FUNGAL INFECTIONS OF THE EYE

 Although fungal keratitis is the most common encountered clinical

entity, other ocu-lar structures, including the retina and orbital soft
tissues, may also be affected. Ocular fungal infections without a sys-
temic infectious component typically fall into the domain of the
ophthalmologist and are not frequently encountered or managed by
non-ophthalmologist clinicians.

FUNGAL RETINITIS AND ENDOPHTHALMITIS

Anatomy
 The retina is a thin multilayered sheet of neural tissue that lines the
inner wall of the posterior eye.
 The term “endophthalmitis” is reserved for describing a
panophthalmic infectious or inflammatory process. Infectious
endophthalmitis can be caused by either exogenous or endog-enous
microbial contamination of intraocular tissues. Exog-enous
endophthalmitis is usually associated with penetrating injury to the
eye, although exogenous endophthalmitis can also result from
contamination of the internal eye by surgical instruments, fluids, and
foreign materials introduced into the eye during surgery.
 n contrast, endogeneous endophthalmitis is principally the result of
hematologic spread of microorganisms from a dis-tant focus of
infection. Endogeneous endophthalmitis occurs most often in
immunocompromised patients, including intra-venous drug abusers,
patients receiving chemotherapy or total parenteral nutrition, as well
as organ transplant recepients and HIV-positive patients.

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 Epidemiology
 The incidence of all forms of exogeneous endophthalmitis fol-lowing
penetrating trauma to the eye is approximately 5%, with more than
10% of these cases being of fungal etiology.
 In contrast to exogenous endophthalmitis, more than 50% of
endogenous endophthalmitis cases are caused by fungi.
 Candida spp. are responsible for the majority of endog-enous
endophthalmitis cases.
 Aspergillus endophthalmitis is most common in organ transplant
recipients, neutropenic patients, patients receiving
chemotherapeutic agents or corticosteroids, and those under-going
valvular cardiac surgery.

Pathogenesis
Endogenous fungal endophthalmitis
 Endogenous endophthalmitis likely starts by hematogenous spread
of the fungus to the choroid followed by contiguous spread to the
adjacent retina. The high blood flow to the choroid and outer retinal
layers (150 mm/s), compared to a lower flow to the inner retinal
layers (25 mm/s), makes this tissue vulner-able to both infectious as
well as metastatic seeding.

Exogenous fungal endophthalmitis

 Cataract removal with intraocular lens implant and corneal
transplantation are the ocular surgical procedures most often
associated with postoperative fungal endophthalmitis. Con-
taminated irrigating solutions, intraocular lenses, ventilation system,

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 and hospital construction activity have been reported as potential
underlying causes of postsurgical exogenous fun-gal
endophthalmitis.

MYCOLOGY
Candida species
 Candida albicans is the most frequently isolated species although
other non-albicans species have been implicated

Aspergillus species
 Aspergillus spp. are the second most common fungal genus
responsible for endogenous endophthalmitis,

Clinical manifestations
 The most common ocular symptoms of fungal endophthalmitis are
redness, pain, and diminished or blurred vision in the involved eye.
Examination of the external eye typically shows hyperemia of the
ocular surface with dilation of the surface vessels. Occasionally,
hypopyon may be visible: whitish layer of inflammatory cells and
debris in the inferior anterior chamber.
 Biomicroscopic examination of the eye with the slit lamp may reveal
white blood cells and flare in the anterior cham-ber, as well as
vitreous haze. Flare refers to protein leaking into the normally
optically clear aqueous from incompetent intraocular vessels.
 Fundus examination by indirect ophthalmoscopy reveals
chorioretinal infiltrates.

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 in patients susceptible to opportunistic infections, any new visual
symptoms should prompt immediate consultation with an
ophthalmologist to allow for early recognition.

