STEPHEN G. WALLER and ANTHONY P. ADAMIS
Table Of Contents
ETIOLOGY AND EPIDEMIOLOGY
|Physicians have struggled for thousands of years with an unsightly elevated
peribulbar lesion known as the pterygium. It takes its name from
the Greek word for wing and was described by Hippocrates, Galen, and others.1 A pterygium is a horizontally oriented triangular growth of abnormal tissue
that invades the cornea from the canthal region of the bulbar conjunctiva. Its
development is unrelated to antecedent injury or inflammation.|
A pterygium can be divided into three recognizable parts: body, apex (head), and cap (Fig. 1). The raised triangular portion of the pterygium with its base toward the canthus is the body, while the head forms the apex of the triangle, just posterior to the cap. A subepithelial cap or “halo” may be present just central to the apex and forms its leading edge.2
The high frequency of recurrence and aggressive nature of recurrent pterygia are challenging clinical problems. In this chapter we will review the current knowledge regarding pterygium, with emphasis on the numerous techniques used in its management.
|A pterygium can be clinically distinguished from two similar conditions, pinguecula
and pseudopterygium. The former is a small, elevated, yellowish
mass confined to the limbus and bulbar conjunctiva in the intrapalpebral
fissure and may occasionally become inflamed. Surgical excision
is rarely indicated, but if done, the lesion tends not to recur.3 Both its prevalence and incidence increase with age.4 Pingueculae are common in both temperate and tropical climates and occur
with similar frequency in both sexes.4 Exposure to ultraviolet light does not increase the risk of developing
Pterygium-like growths presenting at an oblique angle should suggest an alternate diagnosis, such as pseudopterygium or Terrien's marginal degeneration.7 Pseudopterygium may mimic the appearance of pterygia, since it is a fibrovascular scar arising in the bulbar conjunctiva that extends onto the cornea.2 In contradistinction to pterygium, pseudopterygia are the result of previous ocular surface inflammation from such varied causes as trauma, chemical burns, cicatrizing conjunctivitis, surgery, or peripheral corneal ulceration. The identifying feature of pseudopterygia is their lack of adhesion to the corneal limbus. A probe or muscle hook can easily pass underneath pseudopterygia at the limbus, whereas usually it cannot with true pterygia.7 The lack of organization of pseudopterygia into recognizable parts (cap, head, and body) and their tendency to occur outside the interpalpebral space further distinguish them from true pterygia.
Ninety percent of pterygia are located nasally.7 Nasal and temporal pterygia can occur in the same eye, but isolated temporal pterygia are extremely rare.8 Both eyes are frequently involved, but often asymmetrically. It is unusual for the apex to extend across the midline.9 In rare instances, extensive pterygia can advance from the medial and lateral limbus to touch in the visual axis, causing marked loss of acuity (personal observation by senior author).
The differential diagnosis of pterygium is rather large. The most common acquired limbal masses, in order of their frequency, are pterygium, pseudopterygium, papilloma, squamous cell conjunctival carcinoma, conjunctival melanoma, and pagetoid or sebaceous carcinoma.10 Other rarer lesions include epithelial cyst, pyogenic granuloma, keratoacanthoma, adenoma, fibroma, fibrochondroma, fibrous histiocytoma, angioma, lymphangioma, Kaposi's sarcoma, alveolar endothelioma, neurolemmoma, malignant schwannoma, mycosis fungoides, juvenile xanthogranuloma, leukemia, episcleral osseous choristoma, ectopic lacrimal tissue, lipoma, amyloid, blue nevus, nevus, and limbal dermoid.10 Because of their appearance, most of these lesions are easily distinguished from a pterygium.
