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FUNGAL INFECTIONS OF THE EYE

Sengul Ozdek, MD, Associate Professor in Ophthalmology,
sozdek@gazi.edu.tr
FUNGAL EYE INFECTIONS
INTRODUCTION TO THE CLINICS OF FUNGAL EYE INFECTIONS:
Before starting the clinics of fungal infections, we will give an outline for the ocular anatomy (1). Eye can be divided into 3 segments for the purpose of education as:
1. Eyelids and lacrimal system,
2. Orbits and adjacent soft tissues,
3. Eyeball: anterior and posterior segments (figure 1)
Eyelids are protective barriers for the globe. They protect the globe from dangers of the outside world. There is an orbital septum in each eyelid which acts as a barrier for the prevention of spread of infections through the orbital soft tissues. Conjunctiva, the innermost lamella of the eyelid and outermost structure of the globe, is another barrier for microorganisms on the anterior surface of the globe from freely entering into globe or orbital soft tissue along its surface. Lacrimal system is composed of a secretory part; lacrimal gland, accessory lacrimal glands in conjunctiva, and an excretory part; starting from puncta, canaliculi, lacrimal sac, nasolacrimal canal ending in the inferior meatus of the nose. Tears protect the globe from infections by rinsing the surface of the eye.
Orbits are cone shaped bony cavities which involve the globes, extraocular muscles, fat and other soft tissues. They consist of 7 bones forming a safe room for the globes. The periosteum of the orbita fuses anteriorly with the orbital septum and posteriorly with the dura mater. Abscesses usually localize in the subperiosteal space. The roof, medial wall, and floor of the orbit are neighbors of paranasal sinuses, (the maxillary, frontal, ethmoid, and sphenoid sinuses). The paranasal sinuses may be the source of an orbital infection because of this close anatomical relationship. Medial orbital wall is the thinnest of the orbital walls and is the weakest point for the orbits. Infections of the ethmoid sinus in children commonly extend through the intact lamina papyracea (medial wall) causing preseptal and orbital cellulitis. The lateral wall of the sphenoid is also the medial wall of the optic canal. Therefore, infections of the sphenoid sinus may involve the optic nerve, resulting in visual loss or visual field abnormalities. Direct communication between the orbit and adjacent structures, through the apertures like the superior and inferior orbital fissures, nasolacrimal duct, and the optic canal may serve as a direct passage for an infectious process between the orbit and surrounding structures.
Eyeball is composed of 3 layers: outermost is the fibrous layer consisting of cornea and sclera, middle layer is uvea consisting of iris (anterior part), ciliary body (middle) and choroid (posterior), and the innermost layer is retina. Crystalline lens and iris divides the eyeball into chambers like anterior and posterior chambers which are full of aqueous humor secreted by nonpigmented epithelium of the ciliary body, and vitreous space which is full of gel like vitreous.
Defense mechanisms of the eye start from eyelids, eyelashes, tear film, cornea and conjunctiva with blink reflex and by providing mechanical barrier. In addition to mechanical washing of the ocular surface, tear film contains several immunologically active substances necessary for ocular defense. The mucin contained in tears prevents Candida spp. from adhering to contact lenses, likely by entrapping the microorganisms (2). Defense mechanisms of the cornea and other parts will be discussed in the related sections.
Fungal infections of the eye will be discussed according to the anatomical part of the eye involved in the disease.
EPIDEMIOLOGY:
The incidence of ocular fungal infections has increased substantially over the past decades because of the increased number of patients with acquired immunosuppression secondary to extended use of immunosuppressive agents, long term broad spectrum antibiotics and AIDS (3-9). The yeast Candida albicans is the most common cause of endogenous endophthalmitis which usually develop in immunocompromised patients having chronic underlying systemic disease, an associated septicemia for which broad spectrum systemic antibiotic therapy is being administered, intravenous hyperalimentation with chronic indwelling catheters or an organ transplantation that requires immunosuppression (4,8). Intravenous drug abusers, patients with diabetes and AIDS are also at high risk for endogenous endophthalmitis.
Exogenous fungal endophthalmitis (FE) usually follows a keratitis, trauma or intraocular surgery. The mycotic causes of exogenous endophthalmitis are mainly Candida species especially in postsurgical group (10-12), whereas Fusarium species were found only in the posttraumatic and postkeratitis groups (13-14).
Fungal infections of the cornea are relatively infrequent in the developed world, but constitute a larger proportion of keratitis in many parts of the developing world especially tropical countries (14-20). Fungal keratitis may constitute 6 to 53% of all cases of ulcerative keratitis, depending on the country of origin of the study (18-20). Fungal keratitis is a major blinding eye disease in Asia (19-20). In temperate climates, such as Britain and the northern United States, the incidence of fungal keratitis remains very low. Corneal trauma contaminated with plant material is the most common scenario for fungal keratitis. Filamentous fungi, such as Fusarium solani and Aspergillus flavus, may constitute up to one-third of all cases of traumatic infectious keratitis (15-20). In the northern parts, however, candida infections predominate and corneal disease and local/systemic immunosuppression are associated with these infections (15).
