Over nearly three decades of performing pterygium surgery and constantly honing the technique to cosmetic and yet visually accountable outcomes, I came to realize that many ancillary developments in technology and material were nearly essential to such high expectations in outcomes and safety.

Having observed surgeons and worked with patients from all over the world, it has become clear to me that no two surgeons have an identical surgical approach or philosophy to pterygium, and that no two patients have ever presented with an exactly similar pathology.

The acceptance of this reality in itself leads to this chapter where my coauthor reviews ancillary adjuncts to pterygium surgery and their impact, both negative and positive leaving open a platform for each surgeon to still not change their own time-trusted techniques drastically but maybe encourage a small change along the way.

Pterygium surgery, like cataract surgery, was first described thousands of years ago by Sushruta in India. ¹ He described a bare sclera technique of pterygium removal and discussed the fact that improper removal would result in recurrence. However, unlike the spectacular success rate of modern-day cataract surgery compared to his description of couching cataracts, the improvements made in pterygium surgery are relatively modest without exciting breakthroughs. Even in the modern times, it continues to be plagued by high recurrence rates and extended surgical times.

Recurrences after pterygium surgery occur due to regrowth of fibrovascular tissue from the conjunctiva and episclera over the limbus and onto the cornea due to lack of the barrier of the normal limbal stem cells. In the bare sclera method of pterygium surgery, the pterygium is excised, and no further procedures are performed. The fibrovascular tissue peripheral to the pterygium rapidly replicates and grows back over the existing defect, resulting in a recurrent pterygium. However, if the barrier is recreated either by transplanting limbal cells from another area as in a conjunctival limbal autograft (CLAU), or by delaying the growth of the fibrovascular tissue until existing stem cells peripheral to the area of the pterygium expand and cover the defect, the risk of recurrence can be theoretically reduced.

It is well established that CLAU significantly decreases recurrences compared to other methods of pterygium surgery. ^2,​3 However, harvesting CLAU takes a considerable investment in surgical time, and CLAU is not always possible in cases with extensive scarring, double header, or recurrent pterygia. In these cases, the alternatives include amniotic membrane or buccal mucus membrane transplantation, which have lower recurrence rates than bare sclera has, but still have a much higher recurrence rate than CLAU. Therefore, a large variety of ancillary therapies have been investigated to reduce recurrence rates and to improve surgical times.

9.2 Ancillaries

9.2.1 Cytostatics

Cytostatic medications are used in chemotherapy of cancers to inhibit cell growth. Unlike typical cytotoxic chemotherapeutic agents, such as cyclophosphamide, that kill the tumor cells, these medications work by inhibiting cellular replication. These drugs most commonly used for pterygium surgery are mitomycin C (MMC) and 5-fluorouracil (5-FU). They inhibit cellular replication by inhibiting deoxyribonucleic acid (DNA) synthesis; cells then undergo apoptosis and fibrotic activity is reduced.

9.2.2 Mitomycin C

Mitomycin C (MMC) is an alkylating agent that is derived from Streptomyces caespitosus. It has been used in pterygium surgery since the 1960s in Asia, but became popular in the western world since the late 1980s. It inhibits the synthesis of DNA in all cells at all stages of the cell cycle. Cell death from apoptosis occurs, as cells are unable to repair the injury caused by alkylation. In addition, it inhibits messenger ribonucleic acid (mRNA) and has antiangiogenic properties. As it works on all stages of the cell cycle, it is a very potent inhibitor of fibroblast proliferation, collagen deposition, and vasculogenesis. As anticipated, these effects decrease inflammation and fibrovascular proliferation, thus reducing the risk of recurrences after pterygium surgery. ⁴ In addition, the inhibitive effect of MMC on fibroblast proliferation may also decrease the density of scarring under the head of the pterygium after removal. ⁵ MMC has been used with the bare sclera technique as well as with autografts and amniotic membrane transplantation (AMT). ⁶ All the studies attest to its efficacy in reducing recurrences with the possible exception of CLAU surgery in primary pterygia where studies indicate that there may not be any additional benefit to adding MMC, but the adverse events may increase compared to those with CLAU alone. ⁷

However, these very same antimitogenic effects also contribute to the risks associated with MMC use. Irritation of the ocular surface and photophobia are common symptoms associated with pterygium excision but are exaggerated with the use of MMC. However, MMC use has also been associated with various vision-threatening complications, such as necrotizing scleritis, sterile melts and calcification, corneal ulceration and edema, delayed epithelial healing, and iritis (▶ Fig. 9.1). ^8,​9,​10 The risk of these complications ranges widely and may be related to the concentration of MMC, the duration of its contact with the ocular surface, and the surgery performed (whether bare sclera or grafted). Increasing the dose and duration of MMC, while decreasing the risk of recurrence, increases the risk of complications. Therefore, it would be prudent to use MMC only in high-risk or recurrent cases of pterygium and at the lowest doses possible.