|In its earliest stages, a pterygium arises in the interpalpebral fissure
as an elevated, fleshy mass on the bulbar conjunctiva near the limbus. Engorged
radial vessels appearing over the pterygium and adjacent conjunctiva
usually signal a period of rapid growth. The bulbar conjunctiva
may become increasingly taut as the pterygium enlarges toward the
limbus. Symptoms of burning, irritation, lacrimation, and foreign body
sensation may accompany the growth of a pterygium onto the cornea.7 Significant astigmatism may be induced either with or against the rule
as sectoral corneal steepening occurs. The astigmatism is often irregular
and may lead to decreased vision. Gaze-evoked Descemet's folds
and 20 diopters of astigmatic change have been observed in a patient
with a pterygium containing a densely fibrotic central band (Wagoner
M, Loughnan M, unpublished observation, 1993). As the apex approaches
the visual axis, glare and decreased contrast sensitivity appear.11 In severe cases, symblepharon formation may limit ocular motility and
result in diplopia.|
For poorly understood reasons, the growth of a pterygium may stop at any stage during its evolution. Decreased elevation and vascular injection, along with a fading of the subepithelial cap, are usually seen. The lesion may remain quiescent for the remainder of the patient's life or resume growth again at a later time. Older, static lesions are often associated with an arcuate line of iron deposition in the superficial cornea immediately central to the cap (Stocker's line).7
The decision to remove a pterygium is dependent on the patient's willingness to tolerate symptoms and interest in cosmetic improvement. When a decision to proceed with surgery is made, it must be with the full knowledge that recurrent pterygia grow more aggressively and are more difficult to treat than the primary lesion. With recurrence, there is a higher incidence of growth into the visual axis and of symblepharon formation.7 Virtually all postoperative recurrences occur within 1 year, often within 6 to 8 weeks of surgery.12
|ETIOLOGY AND EPIDEMIOLOGY|
|There is a worldwide distribution of pterygium, but it is more common in
warm, dry climates.13 Prevalence is as high as 22% in equatorial areas and less than 2% in latitudes
above 40°.14 A large case control study in Australia identified a number of risk factors
for the development of pterygium.15 There was a 44-fold greater relative risk of pterygium development for
persons living in the tropics (less than 30° latitude), 11-fold for
working in a sandy, outdoor environment, 9-fold for patients without
a history of wearing spectacles or sunglasses, and 2-fold for those
who never wear a hat. Another study demonstrated a higher prevalence among
men. However, the difference between the sexes was eliminated when
only indoor workers were considered.16|
In the northern climates, pterygium is almost exclusively confined to fishermen and rural workers.17 Taylor and colleagues found a statistically significant association between ultraviolet light exposure (both UV-A and UV-B) and the development of pterygium in a large group of Chesapeake Bay fishermen.18 From these studies, the relationship between ultraviolet radiation and the formation of pterygia is strong.
Ultraviolet light exposure may not be the only factor associated with the development of pterygium. Among Punjabi workers, those exposed to a dusty, indoor environment had a higher prevalence of pterygia than Punjabi workers who experienced higher levels of outdoor ultraviolet radiation.19 One study of pterygia among welders who are exposed to increased levels of ultraviolet light showed a direct relationship between the length of employment and the incidence of pterygium.5 In contrast, a more recent study found pterygium to be rare (less than 0.5%) among welders.6
Local drying of the cornea and conjunctiva in the interpalpebral fissure from tear film abnormalities may lead to new fibroblastic growth according to one theory.20 The increased incidence of pterygium in windy, dry climates is consistent with this hypothesis.
