INTRODUCTION

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This is a comprehensive review of the fungal and parasitic diseases of the eye. Numerous fungi and parasites infect the eye either by direct introduction through trauma or surgery, by extension from infected adjacent tissues, or by hematogenous dissemination to the eye. The majority of the clinically important species of fungi and parasites involved in eye infections are reviewed in this article. The fungi are discussed in relation to the anatomical part of the eye involved in disease, whereas parasites are discussed by the diseases they cause. Emphasis has been placed on literature published within this decade, but prior noteworthy reviews and case reports are included. A glossary of the ophthalmologic terms used is provided at the end of the paper (Appendix A). We suggest that the works of Beard and Quickert (26a) and Snell and Lemp (252a) be consulted as references concerning the anatomy of the eye.

ANATOMY OF THE EYE AND ITS RELATIONSHIP TO INFECTIOUS PROCESSES

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Orbits, Their Soft Tissue Contents, and Adjacent Structures

The orbits are pear-shaped bony cavities that contain the globes, extraocular muscles, nerves, fat and blood vessels (Fig. 1, left). The walls of the orbit are comprised of seven bones. The periosteal covering of the orbital bony cavity fuses anteriorly with the orbital septum and posteriorly with the dura mater. Abscesses can localize in the subperiosteal space. The roof, medial wall, and floor of the orbit separate it from adjacent paranasal sinuses, including the maxillary, frontal, ethmoid, and sphenoid sinuses. The paranasal sinuses arise from and drain into the nasal cavity. Thus, an intimate anatomical relationship exists between the orbit and the adjacent paranasal sinuses, and the latter may be the source of an orbital infection (Fig. 1, right).

View larger version (67K): [in this window] [in a new window]   FIG. 1.   (Left) The human eye in situ with the tunics peeled back, exposing a portion of the vasculature of the retina, lens, and anterior chamber as seen from the side. (Right) The relationship of the paranasal sinuses to the eye. The top figure shows a side view. (Bottom left) Relationship of the sinuses with the orbit as seen by coronal section just posterior to the bridge of the nose. (Bottom right) Relationship of the sinuses with the orbits with the head tilted backwards.

The thinnest bony walls of the orbit are the lamina papyracea, which cover the ethmoid sinuses. They are commonly involved in any fracture of the orbit from force to the periorbital area. As a result of fracture, sinus microbiota has direct ingress to the orbital tissues. Infections of the ethmoid sinus in children commonly extend through the lamina papyracea (without fracture), causing orbital cellulitis. The lateral wall of the sphenoid is also the medial wall of the optic canal. Therefore, infections of the sphenoid sinus may impinge on the optic nerve, resulting in visual loss or visual field abnormalities.

There are several important communications through apertures in the bony orbit to adjacent structures, including the superior and inferior orbital fissures, the lacrimal fossa and nasolacrimal duct, and the optic canal. These apertures may serve as a direct passage for an infectious process between the orbit and surrounding structures.

The adult human eye is approximately 24 mm in anterior-posterior length and is 6 mm³ in volume. The basic structure of the globe consists of three concentric layers or tunics. The outermost tunic is comprised of the cornea and sclera. The middle tunic is the uveal tract. It consists of the choroid, ciliary body, and iris. The innermost tunic is the retina (Fig. 1, left).

The posterior outer layer of the globe is the sclera, which is comprised of collagen and ground substance. The scleral width ranges from 0.3 to 1.0 mm. The sclera is essentially avascular except for superficial episcleral vessels and the intrascleral vascular plexus. The choroid is a vascular tunic that comprises the posterior portion of the uveal tract. The purpose of this highly vascularized tissue is to provide nutritive support to the outer layer of the retina. The blood flow and oxygenation of the choroid are very high compared to the other tissues in the body. Because of these qualities, the choroid may serve as a fertile site for the proliferation of hematogenously spread pathogens.

The anterior chamber is a space bordered anteriorly by the cornea and posteriorly by the iris diaphragm and pupil and is filled with aqueous humor (Fig. 1, left). The aqueous humor, produced by nonpigmented ciliary epithelium in the posterior chamber, passes through the pupillary aperture into the anterior chamber, where it exits. The cornea is avascular, and its stroma is composed of highly organized collagen fibrils. A tear film comprised of three layers covers the anterior surface of the cornea.

The iris is the anterior extension of the ciliary body that forms a contractile diaphragm in front of the anterior surface of the lens. It separates the anterior and posterior chambers. The central aperture in the iris is the pupil, which constantly changes size in response to light intensity.

The posterior chamber is bordered anteriorly by the iris diaphragm and pupil and posteriorly by the lens and zonules (Fig. 1, left). The lens is an avascular biconcave crystalline structure centrally located in the posterior chamber. It continues to grow throughout life, receiving nutrition from the aqueous and vitreous humors.

The vitreous is a gel-like substance occupying the posterior segment of the eye. It consists of a collagen framework interspersed with hyaluronic acid. In its normal state, it is optically clear, whereas during intraocular inflammation it may become hazy.

The inner cell layer axons in the retina exit the globe to make up the optic nerve (Fig. 1, left). This nerve is surrounded by pia mater, arachnoid, and dura mater meningeal coverings, which are direct extensions from the cranial vault. The optic nerves are vulnerable to infectious processes originating both within the cranial vault and within the orbits.

OCULAR DEFENSE MECHANISMS

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Anatomic Defenses

The surface of the eye is armed with mechanical and immunologic functions to defend itself against a hostile environment. The defense mechanisms are native and acquired, both generalized and specific (8). It is manifestly obvious that exposed portions of the eye possess a remarkable defense against microorganisms. To breach this defense, trauma in some form is usually required.

The eyelids provide mechanical protection of the ocular surface. The lashes initiate the blink reflex to protect against airborne particles or trauma. The cornea is exquisitely sensitive, and tactile stimulation of its surface will also initiate the blink reflex. The lids sweep over the anterior surface of the globe directing tears, debris, microbes, and allergens to the lacrimal excretory system. Lipids secreted by the meibomian glands maintain the stability of the tear film.

