Contact Lens-Induced Limbal Stem Cell Deficiency
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Contact Lens-induced Limbal Stem Cell Deficiency
Limbal stem cells (LSCs) are a vital set of cells that reside in the basal limbal region, serving as both a source of progenitor cells that differentiate to replenish corneal epithelium and as part of the limbal barrier between the conjunctiva and cornea. Loss or dysfunction of these cells can lead to the inability to repair and renew corneal epithelium, a pathology known as Limbal Stem Cell Deficiency (LSCD). This can ultimately result in pathologic changes such as persistent epithelial defects, corneal conjuctivalization, neovascularization, scarring, etc. Among the variety of etiologies that can cause LSCD is contact lens-induced LSCD, an often asymptomatic cause of LSCD.
An estimated 45 million people in the United States wear contact lenses (CL), among which two-thirds are female. Of these 45 million people, it is estimated that 2.4-5% of CL wearers may develop LSCD ranging from subclinical signs to symptomatic disease. It has also been reported that 15% of all cases of LSCD can be attributed to CL use. The vast majority of studies focus on exclusive soft CL use induced LSCD but LSCD can also develop in patients in rigid gas permeable (RGP) lenses and poorly fitted scleral lenses.
The duration of CL use has been demonstrated to have a positive correlation with LSCD. In a review article, Rossen et al report that the mean duration of CL use associated with LSCD is 14.2-17.6 years with daily use of 12.5-16.25 hours. Given that CL use is most commonly bilateral, disease presentation is also generally bilateral. However, asymmetry is often present and the fellow eye may have subclinical disease. Early diagnosis is important as patients are often asymptomatic initially and can benefit from early medical management; soft CL wearers would benefit from annual screening examinations.
While female wearers represent the majority of CL wearers in the US, there is a disproportionately higher rate of CL-induced LSCD among women, with studies estimating 67-93% of CL-induced LSCD cases being in women. It is possible that this may have correlation with the higher prevalence of dry eye secondary to differences in hormonal factors in women, however this still requires further investigation.
Contact lenses can induce mechanical trauma on the ocular surface as even properly fitted lenses may move 0.1-0.4mm with blinking. The movement of the lens against the eyes during blinking can induce friction as tears are dispelled from the interface between the lens and ocular surface. The superior limbus can become a site of chronic trauma because of the higher pressure experienced during blinking. Conversely, the reduced eyelid pressure in the inferior limbus leads to less trauma and this may be an explanation for why CL-induced LSCD is less often inferiorly located. Differences in eye and eyelid anatomy such as physiologically dryer eyes and narrower palpebral apertures which are more often found in Asian populations may also contribute to increased mechanical trauma from contact lens use.
Tear film stability is susceptible to disruption by CLs via multiple mechanisms including the lipid layer thinning, delayed tear film spread, osmolarity changes, and compositional changes (e.g. amounts of antioxidants, glycocalyx, mucin, protein, lipids, neutrophils). While it is difficult to elucidate how the characteristics of different CLs (e.g. lens fit, lens design, material, etc.) affect specific elements of the tear film, it is clear that these changes in the tear film further enable the adverse effects of mechanical trauma induced by contact lens wear.
Lens Disinfecting Solutions/Preservatives
Though phased out in the 1980s, the use of the preservative thimerosal in lens cleaning solution has been documented to cause a range of corneal pathology such as superior limbic/diffuse keratoconjunctivitis, keratitis, and pseudodendritic lesions. More recently, studies comparing solutions with polyhexamethylene biguanide (PHMB) preservatives to hydrogen peroxide-based solutions have detected more corneal staining in the solutions that contain preservative. However, despite using the same solution for both CLs, patients often present with asymmetric LSCD which suggests that factors beyond the preservatives such as underlying differences in the ocular surface, contact lens material and other ingredients in the lens disinfecting solutions may play a contributory role in LSCD pathogenesis.
The avascular corneal tissue receives part of its oxygen supply from the atmosphere and the use of CLs sets up a hypoxic environment that impedes corneal oxygenation. This is evidenced by the increase in lactate dehydrogenase levels found in the tear film of CL wearers. As with the increased pressures experienced in the superior limbus during blinking, there is a relative increase in hypoxia in this region as well, further exacerbating the detrimental effects of mechanical trauma from CL wear.
