Bilateral Placoid Choroiditis in an HIV-Positive Patient With Cryptococcus neoformans Meningitis and Disseminated Cryptococcal Disease

Abstract

Purpose:

We report a presumptive case of bilateral placoid choroiditis secondary to disseminated Cryptococcus neoformans infection and review the literature on choroidal involvement of C neoformans.

Methods:

A case report is presented.

Results:

A 35-year-old HIV-positive man presented with disseminated cryptococcal infection. Cryptococcal meningitis was confirmed by lumbar puncture, and skin involvement was confirmed by microscopy of scrapings from a papular, umbilicated, ulcerated lesion. Ophthalmologic examination revealed intact visual acuity, clear vitreous, and multiple yellowish, placoid-appearing choroidal lesions in the posterior pole bilaterally.

Conclusions:

Multifocal choroiditis caused by C neoformans is an uncommon manifestation of disseminated infection, and placoid yellowish choroidal lesions are an unusual variant. These findings must be differentiated from choroidal tuberculosis and other infections. Multifocal choroiditis typically occurs in AIDS patients and may precede the presentation of meningitis. In such patients, choroidal lesions warrant investigation for systemic, life-threatening opportunistic infections.

Introduction

Cryptococcus neoformans (C neoformans) is an encapsulated fungus that infects immunocompromised individuals. Since 1981 and the beginning of the AIDS epidemic, C neoformans infection has primarily involved antiretroviral therapy (ART)-naive HIV-positive patients with a CD4 count of less than 100 cells/μL, with the global prevalence of cryptococcal antigenemia in this well-defined patient group estimated to be 6.0%. ¹

Although the portal of entry of Cryptococcus is most commonly the lung, resulting in pulmonary infection, cryptococcal meningitis is the primary clinical entity of importance. The global annual incidence of cryptococcal meningitis is more than 220 000 cases, accounting for 15% of AIDS-related mortality. ¹

Ophthalmic disease typically develops secondary to meningitis and other forms of central nervous system (CNS) involvement, with papilledema occurring in up to one-third of patients. ² Elevated intracranial pressure commonly causes late optic atrophy and vision loss. Other ocular manifestations related to CNS disease include diplopia, ophthalmoplegia, nystagmus, or ptosis. ³ Choroidal disease is uncommon, having not been clinically identified in a single patient among a pre-ART case series of 1163 patients with HIV, but it has been well described in a pathologic report from that era. ^4,5

Herein, we describe an unusual manifestation of presumptive cryptococcal choroiditis and discuss the clinical importance of this finding in the context of a review of the literature. This report underscores the importance of routine and timely dilated indirect ophthalmoscopy for all patients newly diagnosed with HIV/AIDS with CD4 counts of less than 100 cells/μL.

Methods

Case

A 35-year-old man initially presented with intermittent cough, night sweats, and weight loss. A diagnosis of HIV/AIDS was made as the patient was found to have a CD4 count of 75 cells/µL and oral candidiasis on physical exam. In addition, the diagnosis of active tuberculosis (TB) was suspected based on constitutional symptoms and chest radiography and was established by positive sputum smear microscopy. Full anti-TB therapy was initiated with rifampicin, isoniazid, pyrazinamide, and ethambutol for 2 months followed by rifampicin and isoniazid for 4 months. On completion of treatment for TB, the patient was commenced on ART with zidovudine, lamivudine, and efavirenz.

Approximately 6 months later, the patient presented with blurry vision and severe headaches of 3 weeks’ duration. Cryptococcal meningitis was diagnosed by lumbar puncture and detection of cryptococcal antigen in the cerebrospinal fluid. He was started on amphotericin intravenously 1 mg/kg for 14 days, and then transitioned to oral fluconazole 800 mg daily.

Eight days into amphotericin therapy, the patient was examined by an ophthalmologist with uveitis training and familiarity with ocular complications of AIDS. The examination was conducted at a hospital devoted to HIV/AIDS care and was limited to indirect ophthalmoscopy. The patient had no ocular complaints and visual acuity was 20/20 in each eye. Fundus exam revealed clear vitreous and multiple creamy, hypopigmented placoid choroidal lesions approximately 300 to 750 µm scattered throughout the posterior pole of both eyes (Figure 1). Because we could not perform an optical coherence tomogram or fluorescein angiogram, we cannot rule out some outer retinal involvement as well.

Figure 1.

Fundus photographs demonstrating multiple creamy, hypopigmented placoid choroidal lesions 300 to 750 µm in size scattered throughout the posterior pole of the (A) right and (B) left eyes.

