4. 25. Cameron ME, Harrison A. Ocular cryptococcosis in Australia, with a report of two further cases. Med J Aust 1970;1:935-8. 26. Beyt BE Jr, Waltman, SR. Cryptococcal endophthalmitis after corneal transplantation. N Engl J Med 1978;298:825-6. 27. Weis RF, Everett ED, Sprouse R, Elfervig JL. Endogenous cryptococcal endophthalmitis. South Med J 1981;74:482-3. 28. Church WH, Palace J, Dick DJ, Gould FK. Cryptococcal choroidoretinitis and immunodeficiency. Postgrad Med J 1987;63:969-71. 29. Carney MD, Combs JL, Waschler W. Cryptococcal choroiditis. Retina

1990;10:27-32. 30. Winward KE, Hamed LM, Glaser JS. The spectrum of optic nerve disease in human immunodeficiency virus infection. Am J Ophthalmol 1989;107:373-80. 31. Diamond RD, Bennett JE. Prognostic factors in cryptococcal meningitis. A study in 111 cases. Ann Intern Med 1974;80:176-81. 32. Fromtling RA, Shadomy HJ. Immunity in cryptococcosis: an overview. Mycopathologia 1982;77:183-90. 33. Bennett JE, Dismukes WE, Duma RJ, et al. A comparison of amphotericin B alone and combined with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 1979;301:126-31. 34. Saag MS, Powderly WG, Cloud GA, et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. N Engl J Med 1992; 326:83-9. 35. Savani DV, Perfect JR, Cobo LM, Durack DT. Penetration of new azole compounds into the eye and efficiacy in experimental Candida endophthalmitis. Antimicrob Agents Chemother 1987;31:6-10. 36. Filler SG, Crislip MA, Mayer CL, Edwards JE Jr. Comparison of fluconazole and amphotericin B for treatment of disseminated candidiasis and endophthalmitis in rabbits. Antimicrob Agents Chemother 1991;35:288-92. 37. Fujita NK, Hukkanen J, Edwards JE Jr. Experimental hematogenous endophthalmitis due to Cryptococcus neoformans. Invest Ophthalmol Vis Sci 1983;24:368-75. 38. Souri EN, Green WR. Intravitreal amphotericin B toxicity. Am J Ophthalmol 1974;78:77-81. 39. Kauffman CA. Flucytosine. In: Peterson PK, VerhoefJ, eds. The antimicrobial agents annual. 3rd ed. New York: Elsevier, 1988:246-50. 40. Arndt CAS, \N/lsh TJ, McCully CL, Balis FM, Pizzo PA, Poplack DG. Fluconazole penetration into cerebrospinal fluid: implications for treating fungal infections of the central nervous system. J Infect Dis 1988;157:178-80. 41. Walsh TJ, Foulds G, Pizzo PA. Pharmacokinetics and tissue penetration of fluconazole in rabbits. Antimicrob Agents Chemother 1989;33:467-9.

Cryptococcal endophthalmitis: case report and review.

Cryptococcus neoformans is an opportunistic fungus with a predilection for infecting the meninges. Ocular sequelae of cryptococcal infections of the C...
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