Patients younger than the age of 15 rarely acquire a pterygium. Although the prevalence of the lesion increases with age, the highest incidence occurs between the ages of 20 and 49.16 Recurrences may be more frequent in young adults than older individuals.12 Pedigree analysis has demonstated families with a dominant mode of inheritance, although most cases appear to be sporadic.21
|Both pterygium and pinguecula share a highly characteristic histologic
appearance.22 Four features predominate: (1) hyalinization of the subepithelial connective
tissue of the substantia propria; (2) diffuse or lobular collections
of eosinophilic granular material and an increased number of fibroblasts
and other cells; (3) an increased amount of thickened and tortuous
fibers that stain strongly with elastic stains immediately adjacent
to and beneath the hyalinized region (elastotic material); and (4) concretions
within the hyalinized and granular areas that may show either
eosinophilia or basophilia.7|
The term elastotic degeneration was originally used to describe the fibers within the pterygia and pinguecula that stained with Weigert's and Verhoff's elastic tissue stains.23 However, incubation with the nonproteolytic enzyme elastase produced virtually no evidence of elastolysis.24 Hogan and Alvarado have proposed that the elastotic material is primarily derived from degenerated collagen and secondarily from preexisting elastic fibers and from abnormal fibroblastic activity and ground substance.25 More recently, ultrastructural analysis has shown that a large component of the elastotic material is the result of newly synthesized elastic fiber precursors and abnormal maturational forms of elastic fibers (elastodysplasia) that undergo secondary degeneration (elastodystrophy).22 Immunohistochemical staining shows the slow release of collagen, particularly types I through IV.26 The reason that the fibers do not react to elastase digestion may be because the enzyme acts on normal elastin exclusively.14 Histologically and ultrastructurally, pterygium and pinguecula resemble actinic degeneration of the skin. Actinic degeneration is believed to represent the degenerative changes that result from radiation-activated fibroblasts that secrete elastic tissue precursors.22 The same process may be operative in pterygium and pinguecula.7
Activated fibroblasts in the tissue surrounding Bowman's layer are shown by transmission electron microscopy of the leading edge (cap) of pterygia. The fibroblasts fragment and destroy Bowman's layer and a variable amount of superficial stroma.14 The invasion of cells accounts for the dense corneal adherence of the head of the pterygium and contributes to its vasculature and bulk.4 Because Tenon's capsule is interposed between the pterygium and the episclera, the thickened body of the pterygium is not adherent to the sclera. Acanthosis, parakeratosis, hyperkeratosis, and rarely even squamous cell carcinoma are secondary epithelial changes seen on the surface of pterygia.23
After surgical removal, a pterygium may recur. Clinically, the recurrent mass appears as an elevated growing fibrovascular scar arising from the excision site.7 Unlike its precursor, this process is thought to have no relationship to ultraviolet irradiation.27,28 Spencer believes the term “recurrent pterygium” is inappropriate because the subepithelial tissues do not contain the characteristic degenerated amorphous connective tissue of a true pterygium.23 Cameron likens the recurrence to that of a keloid in the skin.29 Angiogenesis factors may be involved in assisting the exuberant response of the vessels to surgical injury.9
Biochemical and immunologic changes accompany the morphologic changes in pterygia.7 The nongoblet epithelial cells of the pterygium synthesize anomalous mucus glycoproteins, with sugar residues different from those identified in the mucus glycoproteins of normal conjunctival epithelium.30 The glycosaminoglycans in pterygia contain much more neutral sugar and sialic acid than the glycosaminoglycans from normal conjunctiva; however, the total hexosamine and uronic acid levels are comparable in both tissues.31 The amino acid hydroxyproline is found in large quantities in pterygium compared with normal conjunctiva.31,32 Immunofluorescence staining of 26 pterygia revealed IgG and IgE in all samples tested and none in control conjunctiva, raising the possibility of a Gell-Coombs type I hypersensitivity reaction in which antigens, such as dust or pollen, may contribute to pterygium formation.33
Mild symptoms of photophobia and injection from a small pterygium can often be managed by avoiding smoke- and dust-filled environments. Topical, preservative-free lubricants, vasoconstrictors, and a mild nonpenetrating corticosteroid, such as medrysone 1% (HMS: Allergan Pharmaceuticals, Irvine, CA) can safely relieve symptoms when used judiciously.7 To prevent progression, some authors have advocated the use of ultraviolet-blocking spectacles.14,18 Both UV-A and UV-B protection have been recommended by Taylor and associates based on the results of their epidemiologic study.18
The first report of a surgical treatment of pterygium is more than 3000 years old.34 Many variations of this procedure since that time have been published.13,35,36 Only the most common operative techniques in present use, with adjunctive therapies, are discussed here.
A technique practiced by the ancient Greeks is avulsion of the pterygium. Refinements of the technique have been described in modern times.34,37-40 Its contemporary proponents contend that the operation is simple and avoids accidental, deep dissection into the cornea when the apex of the pterygium is removed.41 The recurrence rate (23%–75%) is similar to other techniques for primary removal.42
Excision (Bare Sclera)
One of the most popular methods for the removal of primary pterygium is excision of all remnants of the pterygium, leaving the underlying bare sclera exposed (Fig. 2). Sharp dissection from the corneal side and from the uninvolved perimeter of normal conjunctiva is necessary. The cornea is left as smooth as possible, and all of Tenon's capsule from beneath the pterygium is excised.
