Introduction
Chemical exposure to the eye can result in trauma ranging from mild irritation to severe damage of the ocular surface and anterior segment with permanent vision loss. Chemical burns constitute 7.7%–18% of all ocular trauma. The majority of victims are young men. Injuries usually are caused by accidents at work or home but also may be deliberately caused by assault. Many victims report not wearing proper eye protection at the time of the injury. In the household setting, numerous chemicals exist in the form of solutions in automobile batteries, pool cleaners, detergents, ammonia, bleach, and drain cleaners. Although most injuries caused by these are mild with minimal sequelae, but in severe cases, management can be a challenge ( Fig. 4.26.1 ).
Alkali Injuries
Alkali injuries occur more frequently and are more severe than acid injuries. Alkalis penetrate more readily into the eye compared with acids, damaging the stroma and the endothelium, as well as intraocular structures, such as the iris, lens, and ciliary body. Common causes of alkali injury include ammonia (NH 3 ), lye (NaOH), lime (CaOH] 2 ), potassium hydroxide (KOH), and magnesium hydroxide (Mg(OH) 2 ). Lime, found in cement and plaster, is the most common cause of alkali injury. Damage from lime injury is limited, however, because of the precipitation of calcium soaps that limit further penetration. Lye and ammonia are associated with the most severe alkali injuries. Ammonia can be detected in the anterior chamber with a rise in aqueous humor pH within seconds of exposure. Irreversible intraocular damage has been noted to occur at aqueous pH levels of 11.5 or greater.
Acid Injuries
Acids cause superficial damage but generally cause less severe ocular injury than alkalis, as the immediate precipitation of epithelial proteins offers some protection by acting as a barrier to intraocular penetration. Very strong or concentrated acids, however, can penetrate the eye just as readily as alkaline solutions. Sulfuric (H 2 SO 4 ), sulfurous (H 2 SO 3 ), hydrochloric (HCl), nitric (HNO 3 ), acetic (CH 3 COOH), formic (CH 2 O 2 ), and hydrofluoric (HF) acids are frequent causes of acid burns. The most common cause is sulfuric acid, which is found in industrial cleaners and automobile batteries. Hydrofluoric acid causes the most serious acid injuries because of its low molecular weight, which allows easier stromal penetration. The injury may be compounded by thermal burns from heat generated by the acid’s reaction with water on the tear film.
Pathophysiology
The severity of ocular injury from alkali or acid is related to the type of chemical, the concentration of the solution, the surface area of contact, the duration of exposure, and the degree of penetration. The hydroxyl ion (OH − ) of alkaline solutions saponifies fatty acids in cell membranes leading to cell lysis, with subsequent hydrolysis and denaturation of proteoglycans and stromal collagen. The hydrogen ion (H + ) of acidic solutions alters the pH, whereas the anion causes protein binding and precipitation in the corneal epithelium and superficial stroma. This protein precipitation produces the typical ground-glass appearance of the epithelium and acts as a barrier to further penetration. If penetration of either alkali or acid occurs, the hydration of glycosaminoglycans leads to loss of stromal clarity. Loss of proteoglycans from the stroma results in shrinkage of collagen and can lead to an acute rise in intraocular pressure (IOP) as a result of distortion of the trabecular meshwork. The release of prostaglandins also contributes to the rise in IOP following alkali and acid injuries. Chemical penetration into the eye may acutely damage stromal keratocytes, stromal nerve endings, corneal endothelium, iris, trabecular meshwork, and ciliary body.
In addition to corneal and intraocular injury, chemical burns result in damage to the conjunctiva, limbus, and eyelids. Damage to palpebral and bulbar conjunctiva can lead to loss of goblet cells and chronic dry eye disease. Ischemic necrosis of the conjunctiva causes loss of vascularization at the limbus and loss of limbal stem cells, as well as infiltration of leukocytes. Damage to the corneal epithelium with injury solely to Bowman’s layer and anterior stroma may lead to recurrent corneal erosions. Damage to the limbal stem cells, however, can result in persistent corneal epithelial defects, conjunctivalization of the cornea, presence of goblet cells within the corneal epithelium, and superficial and deep neovascularization. Late sequelae of severe burns include cicatrization of the conjunctiva with symblepharon formation and entropion. Coagulation of the posterior lid margin may cause posterior displacement of meibomian gland orifices with trichiasis.
