OCULAR SURFACE DISEASE

Severe Forms of Ocular Surface Disease

An in-depth look at less frequent types and their treatment options.

By Karen G. Carrasquillo, OD, PhD, FAAO; Alan Kwok, OD, FAAO; & Chirag Patel, OD, FAAO

As indicated in the February 2014 Contact Lens Spectrum article “Scleral Lens Applications in Unique Populations,” by Dr. Carrasquillo and Melissa Barnett, OD, FAAO, the ocular surface ecosystem requires proper lid function, a healthy and stable tear film, proper function of the lacrimal and accessory glands, and the proper balance in growth factors and nutrients to promote its sustainability. One of the most commonly observed forms of ocular surface disease (OSD) affecting the ocular surface ecosystem is keratoconjunctivitis sicca (KCS)—either aqueous-deficient or evaporative forms. In this article, we will review treatment options for less prevalent but more severe forms of OSD.

Ocular Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) that develops from allogeneic bone marrow transplantation (BMT) or stem cell transplantation (SCT) is a major cause of morbidity and mortality (Townley et al, 2011). Ocular involvement can occur in both acute and chronic forms of GVHD, albeit more often in the chronic form, and it occurs in 40% to 90% of patients who develop GVHD (Ferrara et al, 2009; Franklin et al, 1983).

Signs and Symptoms Ocular signs and symptoms typically manifest six to 12 months after BMT (Tichelli et al, 1996) (Figure 1); they present based on the localized effect on the ocular tissue and may mimic typical dry eye with complaints of photophobia, pain, burning, foreign body sensation, fluctuating vision, excessive tearing, and erythematous, irritated eyes (Townley et al, 2011).

Figure 1. Ocular signs of GVHD.

Treatment It may seem intuitive, given the systemic etiology of GVHD, that treatment and prevention for ocular GVHD would heavily rely on systemic immunosuppressive therapy; however, many ocular symptoms don’t necessarily respond to systemic treatment, and immunosuppressive therapy is frequently not desired.

When aiming for prophylaxis, the first line of therapy typically consists of cyclosporine A with the addition at times of methotrexate (Townley et al, 2011). The addition of systemic corticosteroids is not as effective in prophylaxis (Storb et al, 1990).

For both acute and chronic forms of GVHD, the first line of therapy is systemic steroids, followed by other immunosuppressants such as mycophenolate, sirolimus, tumor necrosis factor, extracorporeal photophoreisis, tyrosine kinase inhibitors, and others (Bolwell et al, 2004).

When addressing the ocular signs and symptoms of GVHD, the first line of therapy is surface lubrication with artificial tears (ATs). As symptoms become more severe, additional forms of topical or local treatments are needed. Occlusion of the nasolacrimal duct, using either punctal plugs or cautery, can be an effective method of conserving moisture when treating KCS signs and symptoms in GVHD.

First described by Beetham (1935), punctal occlusion has become one of the most common forms of dry eye management used in clinical practice today. While numerous reports have demonstrated its efficacy in relieving symptoms of dry eye syndrome, most practitioners would agree that proper patient selection is critical for success. It’s worth highlighting that a higher incidence of punctal fibrosis is observed in GVHD patients, resulting in silicone punctal plug failure and requiring thermal cauterization (Balaram et al, 2005; Balaram et al, 2001).

Autologous serum eye drops (ASEDs) can be used as an adjuvant or substitute to ATs. ASEDs contain many components in similar concentrations to those found in tears, such as epithelial growth factor, transformer growth fibroblast ß factor, platelet derived growth factor, and hepatocyte growth factor in addition to vitamin A and fibronectin; they have been shown to play a role in the maintenance of a healthy ocular surface ecosystem (Kojima et al, 2005).

Other forms of therapy include treatment with topical anti-inflammatory medications. Some of these address the pathogenesis of ocular GVHD versus just symptoms. Topical cyclosporine A is often used as it inhibits T-cell activation and down-regulates inflammatory cytokines that are thought to be involved in the pathogenesis of ocular GVHD (Nussenblatt and Palestine,1986).

Others that show promise are tacrolimus and tranilast. Tacrolimus’ mode of action is similar to that of cyclosporine A and has greater potency (Kino et al, 1987). Use of topical tranilast (although not readily available in the United States) in patients who have GVHD resulted in a statistically significant increase in Schirmer’s tests of tear production versus a controlled group at three months (Ogawa et al, 2010).

Other, less specific, anti-inflammatory agents are topical corticosteroids. The higher ocular concentrations that are achievable with topical versus systemic use of steroids seem to be key in suppressing cell-mediated inflammation (Mohty et al, 2002). The use of the latter isn’t without risks, though, as poorly monitored use may lead to steroid-induced cataracts, glaucoma, corneal thinning (melting in worse cases), and infectious keratitis (McGhee et al, 2002).