The nonkeratinized squamous epithelium of the conjunctiva and cornea serves as a protective anatomic barrier against pathogens. The basement membrane and cellular junctional complexes of the cornea contribute to its impermeability (184). Indigenous ocular flora of the lids and mucosal ocular surface serve a protective function by limiting the opportunity for pathogenic organisms to colonize the surface (89).

The vascular supply to the surface of the eye is a major conduit of the immune defenses. The ocular inflammatory response involves vascular dilation and exudation of immunologically active substances and cells, including macrophages, polymorphonuclear leukocytes, and lymphocytes (167).

The tear film is comprised of three layers: oil, aqueous, and mucous. These layers are produced by the meibomian glands, the lacrimal glands, and the goblet cells of the conjunctiva, respectively. The aqueous layer comprises the majority of the 7-µm-thick tear film. It is produced at a rate of ~1 µl per min. The tear pH, ~7.14 to ~7.82, likely contributes to the neutralization of toxic substances (167). Tear flow mechanically bathes the anterior surface of the eye, preventing the adherence of microorganisms, and flushes allergens and foreign particles into the lacrimal excretory system. The mucous layer of the tear film entraps foreign material, which facilitates its removal (1). For example, the mucin contained in tears prevents Candida spp. from adhering to contact lenses, likely by entrapping the microorganisms (34). The tear film contains several immunologically active substances that participate in both general and specific ocular defense (Table 1).

Beneath the protective epithelium of the conjunctiva lie a vascular network and lymphoid structures. The conjunctiva-associated lymphoid tissue is subepithelial tissue packed with B and T lymphocytes. B-cell precursors mature when exposed to local antigen, proceed to regional lymph nodes where they transform into plasma cells, and then return via the bloodstream to the conjunctiva, where they produce their specific immunoglobulin A (IgA). Similarly, T-cell precursors are locally sensitized, travel to regional nodes, and then hematogenously return to the conjunctiva to provide cellular defense (46).

The cornea is avascular and possesses limited immune defenses. The two main components are the Langerhans cells (dendritic cells), which modulate B and T lymphocyte activity in the cornea, and immunoglobulins, which are concentrated in the corneal stroma (167). The corneal surface is covered by a glycocalyx associated with a layer of mucous glycoprotein. A subtype of the IgA cross-links with the mucous glycoprotein to cover and protect the anterior surface of the cornea (184). Upon injury, the corneal epithelium may release a thymocyte-activating factor that incites a local immune response to include polymorphonuclear cells, lymphocytes, and fibroblasts (184).

Langerhans cells are concentrated in the epithelium of the peripheral cornea and conjunctiva but sparse in the central cornea (184). Like macrophages, they possess receptors for immunoglobulins, complement, and antigen. The Langerhans cell recognizes, phagocytizes, and processes certain antigens for presentation via the epithelial surface and stroma (167). Langerhans cells stimulate helper T and B cells that collaborate with other lymphocytes (killer, suppressor T cells) to enlist a strong cellular immune response. During inflammation Langerhans cells migrate toward the center of the cornea and may participate in the secretion or release of inflammatory mediator substances (105). T cells are mainly present in the conjunctival substantia propria, whereas B cells are more concentrated in the lacrimal gland (167).

Polymorphonuclear leukocytes possess the ability to ingest and kill microorganisms by two main pathways. The absence of polymorphonuclear leukocytes is associated with fungemia with Candida, Aspergillus, and Fusarium spp. The oxygen-dependent pathway is based on postphagocytic intracellular production of oxygen radicals (oxidants). The oxygen-independent pathway is based mainly on the function of antimicrobial proteins called defensins. Defensins are peptides that possess broad-spectrum antimicrobial activity in vitro, killing a variety of gram-positive and gram-negative bacteria and some fungi (167), including a wide range of ocular pathogens (60).

FUNGAL INFECTIONS OF THE EYE

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Epidemiology of Fungal Eye Infections

Ophthalmologists and optometrists, in particular, and clinicians, in general, must be knowledgeable of the pathogenesis of fungal eye infections. Mycotic eye infections are commonplace. For example, the yeast Candida albicans is the most common cause of endogenous endophthalmitis. Filamentous fungi, such as Fusarium solani and Aspergillus flavus, may constitute up to one-third of all cases of traumatic infectious keratitis (157). Furthermore, patients with AIDS may contract many different fungal infections of the eye and adjacent structures (Table 2).

In fungal eye disease, the pathogenesis of the infections is inextricably linked to the epidemiology. Therefore, in discussing the epidemiology of fungal eye infections, it is worthwhile at the outset to state several proposed pathogenetic principles of fungal eye disease. (i) It is likely that sustained fungemia with even saprophytic fungi will lead to endophthalmitis. (ii) At the time of initial infection with some of the dimorphic, pathogenic fungi, such as Histoplasma capsulatum and Coccidioides immitis, an unrecognized fungemia occurs and often leads to endophthalmitis. (iii) The paranasal sinuses, because of their direct communication with the ambient air, harbor saprophytic fungi, which may erode the bony walls of the sinus and invade the eye in certain circumstances, e.g., in a patient with neutropenia. (iv) Trauma, either from vegetable matter or surgery, may introduce saprophytic fungi into the cornea and/or adjacent tissue, giving rise to invasive disease.

The epidemiology of endogenous endophthalmitis reflects both the natural habitats of the involved fungi and the habits and health status of the patients (Table 3). Candida endogenous endophthalmitis occurs as a direct result of the success of modern medical practice that sustains patients' lives with broad-spectrum antibiotics, indwelling central venous lines, parenteral nutrition, abdominal surgery, and cytotoxic chemotherapy. The recent origin of this disease is established by the fact that Candida endophthalmitis was first recognized clinically in 1958 (275). Candida and Aspergillus spp. also cause endophthalmitis in intravenous drug users. Virtually any intravascular prosthesis or device may become contaminated by bloodborne opportunistic fungi, and fungemia arising from such infection may lead to endogenous endophthalmitis.

