| disease | Fungal Corneal Ulcer |
Fungal corneal ulcer was first reported by Leber in 1878. Previously, due to its low incidence, it was rarely mentioned in the literature. After the 1950s, reports from abroad gradually increased. Over the past decade, there has been a noticeable upward trend in the incidence of this disease in China. In fact, among those cases of so-called "serpiginous corneal ulcer" that do not respond to antibiotic treatment, some may be fungal in nature, which warrants attention.
bubble_chart Etiology
This disease is caused by the direct invasion of fungi into the corneal infection. Scraping necrotic tissue from the ulcer surface of the infected cornea for smear examination often reveals fungal hyphae. Inoculating the necrotic tissue onto fungal culture media can result in fungal growth. There are dozens of fungal species pathogenic to the human cornea. Data analysis identified 21 genera and 25 species, primarily Aspergillus, followed by Fusarium.
From 1964 to 1976, a hospital cultured 204 strains of fungi from 318 clinical cases of fungal corneal ulcers, which were identified by the Institute of Microbiology, Chinese Academy of Sciences.
From 1957 to 1965, domestic literature reported 13 cases involving species such as Candida albicans, Aspergillus, Fusarium, yeast, and Cephalosporium.
Foreign literature primarily reports Aspergillus, Fusarium, Candida albicans, and Cephalosporium.
Most cases have a predisposing history at onset. The disease is often closely related to minor plant injuries during agricultural labor. In our hospital's cases, the most common predisposing factor was injury from rice grains during threshing, followed by abrasions from plant branches or leaves and foreign bodies like dust entering the eye. It can also occur as a secondary fungal infection in patients with long-standing corneal inflammation of other etiologies. Some foreign studies suggest a link to the misuse of antibiotics or corticosteroids in the eye.
Corneal trauma causes epithelial damage. Injurious agents such as rice grains, plant branches, leaves, or dust often carry fungi. When the corneal epithelium is damaged, fungi can be inoculated into the cornea, leading to infection. The incubation period is typically 1–4 days, averaging 2.4 days.bubble_chart Clinical Manifestations
Initially, there may only be ocular foreign body sensation or irritation, accompanied by blurred vision. In cases with a history of trauma, ulcers develop several days after the injury, progressing relatively slowly, which differs from the rapid progression of Pseudomonas aeruginosa corneal ulcers post-trauma.
Early symptoms such as eyelid redness, swelling, photophobia, and tearing vary in severity. In severe stages, these irritative symptoms often become milder. Congestion is usually severe, primarily mixed, and some cases may present with a small amount of grayish-white discharge.
Due to differences in fungal strains, duration of infection, and individual variations, the clinical appearance of ulcers can vary significantly. Typical early ulcers are grayish-white or milky-white, often irregular in shape. The surface is rough, dense, and slightly elevated. The density distribution of the ulcer and infiltration is uneven, and the boundary between the ulcer and healthy corneal tissue is usually clear, with irregular edges.
Larger ulcers are often yellowish-white, mostly irregularly round, with a surface that appears dry and rough, resembling "mossy debris" or "toothpaste." The stromal infiltration is dense, and the ulcer edges are slightly raised. If the lesion progresses, nodular or root-like stromal infiltration may appear around the ulcer.
Some describe fungal keratitis using the following terms.Hyphal mat: This refers to the hyphae and necrotic tissue adhering to the ulcer surface. It is white, opaque, slightly raised, and clearly demarcated from healthy corneal tissue. It can be scraped off, revealing a more transparent ulcer surface.
Hyphal focus: This is a lesion where fungal hyphae invade the corneal stroma. The surface is slightly raised, dry, and rough. The density of infiltration in the turbid area varies. The texture is hard, and when scraped with a blade, the debris on the blade tip is loose. The ulcer remains turbid and opaque after scraping.
Hyphal focus edge: Some ulcer edges appear rough and uneven. Sometimes, root-like infiltrations extend outward, termed "pseudopods," or isolated nodular round infiltrations appear around the ulcer, called "satellite lesions."
Reaction ring: Around the hyphal focus, there is a circle of inflammatory cell infiltration, usually not very wide (about 1–2 mm), representing the body's defensive response to the hyphae. Some refer to this as the "immune ring."
Demarcation groove: Located between the hyphal focus and the reaction ring. This area has the highest concentration of inflammatory cell infiltration, resulting from superficial tissue necrosis and grade I depression forming a shallow groove.
Slit-lamp examination of fungal corneal ulcers reveals progression from superficial to deep layers. Early ulcers are superficial, with little change in corneal thickness. The ulcer base shows dense stromal infiltration, which may involve 0.2, 0.4, or 0.6 of the corneal thickness. Although stromal edema is mild, it is often full-thickness. The endothelium opposite the hyphal focus often shows edema, roughness, and thickening, accompanied by folds, termed "endothelial patch." Sometimes, the entire cornea exhibits diffuse fog-like edema, indicating ulcer progression.