As it relates to the balancing act of systemic and topical immunosuppressant use, it’s worth highlighting that oftentimes, tapering of the systemic immunosuppressant leads to ocular GVHD flare-ups. To manage these, the dose of topical immunosuppressant (typically in the form of a topical steroid) should be adjusted to manage the acute flaring of symptoms.

Other forms of local treatments include the use of soft contact lenses (Russo et al, 2007); in the more severe forms of GVHD-associated KCS, providing prosthetic replacement of the ocular ecosystem (PROSE) treatment with scleral lenses is a great alternative for reducing signs and symptoms (Kikuchi et al, 2007; Schornack et al, 2008) (Figure 2).

Figure 2. Ocular signs of GVHD prior to scleral devices (A, B) and after three hours of device wear (C, D).

Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) and its more severe form, toxic epidermal necrolysis (TEN), are rare immune complex-mediated hypersensitivity disorders affecting the skin and mucosal membranes that result in blisters and sloughing of epithelium. Classification is based upon involvement of the total body surface area (BSA): less than 10% is classified as SJS, greater than 30% is TEN, and in between 10% and 30% is termed SJS/TEN overlap. Etiology is predominantly from medications and less frequently from infections. Common drug offenders are antibiotics such as sulfonamides, anticonvulsants, and also non-steroidal anti-inflammatory drugs (NSAIDs). Misdiagnosis is not uncommon, and primary treatment goals are to suppress inflammation and clear airway complications, which are a source of mortality.

Signs and Symptoms Ocular involvement is common (Yip et al, 2007; Gueudry et al, 2009) and can be classified under acute and chronic phases (Table 1). During the acute phase, there is inflammation of the ocular surface involving the cornea, bulbar and tarsal conjunctiva, and lid margins that result in keratinization, symblepharon, and limbal stem cell deficiency (Figure 3). Recent evidence suggests that intervention during the acute phase results in better long-term outcomes (Shammas et al, 2010; Gregory, 2011). The goal of these early interventions is to subdue the inflammatory response and limit severe scarring. Topical steroids used judiciously to avoid systemic complications are advocated (Ciralsky and Sippel, 2013). Amniotic membrane transplantation (AMT) over the entire ocular surface in the acute phase has also shown to be effective in reducing scarring and cicatricial changes that are so problematic in the long term (Gregory, 2011; Shammas et al, 2010). A third early intervention proposed by Tomlins et al (2013) involves the use of a ring to prevent symblepharon between the tarsal conjunctiva and cornea and/or the bulbar conjunctiva.

Figure 3. Signs of corneal conjunctivalization/limbal stem cell deficiency in SJS.

Patients who do not receive these early interventions unfortunately progress to more cicatricial changes, such as shortened fornices (Figure 4), symblepharon, and keratinization of the tarsal and bulbar conjunctiva (Figure 5) and eyelid margins (Figure 6). The cornea can be impacted by neovascularization (Figure 7), keratinization, and persistent epithelial breakdown (Figure 8). Combined with decreased tear production from scarred lacrimal glands and goblet cells, patients often suffer from pain, photophobia, and severe dry eye symptoms such as burning and foreign body sensation. Trichiasis (Figure 4) adds to the discomfort and requires frequent and regular epilation. Limbal stem cell deficiency further clouds the picture, resulting in migration of conjunctival epithelium into the cornea and substantial neovascularization of the cornea. This makes the cornea more prone to persistent epithelial defects and could ultimately lead to perforation if not managed.

Figure 4. Shortened fornice and trichiasis in SJS.

Figure 5. Keratinization of the palpebral (A) and bulbar (B) conjunctiva in SJS.

Figure 6. Keratinization of the lid margins in SJS.

Figure 7. SJS with profuse central neovascularization (A) and (B) post-penetrating keratoplasty (PKP) with neovascularization.

Figure 8. Persistent epithelial breakdown in a SJS patient.

Treatment Management goals are aimed at alleviating the debilitating symptoms and maintaining the ocular surface. ATs are the first line of treatment, but generally need frequent instillation and provide limited relief.

ASEDs, as mentioned earlier, have become a viable treatment option for many dry eye patients including those who have SJS. Presently, there are no universally established protocols for ASED preparation, though many of the following steps are common to many laboratories:

• Informed consent

• Serology to screen for blood-borne diseases

• Phlebotomy

• Clotting

• Centrifuge

• Dilution to 20% or 100% with balanced saline solution

• Store frozen

Once obtained, ASEDs are prescribed every two hours with application six to eight times a day.

