Article Date: 7/1/2012

CooperVision Launches Multifocal Daily Disposable
CASE STUDY

A Case of Cryptoccocal Choroiditis in an HIV-infected Man

The lesson here is that an eye exam can save lives.

Christopher J. Brady, MD • Carl D Regillo, MD

A 42-year-old African-American man was referred for vision loss in the right eye. He had a history of untreated HIV infection and prior pneumocystis pneumonia. He had presented to another hospital one week prior with malaise and fevers. A presumptive diagnosis of Mycobacterium avium intracellularae was made, and ethambutol therapy was initiated.

Shortly after beginning ethambutol, the patient experienced rapidly progressive, painless loss of vision in the right eye. On review of systems, the patient described intermittent headaches and right eye pain. He denied neck stiffness and subjective fevers or chills. His vital signs were within the normal limits.

His uncorrected distance visual acuity was finger counting at three feet in the right eye and 20/25 in the left. Intraocular pressure was 9 mm Hg in both eyes. The pupils were equally round and reactive with no relative afferent papillary defect. Ocular motility was full, and visual field testing by confrontation was grossly full bilaterally.

An external examination of the face revealed several 0.5-5-mm pearly white papules with umbilicated centers. A slit-lamp examination of the anterior chamber and ocular adnexa was unremarkable. On the dilated fundus examination, the vitreous was clear in both eyes. The optic nerve head was pink and well perfused bilaterally.

Christopher J. Brady, MD, is an fellow in vitreoretinal surgery at the Wills Eye Institute in Philadelphia. Carl D. Regillo, MD, is director of the Wills Eye Retina Service and professor of ophthalmology at Thomas Jefferson University in Philadelphia. Neither author reports any financial interest in any product mentioned in this article. Dr. Brady can be reached via e-mail at brady@jhmi.edu.

Vascular tortuosity was evident in both eyes, as were nerve fiber layer hemorrhages and infarctions. Multiple yellow-white choroidal plaques were seen bilaterally. A plaque was noted beneath the fovea in the right eye (Figure 1).

Figure 1. Color fundus photos of the left (a) and right (b) eyes reveal multiple deep yellow-white plaques prior to therapy.

The hospital at which the patient had previously been admitted was contacted, and the mycobacterial culture obtained during his prior hospitalization was discovered to be growing budding yeast consistent with Cryptococcus. Additionally his CD4+ count was 4/mm3.

A diagnosis of multifocal choroiditis, likely secondary to Cryptococcus, was made, and the patient was admitted to the internal medicine service for intravenous antifungal therapy. A lumbar puncture revealed an opening pressure of 8 cm of water and a positive cryptococcal antigen at a dilution of 1:256.

An India ink smear of the cerebrospinal fluid was positive for cryptococcal forms. Peripheral blood cultures grew Cryptococcus neoformans. Induction therapy was begun with intravenous amphotericin B and high-dose oral fluconazole (800 mg by mouth daily) for two weeks.

Three days after the initiation of therapy, the patient's distance acuity had improved to 20/80 in the right eye. Fluorescein angiography demonstrated early hyperfluorescence in the areas of choroidal plaque without increasing in size or intensity. Later frames revealed punctate hyperfluorescence within the plaques. (Figure 2) Optical coherence tomography was remarkable for the preservation of retinal architecture with a small area of subretinal fluid overlying one of the choroidal plaques (Figure 3).

Figure 2. Fluoroscein angiography of the right eye demonstrated early hyperfluorescence in the areas of choroidal plaque without increasing in size or intensity (a-c). Later frames revealed punctate hyperfluorescence within the plaques (d).

Figure 3. Optical coherence tomography of the right macula was remarkable for preservation of retinal architecture with a small area of subretinal fluid overlying a sub-foveal choroidal plaque.

Following the patient's inpatient stay, antiretroviral therapy was restarted, and fluconazole consolidation therapy (400 mg by mouth daily) was prescribed for a further eight weeks. After six weeks, his vision had stabilized at 20/100 in the right eye. Most of the choroidal plaques had resolved in both eyes, but residual fibrosis was noted beneath the fovea in the right eye (Figure 4) and the facial paplues had regressed. A maintenance dose of fluconazole (200 mg by mouth daily) was started 10 weeks after the start of therapy.1-2

Figure 4. Fundus photography of the left (a) and right eyes (b) following therapy.

