Methods

This is a descriptive case series of patients with late-onset PUK following alkali ocular injury. Institutional review board and ethics committee approval was obtained for this study. Consecutive cases were selected from the PUK patients followed between 1992 and 2012 in Professor John Dart’s clinic, Cornea and External Disease Service at Moorfields Eye Hospital, London, United Kingdom. The medical records of 5 patients presenting with signs and symptom of delayed-onset PUK following ocular alkali injury were reviewed. A summary of the patients’ characteristics is reported in the Table .

None of the cases had microbiological evidence of infectious PUK or clinical and laboratory evidence of underlying autoimmune diseases, with the exception of 1 patient with a history of Crohn disease. No exposure, dry eye, or impaired corneal sensation was present in any of the eyes included in the study.

Summary of 2 representative cases is reported below. Description and images of Cases 1, 3, and 4 are reported as Supplemental Text and Supplemental Figure (available at AJO.com ).

Description of Representative Cases

Case 2

This subject suffered an alkali chemical injury (ammonia) to his right eye in 1986 at the age of 22. He had been originally seen in 1989 elsewhere for a recurrent sclerokeratitis and lipid deposition in the peripheral stroma. When he came to our attention in 1994, he had a large epithelialized descemetocele under a central tarsorrhaphy. As the corneal epithelial phenotype was found to be conjunctival according to the impression cytology cytokeratin profile, we carried out a successful lamellar keratoplasty using full-thickness tissue and including half of the donor limbus in the graft with diathermy of the major trunks of corneal neovascularization.

Unfortunately, the patient developed a recurrence of the sclerokeratitis 1 year later (1996) with lipid keratopathy and extensive stromal thinning, for which he was started on oral flurbiprofen and steroids ( Figure , Top left). Ultimately, a repeat lamellar keratoplasty was performed in June 1999, which completely epithelialized in a few weeks. In 2000 the patient began using a cosmetic contact lens, even though his visual acuity in the affected eye was 20/30 with the aid of a rigid gas-permeable contact lens.

Peripheral ulcerative sclerokeratitis associated with alkali burn: representative images of the cases included in the series (see case descriptions for details). Characteristic features of the disease, such as peripheral ucerative keratitis associated with ipsilateral anterior scleritis, are visible. (Top row) Case 2. (Bottom left) Case 5, right eye. (Bottom right) Case 5, left eye.

In the following years the patient started suffering from persistent corneal epithelial defects, leading to corneal stromal melt and ultimately a necrotizing peripheral sclerokeratitis with a large superotemporal scleral rupture and uveal prolapse in 2007 ( Figure , Top center), for which a large tectonic sclerocorneal graft was necessary (January 2007). Control of the postoperative inflammation required the use of oral immunosuppression (prednisolone 50 mg daily, cyclosporin A 150 mg twice daily, and mycophenolate 1 g twice daily), which was tapered slowly over time and discontinued in early 2009. The eye ultimately stabilized with hand motion vision, residual bullous keratopathy, and several areas of scleral thinning ( Figure , Top right, detail). Over the years the patient also developed secondary glaucoma that required topical treatment as well as diode laser cyclophotocoagulation in October 2009.

Case 5

This 29-year-old patient suffered a chemical injury to both eyes with ammonia as a result of an assault in 1996. The patient had very few ocular symptoms until late 2008, when he started experiencing increasing redness, photophobia, and discomfort in both eyes unresponsive to topical steroids. He was referred to Moorfields Eye Hospital in July 2009. At his first appointment in our clinic the patient had 20/20 vision in both eyes with bilateral posterior blepharitis and diffuse scleral injection, particularly in the inferior quadrants; inferior corneal thinning with peripheral neovascularization; and an epithelial defect in his left eye. Investigations for autoimmune disease were negative. The patient was started on topical cyclosporin A 2% and systemic immunosuppression with oral prednisolone (80 mg daily) and oral cyclosporin A (250 mg twice daily). There was complete resolution on the oral immunosuppressive treatment, which was eventually discontinued in early 2009 ( Figure , Bottom left, Bottom right) when the patient developed hepatotoxicity. Topical treatment did not control the disease, which reactivated in November 2012. On this occasion he was given another course of oral steroids (prednisolone 40 mg daily) with oral mycophenolate (1 g twice daily). Oral cyclosporin A (150 mg twice daily) was later added to the treatment to achieve better control of the inflammation. Posterior subcapsular cataract extraction was ultimately performed in both eyes with a final visual acuity of 20/30 bilaterally.

Discussion

In this case series, we present 5 cases of PUK with scleritis occurring long after an alkali (ammonia) chemical injury to the eye. This late complication of alkali injury occurred in young male subjects, was noninfectious, and was characterized by recurrent episodes of sclerokeratitis. In all cases, systemic immunosuppressive treatment was necessary to achieve long-term control of the inflammation.

Noninfectious keratitis with corneal ulceration can occur at different stages in chemical injuries, with variable etiology.

In the immediate phase (1–3 days), corneal ulceration can be caused by direct epithelial or stromal lysis and limbal ischemia with secondary stem cell deficiency. The modified Hughes classification of alkali injuries is based on the degree of stromal haze and limbal ischemia. With the exception of Case 1 (grade 4), the severity of the initial alkali injury could not be determined. However, all patients in this series had completely epithelialized after the initial alkali injury.