After a chemical burn, breakdown of the blood–aqueous barrier may result in a severe fibrinous inflammatory reaction. Damage to the ciliary body epithelium can cause decreased secretion of ascorbate, resulting in impaired keratocyte collagen synthesis and deficient stromal repair because ascorbate is a cofactor in the rate-limiting step in collagen synthesis.
Within 12–24 hours of injury, conjunctival necrosis and hydrolysis of cellular and extracellular proteins produce chemotactic inflammatory mediators that stimulate the infiltration of the peripheral cornea with neutrophils. The neutrophils potentiate surface inflammation and release a variety of degradative enzymes such as N -acetylglucosaminidase and cathepsin-D. Damage to the corneal stroma is mediated by the interaction among keratocytes, epithelial cells, and neutrophils. Stromal repair is marked by a balance between collagen synthesis and degradation. Keratocytes are multipotent cells capable of producing new type I collagen as well as type I collagenase, a matrix metalloproteinase (MMP). MMPs are enzymes that can degrade matrix macromolecules, such as collagen. The three major groups of MMPs include collagenases, gelatinases, and stromelysins. Keratocyte activity may be regulated by cytokines from epithelial cells, inflammatory cells, and other keratocytes. A close interaction exists between keratocytes and the overlying epithelial cells; type I collagenase production by keratocytes is both stimulated and inhibited by epithelial cytokines.
Clinical Course
McCulley divided the course of chemical injury into four distinct phases: immediate, acute (0–7 days), early reparative (7–21 days), and late reparative (after 21 days). Clinical findings immediately following chemical exposure can be used to assess the severity and prognosis of the injury. The Roper-Hall classification system ( Table 4.26.1 ) provides a prognostic guideline based on corneal appearance and extent of limbal ischemia. In grade I injury, there is corneal epithelial damage, no corneal opacity, no limbal ischemia, and a good prognosis. In grade II injury, the cornea is hazy but iris details are visible. Ischemia involves less than one third of the limbus, and the prognosis is good. In grade III injury, there is total epithelial loss, stromal haze obscuring iris details, and ischemia of one third to one half of the limbus, and the prognosis is guarded. In grade IV injury, the cornea is opaque with no view of the iris or pupil, the ischemia is greater than one half of the limbus, and the prognosis is poor.
| Grade | Prognosis | Conjunctival Involvement | Corneal Involvement |
|---|---|---|---|
| I | Good | None | Epithelial damage |
| II | Good | Less than 33% limbal ischemia | Stromal haze present but iris details visible |
| III | Guarded | 33%–50% limbal ischemia | Total epithelial loss, stromal haze obscures iris details |
| IV | Poor | Greater than 50% limbal ischemia | Cornea opaque, iris and pupil obscured |
In the acute phase during the first week, grade I injuries heal, whereas in grade II injuries, corneal clarity is recovered slowly. Grade III and IV injuries have little or no re-epithelization, with no collagenolysis or vascularization. IOP may be elevated as a result of inflammation and mechanical distortion of the trabecular meshwork or decreased because of ciliary body damage. During the early reparative phase, re-epithelization is completed in grade II injury, with clearing of opacification. In more severe cases, delayed or arrested re-epithelization may occur. Keratocyte proliferation occurs with production of collagen and collagenase, resulting in progressive thinning and potential for perforation.
In the late reparative phase, re-epithelization patterns divide injured eyes into two groups. In the first group, epithelization is complete or is nearly complete, with sparing of limbal stem cells. Corneal anesthesia, goblet cell and mucin abnormalities, and irregular epithelial basement membrane regeneration may persist. In the second group, limbal stem cell damage is present, resulting in corneal re-epithelization by conjunctival epithelium. This group has the worst prognosis with severe ocular surface damage characterized by vascularization and scarring, goblet cell and mucin deficiency, and recurrent or persistent erosions. Ocular surface abnormalities may be exacerbated by symblepharon formation, cicatricial entropion, and trichiasis. A fibrovascular pannus results if ulceration does not occur, compromising visual rehabilitation.