DISCUSSION

C. neoformans is a ubiquitous encapsulated yeast found in soil. Initial inoculation is through inhalation, causing self-limited pneumonitis that is generally subclinical in immunocompetent hosts. Dissemination to the meninges or bloodstream generally only occurs in the setting of T-cell dysfunction, such as malignancy or HIV infection.1

Before the introduction of amphotericin B in 1956, disseminated disease was usually fatal.2 In the 1980s, the rate of cryptococcal meningitis in patients with AIDS was approximately 5% in Western countries3 and up to 30% in sub-Saharan Africa and Southeast Asia.4 After the introduction of highly active antiretroviral therapy (HAART), the rates declined substantially,5 but it remains a significant opportunistic infection, particularly in patients with limited access to health care.

In an early case series, approximately half of patients with cryptococcal meningitis experienced visual symptoms, most commonly blurred vision but also double vision, orbital pain, and photophobia.6 In the majority of cases, such symptoms are a secondary phenomenon caused by increased intracranial pressure causing papilledema or sixth cranial nerve palsy.7

A more recent series from Rwanda of 80 patients with cryptococcosis and AIDS demonstrated papilledema in 32% of cases.8 Spread of infection into the intraocular space is less common but was reported at least as early as 1942,9 and both the 1964 NIH series6 and the 1993 Rwanda series8 included one case. As late as 1977, prior to the AIDS epidemic, there were only 15 cases of intraocular infection reported in the English-language literature.2

Intraocular Cryptococcus may take the form of chorioretinitis, multifocal choroiditis, neuroretinitis, vitritis, or endophthalmitis.10-14 The organism seems most commonly to reach the eye hematogenously via the choriocapillaris due to its high volume of blood flow, but it may also enter through the retinal circulation or by direct extension along the leptomeninges of the optic nerve.15-17

Multifocal choroiditis in a patient with advanced AIDS has a broad differential, and several serious opportunistic infections need to be considered. Pneumocystis jirovecii, Mycobacterium avium intracellularae, Mycobacterium tuberculosis, Histoplasma capsulatum, Candida, Aspergillus fumigates, Toxoplasma gondii, Treponema pallidum, and Cytomegalovirus can all cause a similar clinical picture in the setting of profound immune suppression.18-20

Additionally, intraocular lymphoma, sarcoidosis, and idiopathic multifocal choroiditis are also possible causes of multifocal choroiditis in any host. An autopsy series of 235 consecutive patients with AIDS in the pre-HAART era found infectious choroiditis in 18 of 235 patients (7.7%).15 In 15 of these 18 patients, the cause of death was thought to be systemic manifestations of the same organism. Because choroiditis was diagnosed in only four of 18 cases during life, the possibility of earlier recognition of a fatal illness by a thorough eye exam is raised.

Given the difficulty of obtaining tissue from the intraocular space, clues to the cause of choroiditis will generally need to come from peripheral blood cultures and serum immunologic testing, in addition to urine, cerebral spinal fluid, and sputum culture. Indeed, most cases of confirmed cryptococcal choroiditis in the literature are from autopsy or enucleation,10,15,21 although the diagnosis has been confirmed by fine needle aspiration biopsy,10-11 at vitrectomy,13 and by retinal biopsy.14

In addition to the current patient, several cases of disseminated Cryptococcus presenting to the ophthalmologist with visual disturbances and only mild, vague systemic symptoms have been reported.14, 22-23

Hematogenously spread choroiditis in the absence of clinically apparent meningitis represents an important opportunity for ophthalmologists to recognize and appropriately triage this life-threatening opportunistic infection. RP

