bubble_chart Overview

Corneal ulceration (or chronic serpiginous corneal ulcer), first reported by Mooren (1867), is also known as Mooren's corneal ulcer. This disease is relatively common in clinical practice, but due to unclear etiology, persistent symptoms, and the lack of specific treatment methods, it remains considered an extremely serious blinding eye disease.

bubble_chart Etiology

The exact disease cause is unknown. For a long time, many scholars have proposed various disease cause factors, but none have been confirmed. Some factors may have a certain relationship with the occurrence of the disease, but they are not fundamental disease causes. The main theories are as follows:

1. Infection theory At the beginning of this century, some suggested that rodent corneal ulcer is caused by a special Gram-positive diplobacillus. Koppe (1918) cured 3 cases using subcutaneous node bacterin, thus believing that subcutaneous node bacillus was the disease cause. Rodigina (1934) isolated a Gram-negative small bacillus similar to Zur Nedden's from the tissue of rodent corneal ulcer, seemingly supporting this infection theory, but it could not be confirmed in other cases.

By the 1940s, many scholars believed that rodent corneal ulcer was related to certain viral infections. It was thought that this lesion exhibited characteristics of viral diseases, such as no response to antibiotic treatment; the pathological changes of the ulcer being localized tissue necrosis; the presence of large mononuclear cells; and intracellular or cytoplasmic inclusion bodies found in the conjunctival and corneal epithelium of the lesions. Some cases were also accompanied by conjunctival follicular proliferation or regional lymphadenopathy.

Katsnelson suggested that the virus causing rodent corneal ulcer is not neurotropic, hence the affected cornea retains normal sensation. It was speculated that this virus might belong to the dermotropic type or a variant dermatropic virus. Corneal trauma serves as a direct or indirect predisposing factor for viral infection, with the virus or its toxins invading through the injury site or the surrounding corneal vascular network and its neovascularization, spreading along the vessels. However, no virus has been isolated from the lesion tissue to date, making this theory difficult to confirm.

2. Internal toxin theory Kuriakose (1963) found that 6 cases of rodent corneal ulcer without concurrent hookworm infection were cured of the ulcer after treatment with tetrachloroethylene for deworming, thus suggesting a link with intestinal Chinese Taxillus Herb worms. Givner (1963) mentioned using a phytopharmacologic test to confirm that the blood of rodent corneal ulcer patients contained toxins that inhibited the root growth of white hyacinth beans, suggesting these toxins were related to ulcer formation. It was further speculated that toxins produced by intestinal Chinese Taxillus Herb worms could also promote ulcer development. These toxins, absorbed into the bloodstream, were thought to accumulate in the vascular loops around the corneal limbus, reaching sufficient toxicity to cause ulceration. Katsnelson (1965) noted that while Kuriakose's hypothesis of hookworm toxins exuding from blood vessels causing ulcers could not explain cases without hookworm infection, the possibility of some toxin influencing the pathological process remained. The ulcer's slow progression, creeping advancement along the vascular invasion front, necrotic pathological changes, and clear demarcation from non-affected areas all suggested a link to the action of toxic products. Thus, this theory once received significant attention from many researchers.

3. Local nutritional and metabolic disorder theory Many have proposed that rodent corneal ulcer is caused by trigeminal nerve nutritional dysfunction, with vitamin B₁ deficiency or local nutritional impairment playing a role. However, this view contradicts the generally good nutritional status and health of most patients, making it hard to explain why the nutritional disorder would be confined to a narrow area of the corneal limbus. Additionally, the preserved sensation in the ulcer area does not align with the idea of the lesion being based on trigeminal nerve injury.

Others believe that vascular impairment factors exist in rodent corneal ulcer, relating it to periarteritis nodosa or Wegener's granulomatosis, with secondary local nutritional disturbances. However, no definitive clinical or histopathological evidence supports this.