Endogenous endophthalmitis occurring as part of disseminated disease with the dimorphic fungi H. capsulatum, Blastomyces dermatitidis, and C. immitis is uncommon. Patients with disease from these fungi have resided in or traveled through the respective areas of endemicity. These are the Ohio and Mississippi river valleys for H. capsulatum; the Lower Sonoran Life Zone for C. immitis, including southern parts of California, Arizona, New Mexico, West Texas, and parts of Mexico and Argentina; and the Southeast and Midwest of the United States for B. dermatitidis. Residence along a waterway may be another important association for exposure to B. dermatitidis (67). H. capsulatum may flourish in bird and bat droppings; therefore, exposure to the fungus may occur through one's occupation, for example, demolition of old bird-infested buildings, or one's hobby, such as camping or spelunking.

Exogenous endophthalmitis, on the other hand, results from trauma to the globe or preceding keratitis. It may also occur as a postoperative complication of lens removal, prosthetic lens implantation, or corneal transplantation. The vast majority of postoperative eye infections are due to coagulase-negative Staphylococcus; however, outbreaks of fungal exogenous endophthalmitis continue to occur episodically. These have been due to perioperative contamination of lens prostheses (204) or contamination of fluids used for irrigation (260) of the perioperative and postoperative eye. Candida species are particularly likely to occur in this setting, and infection may be enhanced by the pre- and postoperative use of topical corticosteroids and antibacterial agents.

Mycotic keratitis is usually caused by filamentous fungi and occurs in conjunction with trauma to the cornea with vegetable matter. In the tropics it is common in male agricultural workers. The fungal genera causing keratitis in the tropics are more diverse and include some, such as Lasiodiplodia theobromae, that do not grow in temperate regions. Eye trauma is the cause of fungal keratitis in temperate areas as well, but the common fungal genera involved are Fusarium, Alternaria, and Aspergillus (71, 293). Keratitis caused by yeasts such as the Candida spp. almost always occur in previously abnormal eyes, e.g., in patients with dry eye, chronic corneal ulceration, or corneal scarring.

Endogenous endophthalmitis is uncommon; however, fungi cause this disease more often than gram-positive or gram-negative bacteria. The term endogenous endophthalmitis implies that bloodborne spread of microorganisms to the eye has occurred. Therefore, infection in the eye is the result of metastatic spread of infection from a distant site, for example, infected heart valves or the urinary tract. In this manner the eye becomes the site of numerous microabscesses. This mechanism of infection is to be contrasted to exogenous endophthalmitis (see below), which arises from the direct introduction of a microorganism(s) into the eye during trauma or surgery. Endogenous endophthalmitis is further distinguished from exogenous endophthalmitis by occurring in a greater number of immunocompromised patients, e.g., patients receiving chemotherapy or total parenteral nutrition, or intravenous drug abusers (Table 4).

Endophthalmitis is recognized clinically by the presence of one or more creamy-white, well-circumscribed lesions of the choroid and retina, often accompanied by inflammatory infiltrates in the vitreous. These lesions can be detected using an ophthalmoscope after dilating the pupils. Often, there is inflammation in the anterior chamber manifested by the presence of a hypopyon. Typical lesions of chorioretinitis are shown in Fig. 2, left. Patients complain of eye pain and may have blurred vision or spots in their visual fields. Patients with endogenous endophthalmitis may have positive blood cultures antedating eye symptoms or signs. In the absence of a positive blood culture or characteristic clinical syndrome, aspiration of the vitreous (or biopsy) may be necessary to establish the causative microorganism.

View larger version (32K): [in this window] [in a new window]   FIG. 2.   (Left) View of the fundus of a patient with C. parapsilosis fungemia complicating total parenteral nutrition for esophageal cancer. A chorioretinal lesion is shown (arrow), and there is accompanying vitreous haze. (Middle left) C. albicans in retinal tissue with both blastoconidia and pseudohyphae present. (Photo courtesy of F. G. LaPiana.) (Middle right) Fundoscopic montage of the eye of a patient with P. carinii. There are edema of the optic nerve head (the circular whitish area in the center from which the blood vessels originate) and scattered multifocal choroidal mass lesions (whitish to yellowish circular lesions). (Reprinted from reference 138 with permission from the publisher.) (Right) C. albicans keratitis in an immunocompromised patient. The dense yellow-white stromal infiltrate resembles bacterial keratitis. It partially covers the pupil. There is a small hypopyon present. (Reprinted from reference 137a with permission from the publisher.)

Why the eye is a common end organ target of fungemia is unknown. However, in a rabbit model of C. albicans endophthalmitis, more fungal elements are found in the eye per gram of tissue than are found in the kidneys of the same animals. Since C. albicans is believed to have a marked tropism for the kidneys and endothelium, the great number of organisms in the eye bespeak a tropism for the eye as well (142, 143). The candidal lesions in the rabbit are identical to those found in humans demonstrating a focal chorioretinitis (Fig. 2, middle left), with a mixture of granulomatous and suppurative host reactions (76). The infection likely begins in the choroid and progresses anteriorly to the retinal layers (226). This may be related mechanistically to the fact that the outer retinal layers, i.e., those considered to be infected first, receive blood from a high-flow system (150 mm/s), whereas the inner layers receive blood from a low-flow system (25 mm/s). It should be noted that drainage from the retinal layers is entirely through the venous system as there is no lymphatic system serving the inside of the globe.

