endophthalmitis for both diagnostic and therapeutic purposes [32].

Treatment

Despite treatment, which generally includes pars plana vitrectomy (PPV), intravitreal amphotericin B, systemic amphotericin B, and oral antifungal agents, the visual prognosis remains grave,andtheriskofmortalityhigh.Amphotericin B is currently the only antifungal agent approved for injection into the vitreous. However, even at low concentrations it may cause focal retinal necrosis. Furthermore, a variety of fungal species, particularly Aspergillus, have shown resistance to amphotericin B [35]. Voriconazole, a second-generation triazole, was developed for the treatment of life-threatening infections. It has potent in vitro activity against Aspergillus species and has been found to be more effective than amphotericin B for the treatment of invasive aspergillosis. Voriconazole is used orally, intravenously, or by intravitreal injections (100 m[mu] g/ 0.1 ml) to treat endogenous Aspergillus endophthalmitis [36].

The use of intravitreal dexamethasone remains controversial, but some protocols recommended using this adjunctive medication to reduce the marked intraocular inflammation in many of these eyes. In patients with persistent vitreous infiltrates and suspected recurrent disease after initial treatment, repeat intravitreous injections of amphotericin B and possibly repeat vitrectomy may be considered.

Cryptococcal Chorioretinitis

Cryptococcus neoformans is a budding, sporeforming, yeastlike fungus, with a polysaccharide capsule, ranging in size from 5 to 10 m(mu)m.

Cryptococcus neoformans has two varieties: var neoformans and var gattii. C. neoformans var gattii is associated with a higher incidence of visual impairment, as compared to C. neoformans var neoformans. The organism has a worldwide distribution. The most common source of infection is droppings from pigeons and other birds. The fungus has also been isolated from soil, fruit,

and milk. Cryptococcus neoformans can enter the body through inhalation and spread hematogenously to end organs, most commonly the brain. The most common ophthalmic manifestation of cryptococcosis is secondary to cryptococcal meningitis or meningoencephalitis [37].

Risk Factors

A normally functioning host immune response is capable of eliminating C. neoformans infection, or can sequester C. neoformans into sites where it can remain controlled via fungistatic and fungicidal host defense mechanisms. The humoral system is activated through the complement cascade. Therefore, the clinical manifestations of this infection can range from an asymptomatic colonization of the respiratory tract to a widespread dissemination depending on the host immune factors.

Most cases of intraocular cryptococcosis reported in the literature are the result of:

•Cryptococcal septicemia associated with severe meningeal infection

•Immunocompromised patients

•Malignant lymphoma, Hodgkin’s disease, and other malignant diseases

•Acquired immunodeficiency syndrome (AIDS)

•Systemic lupus erythematosus

Pathogenesis

The primary lesion of cryptococcal infection is usually in the lung through inhalation of airborne spores, with dissemination most frequently to the meninges and brain or spinal cord. Other reported sites of cryptococcus include the skin, bones, and liver. Direct cryptococcal involvement of the eye is rare and usually associated with disseminated disease [37]. Cryptococcus organisms reach the eye through either direct extension from the optic nerve sheath or hematogenously from a distant focus.

Histological studies show that endogenous ocular cryptococcosis is primarily a choroidal disease, with secondary invasion of the sensory retina and other intraocular structures. Cryptococcus neoformans has also been reported to cause endophthalmitis, uveitis, and retinitis [37]. The histological reaction caused by the organism in the choroid and retina can range from minimal to

no inflammatory reaction or necrosis to granulomatous changes [38].

Clinical Features

Patients sometimes do not complain of visual symptoms; however, a detailed visual perimetry assessment can show dramatic and generalized concentric diminution of visual field in both eyes. Patients sometimes present with visual loss. C. neoformans usually presents intraocularly as a multifocal chorioretinitis characterized by discrete multiple, yellowish white, slightly elevated chorioretinal lesions of different sizes. Retinal necrosis accompanied by retinal hemorrhage (Figs. 9.19 and 9.20) and exudative retinal detachments also have been known to occur [39]. Retinal vessels may be sheathed; vitreitis of variable intensity and papilledema, optic atrophy, and ophthalmoplegia may develop (Figs. 9.19, 9.21, and 9.22). Without treatment, the condition progresses to endophthalmitis [37]. Clinically, this

appears as a diffuse vitritis with haze, debris, and fluffy white vitreous exudates that progressively enlarge to involve the entire vitreous [37]. An unusual presentation is a solitary retinovitreal abscess (Figs. 9.23 and 9.24) [40]. A mild inflammatory reaction is usually present in the anterior segment. If treatment is not instituted, iris neovascularization and cataract may result. Visual outcomes are very poor in most cases.