Another strategy for management is treatment with scleral lenses. They can support the ocular surface with their fluid reservoir and protect the cornea from microtrauma that occurs with each blink from keratinized tarsal conjunctiva and lid margins. Heur et al (2014) found that scleral lens treatment improved vision, symptoms, and comfort for SJS patients, and Ling et al (2013) demonstrated the effectiveness of PROSE treatment in managing persistent epithelial defects refractory to other treatments in patients who have SJS and other severe ocular surface diseases.

Depending on the severity of the limbal stem cell deficiency, transplantation of limbal stem cells can be performed to replace or improve limbal stem cell function, thereby preventing persistent epithelial defects and migration of conjunctival epithelium into the cornea. Allogeneic limbal tissue is harvested from deceased donors or from living, related donors and transplanted on to the patient.

Conjunctival replacement is sometimes necessary if severe scarring or symblepharon is present. Amniotic membrane grafts can be used in addition to oral mucosal grafts to reconstruct the fornix in severe cases of symblepharon (Kheirkhah et al, 2013).

Overall, SJS is a challenging condition in which timely and appropriate ocular management in the acute phase will decrease long-term sequelae such as cicatricialization of the ocular surface and, hence, will improve patient comfort and acuity.

Chronic Exposure

KCS secondary to chronic exposure can have devastating effects on the ocular surface.

Signs and Symptoms While the clinical presentation of exposure keratopathy varies dramatically based on the underlying etiology (Table 2), severe disease can lead to significant vision loss due to corneal scarring, neovascularization, epithelial breakdown, stromal thinning, ulceration, or perforation (Grey et al, 2012). While exposure keratopathy is most commonly associated with cases of orbital disease or cranial nerve palsy, any condition that results in abnormal lid function or reduction in the natural blink reflex can have a negative effect on the ocular surface.

Treatment The treatment strategy depends on the underlying cause of exposure and may include any or all of the following: aggressive lubrication, punctal occlusion, internal or external lid weights, soft or scleral contact lenses, amniotic membrane graft, surgical correction of lid function, or tarsorrhaphy (Williams and Aquavella, 2007).

Like most forms of dry eye, management of exposure keratopathy usually includes several forms of treatment used in tandem. The goal of treatment in these cases should be to maintain the ocular surface through lubrication, while shielding the ocular surface from continued exposure. In general, most clinicians will opt for less invasive options initially and will resort to more invasive and permanent measures if required.

The use of internal and external eyelid weights is effective in managing patients who have corneal exposure secondary to lagophthalmos. In these cases, the addition of a weight to the superior lid promotes proper closure when patients attempt to blink or close their eyes. Surgical implantation of lid weights is a procedure that is usually reserved for patients who have demonstrated success with external weights and whose prognosis for recovery is poor. Complications for this type of treatment include hypersensitivity to the materials used and persistent lagophthalmos due to the placement of an insufficient weight (Zwick and Seiff, 2006). If surgically implanted, the weight has the potential to migrate, extrude, or cause pain and soreness to the upper lid (Baheerathan et al, 2009).

Amniotic membrane grafts have proven to be an effective treatment for epithelial defects caused by a variety of ocular surface disorders (Gris et al, 2002). While the use of amniotic membranes in ophthalmic surgery dates back to the 1940s (de Rötth, 1940), a resurgence in popularity occurred after the procedure was reintroduced by Kim and Tseng (1995). Several reports have shown that amniotic membrane grafts have numerous important healing properties including anti-bacterial, anti-inflammation, wound protection, pain-reduction, and promotion of epithelialization (Gris et al, 2002; Hanada et al, 2001). Grafted amniotic tissue is thought to act as a basement membrane upon which epithelialization can occur (Gris et al, 2002). In addition, the amniotic membrane provides a substitute for collagens and is thought to inhibit collagenase while supplementing growth factors (Hanada et al, 2001).

Once placed, the amniotic membrane is reabsorbed by the cornea and is replaced by new fibrotic stroma. Reviewing two cases of amniotic membrane graft secondary to neurotropic corneal ulcer, Gris et al (2002) noted that the speed of reabsorption was significantly faster in the presence of stromal vascularization.

The use of punctal plugs is considered low risk and is reversible in most cases. Complications include discomfort, onset of new symptoms, spontaneous plug loss, and epiphora (Balaram et al, 2001). In their retrospective study of 50 patients, Balaram et al reported the probability of punctal plug retention at the six-month follow-up visit to be approximately 63%. In addition, the study showed that silicone plugs placed in the upper puncta were 4.3 times as likely to be lost as those placed in the lower puncta, and that replacement plugs were twice as likely to be lost compared to the initial plugs (Balaram et al, 2001).