Diagnosis
 The definitive diagnosis of infectious endophthalmitis is estab-lished
by culture of the aqueous and/or vitreous fluids. Aque-ous fluids can
be obtained at the bedside or in the examining room using the slit
lamp. With the use of topical anesthetic, a 27 or 30 gauge needle
can be passed through the peripheral cornea at the limbus into the
anterior chamber to withdraw 0.1 ml of aqueous fluid.

Treatment
 Since destruction of the delicate ocular tissues, particularly the
retina, can occur rapidly, the importance of early recognition and
intervention cannot be overemphasized.

Treatment for candida

 Intravitreal administration of amphotericin B (0.005 mg/0.1 ml), with
or without pars plana vitrectomy, has been success-fully employed
for Candida but must be used with caution as even low
concentrations (4.1 μg/ml or 8.3 μg/ml) have been reported to cause
focal retina necrosis.
 Fluconazole can be given both systemically, with good intraocular
penetration, as well as intravitreally.
 Voriconazole is more active than amphotericin B, fluconazole,
itraconazole, and flucytosine against all Candida species. Candida

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 albicans is highly susceptible to this agent with a MIC90 of only
0.06μg/ml, while C. glabrata is the least sensitive, with a MIC90 of
2.0 μg/ml. Promising results with combined intravenous voriconazole
and intravenous caspofungin have been reported
 Until comparative studies demonstrate benefit, the use of intravitreal
steroids cannot be recommended.

Treatment for aspergillus

 The prognosis for Aspergillus endophthalmitis is poor. Intravenous
voriconazole and caspofungin with or without intravitreal
voriconazole may become the standard for treatment of Aspergillus
endophthalmitis.

FUNGAL KERATITIS
Anatomy
 The cornea is the transparent, avascular anterior-most struc-ture of
the eye, measuring 10–12 mm in diameter and having a central
thickness of about 0.5 mm. It functions as an anterior refractive
surface which contributes nearly three-quarters of the total refractive
power of a normal human eye. Like the skin, it is the external
anatomic barrier between the environment and deeper tissues; it is
the ocular structure most frequently dam-aged by external trauma.

Epidemiology
 Mycotic keratitis is relatively infrequent in the developed world but
constitutes a large proportion of corneal infections in developing
countries.

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 fungal infections of the cornea are more common in warmer
climates.
 Five percent of all infectious keratitis following refractive keratotomy
such as LASIK is secondary to fungal infection.
 Patients who use extended-wear contact lenses are at increased
risk for all forms of keratitis, including those of fungal etiology.
 Although contact lens wearers are typically young and healthy, the
hypoxia and surface abrasive effect from the contact lens can
compromise the corneal epithelium, thus increasing the risk of
keratitis
 Fungal etiology should always be suspected when patients with
presumed infectious keratitis do not respond to topical antibacterial
agents.

Pathogenesis
 The pathogenesis of fungal keratitis is that of an opportunis-tic
invasion of a compromised eye or an eye traumatized by organic
matter. The inflammatory reaction and tissue destruc-tion in fungal
keratitis are caused by antigenic fungal cellular components,
mycotoxins, and fungal proteases assisting in deeper stromal
invasion.

Mycology
Hyaline filamentous fungi
 Filamentous fungi are the principal causes of mycotic keratitis in
most parts of the world, with Fusarium and Aspergillus most
commonly encountered. Filamentous fungal keratitis appears to

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 occur most commonly in healthy young men engaged in agricultural
work or outdoor occupations.

Dematiaceous fungi
 The dematiaceous fungi are common soil and plant saprophytes
categorized on the basis of their dark pigment. Dematiaceous fungi
are reported to be responsible for 10–15% of all fungal keratitis and
are the third most frequently encountered fungi following Aspergillus
and Fusarium.

Candida
 Candida spp., predominantly C. albicans, usually occur in
immunosuppressed patients, those with ocular surface dis-ease or
lid margin defects, or those receiving long-term topical
corticosteroids.

