Progressive Wave-like Corneal Epitheliopathy

Key Points at a Glance

Key Points of This Disease

• Advancing wavelike epitheliopathy (AWE) is a rare disease characterized by the formation of well-demarcated wavelike plaques on the cornea.
• Abnormal function of corneal limbal stem cells (partial limbal stem cell deficiency) is considered the basis of the pathology.
• It occurs after age 40, with no gender difference. It can be unilateral or bilateral.
• Medications (5-FU, mitomycin C, etc.), contact lenses, surgery, and inflammatory diseases are risk factors.
• Standard treatment is corneal epithelial debridement plus application of 1% silver nitrate solution, and the prognosis is good.
• It is important to exclude corneal intraepithelial neoplasia (CIN) and squamous cell carcinoma as differential diagnoses.

1. What is advancing wavelike epitheliopathy?

Advancing wavelike epitheliopathy (AWE) is a rare disease in which well-defined, thickened, rough plaques form on the cornea. It was first reported by D’Aversa et al. On slit-lamp microscopy, the plaques have a wavy or fern-like appearance and usually extend from the superior corneal limbus toward the center of the cornea.

Onset occurs after age 40, with no gender difference. It can be unilateral or bilateral. Pathological specimens of debrided epithelium show no dysplasia or cellular irregularity, and the conjunctiva is not involved.

Q Is AWE a neoplastic disease of the cornea?

A

AWE is not a neoplastic disease. Histopathologically, no dysplastic findings are observed. However, differentiation from corneal intraepithelial neoplasia (CIN) and squamous cell carcinoma is important, and confirmation by cytology of debrided tissue is necessary. For details, see the section on “Diagnosis and Examination Methods”.

2. Main symptoms and clinical findings

Subjective symptoms

The main symptom is chronic or progressive blurred vision over months to years, sometimes with periods of remission. Ocular irritation, redness, and foreign body sensation are the most common initial symptoms. Rarely, there are asymptomatic cases with only small lesions not involving the visual axis.

Clinical findings (findings confirmed by physician examination)

• Wavy plaques: Well-defined wavy plaques arise from the superior corneal limbus and extend toward the center of the cornea.
• Granular changes on the corneal surface: A granular texture is observed on the corneal surface with scleral scatter. Subepithelial opacities may also be present.
• Fluorescein staining: Shows a pattern of punctate superficial keratopathy with well-defined borders consistent with slit-lamp findings.
• Confocal microscopy findings: Atypical, elongated cells are observed. The nuclear-to-cytoplasmic (N/C) ratio is large, cell borders are indistinct, and nuclei are hyperreflective.
• No infiltration or inclusion bodies are observed. The conjunctiva is not affected.

3. Causes and Risk Factors

The etiology of AWE is not fully understood. A leading theory suggests it is an abnormal response to stimulation of corneal limbal stem cells. The following have been reported as risk factors.

• Medications: 5-fluorouracil (5-FU), mitomycin C, interferon, glaucoma eye drops, acyclovir
• Contact lenses: Both lens wear and storage solutions can be triggers.
• Surgery: Previous eye surgery may damage limbal stem cells.
• Chemical exposure: Exposure to toxic substances.
• Inflammatory diseases: Atopic dermatitis, rosacea, ocular cicatricial pemphigoid.
• Infections and trauma: Eye infections or eye injuries.

Prevention and Daily Care

• If you use contact lenses, avoid continuous wear and manage them properly.
• Using hydrogen peroxide-based disinfecting solutions may reduce irritation from lens storage solutions.
• If diagnosed with AWE, avoid the above risk factors as much as possible.

4. Diagnosis and Testing Methods

The diagnosis of AWE is primarily clinical, based on slit-lamp microscopy and confocal microscopy. Tissue obtained during treatment should be sent for cytology to confirm the diagnosis.

Diagnostic Procedures

• Slit-lamp microscopy: Evaluate the presence, distribution, and fluorescein staining pattern of the wavy plaque.
• Confocal microscopy: Assess for atypical elongated cells and changes in subepithelial nerve plexus density. Regeneration of nerve bundles after treatment can also be observed.
• Cytology: Pathological examination of scraped epithelial tissue to check for dysplasia or malignancy.

Differential Diagnosis

The differential diagnosis of AWE is broad.

• Neoplastic diseases: Corneal intraepithelial neoplasia (CIN), squamous cell carcinoma, carcinoma in situ.
• Corneal epithelial diseases: Superior limbic keratoconjunctivitis (SLK), corneal epithelial dysplasia, hereditary benign epithelial dyskeratosis, vortex microcystic dystrophy, epithelial basement membrane dystrophy.
• Others: Contact lens-related keratopathy, corneal epithelial keratinization, corneal pannus, underlying inflammatory diseases.

