Introduction

Fungi are wide in nature and constitute a prominent and diverse group of microorganisms; however, a relatively small number of fungal species cause serious primary and opportunistic human diseases, and an even smaller number cause fungal retinitis or endophthalmitis. Fungal infections can be endogenous or exogenous. Endogenous fungal infections of the choroid, retina, and vitreous cavity are a complication of disseminated fungal diseases, and the fungi may infect the eye through the bloodstream [1]. On reaching the eye, fungi usually lodge in the choroid or retina, producing choroiditis, retinitis, or chorioretinitis. When this initial focus of infection extends into the vitreous to produce inflammation, which may involve the entire internal structure of the eye, endophthalmitis results. Ocular involvement occurs in 10–29% of patients with fungemia. Risk factors include systemic antibiotics and corticosteroid therapy, bacterial sepsis, prolonged hyperalimentation, recent abdominal surgery, alcoholism, hemodialysis, intravenous drug abuse, immunosuppression(burnedpatients;acquiredimmunodeficiency syndrome [AIDS]; patients with lymphoma, leukemia, or cancer; patients on chemotherapy), and diabetes. Exogenous fungal infections of the eye are a complication of penetrating ocular trauma and intraocular surgery; fungi may infect the eye by extension from periocular and orbital tissues [2].

Fungi can be divided into yeasts and molds. They are eukaryotic organisms, differing from bacteria in ribosome structure, nuclear structure, cell wall composition, and size. They lack chlorophyll, are nonmotile (except for certain spore forms), and may grow as single cells (yeast) or as long, branched, filamentous structures (mycelia). Virtually all fungi reproduce by forming spores through mitosis.

The most common organisms that produce fungal infections are the Candida species, followed by the Aspergillus species, and

Cryptococcus neoformans. Other much less commonly encountered fungi include Sporothrix

schenckii, Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis (Fig. 9.1). Table 9.1 depicts characteristics of fungal infections.

Causative Organisms

Candidiasis

Candida species can cause devastating visual loss. Ocular candidiasis frequently follows an indolent course, progressing from chorioretinitis to vitritis and endophthalmitis (Fig. 9.2). Candida species is the fourth most common cause (9%) of nosocomial infections and is even more prevalent (10%) in the intensive care unit [3].

The incidence of nosocomial candidemia has increased approximately tenfold over the last 20 years [4]. In contrast, the incidence of ocular candidiasis has been decreasing among inpatients with candidemia. Historically, the rate of ocular candidiasis has been reported between 9% and 45%. More recent estimates, however, have shown an incidence of less than 2% [5]. It has been suggested that this trend is related to earlier identification and treatment of candidemia.

Candida species are part of the normal flora of the respiratory, gastrointestinal, and female genital tracts. They constitute commensal yeasts of usually low virulence. However, Candida species may become pathogenic and can cause serious disease in immunocompromised patients.

Candida albicans is the most frequently isolated fungus from ocular infection [6]. Other less common Candida species, including C. parapsilosis (Fig. 9.3) and C. glabrata, may also produce ocular infections [7]. One theory for the greater tendency of C. albicans to produce chorioretinitis compared with other Candida species is because of the differences in the patterns of phospholipase and protease production [8]. Another theory of the different degrees of Candida pathogenicity can be because C. albicans rapidly produces germ tubes in serum, whereas other Candida species do not. It is possible that the

Fig. 9.1 Differential interference contrast microscopy. (a) Candida albicans (yeast cells and pseudohyphae; KOH preparation). (b) Coccidioides immitis (spherules; KOH preparation). (c) Cryptococcus neoformans (the round yeast cells surrounded by polysaccharide capsules; India ink). (d) Histoplasma capsulatum

(rough-walled macroconidia; Sabouraud glucose agar). (e) Aspergillus (stages in development of fruiting bodies). (f) Blastomyces dermatitidis (broad-based budding and thickened cell walls, and globose shape). (Modified and reprinted with permission from http:// www.doctorfungus.org)

germ tubes of C. albicans lodge in the choriocapillaris more easily and frequently than those of other species.