The ulcer development process often begins with infiltration around or at the base, followed by abscess formation, which necrotizes into an ulcer. The necrotic tissue on the ulcer surface continuously dissolves and sheds, gradually thinning the cornea and eventually leading to perforation.Perforation is generally slow, with variable location, size, and shape. The perforation site is often slightly raised, with the iris sometimes visible. Central perforation may give the cornea a slightly conical shape. The perforation rate is approximately 10%.
Sometimes, even before necrotic tissue sheds, the cornea may show "fistula disease water" phenomenon, leading to unnoticed loss of anterior chamber fluid. In other cases, small amounts of iris tissue become visible within the necrotic corneal tissue, another sign of ulcer perforation.
Once perforation occurs, inflammation gradually subsides, but in cases of larger perforations, the anterior chamber often fails to reform. Continuous shedding of necrotic tissue may expose the transparent Descemet's membrane entirely, with the iris clearly visible. Unable to withstand normal intraocular pressure, this can progress to partial or total corneal staphyloma.
When the ulcer tends to heal, eye pain decreases, irritative symptoms improve, sticky secretions disappear, the color of the ulcer changes from yellowish-white to grayish-white, the surface of the ulcer becomes clean, the surrounding epithelium grows inward, and the range of fluorescein staining narrows. Hypopyon and Tyndall phenomenon, as well as corneal posterior deposits, decrease. After the ulcer heals, infiltration and edema in the corneal stroma may still persist, often taking several months to resolve.
During the healing process of an ulcer, new blood vessels may grow into it. Slender, single branches are rare, while dense, short and thick ones are often seen around fungal hyphae foci, resembling a shrinking corneal membrane with its edge retracting inward.
Severe iridocyclitis is one of the characteristic features of fungal corneal ulcers. Approximately 50% of cases may present with hypopyon, ranging from 1 mm to 2–3 mm, with a few cases showing hypopyon filling more than half of the anterior chamber or even the entire chamber. The hypopyon appears milky white or pale yellow; the former is an early sign of the ulcer, while the latter often indicates severe inflammation. The pus is thick and difficult to move. The ulcer, abscess, and hypopyon may merge morphologically, making them hard to distinguish without slit-lamp cross-sectional examination.
There are two types of corneal precipitates. One is brown-gray, powdery, or fine granular, often seen in early-stage ulcers with small affected areas, where the anterior chamber mostly contains no or only a small amount of pus. The other type is pale yellow, paste-like patches or gray-white plaques adhering to the rough corneal endothelium, usually accompanied by hypopyon. If the hypopyon fails to resolve, it may eventually form organized membranes in the anterior chamber angle, iris, or on the lens surface.
Even after a fungal corneal ulcer has healed, with epithelial regrowth and no fluorescein staining, recurrence is still possible in the short term, which distinguishes it from bacterial ulcers.
The diagnosis of fungal corneal ulcer is relatively difficult and should generally be approached from the following three aspects.
1. **Medical History**: Patients with any of the following conditions should undergo further pathogen examination: - Rural patients with a history of agricultural trauma (e.g., rice husk injury), corneal inflammation, or foreign body removal before onset. - Patients whose ulcers remain uncontrolled after prolonged use of multiple antibiotics (topical drops or subconjunctival injections).
2. **Symptoms and Signs**: - White, yellowish-white, or grayish-white ulcers often accompanied by hypopyon, with a relatively chronic progression compared to the disease course. - Ocular irritation symptoms are relatively mild compared to the size of the ulcer.
3. **Pathogens**: - Scraping and microscopic examination of necrotic tissue from the ulcer may reveal fungal hyphae. Inoculating the scrapings onto fungal culture media may yield fungal growth. - Cell cultures are generally negative or show only contamination.
**Methods for Fungal Examination**: The most reliable diagnostic evidence is the detection of fungal hyphae in smears of necrotic tissue from the ulcer surface or fungal growth in cultures of the necrotic tissue. **Specimen Collection Method**: 1. Apply topical anesthesia. 2. Use a sharp blade to scrape a small piece (0.5 mm in diameter) of necrotic tissue from the dense infiltrated area of the ulcer as a specimen. 3. First perform a potassium hydroxide (KOH) smear examination. If additional specimen is available, proceed with fungal culture simultaneously. 4. Avoid excessive trauma to the pupillary area of the cornea and refrain from sampling deep within the ulcer to prevent perforation.
During specimen scraping, preliminary differentiation between fungal and bacterial ulcers can sometimes be made: - **Fungal ulcers**: Necrotic tissue appears "mossy" or "toothpaste-like," loose in texture, and lacks adhesiveness. - **Bacterial ulcers**: Necrotic tissue appears "gelatinous" and is highly adhesive.
**(1) Fungal Smear Method**: - Place a small piece of necrotic tissue on a glass slide. - Add a drop of 5% potassium hydroxide (KOH) solution and cover with a coverslip, applying slight pressure. - Examine under high-power microscopy to identify fungal hyphae. - Abundant hyphae may fill the field of view, while sparse hyphae require careful scrutiny. - A positive smear generally confirms the diagnosis. - Specimens must be examined immediately and cannot be stored.
