Contact lens induced limbal stem cell deficiency (patent described in this chapter). Note the opaque epithelial sheet extending from superior limbus into visual axis (a) which stains with fluorescein in a whorl pattern (b). Taken with permission 
What Is the Diagnosis?
Limbal stem cell deficiency (LSCD) is a state of insufficiency or functional impairment of the limbal stem cells leading to conjunctivalization of the cornea. The presence of conjunctival epithelium over the cornea leads to chronic inflammation, recurrent/persistent epithelial defects, neovascularization, scarring, and loss of vision. Clinically, patients present with decreased vision, photophobia with or without discomfort. The most common etiologies of LSCD are listed in Box 19.1.
In this case, the patient has contact lens-induced LSCD . A retrospective review of 591 soft contact lens (SCL) wearers reported that focal LSCD associated with SCL wear was found in 2.4% of patients . Only 28.6% of them reported symptoms associated with these findings; most were found to have these findings incidentally on routine examination. This supports the fact that LSCD associated with SCL wear may be more common than previously reported. All SCL wearers should be cautioned about this potential complication of SCL wear, and slit lamp examination with special attention to the superior cornea is warranted on an annual basis.
Box 19.1 Etiologies of Limbal Stem Cell Deficiency
Etiologies of Limbal Stem Cell Deficiency
Aniridia (PAX6 related)
Mucous Membrane Pemphigoid
Superior limbic keratoconjunctivitis
Severe limbal inflammation
Limbal surgeries, Mitomycin C
Contact lens wear
Chronic topical medications
What Causes LSCD in Contact Lens Wearers?
Contact lens-induced LSCD almost always has been reported in SCL wearers (it is rare with rigid gas permeable lenses). It is multifactorial and can result from the mechanical friction on the limbus, toxicity from preservatives in contact lens disinfecting solutions, and perhaps hypoxia . It almost always occurs in the setting of dry eyes including Meibomian gland disease.
What Are the Characteristic Signs of LSCD in Contact Lens Wearers?
The superior limbus, which likely sustains more mechanical rubbing from the SCL, is the most common site of involvement. Findings leading to the diagnosis included whorl-like epitheliopathy, corneal conjunctivalization, and late fluorescein staining of the involved epithelium. The earliest sign of the disease is punctate staining in the superior cornea. Some patients may present with 360 disease; these are the patients who are most at risk for total stem cell failure.
What Are the Medical Management Options of LSCD in Contact Lens Wearers?
The first and most important treatment is to ask the patient to completely stop contact lens wear (no part-time wear). Preservative-free artificial tears must be used frequently along with lid hygiene and doxycycline if there is associated Meibomian gland disease. If there is minimal/no improvement after conservative therapy for 2 months, then we start anti-inflammatory therapy, particularly topical corticosteroid drops—if available, preservative free. In most cases, we see a significant response to steroids and continue this therapy as long as there is improvement. Patients are later switched to topical cyclosporine as steroids are tapered. Other treatments which can be used alongside anti-inflammatory therapy include vitamin A ointment 0.01% and autologous serum tears 20% .
The patient was asked to discontinue CL wear (which he had done already) and use frequent non-preserved artificial tears, fluorometholone was changed to topical methylprednisolone 1% (preservative free) four times daily along with lid hygiene and doxycycline 100 mg twice daily for Meibomian gland disease. After 2 months, there was some reduction in the density of the conjunctivalized epithelium; however, it was still within the visual axis. The steroids had to be changed to loteprednol 0.5% given elevation in the IOP. Topical vitamin A 0.01% qhs was added along with autologous serum tears 20% q2h. After 2 months there was slight improvement in the appearance of the cornea, but the patient was still symptomatic.
What Are the Treatment Options for Recalcitrant Contact Lens-Induced LSCD?
Before considering any surgical options, it is important to maximize the health of the ocular surface and tear film, as was done in this case. The next reasonable option is mechanical debridement of the conjunctival-type epithelium. However, as noted in this case, there can be recurrence, especially if it is done too soon (before properly controlling the inflammation and maximizing the health of the tear film) or if there is extensive disease. A more advanced option is to combine the superficial keratectomy with a peritomy and conjunctival recession in the involved area and then using fibrin glue to secure an amniotic membrane over the involved limbus and de-epithelialized cornea.
Another treatment, which may seem counterintuitive, is scleral lenses, particularly the larger diameter ones that can vault over the limbus. The scleral lens can potentially protect the limbus from lid trauma (from blinking) while providing a more stable tear film. We have had success particularly in patients with recurrent disease after a superficial keratectomy.
