Hyperguides

Ophthalmology / Refractive surgery

Pathophysiology of Epithelial Ingrowth

David R. Hardten, MD
Article

David R. Hardten, MD

Introduction

Since the introduction of corneal lamellar refractive surgery, complications unique to the creation of the flap have been a concern.1-5 Operative complications related to the lamellar flap include striae, epithelial ingrowth, flap displacement and diffuse lamellar keratitis. Epithelial ingrowth is a condition in which epithelial cells gain access to the flap interface at the time of surgery or by postoperative migration under the flap edge. Many isolated nests of epithelial cells will regress within a few months with no adverse consequences. However, occasionally, the epithelial cells progress centrally from the flap edge and encroach on the central visual axis. Progressive ingrowth results in flap melting and irregular astigmatism.6-9

Epithelial ingrowth is managed successfully with early surgical intervention, including lifting the lamellar flap and removing the epithelial cells from the stromal bed and undersurface of the flap. Despite surgical intervention, however, epithelial ingrowth may recur. This recurrence is common when poor flap adherence or flap misalignment exists, or with LASIK after radial keratotomy (RK) or astigmatic keratotomy (AK), in which multiple edges that must remain clear of epithelial ingrowth exist. Adjunctive interventions to prevent recurrence of epithelial ingrowth include alcohol debridement, suturing, fibrin tissue adhesive and phototherapeutic keratectomy (PTK).10-15 Progressive epithelial ingrowth can result in flap necrosis requiring flap removal and loss of best-corrected visual acuity secondary to irregular astigmatism.7-9

Incidence

The estimated incidence of clinically apparent epithelial ingrowth after LASIK ranges from 1% to 15% depending on the criteria used to define the presence of epithelial ingrowth.2-5,15-18 Limited forms of epithelial ingrowth are common, with up to 47% reported by pathological examination.19 Epithelial ingrowth affecting vision is less common. After LASIK retreatment, the incidence may be as high as 31%.9,20 Factors that increase the risk of epithelial ingrowth are epithelial defects at the time of surgery, flap misalignment, poor flap adherence, buttonhole flaps, enhancement surgery and post-hyperopic LASIK.1,9,16 LASIK after RK or AK also increases the risk for epithelial ingrowth as the incisions can split at the time of LASIK, allowing epithelial cells access to the interface.8,17 The incidence of epithelial ingrowth in eyes treated with LASIK for consecutive hyperopia after RK ranges from 5% to 7.1% in most series.7,8,17,21

Etiology and Risk Factors

The most common etiology of epithelium in the interface is host epithelium growing beneath the flap rather than meeting and merging with the epithelium on the top of the flap. Edema in the flap under an epithelial defect may reduce adhesion of the flap in the early postoperative period. This allows epithelium to enter the space below the flap. This may be more common in older patients or those who have a history of anterior basement membrane dystrophy or recurrent erosions.22 Epithelium also occurs as a separate nest of cells that are implanted during the surgery, either from the microkeratome blade as it cuts the flap or when cells are dislodged from the surface and then implanted under the flap with other instruments during the procedure.8,15,23 These implantation cysts are uncommon.

If the keratome enters the cornea at a shallow angle, as opposed to a relatively vertical angle, then epithelial ingrowth may be more likely.7,24 Laser treatment of the flap gutter also reduces the barrier of a vertical keratome entry at the edge, which may increase the possibility of epithelial ingrowth.12,16,25

Additionally, if epithelium is already present in the flap from other incisions, these epithelial cells can then spread into the newly opened potential space after the flap is lifted. This may occur following RK or AK, or penetrating or lamellar keratoplasty incisions where epithelial plugs exist deeper in the corneal stroma, or in cases of lift-flap enhancements, where a small amount of clinically insignificant epithelium is present at the flap edge.2,9,20,21,26

Diagnosis and Stages

Authors have defined clinically significant ingrowth using a variety of criteria. Subclinical epithelial ingrowth is common with microscopic amounts of epithelial ingrowth present in many eyes.19 Epithelial ingrowth is often self-limited and usually does not progress toward the center or cause necrosis and melting of the overlying flap. A faint haze along the flap edge is often present in early epithelial ingrowth, which may be difficult to observe at the slit lamp (Slide 1). As long as the haze is less than 2 mm from the edge of the flap, it is usually not clinically significant. Progression to the appearance of vacuoles and whorling pearls or epithelium along with mild irregularity of the flap edge occurs in about 10% of patients, as reported by Asano-Kato and colleagues23 (Slide 2 and Slide 3). In this study, no change occurred over the follow-up period in 25% of eyes, regression occurred in 55% of eyes, and formation of a solid white mass occurred in 10% of eyes.23 The borders are similar distances from the flap edge and the appearance of a peninsula is not uncommon (Slide 4 and Slide 5). The thickness of the epithelial ingrowth may be up to 50 mm to 70 mm and may be noticeable on elevation topography (Slide 6 and Slide 7).





