
Contact Lens Induced Limbal Stem Cell Deficiency

ABSTRACTÂ
INTRODUCTION
Limbal stem cells are critical for maintaining the integrity of corneal epithelium. External insults, including contact lens overwear, can destroy the limbal stem cells and may lead to limbal stem cell deficiency (LSCD). This case report outlines the clinical diagnosis, treatment, and management of a patient with this condition.
CASE REPORT
After being lost to follow up for two years, a 54-year-old African American male presented for a contact lens follow up visit. He reported some discomfort and irritation when wearing his Dyna Z Intra-Limbal contact lenses, which he had not removed in two years. His ocular history was significant for pellucid marginal degeneration. Slit lamp examination revealed characteristic findings of LSCD.
CONCLUSION
LSCD is an anterior segment condition that can be seen in contact lens patients. A thorough slit lamp examination can help to identify changes to the limbal area of the cornea and should allow for accurate diagnosis and treatment to ensure the preservation of the corneal limbal stem cells.
Keywords: limbal stem cell deficiency, limbal stem cells, corneal epithelium
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INTRODUCTION
Deep in the basal layer of the corneal epithelium, specifically in the palisades of Vogt, lie the limbal stem cells.1 These are unipotent adult stem cells that are located in a specialized niche within the limbus of the cornea.1 The environment of this niche has to be highly specialized in order to maintain healthy limbal corneal stem cells. These stem cells are crucial for regeneration of the mature corneal epithelium, the lack of which causes corneal inflammation, infection, pannus, neovascularization or scarring.1,2 Any corneal pathology, including external insults such as contact lens overwear, can lead to a disruption of the specialized limbal niche. These factors can ultimately lead to a condition called limbal stem cell deficiency.
CASE REPORTÂ
A 54-year-old African American male presented for a contact lens follow up visit. He had been lost to follow up for two years. During this time, he reported that he had never taken his contact lenses off. He was wearing a Dyna Z intralimbal lens. The patient reported some discomfort and irritation with his lenses. His ocular history included a diagnosis of pellucid marginal degeneration in both eyes and glaucoma suspect status of both eyes. His medical history included hypertension. Entering visual acuity with the contact lenses in place was 20/25 OD and 20/25 OS. Best corrected visual acuity with manifest refraction was 20/60 OD and 20/40 OS. Extraocular muscles were full and smooth in both eyes. Confrontation visual fields were full to finger count in each eye. Pupillary responses were normal. In the right eye, slit lamp examination revealed 360 degrees of corneal neovascularization, areas of corneal scarring, lipid exudation around the vessels, and mild corneal thinning mid-peripherally and centrally (Figure 1). The staining pattern with fluorescein was whorl-like, diffusely through the cornea, along with a decreased epithelial reflex. There were also a few areas of fluorescein pooling noted on the superior and inferior cornea. In the left eye, there was a frond of neovascularization extending from the inferior cornea superiorly into the inferior border of the pupillary margin. It was noted to be 6 mm in length located in the corneal stroma (Figure 2). In this eye, fluorescing staining revealed stippled punctate areas of corneal staining, especially adjacent to the area of neovascularization. In both eyes, the palisades of Vogt were difficult to appreciate upon slit lamp examination in the superior and inferior limbal areas of the cornea.

Figure 1. Anterior segment photo of the right eye exhibiting  360 degrees of corneal neovascularization, areas of scarring around vessels, and lipid deposits.
Given the above findings, the primary differential for this patient was limbal stem cell deficiency secondary to contact lens overwear. Other differentials that were considered at this time included peripheral infectious keratitis and early corneal ulceration, especially given the patient’s extreme history of contact lens overwear. The patient was extensively educated on proper contact lens care and hygiene and was told to immediately discontinue contact lens wear. The patient did not have functional vision with his glasses given his pellucid marginal degeneration and required the use of medically-necessary contact lenses. Given his poor contact lens hygiene and the slit lamp findings, the patient was suspected to have stage 2 of LSCD. He was started on a tapered course of topical steroid treatment with prednisolone acetate 1%r: QID OU for 1 month then TID OU for 1 month, then BID OU for 1 month, and finally once daily OU for 1 month. He was seen back in one month for a follow up visit and at that visit his slit lamp findings were stable and he was instructed to finish his taper of Prednisolone Acetate 1%. He was eventually re-fit into scleral contact lenses. Since then, the patient has reported greatly improved contact lens hygiene and care. He is frequently monitored in follow up visits and his slit lamp findings and vision have been stable.