Invasive Aspergillus and zygomycete infections have a marked predilection for the orbit and surrounding tissues, including the paranasal sinuses (12, 21, 22). Many different presentations of eye disease by Aspergillus occur even in the healthy host, being more invasive in immunocompromised host. Invasive zygomycosis, “rhino-orbitocerebral zygomycosis” is a devastating complication of diabetic ketoacidosis and the use of immunosuppressive drugs following organ transplant.
FUNGAL ENDOPHTHALMITIS (FE)
FE is an acute or chronic intraocular inflammation caused mostly by Candida and Aspergillus species. Fungi can cause both endogenous and exogenous endophthalmitis. Table 1 lists the fungi causing endophthalmitis.
Endogenous Fungal Endophthalmitis
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. Endogenous FE has been associated with many systemic risk factors, including chronic immune-compromising illnesses (diabetes mellitus, renal failure), indwelling or long-term intravenous catheters, immunosuppressive diseases and therapy (malignancies, human immunodeficiency virus infection or HIV, chemotherapeutic agents), recent invasive surgery, endocarditis, gastrointestinal procedures, hepatobiliary tract infections, and intravenous drug abuse (4-9). Endogenous FE comprises approximately 5 to 7% of cases in large series of endophthalmitis and 62% of endogenous endophthalmitis is caused by fungi with a predominance (approximately 1/3) of Candida albicans (23,24). Five to 78% of patients with systemic candidiasis have ocular involvement.
Ocular presentation of the most commonly encountered agent candida includes a creamywhite, well-circumscribed cottonlike lesion, resembling a “fluff ball,” involving the retina and choroid and extending into the vitreous cavity. The lesion usually is less than 1 mm in diameter, often localized in the posterior pole, and associated with overlying vitreous inflammatory cells (figure 2) (8). The infection is called as Candida chorioretinitis when the infection remains localized in the retina and choroid (figure 2, right eye), however, if it extends into the vitreous as an abscess or fluff ball with vitreous haze, it is then referred to as Candida endophthalmitis (figure 2 left eye). More than one half of patients will have vitreous involvement. Vascular sheathing of the retinal vessels may be present, and an associated iridocyclitis is common. One to two thirds of patients have bilateral involvement of the fellow eye, and one half of patients have multiple lesions when first examined (23-27). Multiple yellow-white vitreous abscesses are classically referred to as a “string of pearls”. Figure 3 shows a very typical picture of these pearls in one of our culture proven candida endophthalmitis cases. Candida chorioretinitis is the most common fungal infection of the retina (28). Animal studies have found that Candida may have a greater propensity for the eye than do other species of fungi (28).
The most common symptom at presentation of endogenous FE is decreased vision. Red eye may be absent in more than half of the cases (4). Candida endophthalmitis can masquerade as uveitis and have a gradual onset with a relatively indolent course. It was found to be associated with an incorrect initial diagnosis of uveitis which may reach up to 50% (23,24). This underscores the need for the ophthalmologist to maintain a high suspicion of endogenous endophthalmitis for patients with intraocular inflammation and a recent history of hospitalization, significant medical comorbidities, or a history of candidal infection.
Diagnosis of endogenous FE often is difficult with the cultures and limited to clinical findings. Cultured fungus from the vitreous confirms the diagnosis but is rare because the organism often is confined to the retina and only inflammatory cells are found in the vitreous itself (29). Blood and urine cultures may also confirm the diagnosis when the infection is known to be endogenous. However, because of the prolonged culture time, slow growing or fastidious fungal organisms are often undetected. Binder et al showed that, aside from blood and eye specimen cultures, half of patients showed an additional systemic infection, most frequently a urinary tract infection (24).
Although Candida species are clearly the most-common causes of endogenous FE, other fungi are occasionally encountered. Aspergillus species are the second most common cause of FE. 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 (28). Aspergillus endophthalmitis may be encountered especially in patients with neutropenia, taking pharmacologic doses of corticosteroids (often for chronic lung disease) and intravenous drug addicts (12). Patients with endogenous FE caused by Aspergillus generally had worse visual outcomes compared with those caused by Candida species (23,24). In cancer cases, on the other hand, spectrum of fungal agents causing FE may be completely different. Lamaris et al has reported a review of 23 FE cases in a tertiary care cancer center, 65% of which being induced by molds like fusarium (4).

