NSAID-induced Corneal Melt : Clinical

Importance, Pathogenesis, And Risk

Mitigation
Basil Rigas, MD, DSca,*, Wei Huang, MDa,b,c, Robert Honkanen, MDb

Oleh : Pembimbing :

Evi Sriwahyuni dr. Moch Iwan Kurniawan, Sp. M

111 2018 2024

 Abstract
Corneal melt, an ophthalmological condition in which corneal epithelium is lost
accompanied by thinning of the corneal stroma, can lead to corneal perforation and cause loss of
vision. Corneal melt is the most serious side effect of topical Nonsteroidal Anti-inflammatory
Drugs (NSAIDs), one of the topical treatments of ocular inflammation. Nsaid-induced Corneal
Melt (NICM), initially doubted, is real, having been reported by multiple groups. NSAID dose
and duration of treatment may be important for NICM
INTRODUCTION
 Corneal melt, also known as corneal melting, is a condition in which
the corneal epithelium is lost and accompanied by thinning of the corneal
stroma. Corneal melt is associated with various conditions such as
infections, sterile inflammation, and surgical or chemical injury to the
cornea collectively a significant cause of blindness. The importance of
corneal melt derives from its clinical consequences—ocular morbidity
including loss of vision—and the paucity of efficacious treatments.
 Corneal melt has been associated with topical nonsteroidal anti-inflammatory drugs

(NSAIDs) since 1999, and this association, controversial at first,  but now generally accepted,

influences therapeutic decisions. Topical NSAIDs are important in the treatment of a wide

range of ophthalmological conditions including allergic conjunctivitis, ocular

inflammation, pain caused by ocular surgery, and cystoid macular edema after cataract

surgery.  Therefore, the association between NSAIDs and corneal melt represents a significant

challenge for ocular pharmacology.

OCULAR NSAIDS
 Effects and Side Effects
Topical ophthalmic steroids were for years the main treatment of many forms of
ocular inflammation. Steroids are thought to exert their anti-inflammatory activity by
inhibiting phospholipase A2 and its downstream cyclooxygenase (COX) and
lipoxygenase pathways.

NSAIDs, lacking corticosteroid features including its toxicity, succeeded

corticosteroids as the mainstay of the treatment for ocular inflammation. Topical
ophthalmic NSAID products approved for use in the US include diclofenac,
flurbiprofen, ketorolac, bromfenac, and nepafenac. Indomethacin is approved in
Europe.
 Therapeutic applications
As documented by several individual studies and a recent network meta-analysis, NSAIDs are

efficacious in relieving anterior chamber inflammation compared with placebo. Diclofenac,

nepafenac, ketorolac, and bromfenac demonstrated relatively greater effects than other NSAIDs.
The Food and Drug Administration has approved ophthalmic
NSAIDs for use in four areas

1. Pain and inflammation associated with cataract surgery

2. Pain associated with corneal refractive surgery

3. Inhibition of intraoperative miosis,

4. Seasonal allergic conjunctivitis (Ketorolac).

 Topical ophthalmic NSAIDs are commonly used in the treatment of
postoperative inflammation after cataract and surgical refractive procedures, such
as surgery for glaucoma, vitreoretinal diseases, and strabismus. FDA has
approved ketorolac and diclofenac for the reduction of pain and photophobia after
refractive surgery.
Side effects
The most common local adverse events of ocular NSAIDs are conjunctival stinging (at

times intense, but usually transient), burning, hyperemia, and corneal anesthesia  and the

less frequent are contact dermatitis and a local anesthetic effect.

Corneal complications of topical NSAIDs include superficial punctate keratitis, corneal

infiltrates, and epithelial defects. The most severe of all is corneal melt.
 NSAIDs reach the systemic circulation only infrequently, mainly through the nasal
mucosa.  There have been reports associating topical ophthalmic NSAIDs with systemic toxicity
such as asthma exacerbation, gastrointestinal erosions, and bleeding.  Studies in rabbits using
radiolabeled ketorolac showed that ketorolac administered to the eye was completely absorbed
systemically, but it is unclear if these findings are duplicated in humans
 THE NSAID
USE–CORNEAL MELT
ASSOCIATION
 The potential association between NSAID use and corneal melt was first reported in 1999.
Responding to a survey, members of the American Society of Cataract and Refractive Surgery
reported severe complications after topical NSAID use, including corneal melt.  
There were two press releases at that time, and Alcon suspended distribution of generic
diclofenac shortly thereafter.  This astute clinical analysis was followed by several case reports and
small case series.
In 2000, Lin and coworkers  reported on five cases of NICM after ocular surgery seen over a
four-month period, with four of them progressing to corneal perforation.
 The data summarized here make it clear that the administration of ocular NSAIDs

often requires an additional “trigger” to induce corneal melt. Therefore, recognizing

conditions that enhance the risk of NICM may be clinically important. Diabetes,

systemic immune diseases, and ocular surface diseases that compromise the cornea

appear to be risk factors. 