The excision of a superficial layer of corneal tissue at the time of pterygium removal was recommended by Castroviejo.3 Along with a superficial keratectomy, his procedure of choice for recurrent pterygia included removal of all corneal and scleral vascularization in the area of the excision. While emphasizing the importance of not weakening or perforating the cornea, he described a shallow, smooth dissection of the fibrovascular tissue comprising the pterygium and any opacification of the cornea. The surgical technique has also been described by Hersh.43 Using fine forceps, the surgeon keeps the pterygium tissue under tension and minimizes the excision of unaffected tissue, particularly at the limbus (Fig. 3). A recent report described the use of a 23-gauge needle, bevel up, as the cutting instrument for the superficial dissection.44
It is common to pursue meticulous excision of all abnormal tissue, including cleaning the limbal site with a sharp surgial blade and polishing the area with a diamond bur. The goal is smoothness of the surface of the excision, not the complete removal of all opacity.
There is a significant body of literature supporting the bare sclera technique.36,37,45 However, controlled studies of recurrence have not been performed. Youngson46 reported the outcome of 100 bare sclera operations and noted a recurrence rate above one third. Sugar47 hypothesized that by the removal of all remnants, healing conjunctiva becomes adherent to the sclera and is less likely to migrate onto the cornea. He recommended suturing the edge of remaining normal conjunctiva to sclera and believed that the healing of corneal epithelium would prevent extension of conjunctival epithelium and recurrent pterygium tissue onto the cornea.
Excision With Primary Closure
The concept of undermining the adjacent normal conjunctiva, with presumably less ultraviolet light exposure, and reapproximating the wound margins is finding renewed interest.48–50 Rotation of a flap of superior conjunctiva is thought to prevent recurrence and provide a smooth surface at the limbus to encourage proper tear film distribution.3 A technique of sliding conjunctival flaps from both inferior and superior limbus to close the wound (Fig. 4) has been reported to have a 1-year recurrence rate of only 5%.51
The “merest sclera” technique was examined in a series of 800 cases from the Virgin Islands.52 With this technique, the head and midbody of the pterygium are excised and a tenonectomy is extended beneath the conjunctiva to the adjacent rectus muscle, particularly in young patients or large lesions. Relaxing conjunctival incisions are made both superiorly and inferiorly along the limbus, and the conjunctiva is closed primarily and meticulously (Fig. 5). The rare recurrences (2.1%), defined as regrowth of fibrovascular tissue onto the cornea, occurred only in 2 cases with wound infection and in 15 cases with wound dehiscence from this large series.
Transplantation of the Head of the Pterygium
Among the early theories of pterygium recurrence was the idea that the head of the pterygium was the cause of its growth. Desmarres53 first reported transplantation of the head of a pterygium away from the cornea, beneath the superior edge of adjacent normal conjunctiva.
Stocker54 described a method of conjunctival z-plasty for primary closure (Fig. 6). An alternate type of z-plasty was described by Wilson and Bourne55 and consists of placing a flap of normal tissue between the body of the pterygium and the corneal limbus. No data on recurrence using this method are available, but the authors argue that the normal tissue acts as a barrier to the regrowth of the pterygium and preserves the superior bulbar conjunctiva for use in a conjunctival autograft procedure in the event of a recurrence.
Kenyon and associates56,57 described the transplantation of free autografts of superotemporal bulbar conjunctiva from the same eye to close wounds after the excision of advanced or recurrent pterygium. They used this method on 57 eyes of 54 patients, nearly 80% of which were recurrent. Mean follow-up of 2 years detected only three (5.3%) recurrences after autograft transplantation. Fourteen patients had restrictive adhesions causing diplopia in the opposite field of gaze, all of which resolved after surgery. The authors emphasize taking minimal subconjunctival tissue, to prevent scarring and retraction of the graft (Fig. 7).