9.2.3 Intraoperative

Using MMC intraoperatively is the most common technique used in literature. MMC is usually applied in concentrations between 0.02 and 0.05% after the pterygium is excised. ^3,​6 It is usually applied using a soaked sponge either to the bare sclera or to the Tenon’s capsule surrounding the excised area. It is kept in situ for 3 to 5 minutes and is thoroughly washed out with balanced salt solution. The advantage of this method is that it is easy to use and is able to be titrated to some extent by modifying the concentration and duration. There is a plethora of articles in literature attesting to the efficacy of MMC in preventing recurrences in primary as well as recurrent pterygia, and it is a well-established adjunct to pterygium surgery. However, it is associated with all the complications of MMC, including scleral melts and ocular surface toxicity. ¹¹

9.2.4 Preoperative MMC

The disadvantage of intraoperative MMC is that the actual dose of MMC that the eye is exposed to is unpredictable. Preoperative MMC has the advantage that the exact total dose of MMC can be precisely titrated. In this method, MMC is injected under the head of the pterygium, at various times ranging from a month prior to the day before surgery. ^12,​13 However, studies have not found a significant difference in either the efficacy or the adverse events with this modality as compared to intraoperative application and is not used widely. ¹⁴

9.2.5 Postoperative MMC

The first reports of using MMC for pterygium surgery used the postoperative, topical approach. ¹⁵ The drops were started either immediately or approximately a month following surgery. Although the recurrence rates of topical MMC are similar to intraoperative MMC, the complications are significantly higher, and this method is not recommended currently. There is a single report of using a single-drop topical MMC immediately post surgery with similar reduction in recurrence as intraoperative, but lower risk of complications such as scleral necrosis and epithelial toxicity. ¹⁶

9.2.6 5-Fluorouracil

5-FU is a pyrimidine analog that inhibits DNA synthesis in the S phase of the mitotic cycle and, therefore, primarily prevents replication of rapidly proliferating cells only. It is thus a much weaker inhibitor of pterygium recurrence. ¹⁷ It has similar side effects as MMC and is, therefore, used much less commonly with pterygium surgery. ¹⁷

9.2.7 Anti-vascular Endothelial Growth Factor Agents

Vascular endothelial growth factor (VEGF) has been found in abundance in pterygium tissue leading to the speculation that it has an etiological role in the development of pterygia. ¹⁸ In addition, higher levels of VEGF in pterygium excision specimens have been found to correlate to more significant recurrences. ¹⁸ Therefore, logic suggests that the use of anti-VEGF drugs may be beneficial in reducing recurrences after pterygium surgery. Bevacizumab is the most commonly studied anti-VEGF agent used in pterygium surgery. It is typically injected into the pterygium prior to surgery or used postoperatively either as an injection or topical drops. ^19,​20 Unfortunately, the results have been mixed with some studies indicating a significant reduction in recurrences with a much better safety profile than MMC, while others have found no significant effect. ^21,​22 Subconjunctival injections of anti-VEGF agents for recurrent pterygia also had similar mixed results. While some studies showed that there was a reduction in the vascularity and size of recurrent pterygia, others showed that the effect was only temporary and increased back to baseline a few weeks later. ^23,​24

9.2.8 Cyclosporine

Cyclosporine A (CsA) was initially isolated from the filamentous fungus Tolypocladium inflatum as an antifungal agent by Sandoz. However, it was soon found to be a potent anti-inflammatory and immunosuppressant agent and is used widely to prevent transplant rejection. These immunomodulatory effects have led to its widespread use in ophthalmology and ocular surface disorders, such as dry eye and vernal keratoconjunctivitis. Recently, there have been several reports of its use in preventing pterygium recurrence. Its mechanism of action is thought to be its binding to T-lymphocytes and inhibiting calcineurin. This, in turn, inhibits the inflammatory cascade mediated by matrix metalloproteinases that breaks down the collagen and stimulates the production of fibroblasts and vasculature.

Unfortunately, CsA is a large molecular weight hydrophobic molecule that does not dissolve in aqueous solutions. Therefore, commonly available commercial CsA formulations are nanoemulsions (Restasis in the United States and Ikervis in the European Union). They are both approved for the treatment of dry eye, and their use in pterygia is off-label. CsA is useful in pterygia as it is an effective inhibitor of pterygium fibroblasts and, additionally, endothelial cell proliferation and angiogenesis.

A prospective study of 31 patients with bilateral pterygia was conducted by Yalcin Tok et al. ²⁵ All pterygia were removed using the bare sclera technique. Subsequently, one eye of each patient had been assigned to postoperative topical CsA (Restasis) for 6 months, while the fellow eyes served as controls. They found that the pterygium recurred in 13% of the CsA eyes, while 45% of the control eyes had recurrence of pterygia. Other randomized controlled studies have shown similar improvements in the recurrence rates with the bare sclera as well as conjunctival flap techniques. ^26,​27

9.2.9 Sealants

9.2.9.1 Fibrin Glue

The use of fibrin to close ocular wounds is not new. In 1950, Tassman ²⁸ and Town and Naidoff ²⁹ simultaneously published reports describing the use of fibrin glue to close conjunctival wounds as well as cataract surgery wounds. They used either autologous plasma or commercially available plasma and reconstituted, commercially available thrombin. They found that the wound closure was immediate and stable. It was used in pterygium surgery in the 1990s along with sutures, but it was only when fibrin glue became commercially available that it was used widely for fixation of grafts in pterygium surgery. Tisseel and Evicel are two of the commercially available fibrin-based sealants used routinely in surgery. ³⁰ They are both made from pooled plasma and consist of two components, fibrinogen and thrombin, which are mixed together to make a fibrin clot.

Fibrin sealants are now a well-established method for fixing both CLAU as well as AMT during pterygium surgery. Randomized controlled studies have shown that fibrin sealants significantly decrease the surgical time, and the risk of recurrence is as low as, or lower than in suture fixation. ^31,​32 The rationale behind this is that the immediate adherence of the graft results in lower fibroblast activity and less inflammation. However, the complication rate is higher too, with the major complication being graft dehiscence and graft loss (▶ Fig. 9.2). Additionally, there is a theoretical risk of transmission of blood-borne diseases.

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