The most common cause of endogenous fungal endophthalmitis is C. albicans (287). Endogenous fungal endophthalmitis by definition follows fungemia; therefore, it is important to note that Candida species are the fourth most common cause of positive nosocomial blood cultures in the United States, exceeding the number of positive cultures of any single gram-negative bacterial genus (21). It is estimated that some 120,000 patients contract disseminated candidiasis (i.e., candidemia) per year in North America (58), and the usual estimates of the incidence of candidal endophthalmitis in patients with candidemia are around 30% (32, 196; J. R. Griffin, R. Y. Foos, and T. H. Pettit, presented at the 22nd Concilium Ophthalmologicum, 1974); thus, the disease is fairly common. If the definition of chorioretinitis is more stringent, i.e., if nonspecific lesions such as cotton wool spots and retinal hemorrhages are eliminated, the incidence is much less, on the order of 9.3% (70, 226).

The pathogenesis of candidemia remains unknown but is likely multifactorial. There are characteristic clinical features of patients with candidemia, with one or another feature being found in each patient. These include the use of broad-spectrum antibiotics that eliminate competing normal microbiota of the host, the presence of central venous catheters, the administration of total parenteral nutrition, prior abdominal surgery, and/or neutropenia (164). One or all of these factors are sufficient to place a patient at risk for candidemia and, hence, for endophthalmitis. Neutropenia, although a risk factor for candidemia, reduces the incidence of candidal endophthalmitis in the rabbit model (122) and perhaps in patients as well (78). This suggests that the chorioretinal lesions are probably a reflection of a vigorous host response rather than just the sheer number of infecting microorganisms.

During the introduction of total parenteral nutrition in the 1970s there was a marked increase in the number of patients with Candida endophthalmitis (77), which is likely related to the prolonged use of central venous catheters. Candida endophthalmitis has also been reported to occur after induced abortion (49), in the postpartum state (43), following treatment of toxic megacolon (123), and as a consequence of intravenous drug abuse. An addict's use of intravenous brown heroin often leads to a characteristic syndrome, at one time common in Europe, that includes pustular cutaneous lesions, endophthalmitis, and osteomyelitis. C. albicans can be isolated from all of these lesions (74). The microorganisms in this syndrome may be acquired from the drug abuser's own skin surface (79). Candida endophthalmitis may also occur after intravenous placement of a foreign device, such as a pacemaker (243), and following repeated intramuscular injections of medications, such as anabolic steroids (285). Species of Candida other than C. albicans are capable of causing endogenous endophthalmitis and may do so in proportion to their ability to cause candidemia (20, 53, 133, 243).

Although Candida species are clearly the most-common causes of endogenous endophthalmitis, other fungi are occasionally encountered. Aspergillus species are the second most-common cause of fungal endophthalmitis (291). Aspergillus spp. may be less capable of causing endophthalmitis than Candida spp.; an example of this is the rabbit endogenous endophthalmitis model, in which larger inocula of Aspergillus spp. are required to cause the disease than with C. albicans (93). Many species of Aspergillus have been reported to cause endophthalmitis, but Aspergillus flavus is probably the most common (219), followed by Aspergillus fumigatus, Aspergillus niger, Aspergillus terreus, Aspergillus glaucus (281), and Aspergillus nidulans (271). Endogenous Aspergillus endophthalmitis may be encountered in neutropenic patients or in patients taking pharmacologic doses of corticosteroids, often for chronic lung disease. Aspergillus endophthalmitis has even been reported to occur following severe periodontitis, although entry of Aspergillus spp. into the bloodstream through the mouth certainly is not common (172). Intravenous drug addicts are at particular risk for disseminated aspergillosis (69). Aspergillus endophthalmitis has been reported in addicts abusing a mixture of intravenous cocaine, pentazocine, and tripelennamine. Three such individuals from Louisville, Ky., were infected with A. flavus in this manner (23). Patients receiving large doses of corticosteroids for lung disease may have negative blood cultures but evidence of severe Aspergillus endogenous endophthalmitis. Endophthalmitis, therefore, is the sole manifestation of disseminated disease and must be established by aspiration of the vitreous (281). Aspergillus endophthalmitis has also arisen in recipients of solid-organ transplants, in which the donated organ was the likely source of the fungus (16, 139). Pathologic specimens of invasive aspergillosis usually demonstrate angioinvasion by the hyphae, and thus Aspergillus species may possess a tropism for vascular tissue (279).

The emerging pathogens of the genus Fusarium have been reported to cause endophthalmitis in neutropenic hosts (160), in an intravenous drug abuser (94), and in a patient with AIDS (106). Penicillium spp. also have caused endogenous endophthalmitis in an intravenous drug abuser (265). As mentioned in connection with C. albicans, endogenous endophthalmitis may occur from fungi seeding the bloodstream from a catheter or endocarditis. Pseudallescheria boydii has caused endophthalmitis from an infected porcine allograft of the aortic valve (259) and even in a patient without risk factors for the disease (193).

The four dimorphic fungi H. capsulatum (165), B. dermatitidis (158), Sporothrix schenckii (2), and C. immitis (96) as well as Cryptococcus neoformans (59) may cause endogenous endophthalmitis as part of disseminated disease. Within the region of H. capsulatum endemicity in North America, roughly the Ohio and Mississippi river valleys, there is a well-described syndrome attributed to infection with H. capsulatum. This entity is known as presumed ocular histoplasmosis (POH), which occurs in immunocompetent individuals and is recognized by the presence of multiple diskiform atrophic chorioretinal scars without vitreous or aqueous humor inflammation. POH is said to affect 2,000 new individuals a year in areas of endemicity and in some cases may lead to visual loss and blindness (165). The lesions are usually burned out, but not all of them are static and some may reactivate (41). The lesions are thought to arise from the hematogenous spread of the fungus following initial infection. The initial infection, acquired by inhalation of microconidia into the lung, spreads throughout the body, including the eye, and is soon controlled by a competent host immune response (175, 249). H. capsulatum is not detectable in the scars of POH. However, there is strong epidemiological evidence, principally deriving from skin test surveys, linking the scars to histoplasmosis (95, 252). A primate model demonstrates pathology identical to that found in humans (250, 251). Similar lesions to those of POH are, however, observed in Europe, where histoplasmosis is rare (264), and therefore, it is likely that similar chorioretinal lesions are the end result of several different infectious agents. Active endophthalmitis in patients with disseminated histoplasmosis secondary to AIDS or immunosuppression occurs and is associated with numerous budding yeast cells in the choroidal tissue and endothelium (41, 88, 231). In some cases the endophthalmitis is accompanied by yeast cells in the anterior chamber angle structures such as the iris, ciliary muscle and canal of Schlemm (41, 88). Two cases of disseminated histoplasmosis, established by elevated H. capsulatum antigen in blood and urine and high complement fixing antibodies, occurred in immunocompetent brothers. Their disease was associated with choroiditis, which appears to progress to typical POH lesions (136). Thus, the link between active histoplasmosis and POH may be made by these and similar cases.