Cautery spots are used to delineate the involved area of conjunctiva to be excised. Sharp, superficial excision of the head of the pterygium from the involved cornea to the limbus is done. The conjunctiva and Tenon's capsule are bluntly and meticulously dissected from the horizontal rectus muscle, leaving behind the bare sclera and exposed rectus muscle. Conjunctiva is secured to the sclera with absorbable suture (e.g., 8-0 Vicryl) on a spatulated needle. Calipers are used to determine the size of conjunctival graft required to resurface exposed sclera and horizontal rectus muscle. The globe is rotated inferomedially to expose an area of uninvolved superior bulbar conjunctiva. Dimensions are marked with several cautery spots, as large as 15 mm by 15 mm and extending to the limbus. Free grafts are dissected as thinly as possible, taking minimal subconjunctival tissue. If the graft is excised such that cautery marks remain with the graft tissue margins, then the epithelial surface can be readily identified when the graft is repositioned. The donor site does not require suturing, but the conjunctival margins can be advanced to the limbus with two interrupted sutures. The free graft is transferred into the recipient bed and secured to adjacent conjunctiva and episclera with interrupted sutures of 8-0 Vicryl; 10-0 nylon is used for the limbal edge of the graft.7,56,57
Shaw58 described the use of a paper template to aid in harvesting conjunctiva in the proper size and shape and as a scaffold to transfer, orient, and support the graft during suturing at the new site. His series of 28 cases with free autograft transplantation had only two (7%) recurrences.
The only randomized trial of conjunctival autograft treatment of pterygium had too few patients to show a statistically significant effect in preventing recurrence, when compared with bare sclera excision.12 After 15 months' follow-up, recurrence was 21% (3 of 19) in the autograft group and 37% (6 of 16) in the excision-only group. Younger patients were much more likely to have a recurrence, and all recurrences were noted by the patient within 6 to 8 weeks of surgery.12
There is a growing body of data that corneal epithelial stem cells are located at the limbus.59–64 The stem cells generate new corneal epithelial cells in addition to inhibiting conjunctival epithelial invasion of the cornea.65 Transplantation of limbal stem cells may be necessary for patients who have undergone multiple pterygium excisions with extensive damage to the limbus. There are little data on the efficacy of this approach.66
Lamellar or Penetrating Keratoplasty
It is not unusual after surgery for recurrent pterygium to have significant residual scarring and thinning of the cornea. In such cases, lamellar corneal graft tissue can be used to replace thin or scarred portions of the cornea. Moore67 has described the details of the surgical technique of lamellar keratoplasty for pterygium.
Poirer and Fish68 had no recurrences in a group of 15 patients, with follow-up of 4 months to 2 years. In another report, there were no recurrences among a series of 9 patients, each treated with rectangular lamellar keratoplasty for recurrent pterygium.69 Length of follow-up is not mentioned. Recurrence of pterygia in 3 of 5 cases treated with lamellar keratoplasty was noted in another series.47 Recurrence was noted in an average of 102 days after surgery. A description of 11 cases did not mention length of follow-up, but in 5 of the patients cure was complete and 4 patients had recurrence of less than 2 mm on the graft.70
Use of a corneal trephine (usually 8 mm) to incise the limbus to a depth of 0.3 mm after superficial excision is part of one lamellar technique.71 The host bed is then dissected, with attention to creating a smooth surface. The defect is filled with a 0.4-mm thick fresh donor button, sutured in place with interrupted 10-0 nylon. The authors report three recurrences among nine cases, after mean follow-up of 2 years. They also note that lamellar keratoplasty is not a complete barrier against regrowth of pterygia, but recurrent lesions remained smaller with thicker underlying tissue, restoring normal anatomic features.
The successful use of a lamellar graft of precarved lyophilized tissue has also been described.72 Its advantages include replacement of an intact Bowman's layer, immediate availability, and long-term storage (up to 2 months), but the cost and technical difficulty of use are challenging problems. Thirteen cases were treated with lyophilized donor tissue of 0.3 mm thickness after lamellar dissection of the entire area covered by the pterygium. Donor tissue was sutured in place on the cornea, and adjacent normal conjunctiva was used to cover the bare sclera. Only one repeat excision was needed after mean follow-up of 23 months. Best corrected visual acuity and astigmatism was stable.
In the setting of thinning and impending corneal perforation or scarring of the visual axis of the cornea, penetrating keratoplasty must be considered. In this rare instance, a modified technique with decentration of the graft and careful suture placement in the thinned area is recommended.
A number of adjunctive therapies have been described to decrease the risk of recurrence after the surgical removal of a pterygium. Each has its attractive features, but none is without drawbacks.