4. Collagenase Theory Brown (1969) discovered that the collagenase activity in the conjunctival tissue at the edge of Mooren's corneal ulcer was significantly increased. He proposed that the occurrence of this disease is closely related to the collagenase activity in the conjunctival tissue. From 1972 to 1975, he further studied the pathology of the conjunctival tissue adjacent to the ulcer and measured collagenase and proteolytic enzymes. Additionally, he treated 7 cases (10 eyes) of Mooren's corneal ulcer using collagenase inhibitors and excision of the diseased conjunctiva, resulting in the cure of 8 eyes. It was also confirmed that the metabolic products produced by the cultured diseased conjunctiva, ulcerated corneal stroma, and epithelial tissue could degrade collagen and corneal glycoproteins. Brown also suggested that the abundant plasma cells in the diseased conjunctival specimens might be the source of collagenase and proteolytic enzymes or inducers of other enzyme-producing cells. Others have proposed that the active neutrophils in the ulcer area and adjacent tissues are the source of ulcer enzymes, as neutrophil granules are a specialized form of primary lysosomes containing various hydrolytic enzymes, including collagenase and glycoproteinase. The debate regarding the source of ulcer enzymes remains to be confirmed by further research.

It is still not entirely clear whether this collagenase theory is the direct cause of Mooren's corneal ulcer or a consequence of the ulcer. In other chronic corneal ulcers and alkali-burned corneal epithelium, collagenase activity is also increased. Therefore, using increased collagenase activity to explain the occurrence of Mooren's ulcer lacks specificity.

5. Autoimmune Theory Research over the past decade has shown evidence of autoimmune phenomena and immune pathology in cases of Mooren's corneal ulcer. Most scholars believe that this disease is likely an autoimmune disorder. Schaap (1969) was the first to use indirect immunofluorescence techniques to detect circulating antibodies against corneal epithelium in a patient with Mooren's corneal ulcer. Brown (1975) found a large number of plasma cells in the subepithelial tissue of the conjunctiva in affected eyes, indicating an antibody-dependent mechanism. Subsequently, direct immunofluorescence techniques revealed immunoglobulins (IgG, IgM) in the conjunctival epithelial cells of three Mooren's corneal ulcer patients. Additionally, in two active ulcer cases, complement (C₃) was found coexisting with immunoglobulins.

Mondino et al. (1978) conducted a study on cell-mediated autoimmunity in seven Mooren's corneal ulcer patients. Using the macrophage migration inhibition factor test, they demonstrated that six of these patients showed a positive reaction to corneal antigens. These results suggest that both cell-mediated and humoral autoimmunity may play significant roles in Mooren's corneal ulcer.

Some scholars believe that the immune phenomena in Mooren's corneal ulcer, particularly antibody production, are likely due to altered antigen stability in the conjunctiva and cornea following ocular tissue injury or infection. This leads to antibody production, which is not truly "autoimmune" but rather a secondary autoimmune response. The pathological progression of the ulcer begins with autoimmune dissolution of the corneal epithelium, followed by the release of collagenase, which exacerbates the dissolution and destruction of corneal stromal collagen.

Rahi (1976) proposed that the immune phenomena in Mooren's corneal ulcer depend on the active role of the complement system. The presence of C₃ in biopsy specimens suggests that this immune response belongs to complement-dependent hypersensitivity (Type II hypersensitivity).

bubble_chart Pathological Changes

Corneal ulcer is a progressive necrotic lesion of corneal tissue, often accompanied by chronic inflammatory changes. The ulcer and tissue necrosis are usually confined to the anterior half of the cornea, and the slow progression of the ulcer occurs simultaneously with the tissue repair process, resulting in characteristic histopathological changes.

Histopathological findings show that the advancing edge of the ulcer is primarily infiltrated by white blood cells, mostly lymphocytes, with a few plasma cells and polymorphonuclear leukocytes, and occasionally eosinophils. The cornea at this site is thickened, with swollen and hyperplastic epithelium, and necrotic and degenerated collagen fibers. At the overhanging edge of the ulcer, the anterior elastic membrane of the cornea remains intact, while the anterior 1/3 or 1/2 of the corneal stroma and the anterior elastic membrane are absent in the ulcer area.