Given the broad range of disease severity and asymmetric presentation in bilateral CL wearers, it is likely that the aforementioned issues work in tandem as part of a multifactorial pathway in the pathogenesis of CL-induced LSCD. Rossen et al. proposed a three part mechanism in which 1) the loss of lubrication from the tear film leads to increased friction and limbal trauma, 2) the ocular surface subsequently experiences prolonged exposure to disinfecting solutions and preservatives because of less irrigation from the tear film, and 3) increased inflammation from desiccation, hyperosmolar changes and hypoxia. These factors may also contribute to different degrees in individual patients as some patients have localized disease to the superior cornea which may be attributable to mechanical trauma while others have 360-degree disease that may more likely point towards solution toxicity. It is also possible that some of the epidemiological differences in underlying risk factors described earlier may be contribute a “first hit” in a two-hit hypothesis proposed by Chan and Holland.
Patients are commonly asymptomatic at initial presentation (71.4% in a retrospective study of CL-induced LSCD with corneal conjunctivalization) but symptomatic individuals may experience nonspecific symptoms including decreased vision, tearing, irritation, pain, photophobia, blepharospasm, redness, dryness.
The diagnosis of CL-induced LSCD is made clinically through characteristic slit-lamp examination findings in the setting of a history of oftentimes prolonged CL use for many years. The limbal palisades of Vogt are useful in evaluating LSCD as their absence may indicate loss of the limbal niche. However, they may not be visualizable in some patients despite normal anatomy, therefore it is their presence instead that is more helpful in ruling out LSCD. The loss of the limbal stem cell barrier allows for the invasion of conjunctival tissue into the cornea, which can be visualized as more opaque epithelium than the normal corneal epithelium. This key slit lamp finding in LSCD can also be seen as whorls of opaque epithelium because of the spiral pattern in which the epithelium grows from the limbus onto the cornea.
Fluorescein staining is an extremely valuable tool in the diagnosis of LSCD. Superior limbal involvement is more common (44-79%), whereas inferior involvement is much rarer (6-12%). Early on in the disease progression, punctate staining in a curve-like path may be the only apparent sign. Over time, these punctate changes join into a more linear pattern which can further progress to a confluent sheet. With conjunctivalization of the cornea, a characteristic late-staining pattern appears. This reflects the fact that conjunctival epithelium is more permeable to fluorescein than corneal epithelium because the tight junctions in this type of tissue are “less tight”. Ultimately, a corneal pannus may form once a broad sheet of conjunctival epithelium spreads across the cornea and begins to neovascularize as this type of tissue lacks the anti-angiogenic properties of the original corneal epithelium.
Superior Limbic Keratoconjunctivitis (SLK)
SLK shares much overlap with LSCD as both conditions demonstrate limbal inflammation and superficial punctate keratitis, specifically in the region of the superior limbus. Moreover, trauma and dry eye both play a contributory role in the pathogenesis of both conditions. However, SLK more consistently presents bilaterally and is associated with thyroid dysfunction rather than contact lens usage. Medical treatment with large diameter bandage CL or surgical treatment with superior perilimbal conjunctival resection with or without cauterization can lead to resolution of SLK.
CL-induced peripheral neovascularization
Peripheral neovascularization of up to 1-2mm of the cornea in the absence of changes in the corneal epithelium can be considered normal in CL wearers. Although this neovascularization occurs from hypoxia, inflammation and subsequent edema, there should not be changes in the epithelium without co-existing LSCD.
Conjunctival/corneal intraepithelial neoplasia (CIN)
Neovascularization can also be seen in CIN which commonly presents as a raised, circumscribed vascularized growth. It can be distinguished from CL-LSCD with exfoliative or impression cytology which will demonstrate hyperplastic, dysplastic or anaplastic cells.
Other causes of neovascularization
Causes of neovascularization that are not related to CL use include infections, inflammatory conditions, congenital disease (i.e. aniridia), degenerative disease and trauma.
Contact Lens Discontinuation/Change
The most immediate treatment available for CL-induced LSCD is the complete discontinuation of contact lens use. Studies report widely varying outcomes with CL use cessation, with Jeng et al reporting that 11 of 18 eyes stabilized or improved with this treatment while 12 of 12 patients with severe disease failed conservative management in another study. Therefore, it is likely that cessation alone is not always sufficient to treat LSCD, particularly in those suffering from severe disease.
After resolution of the CL-induced LSCD, it may be permissible to return to soft CL use. Consideration should be given to the possible contributing factor(s) of the lens (e.g. lens type, fit, cleaning solution, etc.) and changes should be made accordingly. Scleral lenses that can vault the limbus help to avoid limbal trauma and can play a therapeutic role in managing CL-induced LSCD. In a recent study of 31 eyes fitted with Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) scleral devices, Kim et al noted improvement in best-corrected distance visual acuity (BCVA) and in corneal epithelial defects but did not note any significant differences in other corneal findings such as conjunctivalization or neovascularization.