 

Fluorescein staining is helpful to detect elevation of the flap in the region of the epithelial ingrowth through negative staining. In the early stages of epithelial ingrowth, fluorescein may spread into the interface from the surface, indicating that a connection to the outside exists due to poor adherence of the flap to the stromal bed. Additionally, staining of the flap edge occurs when the flap melts or when the overlying epithelium is not able to heal on top of the flap. The flap edges become eroded and lose the typical round shape due to the liberation of collagenase from the hypoxic epithelial cells retained under the corneal flap. The flap edge may appear fibrotic and have a rolled appearance.

Visually significant epithelial ingrowth is usually caused by encroachment on the visual axis and may be associated with flap melt or creation of an epithelial fistula near the flap margin, causing persistent irritation. Epithelial ingrowth affects visual acuity directly by growth into the visual axis or, more commonly, indirectly by causing irregular astigmatism via interface elevations or flap melting near the axis.

Pathology

Early epithelial ingrowth pathologically appears as relatively normal looking multilayered squamous epithelium. In the later stages of epithelial ingrowth, degrading or degraded epithelial cells with only scarce cellular elements surrounded by amorphous material are be found. Larger than normal collagen fibrils appear in these areas with a capsule of connective tissue similar to scar formation.27,28 Epithelium in the interface stimulates keratocyte proliferation and apoptosis.29

Treatment

The typical indication for treatment is visually significant epithelial ingrowth through encroachment on the visual axis with induced irregular astigmatism (Slide 6 and Slide 7). Creation of an epithelial fistula near the flap margin may cause persistent irritation, which is another indication for surgical treatment (Slide 4). A variety of removal methods of the epithelial cells have been suggested including blunt scraping, excimer laser PTK, and the use of adjuncts such as cryotherapy, alcohol, cocaine, Nd:YAG laser, mitomycin C, sutures or glue. One reason for the varied removal methods is the difficulty in preventing recurrences. The removal of epithelial cells from the interface is relatively straightforward; however, reinvasion of the interface by epithelium is common.4,5,14,16,30 In two patient series, 23% to 34% of patients had a clinically significant recurrence in which further procedures were proposed.14,16

Alcohol has been an adjunct in the removal of the invading cells to increase the likelihood of removal of all epithelial cells.14,16,31 One plausible contribution to recurrence is failure to completely remove all cells from the interface and the maintenance of an epithelial fistula. Because alcohol decreases the adherence of epithelial cells, it potentially facilitates complete removal of the cells. However, in a retrospective study, the clinically significant recurrence rates in a group in which alcohol was used was 36%, which was similar to a 31% recurrence rate in eyes where alcohol was not used.14 In all patients with a clinically significant recurrence, the ingrowth occurred in the original location. This supports the concept of the epithelium's causing localized remodeling of the stromal interface, giving rise to the creation of a space for epithelial cells to re-accumulate. Alcohol was also associated with flap melting in Vroman's and Karp's study.31


SLIDE 8

Recurrence rates may be lessened through a combination of complete removal of cells from all involved surfaces using a thorough mechanical technique and also the closure of the fistula present in the stromal interface by means of adhesives or sutures.4,5,13,16,30,32 The sooner it is decided to proceed with removal occurs, the more likely the risk of recurrence would be decreased as there would be less time for stromal remodeling and fistula formation to occur.

However, this theory was not supported by Lahners and colleagues,14 whose study evaluated time to removal with recurrence rates where, in eyes with clinically significant recurrence, removal was performed an average of 37 days after original procedure, as compared to 57 days in eyes with no clinically significant recurrence. In the study, however, more severe cases were referred and surgery performed at an earlier time after the prior surgery.

When fibrin adhesive (Tisseel, Baxter, Deerfield, IL) is used to seal the fistula, it is important to confirm that no allergy to bovine products exists. Tisseel glue has been used in Europe for more than 20 years, primarily as an adjunct to hemostasis in cardiovascular surgery and trauma,33 and was approved for this indication by the Food and Drug Administration in 1998. The use of fibrin glue in ophthalmology has recently been reported for retina, conjunctival and corneal applications. It is considered an off-label use.34-39

The use of fibrin adhesive as a sealant reportedly prevented further epithelial ingrowth in three patients with recurrent epithelial ingrowth.13 The author has now used fibrin adhesive in 27 eyes with recurrent epithelial ingrowth. Fifteen percent of the eyes that had recurrence of epithelial ingrowth responded to a second procedure with Tisseel glue. The glue was well tolerated in all eyes, and no other complications were associated with its use (Slide 8).