DISCUSSION
Deep in the basal epithelial layer of the cornea, cells that are responsible for the regeneration of mature corneal epithelium can be found.1 These are known as limbal stem cells. Limbal stem cell deficiency occurs when there damage or loss of these cells, creating an inability of the corneal epithelium to regenerate appropriately.1 Although there are a wide variety of conditions that can lead to LSCD, such as congenital, autoimmune, and traumatic, contact lens overwear is a fairly common cause of LSCD.2
Limbal stem cells are located in pigmented crypts in the palisades of Vogt within the basal cell layer of the corneal epithelium. These stem cells are integral to maintaining corneal transparency and provide a physical barrier between the conjunctiva and cornea.3 Damage to these limbal stem cells could ultimately lead to the replacement of the corneal epithelium by the conjunctival epithelium.3 Neovascularization of the stroma and epithelium is another hallmark of limbal stem cell deficiency.4
The pathophysiology of LSCD can vary depending on the source of the damage to the limbal stem cells. Conditions that damage the limbal stem cells may result in an impairment of corneal epithelial integrity and can lead to LSCD.5 When it comes to contact lens wear, the exact pathophysiology of contact lens induced stem cell deficiency is not fully understood. Contact lens overwear, poor contact lens fitting, low oxygen permeability of the material, and even toxicity from contact lens solutions have been thought to cause damage to the limbal stem cells.6
Patients with LSCD may present with a wide variety of symptoms. They can present with conjunctival hyperemia, decreased vision, foreign body sensation, and tearing.4Â These symptoms are often nonspecific.4 Some patients may also present with debilitating episodes of recurrent epithelial erosions.1 Early and accurate diagnosis of LSCD is crucial, as treatment is mainly aimed at preventing progression of this corneal disease. A thorough slit lamp examination is crucial in diagnosing this condition. Early stages of this corneal disease may present with findings such as neovascularization of the cornea, conjunctivalization of the cornea, loss of limbal anatomy, and whorl-like fluorescein staining.1,5 Subtle signs of LSCD, especially in mild or early stages, can only be noted with fluorescein staining and cobalt blue lighting.4 The fluorescein staining may vary, especially in early disease stages. In the mild stage, there can be loss of the limbal palisades of Vogt and an irregular corneal surface can be noted.4 The fluorescein also tends to pool on the affected areas.4 This is because the metaplastic epithelium is thinner and lacks cellular tight junctions.4 The fluorescein staining in early disease stages may also present as punctate fluorescein staining adjacent to the affected area.6
Characteristic findings of moderate stages of LSCD include fluorescein staining and epithelial thinning in a characteristic vortex pattern.4 There can also be superficial corneal neovascularization.4 Severe stage LSCD can present with devastating corneal findings such as stromal scarring and opacification, and even recurrent or persistent corneal epithelial defects.4,6
Corneal melting and corneal perforation are also possible in very advanced disease stages.1
It is important to consider why there is a characteristic vortex staining pattern. This classic staining pattern is linked to the natural healing process of the corneal epithelium. When there is a defect, epithelial cells migrate from the peripheral cornea to the affected area.7 These cells primarily migrate from the limbal corneal epithelium.8 There is also an increased mitotic rate of the basal epithelium.7 Research has also revealed the direction of epithelialization: the majority of epithelialization occurs from the superior limbus, followed by the inferior limbus, and finally from the horizontal meridians.7,8 This pattern of epithelialization and the flow of the cells from the limbus to the central cornea is what leads to the class vortex keratopathy noted in LSCD.

Table 1. Staging the severity of the condition (based on slit lamp findings) can be used in the treatment of LSCD.
The gold standard tool in diagnosing this condition is using confocal microscopy as there can be limitations with slit lamp clinical examinations.1 Often, slit lamp findings may not be unique to LSCD alone. Therefore, if available, using confocal microscopy to view the limbal structures in vivo has been noted as a way to accurately diagnose LSCD.5
A severity scale has been formulated to help with the staging of LSCD. With limited clinical availability of confocal microscopy, this scale is based on slit lamp findings and categorized into three stages (Table 1).6 These stages are determined by how much of the central cornea is impacted as well as how much of the limbal area is impacted. Staging the condition is important as it can guide treatment and management.
Treatment is aimed at limiting insult to the corneal limbal stem cells. There is currently no generalized treatment plan when it comes to the medical management of LSCD.9 The primary goal of treatment is to prevent progression of corneal neovascularization and opacification.9 Stage I of LSCD is geared towards medical management versus surgical management.9 Initial treatment can range from preservative-free artificial tears, short or long term use of topical steroids, topical cyclosporine and even antibiotics.9 In cases where there is minimal conjunctivalization of the cornea, cessation of contact lens wear and the use of topical corticosteroids can be used to conservatively treat partial cases of limbal stem cell deficiency.
