Limbal Stem Cell Deficiency

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 by Sezen Karakus, MD on June 2, 2023.

A review of Limbal Stem Cell Deficiency, including its etiology, pathophysiology, diagnosis, and treatment.

Disease Entity

Limbal Stem Cell Deficiency


The corneal epithelium is a stratified squamous epithelium from which superficial terminal cells are naturally shed. Limbal stem cell deficiency (LSCD) is characterized by a loss or deficiency of the stem cells in the limbus that are vital for the re-population of the corneal epithelium and to the barrier function of the limbus.[1][2] When these stem cells are lost, the corneal epithelium is unable to repair and renew itself. This results in epithelial breakdown and persistent epithelial defects, corneal conjunctivalization and neovascularization, corneal scarring, and chronic inflammation. All of these contribute to loss of corneal clarity, potential vision loss, chronic pain, photophobia, and failure of keratoplasty if done before addressing this.[2][3]

Partial Conjunctivalization (Limbal Stem Cell Deficiency) - Courtesy of LV Prasad Eye Institute
Full Conjunctivalization (Limbal Stem Cell Deficiency) - Courtesy of LV Prasad Eye Institute


The etiologies can be genetic, acquired, or idiopathic.

Causes of Limbal Stem Cell Deficiency


LSCD has been associated with PAX6 gene mutations, which are also implicated in aniridia[4] and Peter’s Anomaly.[5] Other genetic disorders that have been reported with LSCD include ectrodactyly-ectodermal-dysplasia-clefting syndrome[6], keratitis-ichthyosis-deafness (KID) Syndrome[7], Xeroderma Pigmentosum[8], Dominantly Inherited Keratitis[9], Turner Syndrome[3] and Dyskeratosis Congenita.[10]



Other causes include inflammatory insults such as those seen in Steven-Johnsons Syndrome (SJS) [11], ocular cicatricial pemphigoid[12], and graft versus host disease.[13] Chronic ocular allergy, such as vernal keratoconjunctivitis, is another reported cause.[14] Neurotrophic keratopathy, whether neuronal or ischemic, can lead to this disease as well[2], as can bullous keratopathy .[15]


Any corneal infection, such as herpes keratitis[16] and trachoma, [17] can predispose to this condition.


Acquired causes also include trauma from chemical or thermal burns and prior ocular surgeries or cryotherapies performed around the limbus.[16][18] Radiation and chemotherapy are other potential causes, and systemic[19] as well as topical chemotherapeutic medications may cause LSCD.[20]  LSCD has also been seen with benzalkonium chloride toxicity with glaucoma medications.[21] Inappropriate contact lens use with consequent hypoxia and ocular irritation with the destruction of the limbus may also contribute to both focal and total LSCD.[22] [23]

Tumors/Overgrowth of Other Tissue:

Ocular surface tumors are a known cause of LSCD.[2] Pterygium may also cause a focal acquired absence of limbal stem cells.[24]

Risk Factors

Risk factors for LSCD vary according to the underlying cause, as above.

General Pathology

Pathology typically shows conjunctivalization of the cornea, which can be confirmed by the presence of goblet cells in the cornea. However, the goblet cells may not be identified in approximately one-third of patients.


LSCD is characterized by a loss or deficiency of stem cells that are vital for the re-population of the corneal epithelium.

Corneal transparency is essential for vision. The outer protective stratified corneal epithelium is continuously renewed with vigorous repair mechanisms. These mechanisms are essential as the cornea is constantly desquamating, and any trauma or loss of epithelial cells must be repaired quickly. Corneal epithelium completely regenerates every 3 to 10 days requiring constant renewal of cells.[9] The repair is essential to prevent infection and preserve vision.

Corneal stem cells are located peripherally at the limbus in the basal cell layer in pigmented crypts called the palisades of Vogt.[25] This pigmentation is thought to help protect the stem cells from ultraviolet light damage. In the normal cornea, renewal occurs from basal cells with centripetal migration of stem cells from the periphery.[26][27] This is a structure deeply related to the function of each cell. The stem cells and their progenitors require the vascular nutrition that is found in the stromal vasculature outside the cornea; thus, they must be at the periphery.[28]

Conversely, the cornea is an avascular tissue. It must remain avascular to prevent vascular structures from interfering with light transmission and, thus, vision. The limbus plays an important role in preventing vascularization of the cornea from the conjunctiva; thus, with loss of integrity of the limbus, conjunctival cells migrate to the cornea resulting in corneal neovascularization or conjunctivalization.[29][30] 

Primary Prevention

Primary prevention for LSCD varies according to the underlying cause. Contact lens overwear can be treated with the cessation of lenses and frequent lubrication.[22] Traumatic causes, either mechanical or chemical, may be avoided with the use of eye protection. Treatment of systemic inflammatory disease is necessary to prevent ocular complications. Similarly, treating severe infections before they affect the limbal stem cells is critical to avoid damage in this area.


