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June 27, 2019

Intravitreal Methotrexate for Recurrent Epithelial Downgrowth

Author Affiliations
  • 1Casey Eye Institute, Oregon Health & Science University, Portland
JAMA Ophthalmol. 2019;137(9):1082-1083. doi:10.1001/jamaophthalmol.2019.2151

Epithelial downgrowth is a rare but feared complication of intraocular surgery or penetrating globe trauma, characterized by the intraocular migration of epithelial cells. Despite treatment, epithelial downgrowth can lead to endothelial decompensation, angle-closure glaucoma, intractable pain, and tractional retinal detachment.1 Reported treatments include membrane peel, argon laser, excision of affected intraocular structures, and fluorouracil injection.2 Despite this, more than 50% of patients with epithelial downgrowth undergo enucleation.1

Methotrexate was originally introduced as an antineoplastic agent and later for treatment of systemic, orbital, and ocular inflammatory disorders.3 Given its antiproliferative properties, methotrexate has been used to treat other ocular conditions, including intraocular lymphoma4 and proliferative vitreoretinopathy.5 We report the novel use of intravitreal methotrexate for treatment of recurrent epithelial downgrowth that was not successfully treated with primary surgical and medical treatments.

Report of a Case

A 67-year-old man was referred for an irregular right pupil after uncomplicated cataract surgery without vitreous loss 4 years prior and YAG capsulotomy 1 year prior. The patient’s visual acuity was 20/25 in the affected eye. An examination showed a retracted inferior-temporal pupil margin with ectropion uvea and a fibrotic-appearing membrane that extended to the cataract wound, causing iris contraction (Figure 1A). The patient successfully underwent a membrane peel, and histological testing of the recovered membrane was consistent with epithelial downgrowth (Figure 2).

Figure 1.
Images of Iris
Images of Iris

A, Initial presentation; the iris membrane extends from the temporal clear corneal incision to the pupillary margin, causing ectropion uveae. B, Month 10 after first membrane peel; a slitlamp photograph shows the recurred iris membrane and ectropion uveae. C, The appearance of the eye at month 6 after the second membrane peel with additional argon laser and intracameral fluorouracil administration. Note the temporal recurrence of the iris membrane with ectropion uveae and peripheral anterior synechiae. D, Six months after the third membrane peel with additional argon laser and 2 months after a series of 12 intravitreal methotrexate injections. No recurrence of the iris membrane or ectropion uveae was noted then or 14 months after the last injection. Some cumulative inferior and temporal iris atrophy occurred as a result of surgical trauma from prior peeling of epithelial membranes.

Figure 2.
Epithelial Membrane Stains
Epithelial Membrane Stains

A, Iris epithelial membrane (hematoxylin-eosin, ×20 magnification) of the membrane removed from the iris in case of epithelial downgrowth revealed the corneal epithelium. B, Immunohistochemical stain for pancytokeratin (pancytokeratin [brown] ×20 magnification) was positive, confirming the epithelial origin of the tissue. Periodic acid–Schiff and Masson trichrome stains could not confirm a conjunctival source of the epithelium.

Despite successful removal, the membrane recurred, with repeated iris contraction into the angle at 1 month after the procedure. After 10 months of progression (Figure 1B), a repeated membrane peel was performed with the addition of argon endolaser to the membrane and injection of fluorouracil (mixed in viscoelastic) into the angle.

Again, despite aggressive peeling and these treatments, the membrane recurred and progressed, with pupil dragging, over the next 6 months (Figure 1C). An additional membrane peel and endolaser treatment was performed with the addition of intravitreal methotrexate (400 μg/0.1 mL). The patient then received an intravitreal methotrexate injection weekly for 4 weeks, followed by injections every other week to complete 12 injections total.

Fourteen months after his last injection of methotrexate, there was no membrane recurrence, peripheral iris contraction, or change in pupillary shape. The patient’s visual acuity was 20/25 in the affected eye, and his intraocular pressure remained within normal limits (Figure 1D).


This case report describes intravitreal methotrexate for treatment of epithelial downgrowth. This case was further defined as a recurrent process that did not respond to other known surgical or medical interventions.

Methotrexate is a cancer chemotherapeutic and immunosuppressant drug that works by multiple mechanisms, including antimetabolite inhibition of dihydrofolate reductase in rapidly dividing cells, increasing extracellular adenosine concentrations, and accelerating rates of T-cell apoptosis.3 Owing to its antiproliferative properties, methotrexate has been used to treat other ocular conditions, including intraocular lymphoma4 and proliferative vitreoretinopathy.5

We chose to inject the drug into the vitreous based on previous protocols4 but also based on the presumed longer half-life of some drugs in vitreous space.6 Twelve injections of intravitreal methotrexate, 400 μg/0.1 mL, were chosen to pattern previously reported protocols for treatment of intraocular lymphoma.4 Previous studies have demonstrated safety of intravitreal methotrexate.4

Intravitreal methotrexate may serve as an effective tool in treatment against epithelial downgrowth. Clinical findings were consistent with corneal epithelial downgrowth through the original clear corneal incision. Not only did this patient have resolution of epithelial downgrowth, but he also did not experience any long-term adverse effects secondary to methotrexate. Despite this, we acknowledge that because this is only a single case report, the strength of evidence to support the benefits and risks of this intervention is low. However, given this apparent success, more investigation into the safety, efficacy, and dose-response curve of this drug for various presentations of epithelial downgrowth is merited. Additionally, intravitreal methotrexate may play a role as primary intervention without the use of other agents or surgical modalities, once histological findings are confirmed.

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Article Information

Corresponding Author: Winston D. Chamberlain, MD, PhD, Casey Eye Institute, Oregon Health & Science University, 3375 SW Terwilliger Blvd, Portland, OR 97239 (chamberw@ohsu.edu).

Published Online: June 27, 2019. doi:10.1001/jamaophthalmol.2019.2151

Conflict of Interest Disclosures: The authors are supported by grant P30 EY010572 from the National Institutes of Health and unrestricted departmental funding from Research to Prevent Blindness. No other disclosures were reported.

Additional Contributions: We thank the patient for granting permission to publish this information.

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