REFERENCES

1. Jarvis JN, Harrison TS. HIV-associated cryptococcal meningitis. AIDS. 2007;21:2119-2129.
2. Chapman-Smith JS. Cryptococcal chorioretinitis: a case report. Br J Ophthalmol. 1977;61:411-413.
3. Crump JR, Elner SG, Elner VM, Kauffman CA. Cryptococcal endophthalmitis: case report and review. Clin Infect Dis. 1992;14:1069-1073.
4. Moosa MY, Coovadia YM. Cryptococcal meningitis in Durban, South Africa: a comparison of clinical features, laboratory findings, and outcome for human immunodeficiency virus (HIV)-positive and HIV-negative patients. Clin Infect Dis. 1997;24:131-134.
5. Dromer F, Mathoulin-Pelissier S, Fontanet A, Ronin O, Dupont B, Lortholary O. Epidemiology of HIV-associated cryptococcosis in France (1985-2001): comparison of the pre- and post-HAART eras. AIDS. 2004;18:555-562.
6. Okun E, Butler WT. Ophthalmologic complications of cryptococcal meningitis. Arch Ophthalmol. 1964;71:52.
7. Henderly DE, Liggett PE, Rao NA. Cryptococcal chorioretinitis and endophthalmitis. Retina. 1987;7:75-79.
8. Kestelyn P, Taelman H, Bogaerts J, et al. Ophthalmic manifestations of infections with Cryptococcus neoformans in patients with the acquired immunodeficiency syndrome. Am J Ophthalmol. 1993;116:721-727.
9. Warvi WN, Rawson RW. Torula meningitis. Arch Int Med. 1942;69:90.
10. Hiles DA, Font RL. Bilateral intraocular cryptococcosis with unilateral spontaneous regression. Report of a case and review of the literature. Am J Ophthalmol. 1968;65:98-108.
11. Hiss PW, Shields JA, Augsburger JJ. Solitary retinovitreal abscess as the initial manifestation of cryptococcosis. Ophthalmology. 1988;95:162-165.
12. Shields JA, Wright DM, Augsburger JJ, Wolkowicz MI. Cryptococcal chorioretinitis. Am J Ophthalmol. 1980;89:210-217.
13. Custis PH, Haller JA, de Juan E, Jr. An unusual case of cryptococcal endophthalmitis. Retina. 1995;15:300-304.
14. Sheu SJ, Chen YC, Kuo NW, Wang JH, Chen CJ. Endogenous cryptococcal endophthalmitis. Ophthalmology. 1998;105:377-381.
15. Morinelli EN, Dugel PU, Riffenburgh R, Rao NA. Infectious multifocal choroiditis in patients with acquired immune deficiency syndrome. Ophthalmology. 1993;100:1014-1021.
16. Grieco MH, Freilich DB, Louria DB. Diagnosis of cryptococcal uveitis with hypertonic media. Am J Ophthalmol. 1971;72:171-174.
17. Khodadoust AA, Payne JW. Cryptococcal (torular) retinitis. A clinicopathologic case report. Am J Ophthalmol. 1969;67:745-750.
18. McCluskey PJ, Wakefield D. Posterior uveitis in the acquired immunodeficiency syndrome. Int Ophthalmol Clin. 1995;35:1-14.
19. McCluskey PJ, Wakefield D. Ocular involvement in the acquired immune deficiency syndrome (AIDS). Aust N Z J Ophthalmol. 1985;13:293-298.
20. Carney MD, Combs JL, Waschler W. Cryptococcal choroiditis. Retina. 1990;10:27-32.
21. Avendano J, Tanishima T, Kuwabara T. Ocular cryptococcosis. Am J Ophthalmol. 1978;86:110-113.
22. Rostomian K, Dugel PU, Kolahdouz-Isfahani A, Thach AB, Smith RE, Rao NA. Presumed multifocal cryptococcol choroidopathy prior to specific systemic manifestation. Int Ophthalmol. 1997;21:75-78.
23. Stone SP, Bendig J, Hakim J, Kinnear PE, Azadian BS, Clifford-Rose F. Cryptococcal meningitis presenting as uveitis. Br J Ophthalmol. 1988;72:167-170.



Retinal Physician, Volume: 9 , Issue: July 2012, page(s): 58 - 61