In the acute phase (1–3 weeks), keratitis is often secondary to the influx of leukocytes in the corneal stroma drawn by corneal neovascularization. In the late stages (>3 weeks), recurrent epithelial defects or frank ulcers are usually secondary to epithelial instability secondary to limbal stem cell deficiency or to neurotrophic/exposure damage to the ocular surface. In the cases reported in this series all ulcers occurred years after the chemical injury. None of the cases had evidence of infection, dry eye, or exposure keratopathy. Although we could assume that a variable degree of limbal stem cell deficiency was present in all cases, we do not believe that delayed-onset PUK, with associated scleritis, could have been attributable solely to partial limbal stem cell failure, as this has not been previously reported in this context.

The etiology of PUK is most frequently infectious or autoimmune. None of the patients in this series exhibited clinical or microbiological evidence of infection. There was no evidence of any autoimmune conditions associated with PUK, with the exception of Case 3 with Crohn disease, which has been associated with PUK. In this patient, we cannot exclude that the keratitis could have been secondary to inflammatory bowel disease rather than to the previous alkali injury. The patient was older than the other cases but shared a similar long interval between the chemical injury and the onset of PUK. PUK in Crohn disease usually accompanies reactivations of the intestinal inflammation; in our patient the keratitis occurred when the bowel disease was quiescent, which was the situation throughout the course of the ocular disease.

Two cases of PUK have been previously reported after mechanical ocular trauma. A case of peripheral ulcerative keratitis with necrotizing scleritis was described 1 month after surgical repair for a traumatic scleral rupture. The patient had hepatitis C and mixed cryoglobulinemia. The surgical procedure, rather than the traumatic event, seemed to be linked to the postoperative scleritis. A further case of PUK caused by a retained hard contact lens in the superior fornix was reported by Bhatt and associates. Repeated mechanical trauma or local action of bacterial endotoxins were the supposed triggers of PUK in this patient.

The immunopathogenesis of vasculitic PUK has been thoroughly investigated but not yet clarified fully. Local deposition of immune complexes, a cell-mediated and humoral autoimmune response to corneal antigens, and dysregulation of T suppressor lymphocytes have all been advocated in the initiation of the autoimmune inflammatory process. Neoangiogenesis and lymphangiogenesis occurring in the peripheral cornea provide the afferent and efferent arm for the autoimmune response, with priming of naïve lymphocytes, migration to lymphoid organs, and then homing of targeted lymphocytes to the peripheral cornea.

A similar autoimmune mechanism could be hypothesized in these cases of post–alkali injury PUK. Ammonium hydroxide, the toxic byproduct of ammonia, causes saponification of the lipid layer of cell membranes with consequent liquefactive necrosis and release of various proteins normally sequestered in subcellular compartments. Ammonium hydroxide also produces alkaline proteinases, which permanently alter the structure of proteins. Both released and altered proteins may function as autoantigens. Professional (polymorphonuclear leucocytes, monocytes) and nonprofessional (keratocytes expressing class II major histocompatibility complex) antigen-presenting cells (APCs) have both been found in alkali-burned corneas very shortly after the injury. Also, formation in the cornea of new blood and lymphatic vessels has been shown following alkali injuries. Interestingly, various circulating autoantibodies toward denatured corneal proteins have been reported in rabbits 5 weeks after alkali burns. The influx of immune cells combined with the presentation by APCs of corneal autoantigens could be the underlying process leading to development of PUK in these patients. Detection of circulating autoantibodies against corneal antigen was not performed in our patients.

In all our patients, there was a disease-free interval of several years between the alkali injury and PUK. The corneal autoimmune response may take a long period to develop and/or manifest clinically. A similarly protracted time lag occurs in the delayed-onset keratitis secondary to sulfur mustard gas exposure. Sulfur mustard is a vesicant agent consisting of an aerosol of oily droplets, which are rapidly absorbed by the ocular surface as well as other visible tissues. It causes inhibition of DNA replication and respiratory enzymes, ultimately leading to cell death. The severity of the acute ocular injury depends on the dose of exposure with keratitis, transient intraocular hypertension, anterior uveitis, and limbal ischemia characterizing the most severe cases. The acute lesions usually resolve within a few weeks. Residual corneal opacities and limbal stem cell deficiency may result from the acute exposure and cause chronic/recurrent sequelae.

In 0.5%–1% of all patients exposed to mustard gas, a delayed form of keratitis has been reported to develop 8–40 years after the initial exposures. It is characterized by recurrent episodes of limbal inflammation with associated peripheral keratitis with corneal neovascularization, lipid deposition, corneal stromal destruction, thinning, and, in some cases, perforation. Histologically, the disease closely resembles PUK. It is currently not known why only some of the eyes exposed to mustard gas develop the delayed-onset keratitis. The dose and modality of exposure as well as personal susceptibility may come into account. A local mustard gas–induced vasculitis or autoimmune process has been advocated in the pathogenesis. The clinical appearance, histology, and course of this disease are very similar to the cases hereby reported of delayed-onset alkali-induced peripheral keratitis. In both diseases, a chemical injury that occurred in the past might have triggered an autoimmune mechanism ultimately causing a late-onset PUK.

In conclusion, we report 5 cases of delayed PUK following alkali injury. To the best of our knowledge, this condition has not been described before. A putative autoimmune mechanism underlying the disease is proposed. Further studies are needed to clarify the pathogenesis and better define the therapeutic approach in this rare but sight-threatening condition.