Disseminated blastomycosis is common in dogs and is often accompanied by endophthalmitis (28); for example, 78 eyes in 74 dogs with disseminated disease had endophthalmitis. Canine blastomycosis of the eye always involves the choriocapillaries, and organisms are abundant in the choroid. The disease often progresses to panophthalmitis (38, 39, 246). Endophthalmitis is also seen in humans with disseminated blastomycosis (223), as evidenced by the presence of chorioretinal lesions (108, 223).

Coccidioidomycosis is associated with lesions throughout the eye, including endogenous endophthalmitis (96). Chorioretinal scarring is common in individuals within the region of endemicity with positive skin tests to coccidioidin, a situation reminiscent of histoplasmosis. The chorioretinal lesions presumably occur at the time of initial infection and are usually clinically quiescent and asymptomatic. On the other hand, active chorioretinitis has been described in patients with disseminated disease (96). Anterior chamber disease has been documented in patients with disseminated disease, including iritis and large inflammatory masses in the anterior chamber (61, 96, 180, 298). It is interesting that disseminated coccidioidomycosis in dogs often starts in the posterior chamber and spreads to involve the anterior chamber (15). As previously mentioned, this is believed to be the same route of extension of disease with Candida and B. dermatitidis endophthalmitis.

C. neoformans frequently causes visual symptoms when associated with meningitis. These symptoms are usually due to the swollen brain compressing the optic nerve or edema of the optic nerve itself. However, cryptococcosis may be associated with endophthalmitis manifesting as chorioretinitis, retinal tears, and overlying vitritis (59, 62, 108, 242). Pneumocystis carinii is also an infrequent cause of chorioretinitis in patients with AIDS (Fig. 2, middle right).

As the name implies, exogenous endophthalmitis occurs by introduction of microorganisms into the eye from trauma or surgery. It can also be the end result of preexisting scleritis or keratitis (29). Zygomycosis in the surrounding soft tissue and cryptococcal neuroretinitis may also lead to exogenous endophthalmitis. Patients with exogenous endophthalmitis are rarely immunocompromised. Cataract removal followed by placement of a prosthetic lens and corneal transplantation are the surgical procedures most often associated with postoperative fungal exogenous endophthalmitis.

One report describes 19 patients from one hospital with exogenous endophthalmitis, and there was an approximately equal distribution of patients between the categories of postsurgical endophthalmitis, posttrauma endophthalmitis, and endophthalmitis following keratitis (205). Exogenous endophthalmitis may have a period of latency of weeks to months before clinically detectable disease occurs. Even then the infection is often confined to the anterior chamber, pupillary space, or anterior vitreous. Eighty-four percent of patients in one series received topical corticosteroids before diagnosis, and this may have potentiated the disease by reducing local host immunity (205). The most-common causes of postsurgical exogenous endophthalmitis are gram-positive bacteria, including coagulase-negative Staphylococcus, diphtheroids, and Propionibacterium acnes (287). The mycotic causes of exogenous endophthalmitis, such as yeasts (principally Candida species, including Candida glabrata [42] and Candida famata [211]), were found only in the postsurgical group, whereas Fusarium species were found only in the posttraumatic and postkeratitis groups (205). Other Candida spp. have caused exogenous endophthalmitis after lens surgery (211, 294). An epidemic of postsurgical endophthalmitis with Candida parapsilosis has been reported following the placement of anterior and posterior chamber lenses (260). Fifteen patients had ocular surgery over a 3-month period of time. At the time of surgery all eyes were irrigated with a solution from the same lot that was contaminated with C. parapsilosis.

Paecilomyces lilacinus is a ubiquitous soil saprophyte implicated in cases of keratitis and endophthalmitis after trauma (191, 283). However, a large outbreak of P. lilacinus exogenous endophthalmitis followed intraocular lens implantation; the lenses had been contaminated by a bicarbonate solution used to neutralize the sodium hydroxide sterilant added to the lenses. P. lilacinus was cultured from the bicarbonate solution (204). Such fungi as Aspergillus species (29, 64, 194) and Acremonium kiliense (92) have caused infections following lens surgery. These infections, like postoperative P. lilacinus infections, may arise because of fungal contamination of operative and postoperative irrigating solutions (174, 190, 260).

Fungal pathogens in posttraumatic endophthalmitis are legion and similar to those causing fungal keratitis. Recent reports include Fusarium moniliforme (257), Exophiala jeanselmei (114), P. boydii (44), A. niger (129), Scytalidium dimidiatum (9), Helminthosporium spp. (65), S. schenckii (292), Penicillium chrysogenum (82), and L. theobromae (29).

Fungal infections of the cornea (fungal keratitis or keratomycosis) may constitute 6 to 53% of all cases of ulcerative keratitis, depending upon the country of origin of the study (269). The majority of fungal keratitis occurs after trauma to the cornea in agricultural workers, usually, but not always, with fungus-contaminated plant material (leaves, grain, branches, or wood). The disease may also occur in gardeners and following corneal trauma from indoor plants as well. Occasionally the object striking the cornea is metal. The trauma to the cornea may be so slight as to be forgotten by the patient. Fungal keratitis also occurs with contact lens wear, and this will be discussed later.