SLIDE 9

Epithelial ingrowth has also been treated by suturing the flap edges to prevent access of epithelial cells to the interface.12,30,32 Suturing can induce striae in the flap, may increase irregular astigmatism and requires suture removal. Light PTK applied to the bed and underside of the flap was also described as an adjunct to manual epithelial cell removal.11 This is associated with induced irregular astigmatism when tissue is removed from the stromal flap.

The author's preferred technique for removal of epithelial ingrowth recalcitrant to initial removal is blunt removal of the epithelial cells, alcohol application to loosen extra adherent cells and then sealing the fistula with fibrin glue (Tisseel). If the fistula is elevated, then 10-0 polyglactin sutures (Vicryl, Ethicon, Somerville, NJ) are used before the fibrin glue is applied.


SLIDE 10

Before the flap is elevated, the epithelium is removed along the gutter of the flap for 2 mm on either side of the gutter. If a buttonhole in the flap is present, the epithelium is removed from the top of the flap for 2 mm on all sides of the buttonhole. The flap is then elevated, and the epithelium is removed from the stromal bed with a blunt PRK spatula (Becton Dickinson, Franklin Lakes, NJ) (Slide 9). Careful attention is directed toward the entry site of the keratome blade, as the epithelium is often adherent in this gutter region. The flap is then supported with a metal platform (Rhein Medical, Tampa, FL) to facilitate blunt removal of the epithelium from the back of the flap (Slide 10). Diluted alcohol is then used on a lintless sponge and applied directly to the gutter and back of the flap. The sponge is briefly dipped in the alcohol twice and then dried on a sterile lint-free drape before applying to the gutter area and the back of the flap to prevent excess alcohol from migrating onto the limbus. The application should be light enough that, within 10 seconds, the alcohol evaporates spontaneously. The PRK spatula is then used again to remove any further epithelial cells from the gutter and the back of the flap that have been loosened with the alcohol. Careful attention is paid to the edges of the flap, as the epithelium tends to wrap around the edge of the flap, and the epithelium must be picked off this area.

Once the epithelium is removed from the interface, then the flap is floated back into place with a minimal amount of saline solution. Because the flap has typically been elevated for an extended period, it is important to make certain that any striae are stretched from the flap and that the gutter has been apposed in all areas. Often, the flap has melted from the long-standing epithelial ingrowth and large gutter may exist. Clinical judgment is needed to determine the position of the flap.

After the flap is dried into position, clinical observation of the edges is used to determine if 10-0 sutures are required in elevated areas with loss of tissue under the flap. If needed, 10-0 polyglactin or nylon sutures can be used. Polyglactin has the advantage of being dissolvable and, therefore, they do not always have to be removed. Sutures are typically removed at 2 to 3 weeks postoperatively. The sutures are placed attempting to induce minimal flap distortion, striae or irregular astigmatism. The suture is tied, and the knots are buried along the outer edge, so when removed, they will not lift the edge of the flap. Sutures are not typically needed.


SLIDE 11

The fibrin glue has already been mixed according to the manufacturer's directions, taking care to avoid bubbles in the syringes. The glue comes in a fibrin portion (blue syringe: thick solution) and a thrombin portion (black syringe: thinner solution). Dilution of the thrombin with saline solution in a 1:1 ratio slows the coagulation time of the glue, allowing more time for manipulation of the glue. A duplojet syringe (Baxter, Deerfield, IL) is used to apply the glue, taking care that equal portions of the two portions of the glue are applied to the gutter (Slide 11). The author has not used the glue in the interface, but more as a barrier to epithelialization of the gutter until the interface can form a scar to prevent epithelium from growing into the interface. The glue is dried using the vacuum apparatus on the VISX S4 laser for 8 minutes. An additional layer of glue can be applied if desired. The gutter is the main area to be sealed, but from a practical nature, it is not possible to limit the application to the gutter only.


SLIDE 12

After the drying takes place, Celluvisc (carboxymethylcellulose sodium 1%, Allergan), Zymar (gatifloxacin, Allergan), Acular LS (ketorolac tromethamine, Allergan, and Pred Forte (prednisolone acetate ophthalmic solution 1%, Allergan) are applied as well as a bandage soft contact lens. Neurontin (gabapentin, Pfizer) and Vicodin (hydrocodone, Abbott Laboratories) are helpful systemic agents to reduce pain postoperatively. If epithelial ingrowth recurs, repeating the process will typically prevent further cell growth. Glues such as cyanoacrylate may be useful in very recalcitrant cases to provide a denser barrier.40 However, the glue may be slowly resorbed, leading to discomfort and persistent epithelial healing complications (Slide 12).