With the knowledge that blood vessel growth at the operative site contributes to the recurrence of a pterygium, several workers have advocated the extensive use of intraoperative cautery, particularly at the limbus, to augment the surgical removal of the pterygium.46,73 When used with the bare sclera excision, Townsend4 recommends careful cautery of all vessels in the bare episclera. Rich and associates36 believe that cautery can lead to the formation of hypertrophic scar tissue and discourage its intraoperative use. No data are available on its efficacy.
The use of the argon laser in selected postoperative cases has been described. The technique of applying 50-μm spots to early neovascular fronds and limiting power settings to minimize conjunctival epithelial damage has been reported.73 The recurrence rate is unknown.
Krag and Ehlers74 used the excimer laser to ablate irregularities in the bare scleral surface after pterygium excision. They reported 22 cases (11 primary and 11 recurrent) that were treated with a 1.5-mm diameter spot size and an energy density of 1000 mJ/cm2. The recurrence rate was 91% (20 cases) at 1 year, which the authors attribute to the bare sclera technique, not the excimer laser treatment.
New vessels often herald the recurrence of a pterygium. Postoperative use of topical corticosteroids inhibits the inflammatory reaction and may reduce neovascularization of the operative site.75 Some corticosteroids have direct antiangiogenic effects in addition to their anti-inflammatory effects.76 Several authors have advocated their use four times daily for 2 weeks after the healing of the corneal epithelial defect.38,75,77 Data on the efficacy of postoperative corticosteroids are lacking.
Thiotepa (N,N´,N" triethylene-thiophosphoramide) is a nitrogen mustard alkylating agent with antimitotic properties.7 It is a radiomimetic agent that presumably obliterates proliferating vascular endothelial cells. Its early use in 30 patients by Meacham followed bare sclera excision with the application of 1:2000 (15 mg in 30 ml Ringer's solution) dilution of thiotepa every 3 hours for 8 weeks.78 There was only one recurrence, in a patient who discontinued the use of thiotepa.
Mori79 reported thiotepa use in Japan simultaneously with Meacham. He found a 16% recurrence in a group of patients treated for only 2 weeks. Liddy and Morgan80 used Meacham's regimen after pterygium excision in 26 eyes, with only one recurrence after 2 years of follow-up. In a similarly treated group of 17 patients there was also only one recurrence.76 In the largest series, 65 patients with more than 6 months' follow-up, the recurrence rate was 38% (18 cases).81 However, the 65 patients were part of a consecutive series of 147, the remainder of which did not return for follow-up examinations. The author presumes that most of these patients did not have a recurrence, and believed there was no need for further evaluation. If there were no other patients with a recurrence, the rate would be 12%.
Reported complications with thiotepa include prolonged conjunctival hyperemia, irritation, allergic reactions, bacterial corneoscleritis, and permanent eyelid depigmentation, especially in darkly pigmented patients.82–88 No systemic toxicity has been reported, but these side effects have deterred many ophthalmic surgeons from adjunctive use of thiotepa after pterygium surgery.7
Mitomycin C is an antineoplastic/antibiotic agent isolated from the soil bacterium Streptomyces caespitosus. In rapidly growing cells, it inhibits the synthesis of DNA, cellular RNA, and proteins.87 Effects after systemic administration include bone marrow, renal, and mucous membrane toxicity, although no hematologic or renal effects have been detected with topical use.88
An early description of its topical use appeared in the Japanese literature soon after the first thiotepa report. Kunimoto and Mori89 used a concentration of 0.04% three times daily for 1 to 2 weeks after surgery, with no recurrences. A number of subsequent articles from both Asia and North America have confirmed their good results, with recurrence rates of 2% to 16%.90,91 Among the most impressive results were the double-masked, prospective trial of Singh and colleagues.87 Using doses of 0.4 mg/ml (0.04%) and 1 mg/ml four times daily for 2 weeks, they showed a recurrence rate of 2.2%, compared with the placebo rate of 88.9% after 5 months of follow-up. The weaker dose of mitomycin C had fewer side effects with equal efficacy.