Trauma to the cornea with vegetable matter either introduces the fungus directly into a corneal epithelial defect or, alternatively, the defect may become infected following the trauma. The vast majority of cases of fungal keratitis are due to septate, filamentous, saprophytic fungi. Occasionally zygomycetes such as Absidia (168) or Rhizopus (233) spp. may be implicated in keratitis. On the other hand, the abnormal or compromised cornea, e.g., chronic dry eye, is subject to infection with yeasts, usually Candida species. Such uncommon Candida species as Candida lipolytica and Candida humicola have, however, been reported to cause posttraumatic keratitis (187, 188) and Candida guilliermondii after corneal transplant (3). More than 70 species representing 40 genera of fungi have been reported to cause fungal keratitis (269). The most common cause of fungal keratitis is F. solani and other Fusarium species, Aspergillus species, and Curvularia species (269). There may be a hierarchy of fungi capable of producing keratitis, e.g., from most to least capable, Fusarium, Acremonium, and Phialophora spp. This hierarchy is predicated upon their individual ability to invade and destroy the cornea (156).

Fungal keratitis is recognizable by the presence of a coarse granular infiltration of the corneal epithelium and the anterior stroma (Fig. 2, right). The corneal defect usually becomes apparent within 24 to 36 h after the trauma. There is minimal to absent host cellular infiltration. The absence of inflammatory cells is likely a good prognostic finding, since products of polymorphonuclear leukocytes contribute to the destruction of the cornea. The infiltrate is often surrounded by a ring, which may represent the junction of fungal hyphae and host antibodies (156). Descemet's membrane, an interior basement membrane near the aqueous humor, is impermeable to bacteria but can be breached by fungal hyphae, leading to endophthalmitis (212). Even so, endophthalmitis is a rare consequence of fungal keratitis (29). Pathologic specimens of filamentous fungal keratitis demonstrate hyphae following the tissue planes of the cornea, i.e., laying parallel to the corneal collagen lamellae. Examination of multiple scrapings of the cornea establish the agent of fungal keratitis. In some cases a biopsy may need to be performed. Since many of the filamentous fungi grow slowly, the disease often remains unrecognized and untreated for days or weeks until growth is visually detected, and this delay may contribute to a poor response to therapy.

The abnormal cornea in patients with dry eye syndrome, chronic ulceration, erythema multiforme, and perhaps human immunodeficiency virus (HIV) infection (particularly those with AIDS) is subject to fungal infection, most commonly with Candida species. Candida keratitis usually appears as a small demarcated ulcer with an underlying opacity of the cornea resembling bacterial keratitis. C. albicans was found to be the most common cause of microbial keratitis in a series of 13 AIDS patients (121). Candida keratitis has occurred as well in patients who chronically abused corneal anesthetics (49).

The wearing of hard and soft extended-wear contact lenses is associated with infectious keratitis usually caused by Pseudomonas aeruginosa. Both P. aeruginosa (36) and C. albicans (34) adhere to contact lenses, and the adherence of the former to lens surfaces is greatly enhanced in the presence of tear deposits (35), some of which could conceivably serve as carbohydrate receptors for the microorganisms (147). Adherent microorganisms secrete an extensive exopolymer that is virtually impenetrable to antibiotics and difficult to remove. Contact lenses coated with such biofilms likely increase the risk of infectious keratitis (80). The wearing of contact lenses leads to a relative hypoxia of the corneal epithelium that may lead to measurable changes in the cell surface glycoproteins (145). Perhaps microscopic defects are introduced by lens wear that enhance microorganism adherence to the otherwise nonadherent corneal epithelium (144). Fungal keratitis in association with contact lens wear is almost always due to Candida spp., although Cryptococcus laurentii (217) has been reported. Filamentous fungal keratitis occurs less often with lens wear (200, 261, 296), but the filamentous fungi can actually penetrate the lens matrix (141, 200, 245, 261, 289, 296). Fungi and the bacteria adherent to contact lenses arise from patient handling, including the cleaning and storage of the lenses. These adherent microorganisms also derive from the normal flora of the conjunctiva (181).

Infections of the eyelids, conjunctiva, and lacrimal system. The eyelids may be the site of inoculation of S. schenckii, resulting in a chronic suppurating ulcer (2). It has been contended that eyelid lesions are common in patients with disseminated blastomycosis; however, in a recent survey of 79 patients, only one had an eyelid lesion (24). Blastomycosis, however, may present solely as a conjunctival lesion apart from any external eyelid involvement (248). Paracoccidioides brasiliensis often causes disease of the eyelids and conjunctiva resulting in disfiguring lesions. This systemic mycosis, acquired by inhalation of conidia into the lungs, is endemic to Mexico and Central and South America and has a predilection for mucocutaneous surfaces, particularly the mouth and nares (215). Occasionally the cornea may become infected and lead to blindness (244).

Infections arising from the paranasal sinuses and other sites within or near the orbit. Invasive Aspergillus and zygomycete infections have a marked predilection for the orbit and surrounding tissues, including the paranasal sinuses. Many different presentations of eye disease by Aspergillus occur even in the healthy host. However, patients who are immunocompromised by the use of chemotherapy, corticosteroids, and principally, neutropenia are at particular risk for invasive disease arising in or near the orbit. The conidia of Aspergillus species are common airborne particles that are often found in the paranasal sinuses of healthy hosts that may on occasion be associated with sinusitis or a paranasal sinus fungus ball. These infections are not invasive, and drainage or excision may lead to clinical resolution. Invasive disease in the compromised host may begin as dacryocystitis, masquerade as an optic nerve tumor, or present as an entirely retrobulbar process (155). Orbital disease with Aspergillus in the immunocompromised host may also begin as sphenoid and/or ethmoid sinusitis with erosion of the bony orbit, leading to invasion of the orbital space and proptosis. Proptosis may be the initial sign of fungal sinusitis even in immunocompetent individuals. For example, four otherwise healthy hosts were described with proptosis and sinusitis with Drechslera, Aspergillus, and Curvularia (120) species; the proptosis was present for >5 months in three of the patients.