Table 1: Fungi causing endophthalmitis        
Endogenous endophthalmitis:    C. albicans, C. parapsilosis, C. glabrata, C. tropicalis,
Candida krusei,
Aspergillus spp (A.fumigatus, A.flavus, A. niger, A.terreus, A. glaucus, A, nidulans)
Fusarium spp, (Fusarium solani)
Cladophialophora devriesii, Pseudallescheria boydii, Scedosporium apiospermum,
Rhizomucor and Mucor
H. capsulatum, C. immitis, B. dermatidis, S. schenckii
C. neoformans, Penicillium species.

Exogenous endophthalmitis
Postoperative    Candida species, Aspegillus species,
Posttraumatic/2 to Keratitis  Fusarium species, Aspergillus species
Exophiala jeanselmei, P. boydii, Scytalidium dimidiatum, Helminthosporium spp., S. schenckii, Penicillium chrysogenum, and L. theobromae.
Others:     Cryptococcus, Zygomyozis
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Treatment: The optimal treatment of endogenous FE has yet to be established; the use of systemic antifungals is not discussed (Table 2). Early treatment during chorioretinitis stage is more likely to result in a better visual outcome. Intravenous administration of amphotericin B has been the drug of first choice for the treatment of endogenous FE previously. However, because of the systemic toxicity and side effects of amphotericin B (especially nephrotoxicity), oral fluconazole has become an alternative treatment for endogenous FE. It is tolerated well, has a long half-life, has good intraocular and vitreous penetration, and has no reported ocular toxicity (3, 25,26,30). If the therapeutic response is not satisfactory, intravenous (and intravitreal) amphotericin B can be the treatment of choice. Administration of voriconazole has been associated with favorable outcomes (31). Lastly, pars plana vitrectomy is an effective treatment option in eyes unresponsive to medical treatment. Vitrectomy has also a diagnostic value in indeterminate cases. Very recently combination of moxifloxacin to liposomal amphotericin B, has been reported to add to the antifungal activity in an experimental Candida albicans endophthalmitis model (32).
The prognosis of endogenous FE remains unfavorable, as it is associated with poor visual acuity as well as high overall mortality rates (4,33). Patients with systemic candidemia associated with a debilitating disease, may have a mortality rate of up to 80%.  Mortality rate was reported to be as high as 77% among patients with Candida endophthalmitis and known systemic candidemia, suggesting that ocular involvement is a good predictor of mortality for systemically ill patients (33). The prognosis of endogenous FE is even worse particularly when caused by more virulent species such as Aspergillus. Four-week mortality was reported as 57% in cases with FE associated with malignancy, being highest (73%) especially in those caused by molds (4). Most patients are seriously ill and hospitalized; however, any patient with intraocular inflammation and a history of recent hospitalization or systemic risk factors should raise suspicion of endogenous FE. Unfortunately, visual outcomes remain largely influenced by the causative organism, with Aspergillus having the worst prognosis.
Exogenous Fungal Endophthalmitis
As the name implies, exogenous endophthalmitis occurs by introduction of microorganisms into the eye from trauma or surgery (10-14, 34-39). It can also be the end result of preexisting scleritis or keratitis (13,14). Zygomycosis in the surrounding soft tissue and cryptococcal neuroretinitis may also lead to exogenous endophthalmitis (Table 1). Patients with exogenous FE are rarely immunocompromised (39). The first report on exogenous FE was in 1970 by Jones et al, who summarized the clinical experience in 25 cases, 9 (36%) were cases of exogenous FE (34). Visual acuity outcomes were poor in these 9 eyes, with 7 (78%) being enucleated or eviscerated. There are two more recent papers by Pflugfelder et al (1988) and Wykoff et al (2008) describing large series with exogenous FE (35,36). We will analyze the united information