Role of vitamin E in corneal melt

Tocophersolan (or tocofersolan) is α-tocopheryl polyethylene glycol succinate that, in contrast

to the lipophilic natural vitamin E (α-tocopherol), is water soluble. Tocophersolan was used as an
inactive ingredient in the generic formulation of diclofenac to enhance its aqueous solubility.

In vitro observations that vitamin E succinate inhibits proliferation and migration of retinal

pigment epithelial cells  led to the speculation that tocophersolan and not diclofenac was
responsible for the corneal melt associated with its ocular use.
THE PATHOGENESIS
OF CORNEAL MELT
 The cornea is, unlike any other human tissue,
characterized by transparency, avascularity,
immunological privilege, and the highest
concentration of nerve fibers in the human body. The
corneal epithelium is maintained through constant cell
production and movement in response to cell loss.
 Memproduksi As.
Enzim fosfolipase Arakidonat
Defek Kornea
A2
(COX)

-Prostaglandi
Menyebabkan Memproduksi
-Prortasiklin
reaksi inflamasi mediator radang
-Tromboksan A2

Defek kornea akan

digantikan oleh Limbal Stem Cell Reepitelisasi
epitel baru
Two families of biochemical compounds may be directly relevant to
NICM, Eicosanoids, and MMPs. 

Matrix
Eicosanoid Metalloproteinase
Eicosanoid NSAID
 Matrix
Metalloproteinase NICM

Erosi Stroma

MMPs
• Akan menghidrosis
kolagen pada lapisan
NICM stroma
• NSAID-induced corneal
melt
MMPs • Terjadi peningkatan
• Memecah kolagen tipe ekspresi MMPs
I,II,III,IV, dan V
MMPs • Stroma kolagen tipe I
• Matrix Metalloprotein dan V NSAID
• Enzim yang bertanggung jawab
untuk degradasi komponen
matriks ekstrseluler
 PROPOSED
MECHANISM OF NICM
Proposed mechanism of NICM

The Epithelial

The Stromal
Stage
NICM appears to evolve in two stages :

1. The epithelial stage—marked by a corneal epithelial defect, reduced eicosanoid

levels, leukocyte infiltration, and matrix metalloproteinase–facilitated desquamation

2. The stromal stage, characterized by degradation of stromal collagen by activated

matrix metalloproteinases.

Further understanding of NICM and development of efficacious treatments or safer

alternatives should help eliminate this rare, but severe, side effect of ocular NSAIDs.
CORNEAL MELT INDUCED
BY DRUGS OTHER THAN
NSAIDS
 NSAIDs are not the sole drug group having corneal melt as a side effect. Several topical

and systemic drugs produce a range of changes in the cornea, with some delaying corneal

healing or producing corneal perforation.  Topical ciprofloxacin exemplifies such drugs.

Proparacaine, tetracaine, benoxinate (oxybuprocaine), and lidocaine are the most commonly

used ones. Well-tolerated when appropriately used, their abuse can cause deep corneal

infiltrates, ulceration, and even perforation.

MITIGATING THE RISK OF
CORNEAL MELT
1 • Awareness of this side effect that can no longer be discarded as
circumstantial or unproven is the first step toward risk control

2
• The frequency and duration of administration of ocular NSAIDs
should be restricted to the minimum required; their open-ended
administration should be avoided.

3
• Patients receiving topical ophthalmic NSAIDs should be monitored
closely, especially those with risk factors for corneal melt or after
ocular surgery.

4 • When corneal melt is diagnosed, NSAID eye drops should be

discontinued and aggressive and timely treatment instituted.
CONCLUSIONS
 NSAIDs are not the sole drug group having corneal melt as a side effect. Several

topical and systemic drugs produce a range of changes in the cornea, with some delaying

corneal healing or producing corneal perforation.  Topical ciprofloxacin exemplifies such

drugs.

Because of their potential for abuse, topical ocular anesthetics represent an emerging

significant cause of drug-induced corneal melt.  Proparacaine, tetracaine, benoxinate

(oxybuprocaine), and lidocaine are the most commonly used ones.

 NICM has been recognized as a significant side effect of ocular NSAIDs, thanks to the

initiative of the American Society of Cataract and Refractive Surgery and the response of its

members—a demonstration of superb professionalism and esprit de corps ! By now, several

of its features have been delineated: NICM is real, uncommon but occasionally serious, and

affects more frequently those with risk factors.

THANK
YOU