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Editor,—Continuous renewal of the corneal epithelium is vital for the preservation of a smooth, transparent, refractile surface necessary for clear vision and ocular comfort. The regeneration of corneal epithelial cells takes place through centripetally migrating transient amplifying cells ultimately derived from stem cells located at the limbus.12 Deficiency of these progenitor cells leads to failure of epithelial cell regeneration and its replacement by invading conjunctival epithelium.3This pathological pathway is called limbal stem cell deficiency (LSCD) (see reviews Tseng4 and Tseng and Sun5). Corneal diseases with LSCD are characterised by conjunctival epithelial ingrowth, vascularisation, chronic inflammation, and fibrous ingrowth. Patients with LSCD often suffer from severe photophobia and profound loss of vision.
Cytotoxic agents such as 5-fluorouracil (FU) and mitomycin C are recognised causes of persistent epithelial defect and LSCD,6 when applied locally. Although a case of epithelial erosion arising from systemic cytotoxic therapy has been reported,7 little is currently understood about the pathophysiology of this effect. We were able to accurately correlate the clinical course of a patient with bilateral epithelial pathology arising from systemic hydroxyurea treatment with cytological and histological evidence of LSCD. We describe an unrecognised cause of both reversible and irreversible LSCD in these two eyes, respectively, and suggest that all cases of persistent corneal epithelial failure be investigated for limbal stem cell dysfunction.
A 68 year old man gave a 6 week history of bilateral keratitis prior to referral. He complained of decreased visual acuity with pain, severe photophobia, itching, and redness particularly affecting the left eye. The referring ophthalmologist had treated him with Viroptic (trifluridine, Glaxo-Wellcome Inc, NC, USA) for 3 weeks and Tobradex (tobramycin, dexamethasone, Alcon Laboratories Inc, Fort Worth, TX, USA) for 2 weeks. He had a medical history of chronic myelocytic leukaemia for which he had been treated with hydroxyurea (Roxane, Columbus, OH, USA) at 1500 mg per day for the previous 2 years. He had no other significant ophthalmic or past medical history.
At presentation, the best corrected visual acuity (BCVA) was 6/20 right eye and 6/22 left eye. Slit lamp examination of the both eyes revealed a severe diffuse punctate keratopathy with an irregular corneal epithelium and numerous areas of epithelial breakdown, but no macroepithelial lesions were seen. The fluorescein tear clearance test8 showed delayed tear clearance but no aqueous tear deficiency. Treatment was commenced with preservative-free 1% methylprednisolone (BPEI pharmacy) daily for 10 days and Refresh (polyvinyl alcohol, povidone, Allergan, Irvine, CA, USA) ointment three times daily to both eyes. No improvement was noted after 2 months, while punctate epithelial erosions increased and BCVA decreased to 6/22 in the right eye and counting fingers at 2 metres in the left eye. A severe persistent epithelial defect on the right cornea highlighted by fluorescein staining was observed (Fig 1A) and a 4 × 1 mm macroepithelial defect of the left cornea. A provisional diagnosis of bilateral corneal epithelial keratopathy secondary to chemotherapy was made. Impression cytology (IC) revealed focal LSCD localised to the temporal and inferior portion of the right cornea by exhibiting conjunctival goblet cells and mucins on the cornea and diffuse squamous metaplasia of the left cornea with partial loss of the limbal landmark area.
On the basis of the corneal pathology, and in conjunction with the oncology service, interferon injections were substituted for hydroxyurea as the leukaemia was well controlled. Two weeks later a dramatic decrease in the epithelial keratitis was noted. The right ocular surface was smooth and epithelialised as evidenced by negative fluorescein and rose bengal staining, and the BCVA returned to 6/8. The left eye became less painful with regression of the epithelial defect, but severe superficial punctuate keratopathy (SPK) still persisted, and the BCVA remained at counting fingers at 2 metres. Five weeks later, interferon intolerance led to reintroduction of hydroxyurea. Examination 18 days later revealed a mild corneal epithelial change of the right temporal cornea although the corneal epithelium remained largely intact. An epithelial defect on the left cornea measuring 6 × 4 mm was apparent (Fig 1B). Despite topical antibiotics for 5 days, and preservative-free artificial tears for 2 months, the epithelial defect still persisted on the left eye with a BCVA of counting fingers at 2 metres. Pannus formation on the inferonasal portion of the left cornea led to the diagnosis of LSCD and amniotic membrane transplantation was performed. Histological examination of the corneal pannus revealed positive PAS staining indicating the presence of goblet cell mucin on the corneal epithelium (Fig 1C). This latter finding confirmed the diagnosis of LSCD. Because of total LSCD, epithelialisation was not complete despite amniotic membrane transplantation, and a keratolimbal allograft together with a repeat AMT was performed 3 weeks later.9 Immunosuppression was achieved with systemic cyclosporin 300 mg daily and topical preservative-free methylprednisolone. Complete epithelial healing occurred within 2 weeks (Fig 1D) and 7 weeks later BCVA was 6/8 right eye 6/10 left eye.
The diagnosis of partial (right eye) and total (left eye) LSCD secondary to hydroxyurea treatment was made on the basis of the clinical presentation, and findings from IC and subsequently histopathology. This was confirmed therapeutically by the ultimate success of keratolimbal allograft, which resulted in the rapid and complete re-epithelialisation of the left cornea.
We suggest that the diagnosis of LSCD should not be overlooked in cases of idiopathic corneal epitheliopathy and that a history of the use of drugs known to affect cell cycling—for example, cytotoxic chemotherapy, be specifically sought. If possible, IC should be undertaken as an important diagnostic tool to detect LSCD and to help formulate therapeutic strategies. Once drug toxicity is suspected, cessation or switching to other non-toxic alternatives is advised. Like radiation induced LSCD,10 medical therapy to support and prevent additional attrition of the remaining corneal epithelial cells should be taken to see if the process can be reversed. Once LSCD becomes persistent and irreversible, AMT can help restore the corneal surface if LSCD is partial, but requires additional transplantation of limbal epithelial stem cells if LSCD is total.11 In this case, we chose to use an allogeneic source as the right eye of the patient we described was also limbal deficient.
Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc, New York, USA and in part by la Banque Française des Yeux, Paris, France and the TFC Frost Charitable Trust, UK.
Proprietary interest: SCGT has obtained a patent on preparation and clinical uses of amniotic membrane, and has a financial interest in Bio-Tissue.