of these two studies, since they are similar in most aspects. Total number of cases was 60 (19+41); 25 of which associated with keratitis (41.6%), 19 with surgery (32%) and 16 with trauma (26.6%). The proportion of fungal isolates were also similar in both studies; most of them being molds (86.6%) and 13.3% being yeast. Fusarium species were the most prevalent (30%) organisms, followed by aspergillus species (13.3%), acremonium species (8.3%) and paecilomyces species (8.3%). Molds were the causative agents only in 13.3% of the cases (35,36). Candida species were more prevalent especially in postsurgical group, whereas Fusarium species were found only in the posttraumatic and postkeratitis groups (13-14).
Exogenous FE 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. However, there is a report of a series of 5 patients with relatively early onset (10-62 days) Aspergillus endophthalmitis following cataract surgery (39). An epidemic of postsurgical endophthalmitis with Candida parapsilosis has also been reported (11); 15 patients had ocular surgery over a 3-month period of time. At the time of surgery all eyes were learnt to be irrigated with a solution from the same lot that was contaminated with C. parapsilosis.
Fungal pathogens in posttraumatic endophthalmitis are numerous and similar to those causing fungal keratitis. Reports include Fusarium moniliforme, Exophiala jeanselmei, P. boydii, A. niger, Scytalidium dimidiatum, Helminthosporium spp., S. schenckii, Penicillium chrysogenum, and L. theobromae.
Diagnosis of exogenous FE is mostly possible with intraocular fluid cultures which may be positive in most of the cases (37). Treatment of exogenous FE usually starts with intraocular (intracameral±intravitreal) amphotericin B other than systemic treatment (table 2). Other primary antifungal treatments may be intravitreal voriconazole or miconazole. Oral and subconjunctival antifungal agents may also be added to the treatment especially in the keratitis-associated patients. Systemic antifungal agents include fluconazole, ketoconazole, voriconazole, itraconazole, amphotericin B and miconazole which are especially important in immunocompromised patients. Pars plana vitrectomy would be the best treatment option in eyes unresponsive to medical treatment. Pflugfelder et al (1988) and Wykoff et al have reported that, approximately 90% of the cases received intraocular amphotericin B and 61-84% of the eyes had to have PPV (35,36).
Table 2: Treatment of Fungal Endophthalmitis      
1. Endogenous Fungal Endophthalmitis
a. Systemic antifungal agents: Fluconazole, Voriconazole (Azole compounds)
b. Systemic antifungal agents: Amphotericin B: Parenteral ± Intravitreal
c. Pars plana vitrectomy
2. Exogenous Fungal Endophthalmitis
a. Intraocular (intracameral±intravitreal) amphotericin B
b. Intravitreal voriconazole or miconazole
c. Subconjunctival antifungal agents: when associated with keratitis
d. Systemic antifungal agents: fluconazole, ketoconazole, voriconazole, itraconazole, miconazole, and amphotericin B: important in immunocompromised patients.
e. Pars plana vitrectomy
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Prognosis of exogenous FE depends on the subgroup of etiology. A final vision of 20/400 or better was achieved in 54% of eyes in the most recent paper (36) and almost all were in the keratitis or the postoperative groups. Conversely, although 24% of the eyes were enucleated, 7most of these were among the open-globe patients. Final visual outcomes seem to be variable, with the open-globe–associated patients having the poorest outcomes. Overall, the prognosis in recent papers is becoming better with 44% of patients reaching a final visual acuity of 20/80 or better (36). This improvement in the results may because of the increased and earlier recognition of the disease itself and the resistance of the disease to the antifungal agents used and skipping to the alternative antifungal agents earlier in the clinical course, when resistance is suspected.