In the healing ulcer area, the anterior elastic membrane is destroyed, and the anterior 1/3 to 1/2 of the corneal stroma is lost due to necrosis and sloughing, replaced by highly vascularized tissue. In the early stages, lymphocytes accumulate around the blood vessels, and in the late stage [third stage], they are replaced by fibrous tissue. The irregular base is covered by thickened epithelial cells (7–10 layers), beneath which lies a thin layer of scar tissue. Under light microscopy, this area shows numerous lymphocytes, a few plasma cells, and occasionally giant cells.

The deep stromal layer is nearly normal, with the posterior elastic membrane and endothelium intact.

The subepithelial tissue of the conjunctiva adjacent to the ulcer area is filled with plasma cells, occasionally accompanied by multinucleated cells and monocytes. The episcleral vessels are surrounded by round cell infiltration, with partial granulation tissue hyperplasia and scleral tissue defects.

The cellular infiltration is most dense in the bulbar conjunctiva near the ulcer area, gradually becoming sparser toward the center of the cornea and the periphery of the bulbar conjunctiva.

Under electron microscopy, vacuoles appear in the nuclei of some affected conjunctival epithelial cells, and many rod-shaped and racket-shaped Birbeck granules are present in the intercellular spaces of the epithelial cells. In some cases, plasma cell-like cells (Russell bodies) can also be observed.

Recent immunological studies on corneal ulcer have demonstrated elevated levels of immunoglobulins in the affected conjunctival biopsy specimens, with a general increase in IgG. Brown et al. (1976) found that during the active phase of the ulcer, immunoglobulins (IgG, IgM) and complement (C₃) coexist in the subepithelial and epithelial tissues of the conjunctiva. Indirect immunofluorescence techniques confirmed the presence of circulating antibodies in the conjunctival and corneal epithelium.

The aforementioned histopathological and immunological research results indicate that corneal ulcer aligns with the pathological changes of autoimmune disorders or cross-immune reactions triggered by viral infections, as well as the pathological changes of chronic inflammatory necrosis.

bubble_chart Clinical Manifestations

Corneal ulceration occurs worldwide, with a slightly higher incidence among people of color, and significantly higher among Black individuals compared to whites. Cases have also been reported in China, accounting for approximately 0.03% of ophthalmology outpatient visits.

It can occur at any age, but the onset tends to be earlier in Black individuals living in tropical regions, often affecting young or middle-aged adults. In China, it is more common in middle-aged and elderly individuals, though cases among young adults have also been documented. The youngest reported age of onset is 3–5 years. Males are slightly more affected, with a male-to-female ratio of about 3:2.

Most cases involve one eye, though some patients develop bilateral involvement simultaneously. In many cases, the other eye becomes affected several years after the first. International data report bilateral incidence at around 25%, while domestic reports range from 8% to 40%.

The disease typically progresses gradually, starting at the corneal limbus in the palpebral fissure zone. A superficial gray infiltration develops into a marginal ulcer, which then spreads centrally in a creeping fashion. In the early stages, the ulcer is difficult to distinguish from a simple marginal corneal ulcer. After 2–3 weeks, the advancing edge of the ulcer forms an undermined furrow with a slightly raised overhanging border, exhibiting a characteristic "gnawing" appearance. In rare cases, progressive peripheral corneal involvement leads to a ring-shaped ulcer zone. The ulcer typically erodes about half the stromal depth and rarely progresses deeper to cause Descemet's membrane bulging or perforation.