A retrospective study of 61 eyes with recurrent pterygia examined the effect of 0.2 mg/ml drops twice daily for 5 days on recurrence after repeat surgery.92 Eyes whose first surgery was excision alone had a 9% recurrence after a second excision with supplemental mitomycin C, while eyes that received excision plus irradiation initially had only a 5% recurrence after the second excision and mitomycin C. Three eyes developed recurrent pterygia and symblepharon. Other reports also describe good results with no serious complications using 0.2 mg/ml of mitomycin C.90,93
The motivation for changing to 0.2 mg/ml and more dilute concentrations of mitomycin C is the reports, now numerous, of corneal and scleral ulceration, uveitis, and secondary glaucoma after use of 0.4 mg/ml of mitomycin C.94–99 A detailed report of 10 cases with serious, vision-threatening complications associated with mitomycin C use after pterygium surgery has been published.99 The complications included iritis (8 patients), severe secondary glaucoma (four patients), corneal edema (three patients), corectopia (two patients), sudden-onset mature cataracts (two patients), scleral calcification (one patient), and corneal perforation (one patient). Six patients required a total of 20 return visits to the operating room after their original pterygium surgery. In five eyes, visual acuity remained at 20/200 (6/60)* or less. The authors call for a prospective, multicenter trial of the use of mitomycin C after pterygium excision.99 A separate case report describes a 36-year-old woman who had a corneal infiltrate, scleral ulceration, a pupil peaked toward the ulceration (globe perforation not mentioned), hypotony, vitreous exudates, optic disc hyperemia, and macular edema after using 0.2 mg/ml of mitomycin C three times daily for 3 weeks after pterygium surgery.100 Similar ciliary body and vitreoretinal toxicity has been described in studies on rabbits.101,102 Additional data on the long-term toxicity of mitomycin C are needed.
Metric equivalent given in parentheses after Snellen notation.
Inhibition of proliferating cells in the wound bed can also be accomplished by beta radiation, which presumably reduces mitosis in rapidly dividing vascular endothelial cells. Folkman103 was the first to recognize that the growth of tumors was dependent on angiogenesis. In tumors and deep wounds, where angiogenesis is intensely stimulated, capillary endothelial cells can proliferate as quickly as bone marrow cells.7 Under normal conditions, the mitotic rate of capillary endothelial cells is 100 to 1000 times less than that of bone marrow cells.104 Irradiating the rapidly dividing endothelial cells of a pterygium dramatically slows their proliferation, while sparing the adjacent mitotically inactive cell populations. Ionization is thought to occur in both the nucleus and the cytoplasm of cells.3
Radiation can be administered only by those with a valid federal license from the Nuclear Regulatory Commission (NRC), after the completion of a special training class and approval by the regional office of the NRC.7 A radiotherapist or radiologist administers the beta radiation in most institutions.2
Among the earliest adjunctive therapies after pterygium surgery was the use of radon by Burnam and Neill in 1940.105 Early studies were poorly standardized, with irradiation given in variable amounts with radon bulbs, radium plaques, and x-rays.3 Radon and radium also emitted gamma rays, an additional confounding factor. Beta radiation does not appear to be effective as a sole treatment for established pterygia.106
The introduction of strontium applicators for ophthalmologic use in 1950 brought strontium-90 into use as the standard pure beta (no gamma) radiation source.107 In most subsequent studies, recurrence of pterygium after surgery and beta radiation ranges from 0% to 16%,108–112 with the two largest series to date, 1102 and 1300 cases, reporting rates of 12% and 1.3%.113,114 Strontium-90 is produced by fission of uranium-235 and has a half-life of 28 years.7 In spite of this long half-life, failure due to inadequate irradiation from the applicator after isotope decay has been reported.112
The unit of applied radiation dose is the roentgen equivalent physical, or rep. One rep equals 1.08 rad. Another common unit is the Gray (100 rad equals 1 Gy.)
Applicators vary in diameter and in the rate of delivery of beta rays, although most rates of delivery are on the order of 3000 rep/min.3 Standard dose is in the range of 1000 to 3000 rep.7 Care must be taken to minimize overlap of applications, since the area of overlap will get twice the radiation. A shield is left in place on the applicator to prevent ambient radiation from encountering the cornea, sclera, or physician.