Clinical manifestations
 Symptoms of fungal keratitis include ocular pain, redness,
diminished vision, photophobia, tearing, and discharge. On gross
examination, the eye appears infected, and the cornea may have a
noticeable haze, loss of luster or an area of opacifi-cation. A
mucopurulent discharge may be present. The eyelids may be
erythematous and edematous; reactive blepharospasm can make
examination of the eye difficult.
 Early signs of fungal keratitis, as observed by slit lamp
biomicroscopy, include fine to coarse granular infiltrates in the
anterior corneal stroma, feathery branching of the fungi into the

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 stroma, and inflammatory cells and proteins in the aqueous humor.
Although these signs are by no means universal in fun-gal keratitis,
their recognition by the ophthalmologist should increase the index of
suspicion of a fungal cause. Later corneal findings include an
immune ring that can form focally in the corneal stroma around the
infection, satellite lesions, and an endothelial plaque.

Diagnosis
 Diagnosis should be aggressively pursued with cultures and/or
scrapings of the involved cornea using a platinum spatula, surgical
blades or calcium alginate swabs. Corneal tissue speci-mens should
be inoculated on the surface of solid media by making rows of “C”
shapes and in liquid media by introducing the tip of the spatula into
the broth several times. Most fungi will be visible in culture within 2–
7 days, but several weeks may be required for definitive
identification.
 Corneal biopsy may be performed for patients in whom empiric
antiinfective therapy has been unsuccessful and micro-biologic
diagnosis has not been established.
 The fungi are easily visualized with standard tissue stains;

Treatment
 Natamycin 5% suspension administered topically is widely used for
suspected fungal keratitis. Natamycin is administered to the infected
eye every hour, all day for 1 week and then every hour during the
day while awake for 12 weeks. Large ulcers and Aspergillus

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 infection are less likely to respond favorably to monotherapy with
topical natamycin.
 Topical natamycin combined with oral itraconazole or oral
ketoconazole is widely used for confirmed Aspergillus keratitis.
 In severe cases systemic therapy with ketoconazole (400 mg/day) or
itraconazole (400 mg/day) is advised.
 The use of topical corticosteroids is controversial; some authors feel
corticosteroids are contraindicated for the management of all fungal
keratitis.
 Debridement of the infected corneal tissue followed by coverage
with a conjunctival flap, along with concomitant antifungal therapy,
has been advocated for small non-healing peripheral ulcers
 Cautious use of postoperative topical corticosteroids and topical
0.5% cyclosporine A may reduce the rate of graft rejection.

SINOORBITAL DISEASE
Anatomy
 The orbital septum is an important anatomic barrier in the eyelids
that prevents contiguous spread of infection posteriorly from the
eyelids into the orbital tissues. The septum is a thin fibrous layer
arising from the periosteum along the inferior and superior orbital
rims which fuses into the upper and lower eye-lid retractors

Epidemiology
 The vast majority of orbital fungal infections are secondary to
contiguous spread from infected paranasal sinuses.

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 Mycology
Aspergillus
 Different presentations of Aspergillus infection of the orbit may occur
even in a healthy host.
 Aspergillosis is the most common fungal sinus infection in
immunocompetent patients, causing an indolent, chronic infection
with granulomatous host response, i.e., aspergilloma

Zygomycosis
 Rhino-orbital-cerebral zygomycosis represents the prototype of
fulminant, invasive orbital fungal infections with an acute course in
the immunocompromised host. Zygomycosis originates in the
nasal/sinus mucosa. Diabetic ketoacidosis is the most common
predispos-ing factor (60–80%).

Clinical manifestations
 Facial heaviness or full-ness and nasal discharge are often
presenting complaints. With orbital involvement, non-axial globe
displacement and/or proptosis are seen but typically without
evidence of optic nerve compromise or other cranial nerve
dysfunction.
 immunocompromised patients with invasive fungal sinoorbital
disease typically present with facial pain, headache, or other
symptoms of fulminant sinusitis.
 Facial nerve involvement indicates more extensive disease outside
the retroorbital space and is a grave prognostic indicator.