The diagnosis of LSCD is largely made on clinical grounds. Patient history and clinical observation of corneal conjunctivalization associated with persistent epithelial defects hint strongly at LSCD.[31] Loss of the limbal anatomy and irregular staining with fluorescein, particularly increased late staining, may also be seen.[32]


Patients usually present with pain resulting from recurrent erosions and decreased vision. Other symptoms may include contact lens intolerance, photophobia, tearing, and blepharospasm.[16] The history will vary depending on the etiology. For example, a patient with LSCD from a chemical burn or trauma will give a history of such an event.

Physical examination

If left untreated, the patient with LSCD will present with recurrent epithelial erosions that lead to chronic keratitis, scarring, and calcification.[16] Delayed wound healing and corneal neovascularization occur with loss of limbal stem cells[33], and eventually, a process called conjunctivalization occurs. The corneal surface will be covered by conjunctiva-like epithelium that transforms into a cornea-like epithelium with loss of goblet cells, a process termed conjunctival transdifferentiation.[27] Patients usually suffer from recurrent erosions and decreased vision as a result of an irregular optical interface, weak tensile strength, and an incompetent barrier function.[27]


Patients present with progressive epitheliopathy with hazy, translucent epithelium extending centrally from the limbus, most commonly from the superior limbus. Epithelial staining, from punctate changes to more confluent staining, is broadest adjacent to the involved limbus and extends centripetally into the cornea to varying degrees in a whorl shape.[2] Patients often have evidence of mild to moderate tear film dysfunction, reduced tear film break-up time, or both.[21] Infectious keratitis is a common complication.[32] In late stages, superficial and deep vascularization, persistent epithelial defects leading to ulceration, melting and perforation, fibrovascular pannus, and finally, scarring, keratinization, and calcification can be seen.[34]


Eye pain and blurry vision are common complaints in this disease as the epithelial surface breaks down. Eye irritation, contact lens intolerance, and blurred or decreased vision were the most common symptoms in one study.[21]

Clinical diagnosis

A diagnosis of LSCD requires both clinical signs and symptoms of the disease along with cytological evidence.[30] Typical findings of conjunctival changes to the cornea adjacent to the limbus are a hallmark of the disease.[21]

Diagnostic procedures

Impression cytology shows conjunctivalization of the cornea, and immunohistochemical markers of conjunctiva on impression cytology of the corneal surface (e.g., absence of keratin CK3) confirms the diagnosis.[35] On impression cytology, if the corneal impression is mainly acellular or contains normal corneal epithelial cells, then it is less likely that LSCD exists. However, if the impression consists of a mixture of corneal and conjunctival epithelial cells or mainly conjunctival epithelial cells, then it is highly confirmative of LSCD.[31]

On histopathology of the affected area, there is invasion and overgrowth of conjunctival epithelium, neovascularization, disruption of the basement membrane, and prominent inflammatory cell infiltrates.[36] Pathology typically shows conjunctivalization of the cornea, which can be indicated by the presence of goblet cells in the cornea. However, goblet cells may not be seen in approximately one-third of patients.

In vivo confocal microscopy has also been used to help diagnose LSCD. Changes may include the absence of the palisades of Vogt in the affected sector, metaplastic wing and basal epithelial cells with significantly decreased basal epithelial cell density and subbasal nerve density, and replacement of normal limbal epithelium by vascular fibrotic tissues in late stages.[37]

Differential diagnosis

  • Early ulceration or peripheral infectious keratitis may resemble LSCD.
  • Pterygium may resemble LSCD and would typically be nasal or temporal. 
  • Ocular surface squamous neoplasia may be mistaken for LSCD but can be differentiated by surface markers.

See the figure above for the potential causes of LSCD, though any injury or loss of limbal stem cells or their niche may lead to this disease.