**(2) Fungal Culture Method**: - Place a small piece of necrotic tissue on solid potato or Sabouraud’s agar slant media. - Inoculating multiple media simultaneously can improve the positive culture rate. - Incubate at 37°C and observe daily. Fungal growth may appear as early as the next day. - If no growth is observed after one week, the result is negative. - Culture allows observation of fungal colony morphology and pigmentation, microscopic examination of hyphae and spores for species identification, strain preservation, and drug sensitivity testing. - The positive rate of culture is generally lower than that of smears.
bubble_chart Treatment Measures
Treatment must be prompt. During the ulcer stage, when fungal growth is highly active, drugs sensitive to the fungi should be the first choice. Since fungi often lurk within the corneal tissue and are highly stubborn, the medication must maintain continuous contact with the ulcer surface, guiding the drug to reach sufficient concentration in the deep tissues to eliminate or inhibit fungal activity. So far, the drugs used to treat fungal corneal ulcers are still not ideal. For cases where drug treatment is ineffective, surgery is still required.
The commonly used antifungal drugs are as follows.
1. Amphotericin B is currently a widely used antifungal drug both domestically and internationally. In recent years, domestically produced versions have become available in Shanghai and other areas. The concentration for eye drops is 0.2%, and for ointment, it is 1%. Our hospital has treated over 40 cases with a cure rate of 50–60%.
2. Mercury compounds: 0.1% merthiolate (thimerosal) or 0.01% phenyl mercuric nitrate have shown some effectiveness. Our hospital treated 20 cases of early mild conditions with a cure rate of around 70%.
3. Garlic (Allium sativum): Also has some efficacy against fungi. We used 0.1% eye drops to treat several cases, achieving cures, but the strong irritation to the eyes often made patients reluctant to continue treatment.
Other drugs include 30% sulfacetamide solution, 1–2% potassium iodide solution, and 50,000 units/mL nystatin (mycostatin) solution.
In recent years, some new antifungal drugs have been reported, such as trichomycin, pimaricin, and clotrimazole. However, due to differences in pathogenic strains and treatment methods, clinical evaluations of these drugs vary widely.
In the spring of 1973, the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, discovered a new antifungal antibiotic named aureofuscin. In vitro tests and stirred pulse experiments confirmed its broad-spectrum antifungal effects. The concentration for eye drops is 0.1%, administered every half hour; the ointment concentration is 1%, applied every two hours. After long-term clinical trials in our hospital, over 300 cases were treated with a cure rate of 75–80% and an effectiveness rate exceeding 90%. It is currently a relatively effective antifungal drug and may be widely adopted.
This condition is often accompanied by severe iridocyclitis, requiring full dilation of the pupil with atropine. Corticosteroids can exacerbate ulcer spread and should not be used, whether locally or systemically.
For cases of ulcer perforation or descemetocele, after applying aureofuscin ointment or amphotericin B ointment in the conjunctival sac, a pressure bandage should be applied to promote ulcer healing.
For cases where drug treatment fails, conjunctival flap coverage or penetrating keratoplasty may be performed. During penetrating keratoplasty, the ulcer and adjacent unhealthy tissue must be completely removed. Leaving infected corneal tissue may accelerate the spread of inflammation.
Some ulcer morphologies closely resemble bacterial ones, necessitating careful clinical examination and pathogen diagnosis to differentiate them from bacterial corneal ulcers (Table 10-4).
Table 10-4 Differentiation Between Bacterial Corneal Ulcer and Fungal Corneal Ulcer
| Bacterial Corneal Ulcer | Fungal Corneal Ulcer | |
| Ulcer Formation | Ulcers are often round, with uniform infiltration density. Infiltration is denser in the central area of the ulcer. | Ulcers are mostly irregular in shape, with uneven infiltration density. |
| Ulcer Surface | The surface is smooth, moist, arched, and glossy. Necrotic tissue is sticky and difficult to scrape off. | The surface is rough, uniformly raised, with poor gloss and a dry sensation. There is "moss-like" or "toothpaste-like" necrotic tissue, non-sticky and easy to scrape off. |
| Ulcer Nature | Ulcers are "soft," gray-white or gray-yellow, with surrounding corneal stroma primarily cloudy due to edema, followed by infiltration. The cornea is noticeably thickened. | Ulcers are "hard," white, yellowish-white, or gray-white. Stromal cloudiness is primarily due to infiltration, followed by edema. Corneal thickening is not obvious. |
| Ulcer Edge | Ulcer edges are neat, with a blurred, hazy boundary between the ulcer and healthy corneal tissue. The ulcer spreads outward from the edges. | Ulcer edges are irregular, with a clear boundary between the ulcer and healthy corneal tissue. When expanding, the ulcer may first develop isolated nodular infiltration points or extend root-like stromal infiltration branches. |
