A variety of inflammatory diseases may affect the ocular surface and lead to both conjunctival and limbal stem cell deficiency (LSCD), as well as additional effects on the cornea.¹ Etiologies of inflammatory ocular surface disease (OSD) include dry eye disease (Sjogren’s syndrome, rosacea, meibomian gland dysfunction), infectious (trachoma, herpes simplex), allergic (atopic and vernal keratoconjunctivitis [AKC/VKC]), Stevens-Johnson Syndrome (SJS), mucous membrane pemphigoid (MMP), traumatic (chemical/thermal injuries) and iatrogenic (mitomycin C, drops, multiple surgeries, radiation).

A detailed history and slit lamp examination of the ocular surface can identify most differentiating features of the diverse etiologies (i.e., rash following drug or infection exposure, or cicatricial findings with older age). However, the diagnosis of conjunctival and LSCD can often be overlooked, especially when there are only subtle signs present on examination.

HOW TO DIAGNOSE

Conjunctiva

The conjunctiva can often be used to monitor inflammation. Actively inflamed conjunctiva is characterized by injection, chemosis and the presence of immune mediators.² Chronic and severe conjunctival inflammation can lead to irreversible changes such as deficiency of the goblet cell, mucin and accessory tear gland; subepithelial fibrosis; symblepharon/ankyloblepharon formation; forniceal foreshortening; LSCD; and surface keratinization.³ On examination, fluorescein staining can help identify conjunctival damage, especially epithelial sloughing (e.g., involved areas in acute SJS). Keratinized areas can have a waxy, shiny appearance (Figure 1A, page 23) and cause fluorescein to bead like water droplets. Rose bengal and lissamine green stains identify devitalized cells and areas lacking mucin that are not adequately protected by the tear film.² Eyelid malposition should be noted, and eversion will detect subepithelial fibrosis, symblepharon and foreshortening.

Cornea

Limbal stem cells regulate the renewal of stratified, non-keratinized epithelium, which covers a healthy cornea.¹ Destruction or dysfunction of these cells leads to LSCD, manifesting as corneal conjunctivalization, persistent epithelial defects, scarring, ulceration, neovascularization, chronic pain, keratoplasty failure and ultimately loss of vision. On examination, conjunctivalization is the most reliable diagnostic exam finding.⁴ This is best visualized by late fluorescein staining; as the conjunctival epithelium is more permeable than corneal epithelium, it is seen as a whorl-like pattern of fluorescein uptake increasing over time with areas of negative fluorescein staining from the abnormal conjunctival epithelial elevation (Figures 1B and 1C, page 23).

Another sign is loss of the palisades of Vogt. About 30 years ago, during the early understanding of LSCD, impression cytology was needed to identify and diagnose LSCD; however, now a positive impression cytology result can confirm a diagnosis of LSCD, but a negative result cannot rule it out.⁴ Certain imaging techniques (e.g., confocal microscopy, optical coherence tomography) may show future benefits in diagnosing LSCD, but currently are not standard diagnostic methods in clinical practice.

HOW TO TREAT

Therapy

Minimizing damage from acute conjunctival inflammation is important to prevent the sequelae of conjunctival deficiency.⁵

In addition to treating the underlying etiology, therapy may include aggressive lubrication, topical and systemic corticosteroids, topical anti-inflammatory agents (such as cyclosporine, lifitegrast [Xiidra, Shire]), systemic immunomodulators and amniotic membrane grafts. Control of chronic inflammation with systemic immunosuppression may be necessary in certain diseases, such as MMP, SJS and AKC/VKC.

Contributing factors

Medical treatment should aim to eliminate reversible factors contributing to LSCD, such as contact lens wear, toxic topical medications, severe dry eye, as well as optimizing the tear film, minimizing inflammation and promoting differentiation of healthy epithelium.⁶ Non-preservative topical lubricants (e.g., artificial tears, gels or ointments), punctal occlusion, bandage soft contact lenses (temporary) and scleral contact lenses (long term) help prevent desiccation.

Additionally, oral omega-3 fatty acid supplements, topical agents (e.g., vitamin A, autologous serum, and anti-inflammatory agents [as above]) and amniotic membrane products can promote a healthier surface. Systemic immunomodulators may be necessary in severe disease. Tarsorrhaphies are often underutilized to heal persistent epithelial defects and prevent exposure-related complications.

Surgical treatment

Partial, sectoral LSCD (involving a few clock hours) can be treated with superficial keratectomy of the involved area, combined with an amniotic membrane graft.