In 2001, Dua proposed a new classification system ( Table 4.26.2 ) accounting for more recent advances in surgical treatment of ocular surface burns and the resultant limbal stem cell deficiency. This system is based on clock hours of limbal involvement and percentage of total bulbar conjunctival involvement, and unlike the Roper-Hall classification system, is not based on the degree of corneal stromal haze. The Dua classification system subdivides grade IV Roper-Hall injuries into three additional categories (grades IV, V, and VI) and provides more up-to-date prognostic information for the most severe ocular surface burns. It also includes an analog scale, which allows for more nuanced and flexible recording of injury severity.
| Grade | Prognosis | Limbal Involvement | Conjunctival Involvement | Analog Scale |
|---|---|---|---|---|
| I | Very good | 0 clock hours (none) | 0% (none) | 0.0% |
| II | Good | Less than 3 clock hours | <30% | 0.1–3/1–29.9% |
| III | Good | 3–6 clock hours | >30%–50% | 3.1–6/31–50% |
| IV | Good to guarded | 6–9 clock hours | >50%–75% | 6.1–9/51%–75% |
| V | Guarded to poor | 9–<12 clock hours | >75%–< 100% | 9.1–11.9/75.1–99.9% |
| VI | Very poor | 12 clock hours (total) | 100% (total) | 12/100% |
Therapy
Immediate Phase
Because the area and duration of contact determines the extent of subsequent injury and prognosis, immediate copious irrigation upon exposure is of paramount importance. Irrigation should be continued for at least 15 minutes with at least 1 L of irrigant, until the pH of the ocular surface reaches neutrality. Currently available solutions include normal saline, borate-buffered saline, balanced salt solution, phosphate-buffered saline, lactated Ringer’s, and amphoteric solutions that aim to chelate acids and alkalis and create a reverse osmotic gradient to draw chemicals out of the cornea. Some authors discourage the use of phosphate-buffered saline, which may lead to precipitation of calcium in the corneal stroma. Borate-buffered saline and amphoteric solutions were found to be most effective in reducing aqueous humor pH after an alkali burn. Normal saline and tap water were found to be intermediately effective, and phosphate buffered saline and lactated Ringer’s were found to have the least effective buffering capacity. If access to commercial irrigating solutions is not immediately available, tap water should be used despite the fact that it is hypo-osmolar and may contribute to corneal edema. If an acid burn is suspected, a base should never be used for irrigation in an effort to neutralize the acid. A retained reservoir of chemical in the fornices should be suspected if neutrality cannot be achieved, especially with exposure to lime, which can be embedded in the fornices and the upper tarsal conjunctiva. Eversion of the lids and removal of particulate matter should be performed; a cotton-tipped applicator soaked in ethylenediaminetetraacetic acid 1% may help with the removal of stubborn lime particles. Necrotic corneal and conjunctival tissues should be debrided to promote re-epithelization because this debris provides a stimulus for continued inflammation with recruitment of neutrophils and mucous membrane pemphigoid production.
Acute and Reparative Phases
After irrigation, all efforts should be made to promote epithelial wound healing, prevent infection, reduce inflammation, minimize ulceration, and control intraocular pressure. Topical antibiotics should be used if there is any corneal or conjunctival epithelial defect. Topical and systemic ocular hypotensive medications may be needed. Better outcomes can be expected with prompt re-epithelization, while delayed or absent re-epithelization may require surgical intervention. Bandage contact lenses or amniotic membrane transplantation may be used to promote epithelial healing. Intensive topical corticosteroid therapy every 1–2 hours in the first 1–2 weeks decreases the inflammatory response that can delay epithelial migration, and thus helps enhance re-epithelization in the early phases of injury. Corticosteroid use in the first 10 days of injury has no adverse effect on outcome with little risk of sterile ulceration. Prolonged use of corticosteroids, however, can be deleterious since corticosteroids can blunt stromal wound repair by decreasing keratocyte migration and collagen synthesis. Beyond 2 weeks at the peak of the early reparative phase, suppression of keratocyte collagen production by continued use of corticosteroids may offset the benefits of inflammatory suppression and lead to stromal ulceration. Corticosteroid use should, therefore, be stressed in the first 2 weeks with subsequent taper as dictated by clinical examination. Medroxyprogesterone 1% is a synthetic progestogenic corticosteroid that has weaker anti-inflammatory activity compared with corticosteroids. Medroxyprogesterone inhibits collagenase, but unlike corticosteroids, it minimally suppresses stromal wound repair. As such, medroxyprogesterone can be substituted for corticosteroid after 10–14 days if worsening ulceration is of concern.