As the undermined ulcer edge advances, the remaining ulcer base is gradually covered by neovascular tissue and epithelium originating from the corneal limbus. The surface becomes uneven, slightly notched, with raised granulation tissue and scattered small infiltrates. Some cases present with scar-like features, where the advancing edge shows a gray-white infiltration line, while unaffected areas of the cornea remain intact and transparent. The ulcer continues to progress, often resistant to medication, eventually eroding the entire cornea and leading to blindness. The entire course of the disease may last 3–9 months.

Under slit-lamp examination, the progression of these lesions is more clearly visible. Unless secondary infection occurs, hypopyon is usually absent. There is typically no aqueous flare or iris inflammatory reaction.

From the onset, the condition presents with severe subjective symptoms, including intense pain, photophobia, and tearing. The pain often radiates along the distribution of the ophthalmic branch of the trigeminal nerve and is difficult to alleviate with topical anesthetics or oral analgesics. The severity of symptoms often contrasts with the mild degree of corneal congestion.

Clinically, corneal ulceration is classified into two distinct types:

1. **Malignant Type**—More common in younger patients, often bilateral, with persistent and aggressive progression. Subjective symptoms are severe, ulcer progression is rapid, and the sclera is frequently involved. The perforation rate is high, and the prognosis is poor.

2. **Benign Type**—More common in elderly patients, usually unilateral, with a relatively slower progression. Surgical interventions (such as conjunctival resection or lamellar keratoplasty) often halt disease progression, and the prognosis is relatively better.

bubble_chart Diagnosis

Based on the chronic progressive history and the typical ulcer lesion pattern, clinical diagnosis is not difficult. However, in the initial stage [first stage] of the lesion, it must be differentiated from simple marginal corneal ulcer, corneal marginal degeneration, Wegener's granulomatosis, nodular polyarteritis, or inflammatory ulcer and granuloma at the corneoscleral margin associated with lupus erythematosus.

The inflammation or ulcer caused by corneal marginal degeneration has mild symptoms and slow progression, with no undermined edge at the advancing border. The epithelium in the degenerated area remains intact, and the Descemet's membrane is prone to bulging due to degeneration, commonly occurring at the upper corneal margin.

In Wegener's granulomatosis, the lesion tends to be more on the scleral side, with granulomatous elevation in the affected scleral area and relatively large blood vessels extending into the lesion along the corneoscleral margin. The ulcer presents as a furrow-like shape without an undermined edge.

bubble_chart Treatment Measures

There are many treatment methods for Mooren's ulcer, but there is still no specific measure. Most medications and palliative therapies cannot stop the progressive development of the ulcer, and while surgical treatment can alleviate the condition and control the progression of the ulcer, the recurrence of ulcer lesions post-surgery remains a notable issue.

Currently, several main treatment methods used in clinical practice are introduced as follows:

1. Drug Therapy

(1) Immunosuppressive Therapy

① Corticosteroids: Prednisone, dexamethasone, and cortisone are commonly administered orally. Some advocate that a certain dose is required for efficacy. Topical application of cortisone acetate eye drops or subconjunctival injections should be used with caution or avoided in cases where the ulcer has a tendency to perforate. These drugs can reduce inflammatory reactions and alleviate symptoms to some extent but are detrimental to ulcer repair and may increase the risk of ulcer perforation.

② Methotrexate: 25 mg intravenous injection once a week for 5–6 consecutive weeks.

③ Cyclophosphamide: 100 mg dissolved in 10 mg of normal saline, administered intravenously once daily for 5–10 consecutive days.

(2) Collagenase Inhibitors

① Cysteine and acetylcysteine: Commonly used as a 1.5–3% solution for eye drops, 4–6 times daily. Due to the instability of the solution, it should be prepared fresh or stabilized.

② Sodium edetate: 1–2.5% solution, applied 4–6 times daily.

③ Autologous serum: Since autologous serum contains α₂ globulin, which acts as a collagenase inhibitor, it can protect the ulcer surface and stimulate corneal epithelial regeneration and tissue repair.

(3) Other Medications

① Non-steroidal anti-inflammatory drugs (NSAIDs): Such as indomethacin, aspirin, and phenylbutazone. These drugs can help alleviate symptoms.