FUNGAL KERATITIS
Fungal keratitis (FK) is one of the major causes of blindness especially in Asia. Most of the reports with large series of FK are originated from India (17,19,20,40,41). There are 3 major predisposing factors for FK:
1. Trauma with organic or vegetable matter: Trauma is the key predisposing factor, in healthy young males engaged in agricultural or other outdoor work. There is a history of trauma in more than 5 to 65% of FK cases and trauma was identified as a principal risk factor in 44% of children who had microbial keratitis in southern United States (19,20,41). Trauma related keratitis is mostly filamentous keratitis.
2. Use of contact lenses: Abrasions caused by contaminated contact lenses (especially hydrophilic contact lenses) may predispose to fusarium keratitis (14,18).
3. Pre-existing systemic conditions and ocular surface problems: Insufficient tear secretion, defective eyelid closure, pre-existing epithelial defect, refractive surgeries, herpes keratitis, allergic conjunctivitis, use of eye drops (especially steroids) and systemic problems like diabetes mellitus, immunosuppression may predispose to keratitis mostly associated with Candida albicans and related fungi (14-20, 41,42).
Filamentous fungi form the major etiologic agents of FK. Fusarium species (37–62%) and Aspergillus species (24–30%) have been implicated as main pathogens (Table 3). Other less frequent isolates have been listed in table 3 (20). Yeast like fungi are supposed to be rare pathogens for keratitis (0.7%) (figure 4), however, there is only one series from Wills Eye Hospital reporting the C. albicans as the most common pathogen (45.8%) causing keratitis (15, 42).

Table 3:  Fungi causing keratitis        
Filamentous fungi:   
Main Pathogens:  Fusarium (F. solani, F. oxysporum)
Aspergillus (A. fumigatus, A. flavus)
Others:   Scedosporium (S. apiospermum)
Penicillium (P. spinulosum, P. citrinum)
Acremonium (A. potronii, A. kiliense)
Curvularia (C. lunata, C. geniculata, C. senegalensis)
Bipolaris (B. spicifera, B. hawaiiensis)
Exserohilum (E. rostratum, E. longirostrata)
Coelomycetes (Lasiodiplodia, Colletotrichum)
Yeast-like fungi:  Candida species (C. albicans) (0.7-45.8%)
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Clinical presentation of FK may vary depending on the etiologic agent; however, the most common lesion is indolent and dry, with a leathery, tough, raised surface. The corneal defect usually becomes apparent within 24 to 36 h after the trauma. Symptoms are usually nonspecific, although possibly more prolonged in duration (5–10 days) than in bacterial. Feathery borders or hyphate edges are seen in 70% of patients, and satellite lesions in 10% of patients, with FK. Hypopyon is present in 55% of cases (41). There is minimal to absent host cellular infiltration. When there is an infiltrate, it is often surrounded by a ring, which may represent the junction of fungal hyphae and host antibodies. Descemet’s membrane is impermeable to bacteria but can be breached by fungal hyphae, leading to endophthalmitis (14).
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. Early recognition of the disease is crucial to facilitate a complete recovery. Identification of the pre-existing ocular and systemic diseases usually helps to prevent the misdiagnosis.
Laboratory diagnosis can be made by means of smear, staining, fungal culture, polymerase chain reaction, and confocal microscopy (43,44) (see the lab diagnosis section).
Treatment of FK:
Topical natamycin (5%) or amphotericin B 0.15% is usually the first-line therapy for superficial keratitis. These two drugs are called as polyenes. The drug of choice will be topical natamycin (5%) if hyphae are definitely seen by microscopy and; topical 0.15% amphotericin B or topical fluconazole if yeasts or pseudohyphae are seen on microscopy (16,45). Repeated debridment of the epithelium helps the drugs to penetrate deeper in the cornea. Topical therapy is usually applied hourly for several days and the frequency of application is then gradually reduced. A large prospective study on culture positive 115 FK cases treated with 5% natamycin monotherapy revealed that, predictors of treatment failure were ulcers that exceeded 14 mm, the presence of hypopyon, and identification of Aspergillus. In other words, predictors of poor outcome in FK treated with 5% natamycin monotherapy were larger ulcer size and infection with Aspergillus (46).
Deeper and larger lesions need some form of systemic therapy, such as subconjunctival or intravenous miconazole, oral ketoconazole, itraconazole, fluconazole or voriconazole all of which are in the group of azole compounds (16,20). Intracameral amphotericin B may be another option for these cases.
If medical therapy fails to control the infection, surgery should be considered to save the eye and visual function before the progression of the disease to the peripheral cornea. N-butyl cyanoacrylate tissue adhesive can be used in the management of corneal thinning or perforation associated with active FK which can lead to resolution of infiltration with scar formation in 63% of the eyes (47). Amniotic membrane transplantation may also help in promoting healing. Penetrating keratoplasty is the ideal method to treat nonhealing FK threatening perforation. Structural integrity and eradication of sepsis is achieved in up to 90% of eyes with lower graft clarity rates (48).