Aside from the treatment options presented, a case report by Williams and Aquavella (2007) demonstrated successful treatment of exposure keratopathy with scleral lenses following failure with bandage soft contact lenses, artificial lubrication, lid weight implantation, amniotic membrane graft, and tarsorrhaphy. Scleral lenses simultaneously hydrate the cornea, promoting healing, and protect it from further exposure, stabilizing any refractive errors caused by irregular or insufficient tear film (Gire, 2012; Schornack et al, 2014).

Neurotrophic Keratopathy

Neurotrophic keratopathy (NK) is a degenerative corneal condition caused by impairment of the trigeminal nerve (the fifth cranial nerve, or CN V). In addition to afferent fibers providing corneal sensation, the ophthalmic branch of CN V also supplies trophic factors essential in corneal homeostasis (Müller et al, 2003). Specifically, neurotransmitters and neuropeptides are secreted by the corneal trigeminal nerves that stimulate epithelial cell growth, proliferation, and differentiation. In addition, nerve derived trophic factors are involved with normal epithelial cell maintenance and turnover. Hence, any lesion in CN V can directly result in corneal surface breakdown, impaired wound healing, persistent epithelial defects, and perforation in addition to decreased or absent sensation. Indirectly decreased corneal sensitivity from NK will decrease the tear reflex and subsequently deprive the cornea of trophic factors present in tears for corneal wound healing and homeostasis. Pathologies to the nerve need not be limited to the ophthalmic branch but can be localized anywhere from the trigeminal nucleus to the trigeminal ganglion to the peripheral nerve. Table 3 lists etiologies of neurotrophic keratopathy.

Signs and Symptoms Diagnosis of NK is based upon case history and any clinical conditions associated with trigeminal pathology. Ocular surface observation may reveal anything from mild corneal staining to epithelial breakdown (Figure 9) to stromal scarring. Corneal sensitivity measurements are beneficial to confirm NK diagnosis as well as to determine the severity of corneal sensation loss. It can be detected with a cotton wisp, or more quantifiable measurements can be obtained with corneal aesthesiometers. The Cochet-Bonet aesthesiometer utilizes a nylon thread to measure sensitivity, while newer generations of non-contact versions, such as the CRCERT-Belmonte Aesthesiometer, use an air-jet stimulus to do so (Golebiowski et al, 2013).

Figure 9. (A) HSV dendritic keratitis in a NK patient, and (B) persistent epithelial breakdown in a NK patient.

Additionally, confocal microscopy can confirm abnormal nerve density and morphology in NK and compared to normalized results (Müller et al, 2003).

Treatment Management involves supporting the ocular surface and allowing natural healing processes to occur. ATs can help lubricate the ocular surface, but little else. Directly applying factors known to be instrumental in corneal health and healing are a more effective treatment.

Specifically, fibronectin, substance P, and insulin-like growth factor are essential in epithelial migration during the epithelialization process (Nishida and Yanai, 2009). ASEDs contain many of these factors and can increase corneal sensitivity, improve surface healing, and decrease scarring in NK (Matsumoto et al, 2004). Rao et al (2010) demonstrated an increase in sensitivity and improvement in nerve morphology of NK patients with the use of plasma tears, which is a variation of ASEDs produced at the Alkek Eye Center at Baylor College of Medicine in Houston. Similarly, umbilical cord serum (UCS) is a potential treatment that uses blood drawn from the umbilical cord after baby delivery. UCS is isolated in a similar process used for ASEDs, but has advantages such as the increased volume of blood that can be withdrawn at one time and that it can be used for patients who cannot have their own blood drawn for ASEDs (Yoon et al, 2006).

Various authors have also reported successful outcomes using scleral lenses in NK and exposure patients (Weyns et al, 2013; Schornack et al, 2014; Gire et al, 2013).

Conclusion

As eyecare practitioners, it is important to be familiar with severe forms of ocular surface disease and the various treatment options in the co-management of these diseases. The many scleral lens designs available can play an integral role in managing these patients.

For references, please visit www.clspectrum.com/references and click on document #224.

	Dr. Carrasquillo is director of Clinical Care at the Boston Foundation for Sight, an adjunct clinical professor at the New England College of Optometry, and an advisory board member of the Gas Permeable Lens Institute. She has also authored various publications in her field.
	Dr. Kwok is a graduate of the University of Waterloo School of Optometry who completed a primary care residency at the New England College of Optometry. He was previously a faculty member of the New England College of Optometry specializing in contact lens education and is presently a clinical associate at the Boston Foundation for Sight.
	Dr. Patel has bachelor’s degrees in Biology and Vision Science. He completed his Doctor of Optometry degree at Nova Southeastern University in 2011 and went on to complete a Clinical Research Fellowship in Cornea and Contact Lenses at the University of Houston / Texas Eye Research and Technology Center in 2013. Dr. Patel is a clinical associate at the Boston Foundation for Sight.