In considering surgical options for severe LSCD, it is important to not perform a keratoplasty without first addressing the LSCD, which carries a high risk of non-rejection and rejection keratoplasty failure.⁷ To increase success, the ocular surface and conjunctival inflammation should be quiet for months (or, in LSCD caused by chemical or thermal injuries, up to 12 months) prior to ocular surface stem cell transplantation (OSST); this may require topical and systemic immunosuppression.⁵ Keratinization, severe dry eye and inflammatory OSD are risk factors for OSST failure. Additionally, it is crucial to preoperatively treat glaucoma — even with early drainage device placement — and eyelid/forniceal abnormalities.⁵

Factors for OSST

The most appropriate OSST procedure is determined by several factors, such as disease etiology, laterality, conjunctival involvement, available family donors and general patient health. Certain acquired causes of LSCD (i.e., chemical injury, thermal injury and iatrogenic) may be truly unilateral, and conjunctival limbal autograft (CLAU) is ideal for rehabilitating severe unilateral conjunctival and LSCD.⁵ Simple limbal epithelial transplantation (SLET) and cultivated limbal epithelial transplantation (CLET) have also shown efficacy in treating unilateral LSCD.^8.9

Options for severe bilateral disease include keratolimbal allograft (KLAL, diseased donor), living-related conjunctival limbal allograft (lr-CLAL, living relative donor) and combination procedures (such as Cincinnati procedure).⁵ Conversely, only a few studies have demonstrated the long-term outcomes of allograft CLET and SLET. Both CLAU and lr-CLAL provide goblet cells and fresh conjunctiva in addition to stem cells; this may be ideal for pathology causing both conjunctival and LSCD. Systemic immunosuppression is necessary for allograft procedures, given the limbal vasculature and increased number of Langerhans cells; it is highly recommended to comanage with an organ transplant specialist with immunosuppression medication experience.

Once the ocular surface has been stabilized for three months following OSST, an optical keratoplasty can improve vision if there is significant residual stromal scarring.⁷ A keratoprosthesis is a viable option for patients with inflammatory OSD, especially in the setting of older age or poor health; however, like OSST, inflammatory OSD has a poorer prognosis with keratoprosthesis.

CONCLUSION

Inflammation of the ocular surface can be caused by a variety of etiologies. Identifying conjunctival and LSCD allows the clinician to appropriately treat and manage these difficult diseases. OSST, often needing systemic immunosuppression, can achieve long-term ocular surface stability and improved visual outcomes, even in severe disease. OM

REFERENCES

1. Biber JM. Classification of Ocular Surface Disease. In: Holland EJ, Mannis MJ, Lee WB, eds. Ocular Surface Disease: Cornea, Conjunctiva and Tear Film. New York, NY: Elsevier; 2013:35-44.
2. Jeng BH. Diagnostic Techniques in Ocular Surface Disease. In: Holland EJ, Mannis MJ, Lee WB, eds. Ocular Surface Disease: Cornea, Conjunctiva and Tear Film. New York, NY: Elsevier; 2013:47-54.
3. Vieira A, Mannis MJ. Oculodermal Surface Disease. In: Holland EJ, Mannis MJ, Lee WB, eds. Ocular Surface Disease: Cornea, Conjunctiva and Tear Film. New York, NY: Elsevier; 2013:171-178.
4. Kim KH, Mian SI. Diagnosis of corneal limbal stem cell deficiency. Curr Opin Ophthalmol. 2017;28:355-362.
5. Holland EJ, Schwartz GS. The Paton lecture: Ocular surface transplantation: 10 years’ experience. Cornea. 2004;23:425-431.
6. Kim BY, Riaz KM, Bakhtiari P, et al. Medically reversible limbal stem cell disease: clinical features and management strategies. Ophthalmology 2014;121:2053-2058.
7. Sepsakos L, Cheung AY, Holland EJ. Outcomes of Keratoplasty After Ocular Surface Stem Cell Transplantation. Cornea. 2017;36:1025-1030.
8. Sangwan VS, Basu S, MacNeil S, Balasubramanian D. Simple limbal epithelial transplantation (SLET): a novel surgical technique for the treatment of unilateral limbal stem cell deficiency. Br J Ophthalmol. 2012;96:931-934.
9. Pellegrini G, Traverso CE, Franzi AT, et al. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet. 1997;349:990-993.

About the Author

Albert Cheung, MD, is currently in private practice at Virginia Eye Consultants in Norfolk and on faculty at Eastern Virginia Medical School, Department of Ophthalmology. Contact him at: acheung@vec2020.com.

Financial disclosures: Dr. Cheung reports no financial relationships.