Table 4: Treatment of Fungal Keratitis:       
Superficial (early keratitis):  Topical natamycin (5%) (hyphae)
Topical 0.15% amphotericin B or topical fluconazole (yeasts)
Debridment of the epithelium
Deeper and larger lesions: Subconjunctival or intravenous miconazole,
Ketoconazole, itraconazole, fluconazole or voriconazole (p.o) Intracameral amphotericin B
Surgical Treatment:  Cyanoacrylate tissue adhesive
Amniotic membrane transplantation
Penetrating keratoplasty
_________________________________________________________________________

ORBITAL FUNGAL INFECTIONS
Infections of the orbit usually occur as a secondary process from the surrounding structures, such as the paranasal sinuses, skin, brain, and the nasopharyngeal cavity. The inflammatory conditions that affect the eyelids and the orbit are broadly divided into preseptal (periorbital) and postseptal (orbital) cellulitis. There are, however, some other entities that are grouped within the orbital infection group. The current classification of orbital inflammation was proposed by Smith and Spencer (49) and later modified by Chandler et al. (50). They classified orbital inflammation in 5 groups: group 1 for preseptal cellulitis; group 2 for orbital cellulitis; group 3 refers to a subperiosteal abscess; group 4 classifies a diffuse orbital abscess; and group 5 refers to cavernous sinus thrombosis.
Orbital cellulitis is most commonly caused by bacterial infection. Fungal and viral etiologies occur less frequently. In contrast to bacterial infections which tend to occur in otherwise healthy individuals mycotic orbital cellulitis is often seen in patients with uncontrolled diabetes mellitus or other immunocompromised states such as AIDS, malignancy or steroids use (51). They may be invasive or non-invasive. Fungal etiologies include Phycomycetes (Mucor and Rhizopus sp.), Aspergillus sp., and to less extend Blastomyces, Sporothrix sp and Bipolarina sp. (51). Invasive Aspergillus and Phycomycetes infections have a marked predilection for the orbit and the paranasal sinuses.
Orbital Phycomycosis:
Although mucormycosis is the term used to refer to fungal infections of this class, the correct term is phycomycosis.  Mucor and rhizopus are two genera of the order Mucorales, a subset of the class Phycomycetes. They are saprophytic fungi that are normally not pathogenic to humans. In immunocompromised states, the inhaled spores of Phycomycetes, which are normally eliminated with phagocytosis, start to progress through the nose to maxillary sinuses, ethmoids and orbit. Spread from paranasal sinuses to orbit is usually via the nasolacrimal duct and medial orbit. The thinness of lamina papyracea and perforation of medial wall by blood vessels are the causes of spread through the medial wall. Infection enters to central nervous system (CNS) through the orbital roof, apex and cribriform plate. Organism invades blood vessel walls, causing necrosis, thrombosis, obstruction and ultimately infarction of involved tissues. Internal carotid, middle cerebral, ciliary and retinal arteries as well as cavernous sinus are all subject to this progression.
Individuals predisposed to infection by Phycomycetes include diabetics in ketoacidosis, leukemics, and patients with lymphoma, multiple myeloma, cancer, septicemia, AIDS and burns. Practically all conditions causing immunosupression may be a predisposition to these infections. In a recent global clinical registry study, the most common underlying conditions in 41 cases of invasive zygomycosis were malignancies (63.4%), diabetes mellitus (17.1%) and solid organ transplantation (9.8%) (52). Antecedent bacterial infections are also common in these cases.
The manifestations of the disease may reflect sequential involvement of the nose, sinuses, eye and brain. Rhino-orbito-cerebral (ROC) infection produces characteristic clinical features of low grade fever, periobital pain, headache, lethargy, sinusitis, unilateral facial swelling, black nasal and palatal eschar, decreased vision, afferent pupillary defect, proptosis, and ophthalmoplegia (52-57) (Figure 5). The infection is characterized by a bad smelling seropurulant discharge. Involved tissues are necrotic, with a dark discoloration, resembling clotted blood which is direct effect of vascular thrombosis and tissue infarction. Black eschar formation, -usually a late finding- is a characteristic finding but it is not a necessity for the diagnosis. Orbital apex involvement results in both internal and external ophthalmoplegia. Laboratory tests will reveal elevated sedimentation rate and white blood cell counts. CT and MR imaging are often used in the diagnostic work-up; however, CT findings are nonspecific (58). Biopsy material is crucial for the microbiological work-up (Figure 5).
There is need for a high index of clinical suspicion for early diagnosis. Control of the underlying predisposing illness along with the timely medical and surgical treatment proves extremely important for prognosis. The combined modality of early surgical debridement and antifungal agents is used for treatment of ROC infection (59). Parenteral antifungal treatment with liposomal amphotericin B is the main medical treatment. Surgical treatment is mostly aggressive including orbital exenteration and pansinusectomy with endoscopic sinus surgery; however, timely limited surgical intervention without exenteration may be successful in early and limited cases (Table 5).
