A Review of the Diagnosis and Treatment of Limbal Stem Cell Deficiency

Abstract

Limbal stem cell deficiency (LSCD) can cause significant corneal vascularization and scarring and often results in serious visual morbidity. An early and accurate diagnosis can help prevent the same with a timely and appropriate intervention. This review aims to provide an understanding of the different diagnostic tools and presents an algorithmic approach to the management based on a comprehensive clinical examination. Although the diagnosis of LSCD usually relies on the clinical findings, they can be subjective and non-specific. In such cases, using an investigative modality offers an objective method of confirming the diagnosis. Several diagnostic tools have been described in literature, each having its own advantages and limitations. Impression cytology and in vivo confocal microscopy (IVCM) aid in the diagnosis of LSCD by detecting the presence of goblet cells. With immunohistochemistry, impression cytology can help in confirming the corneal or conjunctival source of epithelium. Both IVCM and anterior segment optical coherence tomography can help supplement the diagnosis of LSCD by characterizing the corneal and limbal epithelial changes. Once the diagnosis is established, one of various surgical techniques can be adopted for the treatment of LSCD. These surgeries aim to provide a new source of corneal epithelial stem cells and help in restoring the stability of the ocular surface. The choice of procedure depends on several factors including the involvement of the ocular adnexa, presence of systemic co-morbidities, status of the fellow eye and the comfort level of the surgeon. In LSCD with wet ocular surfaces, autologous and allogeneic limbal stem cell transplantation is preferred in unilateral and bilateral cases, respectively. Another approach in bilateral LSCD with wet ocular surfaces is the use of an autologous stem cell source of a different epithelial lineage, like oral or nasal mucosa. In eyes with bilateral LSCD with significant adnexal issues, a keratoprosthesis is the only viable option. This review provides an overview on the diagnosis and treatment of LSCD, which will help the clinician choose the best option amongst all the therapeutic modalities currently available and gives a clinical perspective on customizing the treatment for each individual case.

Keywords: Anterior segment optical coherence tomography (AS-OCT); Keratoprosthesis (KPro); Limbal stem cell deficiency (LSCD); confocal microscopy; cultivated limbal epithelial transplantation (CLET); impression cytology (IC); limbal stem cell transplantation (LSCT); simple limbal epithelial transplantation (SLET).

Figure 1

Collage of images depicting the normal ocular surface and limbus (arrows) in pigmented (A, B) and hypopigmented (C, D) eyes.

Figure 2

Collage of images illustrating different grades and etiologies of limbal stem cell deficiency (LSCD). Top row: LSCD due to chemical injury which is partial and sparing the visual axis (A), involving the visual axis (B,C). (D,E) Total LSCD in chemical injury. (F) LSCD in chronic vernal keratoconjunctivitis. Superior cornea shows Horner-Trantas dots (black arrowheads). (G) LSCD in Epidermolysis Bullosa (H) LSCD in mucous membrane pemphigoid.

Figure 3

A representative collage of various diagnostic modalities in limbal stem cell deficiency (LSCD). (A) Fluorescein-stained image showing characteristic stippled staining (yellow arrowheads). (B) Optical coherence tomography line scan showing hyperreflective epithelium indicative of LSCD (white arrowheads). (C) Impression cytology depicting Periodic acid-Schiff positive goblet cells (black arrowheads) and CK19 positive cells on immunohistochemistry (D,E) in vivo confocal microscopy showing decreased sub-basal nerve density.

Figure 4

(A) Optical coherence tomography-angiography (OCT-A) illustrating a normal limbal vasculature with hairpin looped limbal vessels (yellow arrowheads) and surrounding normal perilimbal conjunctival and episcleral vessels. (B) OCT-A in in limbal stem cell deficiency with vascular invasion of the peripheral corneal and distortion of the annular ring of hairpin looped limbal vessels (pink arrowheads).

Figure 5

(A) Partial limbal stem cell deficiency (LSCD) following chemical injury managed with conjunctival limbal autograft (CLAu). (B) Restoration of a stable ocular surface is noted. (C) Total LSCD with leucomatous corneal scarring. (D) Reestablishment of an optically clear visual axis and a stable corneal epithelium with deep anterior lamellar keratoplasty and CLAu.

Figure 6

Algorithmic approach of management of limbal stem cell deficiency (LSCD). LSCT: limbal stem cell transplantation, KPro: keratoprosthesis, MOOKP: modified osteo-odontokeratoprosthesis.

Figure 7

(A) Left eye in a case of bilateral total limbal stem cell deficiency (LSCD) with a wet surface due to Stevens-Johnson syndrome (SJS). A superior conjunctival hooding (yellow arrows) was carried out previously for microbial keratitis with a corneal perforation. (B) A Boston keratoprosthesis in the same eye. (C) Modified osteo-odontokeratoprosthesis in an eye with total LSCD and a dry ocular surface. (D) LVP KPro in an eye with SJS.

Figure 8

Algorithm for surgical technique of limbal stem cell transplantation (LSCT) PK, penetrating keratoplasty; LK, lamellar keratoplasty.

Figure 9

(A) Total LSCD with a thick pannus in a case of chronic vernal keratoconjunctivitis with hyperreflective epithelium (blue arrowheads) on the optical coherence tomography (OCT) line scan (B). (C) A stable ocular surface is observed following allogeneic simple epithelial limbal transplantation. The intact limbal tissues are also visible (pink arrowheads). (D) Restoration of epithelium with a normal reflectivity is noted on the OCT scan (yellow arrowheads).