The depth-dose profile of strontium-90 is nearly ideal for ophthalmic applications.110,115 The maximum dose occurs within 2 mm of the tip of the applicator. Lemp3 has used two 0.5-mm thick, high water content, soft contact lenses to restrict the highest dose to the outer 1 mm of the wound bed. If a dose of 1800 to 2200 rep is applied to the pterygium bed, the anterior surface of the lens receives 70 to 90 rep while the posterior retina receives only 4 to 8 rep.7
Application of beta radiation is probably best done in the immediate postoperative period. Aswad and Baum116 conducted a prospective study in 54 eyes with pterygia, 16 of which were recurrent. Patients were randomized to treatment with 2000 rad either immediately after surgery or 4 days postoperatively. There was no difference in the recurrence rate of primary pterygia between the two groups, but a significantly different rate of recurrence (1 of 6 in the immediate group versus 7 of 10 in the delayed treatment group) was noted in the patients with recurrent pterygium.
Other isotopes have also been used with good results in the immediate postoperative period. A group of Swiss investigators reported success treating recurrent pterygia with excision and 2 to 3 hours of therapy with ruthenium-106, delivered via a scleral applicator shell designed for use with choroidal malignant melanomas.117 Small recurrences were noted in 2 of 17 patients (12%), while others had postoperative restrictive diplopia (1 patient) and mild corneal edema (1 patient). The total dose was 20 Gy, but it was delivered at a rate approximately 100 times slower than strontium-90. The authors hypothesize that low-dose, protracted treatment selectively decimates proliferating pterygium cells, while minimizing effect on healthy corneal and scleral cells. Mean follow-up was about 5 months.
Cataract formation after beta radiation is well known.106,110,112,118 Ionizing radiation can damage the equatorial cells of the lens epithelium, giving rise to the changes that appear in the lens fibers and in the posterior subcapsular region after beta radiation.119 Doses in the range of 1500 to 2500 rep result in peripheral lens changes, but no visual acuity effects are noted. A dose of 8,000 to 10,000 rep is thought to be required for visual axis opacification of the lens.119 Hilgers111 found no lens opacities 5 years after a fractionated dose of 3000 rep, but 6% of eyes developed lens opacities after 3000 to 5000 rep. In another study, sectoral posterior cortical cataracts with visual acuity of 20/30 (6/9) or better were present in 25% of eyes receiving a dose of 2900 to 5200 rad.112 Three of 63 eyes had reduced vision as a result of cataract.
Other complications after beta radiation treatment are less common. Conjunctival hyperemia may persist for several months after treatment.120 Scleral ulceration is a late but potentially devastating complication.106,121,122 Tarr and associates112 found scleral ulceration of greater than two-thirds thickness in 31 of 63 eyes after a follow-up time of 12 years. They did not find significant association with total dose, age, follow-up time, or severity of ulceration in this group. In a retrospective review of more than 1100 consecutive patients, MacKenzie and co-workers113 found some sign of scleromalacia in 13%, a third of whom had severe thinning, when examined 10 years after an average postoperative beta dose of 22 Gy. Another experienced clinician denied any cases of scleral necrosis in 20 years of beta radiation use with a smaller applicator area and suggested the larger applicator areas used in Tarr's group were a major contributing factor in causing scleral necrosis.123
Other less commonly reported complications of beta radiation treatment after pterygium removal are symblepharon formation,112 ptosis, iris atrophy, corneal ulceration, bacterial corneoscleritis,82,124 and fungal panophthalmitis.125
|The management of pterygia and recurrent pterygia is improving, yet many
questions remain unanswered. How should a recurrence be defined? Is
symptomatic elevation of the conjunctiva adequate, or must the recurrent
lesion invade the cornea? How long must one follow postoperative patients
to be confident that recurrence is unlikely? Standardization of
the definition of recurrence, and use of a standard postoperative observation
period would allow easier comparison of future studies.|
Primary closure is being reexamined and offers promise. Conjunctival autograft is safe and effective, but technically difficult and not clearly better than careful primary closure. Mitomycin C and beta radiation must be used with caution and the knowledge that complications may occur months to years later. Future studies may elucidate the cause of these delayed complications and allow better selection of adjunctive therapy after pterygium surgery.
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62. Schermer A, Galvin S, Sun T-T: Differentiation-related expression of a major 64K corneal keratin in vivo and in culture suggests a limbal location of corneal epithelial stem cells. J Cell Biol 103:49, 1986
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