Q How to differentiate AWE from corneal intraepithelial neoplasia (CIN)?

A

In AWE, pathological specimens of scraped epithelium show no dysplastic findings, whereas in CIN, dysplastic cells are present within the epithelium. Cytology of tissue obtained during treatment is key to differentiation.

5. Standard Treatment

The standard treatment for AWE is corneal epithelial debridement followed by application of 1% silver nitrate solution. Silver nitrate is thought to chemically alter abnormal corneal limbal stem cells, restoring normal function. Another theory suggests that silver nitrate induces apoptosis of abnormal cells, allowing epithelial reconstruction by normal stem cells.

Treatment Procedure with Silver Nitrate

1. Instill topical anesthetic (e.g., proparacaine) eye drops.
2. Dip a cotton swab into a sterile 1% silver nitrate solution
3. Roll the swab across the limbus and the affected area
4. Irrigate thoroughly with saline solution
5. Place a bandage contact lens for 3–4 days until epithelialization is complete
6. Treat with topical antibiotics for one week

Symptoms usually resolve within two weeks of treatment. Irregular tissue is replaced by normal-appearing epithelium, and vision returns to baseline in most patients.

Other Treatments

Cryotherapy with liquid nitrogen has also been used with similar efficacy.

Topical steroids and artificial tears are ineffective for improving symptoms of AWE. Antibiotics, hypertonic saline, and bandage contact lenses alone also do not show symptom improvement.

Treatment Precautions

• Since epithelial disease often recurs within months with curettage alone, concurrent use of silver nitrate is important.
• Usually a single treatment is sufficient, but additional treatment may be needed if recurrence occurs.
• After treatment, monitor for signs of infection. Follow up within two weeks.

Q Can AWE recur after silver nitrate treatment?

A

Usually a single silver nitrate treatment results in complete resolution. In some cases, small residual epithelial plaques may be seen, but they rarely occur on the visual axis. If recurrence occurs, additional silver nitrate treatment can provide improvement.

6. Pathophysiology and Detailed Mechanism

AWE is considered a form of partial limbal stem cell dysfunction (LSCD). The corneal epithelium consists of 5 to 6 layers of cells and is dynamically maintained by the division of basal cells supplied by stem cells located in the limbus ¹⁾. Physiologically, one layer of superficial cells is shed and replaced by new cells each day.

D’Aversa et al. proposed that in AWE, abnormal limbal stem cells proliferate and migrate across the entire cornea, forming characteristic wavy plaques. Similarities between AWE and other limbal stem cell dysfunctions include:

• Common subjective symptoms such as foreign body sensation, ocular irritation, and blurred vision
• Lesion pattern spreading from the affected limbus (especially superior)
• Association with glaucoma medications, trauma, contact lenses, and ocular surgery

In AWE, effects on corneal nerves have also been noted. Confocal microscopy shows reduced density of the subepithelial nerve plexus, and regeneration of nerve bundles has been observed after treatment.

---

7. Latest Research and Future Perspectives (Investigational Reports)

For patients: Please read carefully

The following content is currently under investigation or in clinical trials and is not standard treatment available at general hospitals. This is reference information for professionals regarding future medical developments.

Due to the pathological similarity between AWE and other limbal stem cell dysfunctions, the following treatments are theoretically suggested to be potentially effective:

• Cyclosporine eye drops: May improve the microenvironment of limbal stem cells through immunomodulation
• Topical retinoids: Expected to regulate epithelial differentiation
• Interferon alpha-2b: Reported efficacy for ocular surface proliferative disorders
• Autologous serum eye drops: Contain growth factors and may promote corneal epithelial repair

Recent case reports have reported improvement with the combination of 5-FU and preservative-free artificial tears. None of these treatments have undergone formal clinical trials for AWE, and further accumulation of evidence is needed.

---

8. References

1. Ruan Y, Jiang S, Musayeva A, Pfeiffer N, Gericke A. Corneal Epithelial Stem Cells-Physiology, Pathophysiology and Therapeutic Options. Cells. 2021;10(9). doi:10.3390/cells10092302. PMID:34571952; PMCID:PMC8465583.
2. Sitto M, Moshirfar M, Blair K. Advancing Wavelike Epitheliopathy. . 2026. PMID: 32119296.
3. Moratal Peiro B, Calvo Garcia R, Soler Sanchis I, Mata Moret L, Cervera Taulet E. Advancing wavelike epitheliopathy after conjunctival intraepithelial neoplasia. Atipical case report. Arch Soc Esp Oftalmol (Engl Ed). 2022;97(6):337-339. PMID: 35676026.