A repeat superficial keratectomy was performed to remove the irregular epithelium superiorly. This was done at the slit lamp using a Weck-Cel sponge (conjunctival epithelium that grows over the cornea is very loosely adherent and can be removed by gentle scraping with a sponge, while corneal epithelium is much more adherent and can be left intact). The patient was followed daily and any recurrent conjunctival growth from superior cornea was scraped again (“sequential superficial corneal epithelialectomy,” SSCE as described by Dua). Patient noted definite improvement; however by 3 months, the conjunctival-type epithelium had recurred and was obstructing the visual axis.
The patient was referred for scleral lens fitting in both eyes.
What Are the Limbal Transplantation Options for Advanced CL-Induced LSCD?
In patients whose vision is compromised from the disease, limbal transplantation is considered as a last resort option. Harvesting limbal stem cells from the fellow eye of a patient with bilateral contact lens wear is contraindicated given that the other eye, despite looking normal, almost always has compromised limbal stem cells and harvesting a donor graft can induce LSCD. Alternatively, one option which may be considered in patients who have some remaining healthy limbus is an ipsilateral limbal autograft (e.g., from inferior limbus to superior limbus). Although we have not yet tried this procedure in a SCL-related case, we have used it successfully in cases with iatrogenic LSCD (multiple superior limbal surgeries, mitomycin C).
Allograft limbal transplantation is an option for bilateral extensive disease whose vision is significantly compromised. Our preferred option, when a suitable donor is available, is a living related graft and often two pieces of two clock hours (four clock hours total) is enough to restore a healthy corneal epithelium. If a donor is not available, then standard keratolimbal allograft may be performed. As explained later in this chapter, the success of allograft procedures is highly dependent on the proper use of systemic immunosuppression.
The patient was successfully fitted with scleral lenses in both eyes which improved his vision to 20/20 in the right (and left) eye. The appearance of the epithelium did not change significantly and he continued to have evidence of conjunctival-type epithelium in the superior cornea extending into visual axis (spectacle corrected vision was still 20/50 in right eye). A recommendation was made for him to undergo superficial keratectomy, peritomy, and an ipsilateral limbal transplant (CLAU or SLET) from inferior to superior cornea; however, given that he could see 20/20 with the scleral lens, he has deferred this option for now.
Can a Patient with CL-Induced LSCD Go Back to Wearing Contact Lenses?
It is very unlikely that a patient with SCL-induced LSCD could ever go back to wearing SCLs since the disease will recur. However, hard (RGP) lenses may be an option. Given that these patients frequently also have dry eyes, scleral lenses are actually a great option and as mentioned above may actually have a therapeutic role if they are large enough to vault over the limbus. Another option for patients who prefer not to wear spectacles is refractive surgery and both LASIK and surface ablation (especially if there is any stromal haze) have been used successfully in patients with treated LSCD.
In conclusion, LSCD associated with SCL wear can present with varying manifestations and early changes can be asymptomatic. These changes can occur from 1 year to 30 years after SCL wear, so patients who chose to wear SCL must be instructed to follow-up for routine slit lamp examination on an annual basis. Early identification of this process with subsequent cessation of wear is of utmost importance to proper treatment. Additional measures are aimed at restoring a healthy limbal niche using anti-inflammatory therapy and tear film optimization. Scleral lenses may provide a therapeutic effect, while surgical options are considered as last resort.
Case 2: Limbal Stem Cell Deficiency in Aniridia
37-year-old female with a history of congenital aniridia presented with progressive decreased vision in both eyes. She was frustrated with the use of contact lenses, which although helpful for her vision, frequently caused her to develop abrasions/ulcers. Her past ocular history included bilateral cataract extraction at age 19. Besides artificial tears she did not use any other medications. Multiple family members all had aniridia.
On examination, her best corrected visual acuity was 20/300 in both eyes. The intraocular pressure was 31 in her right and 18 in her left eye. Slit lamp exam of the right eye was remarkable for opaque/grayish epithelium extending into the visual axis from the limbus in all quadrants. There were no palisades of Vogt, and there was superficial neovascularization and Salzmann’s like nodules in the periphery (Fig. 19.2a ). The left eye had a similar appearance, although there were a few small remaining pockets of clearer epithelium. The more opaque epithelium demonstrated whorl pattern on fluorescein staining. Fundus exam was remarkable for foveal hypoplasia.
Keratolimbal allograft for aniridia (patient described in this chapter). Pre-operatively, the cornea demonstrates a clear stroma but opaque epithelium extending into visual axis with areas of Salzmann’s nodule like changes (not easily seen in this photo) (a). Intra-operatively, the limbal stem graft is dissected from one piece of 180° cadaver tissue that has been fixed in place using cyanoacrylate glue (b). Three pieces of 180° grafts are secured to the recipient eye using fibrin glue (c). The recipient eye (right eye) at 2.5 years after surgery demonstrating a corneal type epithelium (d)
Why Is This Patient Experiencing a Decline in Her Vision?