② Chinese medicinals: Primarily aimed at clearing liver heat and removing toxin, using improving vision formula or combined with invigorating blood and resolving stasis herbs.

2. Surgical Treatment

(1) Lamellar Keratoplasty

① Partial lamellar keratoplasty (or with sclera): Often performed as crescent-shaped or annular grafts, depending on the extent and shape of the ulcer resection. The graft and recipient bed should align neatly, with the graft slightly larger (about 1 mm) than the bed. The ulcer resection should include nearby pre-lesion areas, extending about 1 mm beyond the ulcer margin. For ulcers near the corneal limbus, the resection should extend 2 mm beyond normal tissue. Although the extent of lesion involvement is often difficult to discern clinically, pathological examination confirms the presence of pre-lesions in the expanded resection area, so the resection should be larger than the lesion area.

The conjunctival lesion at the corneal limbus (including bulbar conjunctiva and episcleral tissue) should also be excised, with a width of about 5–6 mm.

For annular lamellar grafts, the peripheral edge of the central island-shaped cornea must be thoroughly cleared of unhealthy tissue due to the undermining effect of the ulcer, otherwise recurrence is highly likely.

② Total lamellar keratoplasty: Suitable for ulcers in the late stage (third stage), where the erosion is extensive, the central cornea is reduced to a "small island," the surrounding area is eroded and softened, or the ulcer occupies about 3/4 of the corneal circumference. Total lamellar keratoplasty should still include part of the sclera. The diseased cornea and conjunctiva (including affected episcleral tissue) must be completely removed.

(2) Penetrating Keratoplasty: Generally not used during the active phase of the ulcer, mainly performed at least six months after the ulcer becomes inactive, for optical purposes to improve vision. For Mooren's ulcer, subtotal penetrating keratoplasty is preferred because the remaining corneal tissue is thin, making it difficult to suture the graft to the recipient bed. Thus, a larger graft is needed to allow direct suturing to the scleral limbus tissue.

(3) Corneal Limbal Conjunctival Resection: Includes simple conjunctival resection, conjunctival resection with Tenon's capsule, or resection with episcleral tissue. In recent years, combined procedures such as ulcer excision, cauterization, cryotherapy, and conjunctival resection have been more commonly used.

The width of conjunctival membrane excision is 5-10 mm. Histopathological examination indicates that excision with a width greater than 5 mm can avoid residual pathological tissue and prevent recurrence.

The excision of conjunctival membrane and subconjunctival diseased tissue (including the bulbar fascia and episcleral tissue) is more thorough and reliable. The application of cryotherapy or cauterization to the ulcer area is more beneficial for clearing the lesion, destroying neovascularization, promoting ulcer healing, and preventing recurrence.

(4) Lamellar keratectomy The purpose of lamellar keratectomy is to completely remove the diseased tissue. It is suitable for ulcers with a relatively localized range and is not limited by corneal transplant materials, making it more convenient and feasible. However, for cases where the ulcer has eroded deeply, caution should be exercised to avoid corneal perforation due to lamellar excision.

(5) Cauterization and excision The basic principle of cauterization and excision originates from traditional Chinese medicine's hook-cutting and fire cauterization, combined with modern conjunctival excision and debridement. According to Cai Songnian's report, the efficacy of this method in treating Mooren's corneal ulcer can reach 84%.

Surgical treatment for Mooren's corneal ulcer has fundamentally shifted the passive situation of drug therapy. Since the 1960s, there have been numerous reports in the literature. The Ophthalmology Department of Zhongshan Medical College performed lamellar keratoplasty for Mooren's corneal ulcer, achieving a cure rate as high as 89.1%. In recent years, the combined application of conjunctival excision, cauterization, and cryotherapy, supplemented with immunosuppressants and collagenase inhibitors, has significantly enhanced the therapeutic effect on Mooren's corneal ulcer.