Infections of the empty eye socket. Removal of the globe leads to colonization of the exposed tissue by microorganisms. Although conjunctivae of the anophthalmic socket may support more bacteria than the normal eye, there is no difference in the kinds of bacteria that occur (66, 276). Apparently, patients who manipulate their prosthetic eyes frequently have a significantly greater percentage of gram-negative bacteria (276). Fungi do not appear to pose a problem in patients with anophthalmus.

There is no pathognomonic lesion of mycotic infection of the eye; therefore, the clinician must also consider viral, bacterial, and parasitic causes. The diagnosis of fungal infections requires the clinician to (i) establish the presence of ophthalmic pathology (which may require special instruments, such as a scanning slit confocal microscope [87]); (ii) obtain tissue in which the fungus is visualized; and (iii) isolate the responsible fungus. Fungal isolation by culture is particularly important since tissue strains frequently do not allow one to determine the identity of filamentous fungi or yeasts with any degree of certainty. Isolation allows one to perform both authoritative identification and antifungal testing when necessary.

Exceptions to the rule requiring isolation of the fungus from eye tissue would include such entities as endogenous endophthalmitis in which fungi known to cause this disease have been isolated from blood culture and the clinical presentation is compatible with vascular dissemination of the microorganism. Similarly, histoplasmosis and coccidioidomycosis are commonly associated with characteristic chorioretinal lesions, and isolation of the fungus from another anatomical site or measurement of antibody to the fungus is sufficient to establish one of these microorganisms as the cause of the eye disease. Lastly, C. neoformans is capable of causing a number of different ophthalmic presentations, usually in conjunction with meningoencephalitis, and its isolation from blood and/or cerebrospinal fluid is usually sufficient explanation for the associated eye findings. In most other circumstances the clinician will be obligated to establish the diagnosis by isolating the causative microorganism directly from the eye or adnexal tissue.

Cilia and eyelid. Cilia can be removed with forceps and observed directly under the microscope as well as placed on suitable culture media. When entertaining the possibility of fungal infection of the cilia, lids, and conjunctiva, the use of an olive oil overlay to solid medium should be considered in order to isolate M. furfur, which has been invoked as a cause of blepharitis (263, 272). Tissue should be obtained whenever possible, since convincing evidence that an isolate obtained from a swab is a pathogen may be difficult to collect. The presence of a chronic ulcer on or near the eyelid should suggest sporotrichosis or perhaps blastomycosis, and culture of biopsied tissue in the former case will establish the disease, whereas in the latter case, the fungus is usually readily visible in scrapings from the lesion.

Conjunctiva and lacrimal duct and gland. Aspergillus, Fusarium spp. (14, 235), and occasionally C. albicans (232) are cultured from the conjunctiva of healthy and diseased eyes; therefore, it is difficult to establish saprophytic fungal isolates as pathogens of the conjunctiva unless a biopsy is performed, and this is rarely necessary. P. carinii may cause conjunctivitis, but this organism cannot be cultured (220). Material may be expressed from an infected lacrimal duct, or if required, an incision can be made and tissue can be obtained for culture and appropriate stains.

Cornea. The use of an exceedingly thin, round-ended platinum spatula or, alternatively, a scalpel blade or small needle allows for scrapings to be obtained from the corneal surface for stains and cultures (288). Ample tissue is needed, so multiple corneal scrapings are usually performed. Biopsy of the cornea or keratoplasty may be required to provide sufficient diagnostic material. Saprophytic filamentous fungi more often than not cause posttraumatic keratomycosis. Rarely are yeasts involved in posttrauma keratitis (269). The detection of fungal elements in tissue or smears may be enhanced and thus detected with significantly greater sensitivity using acridine orange (135), Calcofluor white (45), or lactophenol cotton blue (40, 270) stains. The first two stains have the added advantage of demonstrating other pathogens, such as bacteria, amoebic exocysts, and microsporidial spores. This may be important, because traumatic injuries to the cornea may involve more than one pathogen. Similarly, the use of a battery of fluorescein-conjugated lectins has been shown to be useful in detection of ocular mycoses (218). The use of such tests as a chitin assay (151) or PCR (192) may prove useful, but these assays currently suffer from a cumbersome technique in the former and lack of detection across fungal genera in the latter.

Remainder of the globe. Establishing the identity of the fungus in some cases of endogenous and exogenous endophthalmitis, scleritis, and panophthalmitis may require biopsy of tissue (sclera) or aspiration of vitreous fluid. Aspiration of aqueous fluid is rarely done to establish the presence of infection. The yield from vitreous fluid is greater than aqueous fluid in cases of endophthalmitis (25). In a recent study of 420 patients with endophthalmitis, it was concluded that the performance of vitrectomy did not enhance the yield of pathogens over aspiration alone. Thus, the authors specifically advise against the use of vitrectomy for diagnostic reasons (25). The surgical implantation of intraocular lenses may lead to pseudophakic endophthalmitis, and the removal of the lens may be required. This material should be sent to the laboratory and divided among appropriate bacterial and fungal stains and growth media.

Contact lenses, prostheses, and ophthalmic drugs and paraphernalia. Contact lens wear is often complicated by bacterial keratitis and occasionally fungal keratitis. The inner surface of the involved lens should be swabbed, and the lens should be sectioned to obtain appropriate stains and cultures (288). Corneal transplants may be a source of infection, and thus, it is recommended that prior to transplantation a small piece of tissue be removed from the corneal rim along with an aliquot of the storage medium, and both should be submitted for culture (288). However, the storage media for corneal tissue do not serve as growth media in and of themselves (224). Ophthalmic drops and contact lens solutions may be the source of infection of the conjunctiva and cornea and of exogenous endophthalmitis. Samples of suspected contaminated solutions can be inoculated directly into liquid media.