Dry Eye Treatment
As discussed earlier, CL use can disrupt the tear film and lead to dry eye which further exacerbates the CL-induced LSCD. Concomitant dry eye in CL-induced LSCD should be treated with preservative-free lubrication aggressively to allow the epithelium to heal. More advanced therapies also exist, such as topical vitamin A (0.01%) and autologous serum tears. Kim et al also reported on treating tear film deficiencies in patients with CL-induced LSCD with vitamin A ointment and punctal/cautery occlusion in addition to artificial tears and lid hygiene. Autologous serum tears produced under sterile conditions from the patient’s own blood may also be used to treat dry eye by providing various epitheliotrophic growth factors and nutrients for the ocular surface. In a case series of 20 eyes with severe CL-induced LSCD (median BCVA 20/100, persistent epithelial defects, >2 quadrants of corneal vascularization), Yeh et al reported regression of epithelial disease and VA improvement by 5 lines or more in 65% of eyes after aggressive treatment with serum tears for 8 weeks.
Topical corticosteroids and cyclosporine can also be used to combat the inflammatory component of the disease process. These topical therapies have been used successfully in 13 patients and 2 patients who had comorbid rosacea demonstrated tear film improvement following lid hygiene and oral doxycycline in a study by Kim et al.
Surgical management can be considered in patients who fail conservative therapy and mechanical debridement (superficial keratectomy) can be performed in office, with some patients demonstrating immediate symptomatic improvement. However, recurrence is frequent and this surgical intervention may be augmented with concurrent medical management such as topical steroids and lubrication.
Amniotic Membrane Transplantation
While the exact mechanism is yet to elucidated, amniotic membranes provide a nourishing environment for the repair of the limbal niche and growth of LSCs. It is also demonstrates anti-inflammatory properties and has a reduced risk of rejection. However, this approach cannot be used alone to treat complete LSCD as it requires that at least some LSCs are present. The membrane is draped over the conjunctiva and denuded cornea and sutured following conjunctival peritomy and scraping of the abnormal corneal epithelium. Multiple studies have demonstrated improvement in LSCD, long-term sympatomic relief and improved visual acuity in patients who received amniotic membrane therapy, and in some cases with the other surgical interventions discussed in this section.
Allograft transplantation is a viable surgical option for LSCD that requires limbal tissue from either a cadaver (keratolimbal allograft, KLAL) or a living relative of the patient (HLA-matched living-related conjunctival limbal allograft, lr-CLAL). Outcomes have been relatively positive with this technique, with 33-86% of eyes demonstrating improvised visual acuity in a variety of studies that looked at both types of source tissue. By harvesting the allograft from a cadaver, there is no risk of complications to the donor eye. However, systemic immunosuppressive therapy is required and this surgical approach can be complicated by acute or chronic rejection, adverse effects from immunosuppressive therapy as well as ocular hypertension. Limbal tissue grafting can be used in conjunction with amniotic membrane transplantation for cases of complete LSCD to help reconstitute the limbal niche before application of the membrane.
It should be noted that autologous LSC transplantation is not recommended as this involves harvesting donor tissue from the contralateral eye. As most patients are bilateral contact lens wearers, it is not uncommon for the contralateral donor eye to have subclinical disease and this likely contributes to the post-surgical complications seen in these donor eyes. Studies by Jenkins and Tan noted initial improvement in disease which were later complicated by conjunctivalization of the recipient eye and epithelial abnormalities in the donor eye respectively. Ultimately, the autologous approach should be reserved for the rare case of unilateral contact lens use where one can be confident that the contralateral eye does not have LSCD.
Laser therapy with an excimer laser can be directed to help treat superficial stromal scarring from LSCD. This has been used to successfully remove anterior corneal scars but it is recommended that this be used after treatment of LSCD because stromal scarring can often regress following restoration of a stable corneal epithelium.
It is important to note that corneal transplantation alone is not considered a treatment for this condition as it is insufficient in the absence of LSCs. Keratoplasty can only provide a temporary intervention that is at high risk of failure from recurrent conjunctivalization because of the inability to heal. Therefore, this technique should be considered as adjuvant therapy following reconstitution of the LSC function (e.g. via LSC transplantation). Results vary with one patient who had total LSC failure achieving 20/30 BCVA in a case report by Nguyen et all while another patient with severe LSCD was treated with AMT, allograft limbal transplantation and PK but ultimately suffered PK rejection. Rossen et al suggest performing deep anterior lamellar keratoplasty following limbal transplantation to manage the scarring, provided that the endothelium is normal, as is generally the case in CL-induced LSCD.
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