Management is typically symptom driven at the early stages of the disease. When limbal stem cell injury is transient, sometimes termed limbal stem cell disease or limbal stem cell distress, conservative medical measures as above may be sufficient.[21][31][38] However, total LSCD must be surgically managed.

Medical therapy

Medical management is aimed at restoring the limbal microenvironment with a stepwise approach based on both stopping traumatic or toxic insults to the limbus and optimizing the ocular surface by improving the tear film, controlling inflammation, and promoting differentiation of healthy epithelium.[21] This includes steps such as discontinuing contact lenses, aggressive lubrication with preservative-free artificial tears, and lid hygiene or warm compresses.[22] When the surface does not respond to such treatment, nightly topical Vitamin A ointment, short-term pulse topical corticosteroids such as methylprednisolone 1%, loteprednol etabonate 0.5% or 0.2%, or prednisolone acetate 1%, and cyclosporine 0.05% should be considered. Punctal occlusion may be performed in patients with significant aqueous tear film deficiency, and patients with rosacea may be treated with oral doxycycline.[21] Autologous serum eye drops may stimulate healing of the corneal surface.[39] A bandage contact lens, the PROSE device, or scleral lens is another option to optimize the health of the ocular surface.[40]

Medical follow up

Improvement in the ocular surface may manifest as decreased pain and increased visual acuity on follow-up examinations. Progressive epitheliopathy with hazy, translucent epithelium extending centrally from the limbus may begin to regress, as may the pattern of epithelial staining with fluorescein[21] As above if the signs and symptoms point to a true LSCD that is not improving, surgery is necessary.


Before surgical intervention, effective assessment of tear film production and eye closure is an important prerequisite to ensure optimal surgical outcomes.[30] Resection of pannus tissue and subsequent amniotic membrane transplant may be helpful with partial or focal LSCD not responding to these treatments.[41][42]

Penetrating Keratoplasty (PK) alone is not a viable option in LSCD as the donor tissue does not include limbal stem cells in such a transplant. In addition, the pre-existing corneal vascularization and inflammation increase the risk of rejection and failure in these patients.[2] Thus, while the transplanted cornea will be temporarily clear, the same problems with its restoration and repair will eventually occur unless a viable source of stem cells to repair the lost cells is found. 

Unilateral vs. Bilateral Disease:

Unilateral LSCD can be treated with autologous limbal stem cell transplants from unaffected eyes, and the benefit is that systemic immunosuppression is unnecessary.[30] However, the removal of stem cells from the contralateral eye risks LSCD in the donor eye. The risk of epithelial problems in the donor eye is low when less than four to six clock hours of limbal tissue and a moderate amount of conjunctiva are removed.[16] Allogeneic transplants from donor eyes are used when the disease is bilateral.[43] Living donor tissue is preferred as cadaveric donor tissue has worse outcomes when transplanted.[44]

Ex Vivo Cultivation:

To minimize the loss of donor limbal tissue and the possibility of inducing LSCD in the donor eye, newer techniques use ex vivo cultivated limbal epithelial cells for transplantation. In this technique, a smaller area (generally 2mm x 2mm) of donor cells is grown in the laboratory on a fibroblast culture medium or graft tissue/amniotic membrane to expand the donor cell population in an attempt to increase success rates and decrease epithelialization time.[45][46] Because using animal feeder cells, such as fibroblasts, to grow explanted cells may represent an unknown risk for a potentially undetected viral transmission, xeno-free transplants on amniotic membrane have been investigated which only use human tissues and cells.[47] 

Limbal Explant Culture.jpg

An even newer technique for unilateral disease called Simple Limbal Epithelial Transplantation (SLET) seeds donor stem cells directly on an amniotic membrane placed on the ocular surface of the recipient, altogether bypassing the need for laboratory conditions of expansion.[48] These techniques may be combined with subsequent penetrating keratoplasty to further improve visual outcomes once the limbal stem cell niche has been restored.[49]


The newest techniques for transplanting limbal stem cells involve hydrogel lenses and plasma polymer-coated contact lenses for in vivo culture and transfer of transplanted cells.[50] These are still in the testing phase in animal studies and some small human studies.