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 In rhino-orbital-cerebral zygomycosis, the affinity of the infecting
organism for blood vessels leads to arterial thrombosis, necrosis,
and infarction. Thick, dark nasal discharge is seen, with the hallmark
black necrotic turbinates and nasal septum. Although tissue necrosis
is considered a classic feature, its absence should not preclude the
diagnosis.

Diagnosis
 Radiographic imaging of the orbit and paranasal sinuses is
invaluable for both the initial evaluation and for monitoring disease
progression and response to treatment.
 Both computed tomography (CT) and magnetic resonance imaging
(MRI) play a role in defining the extent of the infectious process. MRI
provides details of the soft tissue anatomy of the orbit and
intracranial structures superior to those of CT.
 The microscopic demonstration of zygomycetes in KOH mounts or
stained smears is more significant than their isolation in culture.

Treatment
 The treatment of fungal sinoorbital infection is combined sur-gical
debridement and antifungal therapy. Prompt recognition and
treatment are essential for halting the progression of the disease
and preventing death.
 Surgical debridement of all necrotic tissue is crucial, and often
requires multiple surgeries. Wide local excision of all involved and
devitalized tissue is required.

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 Antifungal therapy is a vital adjunctive to surgery and essen-tial to a
successful outcome
 Timing of intravenous amphotericin B is crucial to outcome: when
the treatment was started within 1–6 days of symptom onset, 76% of
patients survived, compared to 36% when the interval was 7–30
days. The initial dose in a critically ill patient is 1–1.5 mg/kg/day for
the first several days. A lower maintenance dose of 0.8–1 mg/kg/day
is used after several days. Once a response is documented by
clinical and radiographic evaluation, the dose can be given every
other day to minimize toxicity.

DACRYOCYSTITIS AND CANALICULITIS

Anatomy
 The lacrimal outflow system begins with the pinpoint opening, the
punctum, in the medial upper and lower eyelids. The superior and
inferior puncta are the proximal. openings of the respective superior
and inferior canaliculi, delicate duct structures intimate with the
medial canthal tendon. The upper and lower canaliculi merge, in
most individuals, into a short common canaliculus before entering
the lacrimal sac. Tears exit from the sac down the nasolacrimal duct
and empty into the nasal passage in the inferior meatus. An
anatomic obstruction in the lacrimal outflow system, usually in the
nasolacrimal duct, predisposes the patient to tear stasis and
infection of the lacrimal sac, also known as dacryocystitis.

Epidemiology

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 Fungal dacryocystitis accounts for 5% of all acquired dacryo-cystitis,
and 14% of cases of congenital dacryocystitis. Women are affected
more frequently with all forms of dacryo-cystitis than men, probably
because of anatomically narrower nasolacrimal ducts, most
commonly affects individuals in their 50s or 60s. Allergy or chronic
inflammation of the nasal mucosa impedes outflow from the duct,
worsening stasis and increasing the risk of dacryocystitis.

Mycology
 Fungi implicated in dacryocystitis include species of Acre-monium,
Aspergillus, Candida, Paecilomyces, Rhizopus, and dermatophytes.

Clinical manifestations
 Dacryocystitis typically presents with erythema, induration, and
sensation of pressure in the medial canthus. Because of retrograde
regurgitation of the infected matter from the lac-rimal sac to the
ocular cul-de-sac, the eye may be red and the eyelids edematous.
Preseptal cellulitis may be seen particularly with rupture of a
distended lacrimal sac.
 Pain frequently is severe and may localize to the glabellar region
due to irritation of the supratrochlear nerve. Dacryocystitis should be
considered in patients presenting emergently with acute pain in the
lower forehead, particularly with a history of tearing, fullness and/or
tenderness in the medial canthus.