Diagnosis

The diagnosis in a patient with a suspected cryptococcal chorioretinal or retinal lesion is complicated by the frequent association between direct intraocular cryptococcal involvement and the disseminated form of the infection, which frequently involves the central nervous system. Fluorescein angiography typically reveals hypofluorescent spots located under the neural retinal without significant leakage in late stages of the angiogram in cryptococcal choroiditis (Fig. 9.25). Multifocal pattern and irreg-

Fig. 9.19 (a–b) Fundus photography showing disk edema associated with multifocal choroiditis and retinal hemorrhages in a patient with disseminated cryptococcus neoformans

infection. (c) Umbilicated skin lesions in an HIV-positive patient. (d) Histology study of skin lesion showing the presence of Cryptococcus neoformans (PAS/Grocott)

Fig. 9.20 (a–b) Multifocal cryptococcal choroiditis. Right (a) and left (b) eye photographs show multiple, yellowish lesions at the level of the retinal pigment epithelium and choroid (Reprinted with permission from

Fig. 9.21 (a) Hemorrhagic papilledema associated to cryptococcal meningitis. (b) Cryptococcal retinochoroiditis with vasculitis. (Reprinted with permission from Arévalo JF, Fernández

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

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

ularly shaped hypofluorescent spots on indocyanine green video-angiography are observed in choroiditis for Cryptococcus neoformans [41]; they have a tendency to be confluent. This finding may be related to an active disease stage than may have involved the choriocapillaris (Fig. 9.26).

If the causative organism is not known, an early diagnostic vitreous tap or vitrectomy may be performed. Identification of the encapsulated organism in cerebrospinal fluid (CSF) stained with India ink is sufficient for making a presumptive diagnosis and initiating treatment pending culture results. India ink preparations are negative in 50% of cases involving the central nervous system. In suspected cases, the urine, CSF, blood, and sputum should be cultured even in the absence

of evidence suggesting genitourinary or pulmonary infection. Cryptococcus neoformans grows well on both blood agar and Sabouraud medium. Growth usually occurs within 24–48 h, producing mucoid, cream or pink colonies. Cryptococcus neoformans is a budding, spore-forming yeast. The organism can be found within histiocytes as well as free in the extracellular matrix in the choroid, either with or without involvement of the overlying retina (Fig. 9.27).

Several serological tests for Cryptococcus have been developed including complement fixation, tube agglutination, immunodiffusion, and an indirect immunofluorescence test. The latex agglutination test for detection of antigen on the cryptococcal polysaccharide capsule is the

Fig. 9.22 (a) Umbilicated skin lesions in a patient with cryptococcal meningitis and disseminated Cryptococcus neoformans infection. (b) Histology study of skin lesion showing the presence of Cryptococcus neoformans.

(c) Fundus photography showing direct nerve invasion associated with multifocal choroiditis and retinal hemorrhages in the same patient with cryptococcal meningitis

Fig. 9.23 Fundus photography showing a large subretinal lesion in the macula due to Cryptococcus infection in a patient with Hodgkin’s lymphoma

most commonly used commercially available test. A titer greater than 1:8 is an indication for treatment. The presence of the antigen should be tested in blood, urine, and CSF if the diagnosis is suspected but not proved.

Morphological characteristics of the organism that allow identification are apparent with periodic acid Schiff (PAS) or methenamine silver stains. Mayer’s mucicarmine will stain the polysaccharide capsule of red, which differentiates

Cryptococcus neoformans from other organisms and artifacts (see Fig. 9.27).

Treatment

Treatment usually consists of amphotericin B or flucytosine, and therapeutic failure or relapse

Fig. 9.25 Fluorescein angiogram of same patient in Fig. 9.20 shows the presence of rounded lesions that were located underneath the neuroretina in an AIDS patient with multifocal cryptococcal choroiditis. These lesions masked fluorescence early during the study (top pictures). There was no significant leakage in the late stages of the angiogram

although some late hyperflourescence may be seen on the nasal aspect of the optic disk in both eyes (bottom pictures). (Reprinted with permission from Arévalo JF, Fernández CF, Mendoza AJ. Chapter 41: Fungal infections. In: Retinal Imaging. Huang D, Kaiser PK, Lowder CY, Traboulsi EI, eds. Philadelphia: Mosby Elsevier: 2006; 366–774)

Fig. 9.26 Indocyanine green video-angiography (ICG-V) of same patient in Fig. 9.20 and Fig. 9.25 confirmed the presence of lesions that were at the level of the choroid. These lesions masked fluorescence throughout the study. Most of these hypofluorescent dark spots were already visible at the early phase of the ICG-V, became more sharply delineated in the intermediate angiographic frames (top

pictures), and remained hypofluorescent in the late frames (bottom pictures) of the retinal pigment epithelium and choroid. (Reprinted with permission from Arévalo JF, Fernández CF, Mendoza AJ. Chapter 41: Fungal infections. In: Retinal Imaging. Huang D, Kaiser PK, Lowder CY, Traboulsi EI, eds. Philadelphia: Mosby Elsevier: 2006; 366–774)

has been reported in approximately 33% of cases. Agents like fluconazole have also been used. Voriconazole is a synthetic derivative of fluconazole, but it has a significantly broader spectrum of activity. Compared with amphotericin B, fluconazole, and itraconazole, voriconazole has the lowest minimum inhibitory concentration for Cryptococcus neoformans, and time-kill assays demonstrate its fungicidal activity. When administered systemically, voriconazole shows excellent bioavailability, penetrating

well into the eye and reaching intravitreal concentrations of 1.0–1.5 mg/mL. It has no significant toxicity in vitro cell cultures when administered in therapeutic concentrations up to 250 mg/ml. Intravitreal voriconazole may therefore be a promising regimen for treatment of cryptococcal endophthalmitis. Early vitrectomy is recommended if severe vitritis fails to clear or worsens under antifungal therapy [37]. Enucleation is considered if the outcome is a blind, painful eye.