Culture media. For almost all specimens, the use of blood agar and Sabouraud dextrose agar containing gentamicin is sufficient for isolation of fungi. Agars containing cycloheximide should be avoided since some saprophytic fungi and C. neoformans are inhibited by this additive. The use of brain heart infusion broth for material from swabs may be helpful in isolation (288).

The presence of endogenous endophthalmitis without a positive blood culture yielding the causative microorganism requires aspiration of the vitreous to establish the cause. Removal of a nidus of fungemia, if such existsfor example, an infected catheter, heart valve, or suppurative thrombophlebitisis usually necessary for cure. Candida endogenous endophthalmitis can be treated with intravenous amphotericin B alone (26). The concomitant use of oral 5-flucytosine has been tried with success. Intravitreal injections of 5 to 10 µg of amphotericin B may be used adjunctively, but the intravenous administration of amphotericin B or an oral azole is required, as the endophthalmitis is just one of the many manifestations of disseminated candidiasis. Oral fluconazole, 100 to 200 mg/day for several months, has successfully treated endophthalmitis as well as disseminated disease (5, 163), although in the rabbit endophthalmitis model intravenous amphotericin B was superior to oral fluconazole (86). In one series of endogenous endophthalmitis with Candida species, 17 eyes were treated with a combination of vitrectomy, intravitreal amphotericin B, and systemic therapy for those patients with marked vitreous infiltrates. All demonstrated a satisfactory visual outcome (83). A combination of vitrectomy and oral fluconazole for 3 weeks was effective in six patients (50). Current regimens with this azole for disseminated candidiasis use 400 to 800 mg/day. These same regimens would be suitable for the treatment of Candida spp. and other yeasts causing exogenous endophthalmitis as well. In one study involving 15 patients with postoperative exogenous endophthalmitis due to C. parapsilosis, the patients were treated with success with a combination of intravenous and intravitreal amphotericin B without removing the lens (260). Success without removing the lens prostheses has been reported in another series of cases of postoperative C. parapsilosis endophthalmitis (137). The efficacy of lipid-associated forms of amphotericin B in Candida endophthalmitis is yet to be determined (186).

Filamentous fungi involved in endogenous and exogenous endophthalmitis may require repeated vitrectomy and injection of amphotericin B (282) or miconazole. Aspergillus spp. and many other filamentous fungi can be treated with amphotericin B, although cure is not predictable. Itraconazole has good activity against Aspergillus spp. and may be more suitable than amphotericin B for dematiaecious fungi, many of which were formerly treated with oral ketoconazole (132). Itraconazole may be the most useful agent for the treatment of Paecilomyces (221) and orbital infections with Aspergillus (171).

Keratitis is usually treated with a topical antifungal, sometimes in conjunction with subconjunctival injections of the same drug and/or oral antifungals. Natamycin applied on an hourly basis is the preferred polyene for topical administration as the deoxycholate salt in amphotericin B is toxic to the cornea. However, lipid-associated amphotericin B may offer an effective but safer alternative and should be further studied (206). Collagen shields impregnated with antimicrobials appear to be a promising approach, and such shields soaked in amphotericin B and replaced daily have been used with success with Aspergillus keratitis (176). The topical use of the antiseptic agent chlorhexidine gluconate at a 0.2% concentration showed efficacy in vitro (169) and in patients with fungal keratitis (209).

Failure to respond to initial therapy may require subconjunctival miconazole and or oral fluconazole or itraconazole. Both azoles have been used to treat Candida keratitis as well (146). Surgical intervention with biopsy, partial keratectomy or keratoplasty may be required. Frequent debridement of the affected corneal surface may be beneficial in some cases.

Treatment of eye infections associated with disseminated disease by the dimorphic fungi is generally that of treating the disseminated infection, although intravitreal and subconjunctival injections of antifungals may be helpful (96).

Toxoplasmosis. Infection by Toxoplasma gondii is thought to affect approximately one-third of the adult human population (91). It is common in warm moist climates such as the Caribbean and Central America (84). However, infection in Europe is common, with prevalence rates as high as 90% in France (173). Two forms of T. gondii are infectious: the tissue cyst which is found in raw or undercooked meat and the oocyst which is present in the feces of the domestic cat, which is considered to be the definitive host. Rarely, individuals may be exposed through the consumption of contaminated drinking water.

View larger version (33K): [in this window] [in a new window]   FIG. 3.   (Left) Recurrent toxoplasmosis around the periphery of an old scar, which is the white central disc. (photo courtesy of F. G. LaPiana.) (Middle left) Corneal scraping stained with Masson trichrome stain demonstrating a polygonal cyst of Acanthamoeba (arrow). (Middle right) Dendritiform epithelial lesions of the lower part of the cornea demonstrated by fluorescein staining in a patient with Acanthamoeba keratitis. (Right) Gram stain of a conjunctival scraping from a patient with microsporidial keratoconjunctivitis demonstrating large gram-positive ovoid microorganisms within conjunctival epithelial cells. (The last three panels reprinted from reference 137a with permission from the publisher.)

Chagas' disease. Chagas' disease, or American trypanosomiasis, results from infection by Trypanosoma cruzi. This infection is endemic in Central and South America and may be responsible for up to 10% of all deaths in some areas (98). Infection occurs when an infected reduvid bug (also called kissing bug) bites a human. At the time of the bite, the insect excretes trypomastigotes of T. cruzi. As the saliva of the insect is irritating, the human will commonly scratch or rub the bite site, thereby introducing the trypomastigotes into the lesion. Once introduced, the trypomastigotes circulate throughout the body with a preference for invading muscle cells, neural tissue, and the reticuloendothelial system. Once intracellular, the trypomastigote divides to become an amastigote which, in turn, continues to