Aniridia is a bilateral, panocular disorder presenting with abnormalities in the cornea, anterior chamber angle, iris, lens, optic nerve, macula, and retina. All patients with congenital aniridia have foveal hypoplasia which leads to various degrees of nystagmus and reduced visual acuity; however this is fixed and does not lead to progressive loss of vision. The most common causes of progressive visual decline in aniridic patients are cataracts, LSCD and glaucoma. Most patients have a visual potential in the 20/100 to 20/200 range. In this case, the main reason for the progressive visual changes is LSCD. This is based on the characteristic opaque late staining conjunctival epithelium extending into the visual axis.
What Is Aniridic Keratopathy?
Aniridic keratopathy (AK) is actually a manifestation of LSCD and can be observed in about half of aniridia patients under age 10, but reaches nearly 100% in adulthood. AK/LSCD is caused by a combination of factors: developmental abnormalities and progressive loss of the limbal stem cell niche with subsequent conjunctivalization of the cornea. AK is highly variable and asymmetric. Signs of keratopathy appear in the first decade of life, with peripheral superficial opacity (e.g., conjunctival epithelium). However over the years, it slowly progresses and involves the central cornea. The peak age for the development of near total LSCD is 30–40, but some may be sooner and some later. Clinically, we suspect that prolonged use of eye drops, namely, glaucoma medications, may lead to faster progression of the epithelial disease in aniridia.
Holland et al. described the progression of AK to LSCD in five distinct stages . Neovascularization may be present at any point during disease development and is not a sensitive indication for severity or prognosis:
Stage I is characterized by abnormal peripheral corneal epithelium. This change is reflected in the increased uptake of fluorescein (late staining).
Stage II is observed once centripetal extension of epithelial changes is noted.
Stage III is characterized by central corneal epithelial changes and peripheral superficial neovascularization.
Stage IV involves the entire cornea with abnormal epithelium in addition to subepithelial fibrosis.
Stage V involves Stage IV accompanied by deep and permanent stromal scarring.
Staging of the disease is important in determining progression and timing of intervention. Stromal scarring which begins in Stage IV highlights the potential of these changes becoming permanent. If the patient develops stromal scarring, then they may no longer qualify for a limbal stem cell transplant alone and thus require additional procedures for therapeutic restoration of the corneal clarity.
How Does PAX6 Mutation/Deletion Affect the Disease?
About two-thirds of aniridia cases are inherited while the rest are sporadic. Most aniridia cases are due to a heterozygous mutation in the PAX6 gene (all sporadic cases should be screened at birth for gene deletions which if present will require screening for Wilms’ tumor in the first 5 years of life). The PAX6 gene plays a vital role in the regulation of genes/proteins that are crucial during eye development as well as normal tissue homeostasis. Previous studies have not found a significant correlation with the type of mutation (or deletion) in the progression of the disease since most of them lead to loss of function. The issue is likely a dosage effect, where having only one functional copy of PAX6 leads to reduced level of PAX6 protein which leads to abnormal development and function of the limbal niche.
It is worth noting that aniridic keratopathy may present in the absence of other classic stigmata of aniridia and be associated with minimally affected irides. These patients often have mutations in PAX6 and once identified can be counseled appropriately . Previously, this condition used to be called by names such as autosomal dominant keratitis, but a more appropriate and encompassing name is PAX6-related keratopathy .
What are the Treatment Measures for AK?
Management of mild AK (Stage I) includes mainly preservative-free lubricants. In moderate keratopathy (Stage II), measures that can improve the health of the epithelium include topical steroids, autologous serum drops, and amniotic membrane transplant. Most of these measures are aimed at improving the health of the ocular surface and enhancing the survival and expansion of surviving limbal stem cells; however, they are temporary and not a long-term solution. Another temporizing measure which can help improve the visual function is RGP/scleral lenses, which help correct the optical irregularities on the surface.
In more advanced disease (Stage III or later), limbal stem cell transplant is recommended. Penetrating keratoplasty as a primary procedure is contraindicated given the inevitable recurrence of LSCD in the graft. Finally another option is keratoprosthesis. It is best not to wait until Stage V since that would necessitate a keratoplasty as well.
How Does One Decide Which Surgical Procedure Is Most Appropriate for Advanced LSCD in Aniridia?