Table 5: Management of Phycomycetes infections.    
1. Early diagnosis of the infection
2. Correction of underlying predisposing disease conditions
3. Treatment of the co-existent bacterial infection.
4. Surgical debridement of the necrotic tissues and getting biopsy material
5. Microbiologic examination of the biopsy material
6. Intravenous antifungal agents (Amphotericin B)
_________________________________________________________________
Prognosis of the disease is still poor not only because of the aggressive nature of the disease, but also because of the delayed diagnosis (60). A poor prognosis was primarily related with uncontrolled underlying disease. Other associated prognostic factor was the extent of disease including orbital or intracranial extension. Survival rate was reported as 51% and liposomal amphotericin B was reported to be associated with improved response and survival rates in a global clinical registry including 41 cases (52).
Orbital Aspergillus Infections:
Aspergillosis is the most common cause of fungal sinusitis and orbital fungal infections. Aspergillus is also a saprophytic fungus that is normally not pathogenic to humans. Usual entry site is through the nose and paranazal sinuses like Phycomycetes. The infection has a predilection for the immunocompomised host, especially in cancer (leukemia and lymphoma) patients. Many different orbital presentations by Aspergillus occur even in the healthy host. 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 (61).
Clinical presentations of orbital invasive aspergillosis are similar to other inflammatory orbital diseases and neoplastic diseases. Therefore, orbital invasive aspergillosis may be misdiagnosed as other diseases, such as idiopathic orbital inflammation and bacterial cellulitis with paranasal sinusitis, which may transiently respond to corticosteroids leading to delayed diagnosis and progression of the infection. Invasive disease in the compromised host may begin as dacryocystitis, masquerade as an optic nerve tumor (62), or present as an entirely retrobulbar process (Figure 6). 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 (63,64).
It was difficult to confirm a diagnosis of aspergillosis by histopathologic examination of tissue samples obtained by endoscopic or other procedures; in several patients, more than one biopsy was needed. High rates of negative biopsy results have been reported, especially because the fungus appears only in late-stage clinical samples. Therefore, if diagnosis is not made on the first biopsy, and fungal infection is still suspected, a second biopsy should be performed, especially before considering treatment with corticosteroids. CT or MRI of the sinuses, orbit, and brain are important in diagnosing this condition, determining the extent
of disease (including bony erosion in adjacent vital areas such as the orbit or skull base), and in planning the surgical approach.
Treatment is similar to phycomycetes infections (table 5). Management often begins with surgical debridement followed by systemic antifungal drug therapy. Some antifungals are used, such as polyenes (amphotericin) and azoles (itraconazole and voriconazole), and other newer classes such as lipid complex nystatin and echinocandins (65). Among them, amphotericin B is a conventional drug for treatment of invasive aspergillosis. However, treatment is often prolonged and can be complicated by adverse effects. The most serious complication is renal dysfunction. Newer formulations, including lipid complex and liposomal forms, have been developed to decrease the toxicity of amphotericin B and indeed seem to be less toxic. There have been some controlled trials comparing amphotericin and newer antifungal agents such as voriconazole or echinocandins. In patients with invasive aspergillosis, initial therapy with voriconazole led to better responses and improved survival and also resulted in fewer severe side effects than the standard amphotericin B initial therapy. Data from various sources suggest that response rates to the different drugs are only 40% to 60% (66). Of the azole class, itraconazole and voriconazole are promising and are safer and easier to administer than amphotericin B. Most experts recommend the maximum daily dose of the chosen antifungal agent(s) until the disease is controlled, and then prolonged administration of oral itraconazole to ensure eradication thereafter. Radical surgical debridement of the orbit, adjacent sinuses, and skull base area may be considered but is often complicated by other factors, including difficulty in determining the extent of the lesion.
Orbital invasive aspergillosis is often fatal with a mortality rate up to 40-50% (64).Poor prognostic factors are reported to be associated with delayed and incorrect initial diagnosis, presence of fever, intracranial extension of infection, and histopathology demonstrating hyphal invasion in blood vessels or adjacent tissue (64,67).