Risk Factors

Factors affecting the increase in fungal disease include [9]:

•Increase in the number of immunocompromised individuals

•Intravenous drug abuse

•Use of broad-spectrum antibiotics

•Immunosuppressive agents

•Intravenous hyperalimentation

•Indwelling intravenous pressure-monitoring devices

•Organ transplantation

•Implantation of prosthetic cardiac valves

•Recent major surgery, especially if involving the gastrointestinal system

•Low birth weight and normal neonates undergoing prolonged hospitalization

•Induced abortion

Pathogenesis

Microscopically, Candida can be found in the inner choroid and later extend into the subretinal space and retina. Candida may produce an acute necrotizing process and a chronic granulomatous reaction by histiocytes and round cells. Rupture of the inner limiting membrane may occur with

Table 9.1 Characteristics of fungal infections (postsurgical and endogenous)a

aModified from Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis; Fundamentals and Clinical Practice. 2nd ed. St Louis: Mosby Year Book; 1996

Clinical Features

Common presenting symptoms include a subacute history of blurred vision with low-grade pain, photophobia, and injection [11]. Early extramacular or peripheral fundus lesions (Fig. 9.6) produce little or no visual symptoms. With macular lesions or significant vitreous (Fig. 9.7) involvement, most patients become symptomatic, unless they are too ill to respond [7]. Progression of the disease leads to visual loss, pain, and redness of one or both eyes.

In candidemia, new visual symptoms—typi- cally floaters and blurred vision—are also correlated with ocular involvement. Donahue and colleagues report normal fundi in 92% of patients with candidemia capable of denying symptoms. These data suggest that the lack of symptoms carries a strong negative predictive value [12].

Signs may include single or multifocal, yel- low-white, fluffy retinal and choroidal lesions from one to several disk diameters in size. These lesions can be unilateral or bilateral, isolated or confluent, and may exist in a satellite pattern. Lesions may increase in size and spread into the vitreous, appearing as “cotton balls” (Fig. 9.8). Vitreous opacities are typically yellow-white and may be connected by strands, producing a “string of pearls” appearance. Vitritis may be so severe as to obscure the view of the fundus, which makes clinical diagnosis difficult. Other signs include lens abscess (Fig. 9.9), vitreous abscesses (Fig. 9.10), intraretinal hemorrhages (Fig. 9.11), and white-centered hemorrhages (Roth’s spots) [1, 13]. Vitreoretinal membrane formation and contraction combined with focal retinal necrosis and scarring are the major causes of permanent visual loss [14].

Fig. 9.2 Fundus photography of Candida endophthalmitis infection with multifocal chorioretinitis and vitreous involvement

vitreous invasion. Budding yeast forms (pseudohyphae) may be found (Fig. 9.4). Abscesses in the retina, choroid, and vitreous and extensive tissue necrosis characterize late stages of infection (Fig. 9.5) [10].

Diagnosis

The diagnosis of Candida retinitis should be considered in patients who present with vitritis accompanied by a chorioretinal focus in the clinical setting of a recent or current debilitating illness or other risk factor for candida infection. Clinical suspicion plays an important role in identifying patients who may have Candida endophthalmitis [15]. Isolation of Candida

Fig. 9.3 (a) Photography of the anterior segment after uneventful cataract surgery showing persistent corneal infiltrate and inflammation; the culture was positive for

Fig. 9.4 Light microscopy. (a)GranulomacontainingCandida albicans. (b) Higher magnification reveals Candida organisms. (Reprinted with permission from Arévalo JF, Fernández CF,

C. parapsilosis. (b) Higher magnification of corneal infiltrate and retrokeratic precipitates

Mendoza AJ. Chapter 41: Fungal infections. In: Retinal Imaging. Huang D, Kaiser PK, Lowder CY, Traboulsi EI, eds. Philadelphia: Mosby Elsevier; 2006; 366–774)

Fig. 9.5 Gross anatomy shows multifocal candidal retina abscess with “cotton ball” vitreous opacities. (Reprinted and modified with permission from Arévalo JF, Fernández CF, Mendoza AJ. Chapter 41: Fungal infections. In: Retinal Imaging. Huang D, Kaiser PK, Lowder CY, Traboulsi EI, eds. Philadelphia: Mosby Elsevier; 2006; 366–774)

species directly from the eye confirms the diagnosis of ocular candidiasis. However, the fungus may not always be detected, even clinically, in certain cases or in cases where the fungus has grown from another site. Fungal cultures can be positive in 44–70% of patients diagnosed clinically. Vitrectomy samples are more sensitive for fungal cultures than vitreous needle biopsies [16]. Anterior chamber aspirate is a poor diagnostic technique; however, anterior chamber taps may prove useful for detecting local production of anti-Candida antibodies [17].

