Corneal toxicity: the epithelium and stroma in iatrogenic and factitious disease

Abstract

Corneal toxicity is caused by chemical trauma and by iatrogenic and factitious disease, which are often overlooked, and which are reviewed here. The clinical signs of iatrogenic disease are usually nonspecific and identical to those resulting from other causes of surface disease. Factitious disease is either the result of mechanical trauma or the abuse of toxic eye drops. One epidemiological study, in a tertiary setting, identified 13% of keratoconjunctivitis cases as iatrogenic. Healing was prolonged taking 7-93 (median 28.5) days. Pathogenic mechanisms vary widely with different drugs and include subclinical scarring, pseudopemphigoid, drug-induced ocular cicatricial pemphigoid, and toxic follicular reactions. There is little readily available data either on the probability of the development of adverse reactions or for the comparison of different drugs. The assessment of the toxicity of topical drugs is currently by the Draize test in rabbits. New in vitro tests on human corneal epithelial cell cultures include ATP assays for cell viability, scanning EM of epithelial microvilli, and vital staining to assess cell membrane permeability and intracellular esterase. Despite their simplicity, these test systems can correlate well with clinical toxicity and provide a toxicity index for drug comparisons. Treatment requires drug withdrawal or substitution by nonpreserved and less toxic preparations. Factitious injury is rare, difficult to diagnose, and should only be considered when all other diagnoses have been excluded. Prevention requires a high level of awareness of the potential for iatrogenic disease, particularly in the high-risk setting of chronic ocular surface disease.

The 2016 Bowman Lecture Conjunctival curses: scarring conjunctivitis 30 years on

“…Blinding scarring diseases Progressive inflammatory and scarring diseases for which systemic immunomodulation is often needed for control of scarring and inflammation Mucous membrane pemphigoid (MMP) 4 Currently 60% of all CC cases in the UK are caused by MMP which now includes the conditions mucosal dominated epidermolysis bullosa acquisita, linear IgA disease and anti-laminin 332 (formerly anti-epiligrin or anti-laminin 5) pemphigoid 18 Drug-induced progressive conjunctival cicatrisation 17 A rare complication of topical medication, usually for glaucoma. A small subset of patients with these diseases develop autoantibody-positive or negative progressive conjunctival indistinguishable from MMP Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) with progressive scarring 33 Only a small subset of patients with these diseases develop autoantibody-positive or negative progressive conjunctival scarring similar to that in MMP which may continue from the acute episode or develop acutely years later…”

“…MMP may occur in these diseases and should be excluded Ocular diseases with no systemic involvement Drug induced scarring 17 Usually due to topical preservatives or unpreserved glaucoma medication and, rarely, other drugs. Inflammation resolves after withdrawing the drops and scarring stabilizes Atopic keratoconjunctivitis 3,5,122 Usually a tarsal papillary reaction in addition to scarring although this may be minimal in severe longstanding cases Trachoma 123 Tarsal scarring typical but symblepharon occurs 124 Adenoviral conjunctivitis [125][126][127] Scarring with entropion and symblepharon are occasionally present.…”

“…17 Oral acetazolamide will often be tolerated by this group of patients, at least for 1-2 weeks to confirm the diagnosis of toxicity/allergy to topical medications. If oral acetazolamide is not tolerated, topical unpreserved iopidine, to which few of these patients have been exposed, can be used as an alternative.…”

“…Active TGFβ drives critical changes in fibroblast metabolism, activation and ECM production in concert with pro-inflammatory cytokines and growth factors that affect fibroblast activity. 17 Alternatively, ALDH/RA might cause its effects through altered cellular energy metabolism via activation of TGFβ or as a consequence of the modulation of the transcription of metabolic genes. 33 The ALDH/RA metabolic pathway and these potential molecular mechanisms are described in Figure 10.…”

The role of difluprednate ophthalmic emulsion in clinical practice

“…BAK is known to break down cell walls by emulsifying membrane lipids, 37 which disrupts the tear film causing immunoallergic reactions, 38 and creates direct toxicity to corneal and conjunctival epithelial cells. Difluprednate ophthalmic emulsion does not contain BAK, and instead uses sorbic acid as a preservative.…”