Studies have shown a clinically significant response to the use of topical steroids.10 This suggests that there is chronic subclinical inflammation in the pathogenesis of early cases of LSCD. When there is damage to the limbal stem cells, there can be a cascade of inflammatory cytokines that induce leukocyte chemotaxis to the injury site.11 A release of pro-angiogenic factors such as vascular endothelial growth factor A (VEGF-A) can lead to corneal neovascularization.11 Corneal neovascularization is a non-specific finding in LSCD.11Â However, the presence of corneal neovascularization indicates the presence of persistent inflammation which can lead to the destruction of the limbal niche.11 Although the use of topical steroids may not prevent neovascularization, they can delay neovascularization and can limit the damage to the limbal niche from the persistent inflammation.11 In the case of the patient in this case, given the minimal conjunctivalization of the cornea, initial treatment was aimed at discontinuing lens wear and beginning topical steroids. Given the extent of corneal neovascularization (as viewed in Figures 1 and 2), a steroid taper was performed over months to preserve as much of the limbal niche as possible.
The use of autologous serum drops have also been shown to be efficacious in the treatment of LSCD.9 If LSCD is a result of contact lens overwear, then it is crucial to address the cause by discontinuing lens wear for a short period of time and/or refitting the patient into a different oxygen permeable material. In cases where patients are wearing rigid gas permeable lenses, refitting into scleral contact lenses have been shown to help with LSCD in order to completely vault the cornea and reduce impact on the limbal stem cells.
Surgical intervention is recommended for cases where the visual axis is involved or there are no more limbal stem cells to replenish the corneal epithelium.9 There are multiple surgical procedures that can be considered on a case by case basis. When patients present with unilateral LSCD, a conjunctival limbal autograft (CLAU) can be performed. During this procedure, the healthy contralateral eye serves as a donor site for free limbal tissue.9 When there is insufficient conjunctiva and symblepharon from the donor eye, CLAU can be combined with a living related-conjunctival limbal allograft (lr-CLAL).9 The benefit of this procedure in such cases is that the amount of transplanted conjunctiva is greater than CLAU alone.9
When donor tissue from the contralateral eye cannot be used, there are other surgical procedures to consider. Keratolimbal allograft (KLAL) is a procedure that uses peripheral and limbal corneal tissue obtained from cadavers. This procedure is ideal in cases of bilateral LSCD, if there is no living relative available, or there is no HLA match.9 It is important to note that KLAL is a recommended procedure when the conjunctiva is intact. If conjunctival reconstruction is required, then lr-CLAL can be combined with KLAL. This is known as the Cincinnati procedure.9 Although the Cincinnati procedure can restore the entire limbus, it requires the use of systemic immunosuppression, which requires frequent systemic monitoring.9 There is also a greater chance of graft rejection. These concerns have led to the development of newer therapies.
Newer procedures are available to consider when surgical intervention is indicated. The benefit of ex vivo cultivated stem cells is that it decreases the risk of graft rejection and limits the possibility of inducing LSCD in the healthy donor eye. Cultivated limbal epithelial transplant (CLET) is a procedure that uses a very small graft from a donor eye.12 These grafts, which are about 2 mm x 2 mm, are grown on fibroblast culture medium or amniotic membrane in a laboratory setting.12 This allows the donor cell population to expand in a laboratory setting, in turn increasing success rates.12 Simple limbal epithelial transplantation (SLET) is another ex vivo procedure that bypasses the laboratory stage that CLET utilizes. In SLET the small graft, similar in size to CLET, is evenly distributed on an amniotic membrane and transplanted to the ocular surface.9 These ex vivo procedures are fairly new in terms of treatment of LSCD and long term data is still required to determine outcomes.
The cause of LSCD is important when considering surgical treatment options. When systemic disease, hereditary disorders, or bilateral chemical injuries are the source of LSCD, then allograft procedures like lr-CLAL and KLAL must be performed.9 As mentioned, the use of allogenic tissue comes with a greater risk of graft rejection and patients must be on systemic immunosuppressants.9 In these cases, an autologous source of epithelial tissue may be considered. Cultured oral mucosal epithelial transplantation (COMET) is an autologous source of epithelium.9 The use of the oral mucosa comes with a myriad of benefits. This tissue is semi-transparent, has a high regenerative capacity, does not lead to scarring in the donor tissue, and is very easy to access surgically.9 As with CLET and SLET, this is still a fairly new surgical treatment option and may be more commonly used in the future as improvements in surgical methods are made.
CONCLUSION
Corneal clarity is crucial to the maintenance of visual function of patients. While there are a myriad of corneal dystrophies and degenerations that may lead to decreased vision, it is also important to be aware of less common conditions like limbal stem cell deficiency. It is important to consider why there is a characteristic vortex staining pattern as this is often the key characteristic that differentiates LSCD from other forms of keratopathy. Patients who wear contact lenses should be thoroughly assessed to achieve the most ideal lens fit and must be properly educated on lens care and hygiene to prevent corneal pathology. In cases where LSCD is suspected, prompt treatment should be administered to ensure that clinical signs do not progress. In severe cases, surgical intervention may be necessary.
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