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FIGURE LEGENDS

FIGURE 1: Anatomy of the eyeball.


EOM: Extraocular muscle, CRA: Central retinal artery, CRV: Central retinal vein





FIGURE 2: Endogenous candida choioretinitis foci in the right eye and significant vitritis (endophthalmitis) in the left eye of a case with pancreatic head tumor having chemotherapy.





FIGURE 3: Pearls in the vitreous cavity seen through pupilla in a bilateral endogenous candida albicans endophthalmitis case.




FIGURE 4: Candida keratitis associated with penetrating keratoplasty. Top left figure shows early infiltration at 2 o’clock position of donor-host cornea border (arrow). The infiltration is getting larger (top right) involving other parts (lower left) in spite of antifungal treatment. Lower right figure shows the vascularized scarring at the end of 6 months.
(Courtesy of Dr. Fikret Akata)







FIGURE 5: 58 year old lady with diabetic ketoacidosis had total ophthalmoplegia with no light perception, left facial nerve palsy, left hemifacial pain, necrotic black skin lesions over the forehead, cheek and lip.  Ethmoidal sinusitis was apparent in MRI films. Surgical debridement of all necrotic tissues together with exanteration of the orbit was performed in addition to intravenous Amphotericin B treatment. Microbiological examination of the tissues revealed …..Buraya aşağıdaki (sağ alt)mikrobiyolojik boya ve görülenlerin tarifini yazarsan sevinirim… (Courtesy of Dr. Onur Konuk)





FIGURE 6: 65 year old diabetic lady with total external painful ophthalmoplegia, proptozis and vision loss in the right eye for the last 2 months. Orbital MRI examination revealed ethmoidal and sphenoidal sinusitis and inflammatory reaction extending around the optic nerve and orbital apex (lower left).Microbiologic examination of the endoscopic sphenoid sinus biopsy material revealed septated hyphea of Aspergillus fumigatus. Treatment started with intravenous liposomal Amphotericin B, local debridment and irrigation of the involved areas with Amphotericin B and continued with oral Itraconazole for 3 months which resulted in total resolution of ophthalmoplegia and inflammatory findings in MRI (Lower right). (Courtesy of Dr. Onur Konuk).



 
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