A general medical exam revealed multiple pruritic papular skin lesions on the arms and trunk with central necrotic ulceration (Figure 2). Histopathology revealed cryptococcal yeast buds on Giemsa smear (Figure 3).

Figure 2.

Multiple pruritic papular skin lesions on the arms and trunk with central necrotic ulceration.

Figure 3.

Giemsa smear showing cryptococcal yeast buds, with arrow indicating a thick, clear cell wall, at 400× zoom.

Results

Patients with HIV/AIDS are prone to various forms of ocular disease. Many organisms are known to cause ocular infection in these patients, and several cases involving C neoformans have been described. Kestelyn et al described the ophthalmic manifestations of 80 HIV patients infected with C neoformans and reported papilledema to be the most common finding, occurring in 31% of the patients in this series. ² Only one patient was found to have chorioretinal involvement attributable to cryptococcal disease, described as a single, white, elevated chorioretinal granuloma.

Cryptococcal meningitis is a lethal disease, with a 1-year mortality of 70% in resource-poor countries despite treatment. ¹ The disease has an insidious onset and may be asymptomatic in its early stages. Most cases of ocular Cryptococcus infection occur in the context of known cryptococcal meningitis, as with our patient. However, several cases in the literature describe asymptomatic choroidal lesions that preceded CNS involvement. ^3,6,7 Ocular examination with indirect ophthalmoscopy allows identification of choroidal lesions similar to those seen in our patient and may serve as an important diagnostic modality; it raises clinical suspicion for early cryptococcal meningitis, providing an opportunity for timely treatment and improvement in patient survival.

The majority of severe vision loss in cases of cryptococcal ocular disease is attributed to optic neuropathy from either infiltration by yeast or compression of the nerve and/or its vasculature from prolonged increased intracranial pressure. ^2,8 There is no clear evidence that the choroidal lesions seen in cryptococcal choroiditis themselves cause symptomatic visual changes or vision loss. The patient in our case had intact vision despite having multiple large chorioretinal lesions involving both maculae, as did the case reported by Babu and colleagues. ³

In contradistinction, Winward et al reported a case of a 26-year-old woman with hand-motion vision in both eyes, presumably due to chorioretinal lesions in the posterior pole, in the setting of normal-appearing optic nerves. ⁹ However, the patient did have cryptococcal meningitis and an abducens nerve palsy suggestive of increased intracranial pressure that may have contributed to vision loss. The prevalence of cryptococcal choroiditis may be higher than appreciated. Morinelli and colleagues reviewed postmortem examinations of 235 patients with HIV and found 7 cases of cryptococcal chorioretinitis, none of which had been diagnosed prior to death. ⁷ This finding further supports the notion that the chorioretinal lesions of C neoformans may not cause significant direct visual dysfunction in the absence of optic neuropathy.

There have been several previously reported cases of cryptococcal choroiditis. Most of these case reports described bilateral yellow-white lesions in the posterior pole. However, none to date have ascribed a specifically placoid morphology to these lesions, although several photos have a similar appearance. ^3,8 Taken together, these articles specifically describe or provide photos that illustrate smaller, deep, atrophic, well-circumscribed choroidal spots rather than larger placoid, ill-defined lesions appearing at the level of the retinal pigment epithelium.

Ultimately, the presentation of cryptococcal choroiditis is variable and may be difficult to distinguish from choroidal tubercles or pneumocystis choroiditis on fundoscopy in this at-risk population. ^7,10 Of note, others have described cases in which more than one infectious organism was found in the choroid of the same patient, or even in the same eye. ⁷ In one study, the average survival after diagnosis of infectious choroiditis was only 25 days, and importantly, most patients died of systemic infection by the same organism that caused the multifocal choroiditis. ⁷ In a patient with a low CD4 count and yellowish choroidal lesions on funduscopic examination, even if asymptomatic, one must consider serum cryptococcal antigenemia test, lumbar puncture to rule out cryptococcal meningitis, and the possibility of disseminated TB.

Conclusions

Ocular cryptococcal infection remains rare, even among HIV/AIDS patients. Cryptococcal meningitis is associated with high mortality in patients with low CD4 counts. Multifocal choroiditis caused by C neoformans is an uncommon manifestation of disseminated systemic infection, and placoid, yellowish choroidal lesions are an unusual variant. These lesions are typically asymptomatic visually and may occasionally precede CNS complaints. Because these findings are nonspecific, they must be differentiated from infectious etiologies, particularly choroidal TB. All ART-naive patients with a CD4 count of less than 100 cells/µL should undergo immediate funduscopic examination with indirect ophthalmoscopy. The detection of choroidal lesions should prompt a thorough investigation for systemic opportunistic infection, the timely treatment of which may affect patients’ survival.