The laboratory should be alerted when a vitrectomy specimen is expected so as to ensure that the specimen is handled appropriately and that culture media for fungi are used. Candida species can be cultured directly on blood agar, but roomtemperature Sabouraud agar without cyclohexamide is recommended when this organism is

clinically suspected. A pasty white colony appears in the culture media (Fig. 9.12). In addition, direct examination of fungi with Giemsa, Gomori methenamine silver (GMS), and periodic acid Schiff (PAS) stains should be obtained.

Culture has been used as the gold standard in the diagnosis of fungal endophthalmitis, but its true sensitivity is not known. Also, it is time consuming. The main reasons for the lack of sensitivity of conventional methods are the small number

Fig. 9.6 Candida chorioretinitis lesion in the inferotemporal arcade. (Reprinted and modified with permission from Arévalo JF, Fernández CF, Mendoza AJ. Chapter 41: Fungal Infections. In: Retinal Imaging. Huang D, Kaiser PK, Lowder CY, Traboulsi EI, eds. Philadelphia: Mosby Elsevier; 2006; 366–774)

of organisms in the eye, the small sample size of the intraocular specimen collected, and a greater tendency for the organisms to be loculated, thus being absent in the collected material. Hence, the collection of a small amount of vitreous by a tap is likely to be subject to greater sampling error in fungal cases. All these factors may contribute to a significant number of culture-negative specimens from cases of fungal endophthalmitis.

A useful, recently introduced diagnostic tool for fungal endophthalmitis is the polymerase chain reaction (PCR). The main advantages of PCR over conventional fungal cultures are the higher sensitivity and the rapid results obtained with PCR. Although PCR does not replace conventional mycologic methods, it helps to make an earlydifferentiationbetweenbacterialendophthalmitis and fungal endophthalmitis. PCR has been used successfully to identify Candida species from an intraocular sample. The major drawback of fungal culture is the prolonged period of time (3–4 days and up to 3 weeks) required for the growth of fungus, whereas the results of PCR are available in less than 24 h [18].

Fluorescein angiography shows hyperfluorescence in the late phases from choroidal neovascularization that may develop in numerous inflammatory and infectious conditions of the posterior segment, including ocular candidiasis. Optical coherence tomography has been useful to demonstrate the development of a macular hole under a Candida albicans “cotton ball” (Fig. 9.13).

Fig. 9.7 (a) Fundus photography of Candida endophthalmitis with vitreous involvement. (b) Candida retinal abscess in the macula. (Part B: Reprinted with permission from Davis

JL. Infectious chorioretinal inflammatory conditions. In: Regillo C, Brown G, Flynn HW, eds. Vitreoretinal Disease: The Essentials. New York: Thieme;1998: 393–415)

Fig. 9.8 Several large and small Candida chorioretinitis lesions with vitreous invasion are noted temporal to the optic nerve head in the right eye. In addition, healed cytomegalovirus retinitis is seen inferonasal to the optic nerve head in this AIDS patient. (Reprinted with permission from Arévalo JF, Fernández CF, Mendoza AJ. Chapter 41: ®. In: Retinal Imaging. Huang D, Kaiser PK, Lowder CY, Traboulsi EI, eds. Philadelphia: Mosby Elsevier: 2006; 366–774)

Fig. 9.9 Photography of the anterior segment showing Candida endophthalmitis with intralenticular lens abscess

Fig. 9.10 Vitreous inflammation and snow ball in the vitreous in a patient with Candida endophthalmitis

Fig. 9.11 Vasculitis, intraretinal hemorrhages, and retinochoroiditis lesion in the macula in a patient with candidiasis diagnosed as toxoplasmosis and treated with corticosteroids