There are several issues that need to be considered: First, is whether the patient is a candidate for systemic immunosuppression. At the time of presentation of total LSCD, most aniridics tend to be younger and healthy and thus are good candidates for immunosuppression. Older patients (above 60), or those with systemic comorbidities such as diabetes may not be good candidates. A patient who is not a candidate for immunosuppression is best managed with keratoprosthesis. In patients who are good candidates for immunosuppression, limbal allograft is the most reasonable first choice. Previously, we used cadaveric tissue (KLAL) for all such patients; however, in recent years we consider lr-CLAL to be the first choice—given the lower risk of rejection—and cadaveric tissue is used only when a first-degree relative is not available.
Another issue that must be considered is whether the eye has had previous transplant surgeries. It is not uncommon that an aniridic patient may have previously undergone a penetrating keratoplasty in the past which has subsequently failed due to recurrent LSCD and/or rejection. In these cases, since the eye has already been sensitized immunologically, the risk of future rejection is significantly higher and therefore our preference is to use a keratoprosthesis, namely, Boston type I.
Another issue is the severity of the glaucoma. A patient with very advanced glaucoma that requires close monitoring of IOP is not a very good candidate for keratoprosthesis since the IOP cannot be measured accurately.
The final issue that must be considered is the status of the stroma and endothelium. When conjunctivalization is not accompanied by deep stromal scarring and fibrosis, then a limbal transplant (as a non-penetrating procedure) is definitely the most appropriate choice since it avoids the need for more invasive interventions. In the case of stromal scarring, a limbal transplant followed by anterior lamellar keratoplasty is also preferred over Kpro. However, in the case of endothelial compensation, especially due to a tube shunt, going straight to Kpro may be more appropriate given the high likelihood of subsequent endothelial failure after keratoplasty.
The patient has minimal stromal scarring; therefore a limbal transplant is the first choice. She has a strong familial history of aniridia, consequently a living related donor was not available and KLAL was recommended. The patient was referred to her primary care physician where she underwent a complete history and physical as well as age-appropriate screening for any malignancy. Laboratory evaluation included CBC, comprehensive metabolic panel (including kidney and liver function tests), Hepatitis B and C screening, QuantiFERON Gold (tuberculosis), and HIV.
What Is the Surgical Technique for KLAL?
First, it is important to specifically request KLAL tissue from the eye bank. We ask for tissue that is from a donor younger than 50, that is less than 5 days old, and has at least 3 mm of conjunctival skirt. We punch the tissue with a 7.5–8 mm trephine—leaving at least 1.5 mm of peripheral cornea. The tissue must then be thinned before it can be transplanted. Our preferred technique for thinning the tissue is to make a single cut in the limbal ring and then using a few drops of medical-grade cyanoacrylate glue to secure the graft to a flat surface (epithelial side up). Once the tissue is secure, we perform a controlled lamellar dissection (using a crescent knife) starting from the conjunctival side (Fig. 19.2b). The last part of the dissection is carried out with a Vannas scissor. The resulting tissue can be secured to the host limbal area with fibrin glue alone (after 360 peritomy and superficial keratectomy). Because the tissue is thin, there is no need to create a “bed,” and also there is minimal step off. Dr. Holland’s technique is similar except that he uses three pieces of 180° grafts that are secured at the anterior corneas with interrupted 10-0 nylon sutures, while the posterior aspects of the graft are secured to the sclera with fibrin glue.
She underwent a right KLAL involving 3 × 180 pieces, which were secured using fibrin glue only (Fig. 19.2b, c ). She was prescribed prednisolone acetate 1% QID, gatifloxacin, and Restasis while continuing her current drops (latanoprost, brimonidine). She was started on systemic immunosuppressive medications on the day of surgery: prednisolone (1 mg/kg), mycophenolate (1000 mg BID), and tacrolimus (4 mg BID). Patient was not started on any systemic antimicrobial prophylaxis given her low-risk status. Patient noted improved vision and by 1 month demonstrated clear cornea and grafts with resolving post-op inflammation and hemorrhage.
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What Is the Current Immunosuppression Protocol in KLAL Patients?
The most widely used protocol is the one developed in Cincinnati (EJH). Management of systemic immunosuppression is best done in collaboration with an organ transplant team given their familiarity with prescribing and monitoring of the medications. The Cincinnati protocol is summarized in Fig. 19.3 and consists of:
Steroids—oral prednisone tapered off by 2–3 months.
T-cell inhibitor—cyclosporine or tacrolimus for 2 years.
Antiproliferative/antimetabolite agent—azathioprine, mycophenolate mofetil, or rapamycin for 3–5 years (or longer).
Infection prophylaxis individualized to patient risk.