Treatment

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 Initial treatment of dacryocystitis is oral antimicrobial therapy. If the
lacrimal sac is distended, needle aspiration with a 16 or 18-gauge
needle can be used to eliminate the associated discomfort and
prevent fistula formation, and the aspirate can be submitted for
culture. Hospitalization is rarely necessary except in debilitated or
pediatric patients.
 In patients with recurrent dacryocystitis or those not responding to
oral therapy, surgical drainage of the infected sac combined with
dacryocystorhinostomy is indicated.
 If the infection recurs after dacryocystorhinostomy,
dacryocystectomy may be warranted, as a nidus of infection can
persist in the sac or duct remnant or both.

OCULAR HISTOPLASMOSIS SYNDROME OR PRESUMED

OCULAR HISTOPLASMOSIS SYNDROME
Epidemiology
 Presumed ocular histoplasmosis syndrome (POHS) is an
inflammatory syndrome that has been associated with systemic
clinical and subclinical infection by Histoplasma capsulatum.
 Ocular histoplasmosis is most commonly seen in middle-aged
people and more frequently in whites.

Pathogenesis
 Histopathologic examination revealed mixed inflammatory cells in
the choroid, loss of retinal pigment epithelium, and adhesions
between outer retina and choroid.

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 Clinical manifestations
 Most patients with POHS are asymptomatic and the fundus changes
are found on routine eye examination. Classically defined fundus
changes include peripapillary atrophy, multiple atrophic choroidal
scars with central hypopigmentation and peripheral
hyperpigmentation, with complete absence of any signs of vitreal
inflammation

Diagnosis
 Diagnosis is made by the classic ophthalmologic findings described
above. Home monitoring for changes in the macula is done with the
Amsler grid or a similar diagram. The Amsler grid is a graph paper
checkerboard with a central dot. The patient is instructed to visually
fixate on the dot using one eye at a time. If the patient notes a new
visual defect in the checkerboard pattern, distortion or blurring of the
lines, prompt examination is recommended to exclude recent
development of a neo-vascular membrane.

Treatment
 Of the pathologic findings that constitute POHS, subfoveal and
juxtafoveal neovascularization present the most significant clinical
problem.
 Since there is no evidence of infection, antifungal therapy does not
play a role in treatment.
 Intravitreal corticosteroids have been used for POHS choroiditis and
have also been explored as a possible treatment for CNV. Molecular
studies of neovascularization suggest that inflammatory cells

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 participate in the neovascular response and corticosteroids may
suppress this response.

CRYPTOCOCCUS
Epidemiology
 The primary site of infection is the lung, but the disease often
manifests in the central nervous system.
 Ocular involvement occurs after cryptococcal meningitis and may
represent hematogenous dissemination or extension through the
leptomeninges.

Pathogenesis
 The pathogenesis of visual loss in cryptococcal meningitis is
uncertain, although it has been attributed by different authors to be
due to: (1) blood-borne dissemination leading to chorioretinitis and
endophthalmitis, (2) optic neuritis due to fungal spread form infected
leptomeniges and/or (3) increase in intracranial pressure.

Clinical manifestations
 Two distinct clinical patterns of visual loss have been seen in
patients with cryptococcal meningitis. The first pattern presents with
rapid visual loss – visual deterioration in less than 3 days, which
tends to be extreme and permanent. These cases are similar to the
presentation of demyelinating optic neuritis
 The second category presents with slow visual loss that tends to be
mild and is often associated with transient visual obscurations or
visual field defects. These findings are likely due to elevated

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 intracranial pressure (ICP) associated with the meningitis.
Papilledema is usually seen, supporting this mechanism as the
cause of visual symptoms.

Treatment
 The prognosis for AIDS patients with systemic cryptococcosis and
choroiditis is poor. Amphotericin B, flucytosine, and fluconazole can
be successfully used in various combinations and various routes of
administration. Serial lumbar punctures are the modality most
commonly used to decrease ICP, although no standardized protocol
has been proposed. Corticosteroids have been used successfully in
anecdotal reports.

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