Topical ascorbate 10% drops every 2 hours, topical citrate 10% drops every 2 hours, and systemic ascorbate (2000 mg per day in divided doses) restore levels depleted from the aqueous following alkali injury. Ascorbate is a cofactor in the rate-limiting step of collagen synthesis and has been shown to decrease the incidence of stromal ulceration. Citrate is a calcium chelator that decreases intracellular calcium levels of neutrophils and thus impairs chemotaxis, phagocytosis, and release of lysosomal enzymes. Applied topically, citrate has been shown to reduce corneal ulceration and perforation. Tetracyclines have been shown to offer protection against collagenolytic degradation. Proposed mechanisms for inhibition of mucous membrane pemphigoid include suppression of neutrophil collagenase and epithelial gelatinase gene expression, inhibition of α 1 -antitrypsin degradation, and scavenging of reactive oxygen species. Autologous serum tears may also be a useful adjunct medical therapy. Topical amniotic membrane suspension drops have been shown to speed epithelial healing in animal models. Topical and subconjunctival bevacizumab as well as subconjunctival triamcinolone have been reported to decrease corneal neovascularization after alkali burns in animals.
Surgical Therapy
Surgical interventions that may help stabilize the ocular surface after severe chemical injury include tarsorrhaphy to promote epithelial healing, superficial keratectomy to remove localized corneal pannus from focal limbal stem cell deficiency, limbal stem cell transplantation for diffuse limbal stem cell deficiency, and amniotic membrane transplantation. Tenoplasty and amniotic membrane transplantation are additional strategies to aid epithelial healing, Tenoplasty attempts to re-establish vascularity to ischemic areas of the limbus and to promote re-epithelization. In this procedure, all necrotic conjunctival and episcleral tissues are excised, Tenon’s capsule is bluntly dissected, and the resultant flap with its preserved blood supply is advanced to the limbus. Limbal stem cell transplantation is covered in Chapter 4.30 .
The amniotic membrane is the innermost layer of the placenta and consists of a stromal matrix, a thick basement membrane, and a single epithelial layer. Amniotic membrane transplantation (AMT) has been found to reduce proteolytic activity, increase goblet cell density, and downregulate conjunctival and corneal fibroblasts. These actions are beneficial in restoring the ocular surface, especially in Roper-Hall grades II and III chemical burns, and may be considered in the acute or reparative phases. Success of AMT in the treatment of grade IV injury may be limited because of stem cell loss and ischemia; when used in conjunction with limbal stem cell transplantation, however, AMT may provide a substrate for stem cell proliferation and re-epithelization. The amniotic membrane has been shown in some studies to promote more rapid corneal re-epithelization and to reduce ocular surface inflammation, vascularization, and scarring. Other studies, however, show similar epithelial healing times and similar long-term outcomes whether or not AMT was performed. If surgical amniotic membrane placement in the operating room is either not possible or impractical, a sutureless cryopreserved amniotic membrane patch is commercially available preloaded in a symblepharon ring and can be easily inserted in the office or at the bedside. Freeze-dried amniotic membrane preparations also are available and can be placed on the cornea under a bandage contact lens.
Penetrating keratoplasty (PKP) and deep anterior lamellar keratoplasty (DALK) for visual rehabilitation after chemical injury can be fraught with complications. Prognosis is poor in the setting of glaucoma, hypotony, limbal stem cell dysfunction, conjunctival cicatrization, entropion, and trichiasis. If intraocular complications are minimized in the setting of an optimized ocular surface and limited deep stromal vessels, PKP or DALK may be performed with favorable results. A large-diameter PKP with or without donor limbal tissue may be considered in the acute and chronic setting. Corneal transplantation provides tectonic support in the event of an impending perforation, and the limbal stem cells of the donor address ocular surface issues. Staged surgery with limbal stem cell transplantation followed by PKP at least 6 weeks later has been shown to significantly decrease the likelihood of corneal graft failure. When it is not possible to rehabilitate the ocular surface adequately, keratoprosthesis surgery may be considered.
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