Beyond Limbal Cells:

Other options aside from keratolimbal allograft transplantation include oral mucosal epithelial transplantation. The use of keratoprostheses, such as the modified osteo–odonto keratoprosthesis and the Boston Keratoprosthesis (KPro)[51] is generally a last resort for total LSCD with poor surface and tear quality. Human embryonic stem cells, hair follicles, umbilical cord, and dental pulp stem cells all show potential in recreating the corneal phenotype, but none has been perfected to date. [30] Each of these is an attempt to recreate the ocular surface to create a clear vision.

Surgical follow up

Postoperative treatment consists of preservative-free topical antibiotics, topical immunosuppressants, and frequent preservative-free artificial tears. Steroids are rapidly tapered in autologous limbal transplantation.[16] Transplantation of an allograft poses a high risk of rejection even in HLA matched recipients. Therefore, graft survival depends on systemic immunosuppression for a prolonged, if not indefinite, period.[49][52]

During the early postoperative period, the limbal explant is carefully monitored for any areas of epithelial loss. Conjunctival epithelium can cross the explant at these sites and gain access to the corneal surface. If conjunctival encroachment is observed, mechanical debridement of conjunctival cells should be promptly carried out.[16]

Similarly, patients should be followed regularly for signs of graft rejection and treated appropriately. Signs of rejection include sectoral limbal injection, edema and infiltration of the graft, punctate keratopathy, epithelial irregularities and defects, and surface keratinization.[53][16] Risk factors for failure of graft include blink-related microtrauma, conjunctival inflammation, increased intraocular pressure, aqueous tear–deficient dry eye, lagophthalmos, and pathogenic symblepharon, all of which should be addressed at follow-up visits should they arise.[54]


Untreated LSCD causes pain, decreased vision, and recurrent epithelial erosions that predispose to infection and loss of vision. Infectious keratitis is common with this disease, and patients who wear contact lenses for extended periods of time, have persistent epithelial defects and use topical immunosuppressive medications are at increased risk.[32] After surgical treatment, there is a risk of rejection from allogeneic transplants.[49] It is possible that the cornea will not remain clear and further surgery, such as repeat stem cell transplant or penetrating keratoplasty, may be necessary.[49]


Cultivated Oral Mucosal Epithelial Transplantation (COMET):

Patients with live-related stem cell transplantation, cultivated oral mucosal epithelial transplantation (COMET), and lamellar or penetrating keratoplasty have poor outcomes even with long-term immunosuppression.[54][55][56] The use of fibrin glue rather than amniotic membrane for COMET and optimizing the ocular surface prior to transplant improved outcomes in a recent study, and it is possible that future modifications to the technique may improve these outcomes further.[57]

Cultivated Limbal Epithelial Transplantation (CLET):

Studies have shown that CLET is as effective as direct limbal transplantation for LSCD while requiring less donor tissue and thus being safer for donor eyes.[45][58][59][60][61] Studies of CLET have shown a 68-80% success rate.[62][63]  In a review of outcomes of cultured limbal epithelial cell therapy published from 1997 to 2011 with data from 583 patients, the overall success rate was 76%.[60] However, the success rate of a transplant is significantly higher with an increased number of transplanted stem cells and failures tend to happen within the first year.[63]

The largest study of xeno-free explant culture transplants showed a 71% success rate in 200 recipient eyes with a mean follow-up of approximately 5 years and up to 10 years.[46][49] Supplemental corneal transplant (PK) has a survival rate of 1 year, with a median survival of 3.3 years.[49]

In a recent meta-analysis of the outcomes of keratolimbal allografting for LSCD, postoperative corrected distance visual acuity (CDVA) was 2 or more lines better than the preoperative visual acuity in 31%to 67% of eyes .[55] 

Simple Limbal Epithelial Transplant (SLET):

In a study of 6 patients with total unilateral LSCD, visual acuity improved from worse than 20/200 in all recipient eyes before SLET surgery to 20/60 or better in four eyes (66.6%), while none of the donor eyes developed any complications. The mean follow-up was 9.2 months.[48]

Boston Keratoprosthesis:

The Boston Keratoprosthesis (KPro) has been found to have good short-term visual and anatomical outcomes in patients with bilateral LSCD[64] with vision of 20/40 or better at 6 months. One large study found that the final postoperative CDVA was 2 or more lines better than the preoperative visual acuity in 86% (18 of 21) of eyes. CDVA was 20/50 or better in more than two-thirds of eyes up to 3 years after surgery, though these prostheses should be used with caution in eyes with SJS and other immune causes as there is an increased retention failure rate.[51] 


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