Prevention

It is better if the patient and surgeon can avoid the development of epithelial ingrowth. What leads to epithelial ingrowth is not always clear, but some surgical techniques may reduce the incidence of epithelial ingrowth. Carefully replacing the flap after LASIK with tight alignment of the edge of the flap with the edge of the bed may provide a barrier to the migration of epithelial cells under the flap. Avoiding excessive irrigation or residual fluid under the flap may promote more rapid flap adherence, again providing a barrier to epithelial cell migration under the flap. Thicker edged flaps may augment this barrier to migration of cells under the flap. Avoiding intraoperative epithelial defects through lubrication of the surface and avoiding LASIK on patients with anterior basement membrane dystrophy is helpful. Avoiding incorporation of the epithelium in the interface during flap lifts may reduce the rate of epithelial ingrowth.

Conclusion

Epithelial ingrowth is a common flap complication with LASIK. Prevention is key; however, when epithelial ingrowth occurs, most cases will resolve spontaneously without loss of vision. Epithelial ingrowth occurs through poor flap adhesion in the periphery allowing epithelial cells access to the interface. If progressive and visually significant, then removal by lifting the flap, blunt debridement, and suturing the flap or sealing the edges of the flap with adhesive may promote wound healing and a barrier to return of the epithelial cells.

References

  1. Hardten DR, Lindstrom RL. Management of LASIK complications. Operative Techniques in Cataract and Refractive Surgery. 1998;1:32-39.

  2. Stulting RD, Carr JD, Thompson KP, et al. Complications of laser in situ keratomileusis for the correction of myopia. Ophthalmology. 1999;106:13-20.

  3. Yildirim R, Devranoglu K, Ozdamar A, et al. Flap complications in our learning curve of laser in situ keratomileusis using the Hansatome microkeratome. Eur J Ophthalmol. 2001;11:328-332.

  4. Spigelman AV. Complications of LASIK. J Refract Surg. 2001;17:475.

  5. Melki SA, Azar DT. LASIK complications: Etiology, management, and prevention. Surv Ophthalmol. 2001;46:95-116.

  6. Castillo A, Diaz-Valle D, Gutierrez AR, Toledano N, Romero F. Peripheral melt of flap after laser in situ keratomileusis. J Refract Surg. 1998;14:61-63.

  7. Francesconi CM, Nosé RA, Nosé W. Hyperopic laser-assisted in situ keratomileusis for radial keratotomy-induced hyperopia. Ophthalmology. 2002;109:602-605.

  8. Forseto AS, Nosé RA, Francesconi CM, Nosé W. Laser in situ keratomileusis for undercorrection after radial keratotomy. J Refract Surg. 1999;15:424-428.

  9. Perez-Santonja JJ, Ayala MJ, Sakla HF, Ruiz-Moreno JM, Alio JL. Retreatment after laser in situ keratomileusis. Ophthalmology. 1999;106:21-28.

  10. Haw WW, Manche EE. Treatment of progressive or recurrent epithelial ingrowth with ethanol following laser in situ keratomileusis. J Refract Surg. 2001;17:63-68.

  11. Wilson SE. LASIK: Management of common complications. Laser in situ keratomileusis. Cornea. 1998;17:459-467.

  12. Lim JS, Kim EK, Lee JB, Lee JH. A simple method for the removal of epithelium grown beneath the hinge after LASIK. Yonsei Med J. 1998;39:236-239.

  13. Anderson NJ, Hardten DR. Fibrin glue for the prevention of epithelial ingrowth after laser in situ keratomileusis. J Cataract Refract Surg. 2003;29:1425-1429.

  14. Lahners WJ, Hardten DR, Lindstrom RL. Alcohol and mechanical scraping for epithelial ingrowth following laser in situ keratomileusis. J Refract Surg. 2005;21:148-151.

  15. Walker MB, Wilson SE. Incidence and prevention of epithelial growth within the interface after laser in situ keratomileusis. Cornea. 2000;19:170-173.

  16. Wang MY, Maloney RK. Epithelial ingrowth after laser in situ keratomileusis. Am J Ophthalmol. 2000;129:746-751.

  17. Lindstrom RL, Hardten DR, Houtman DM, et al. Six-month results of hyperopic and astigmatic LASIK in eyes with primary and secondary hyperopia. Trans Am Ophthalmol Soc. 1999;97:241-255.

  18. Helena MC, Meisler D, Wilson SE. Epithelial growth within the lamellar interface after laser in situ keratomileusis (LASIK). Cornea. 1997;16:300-305.

  19. Kramer TR, Chuckpaiwong V, Dawson DG, et al. Pathologic findings in postmortem corneas after successful laser in situ keratomileusis. Cornea. 2005;24:92-102.

  20. Davis EA, Hardten DR, Lindstrom M, et al. LASIK enhancements: A comparison of lifting to recutting the flap. Ophthalmology. 2002;109:2308-2313.

  21. Clausse MA, Boutros G, Khanjian G, Wagner C, Garabet AL. A retrospective study of laser in situ keratomileusis after radial keratotomy. J Refract Surg. 2001;17:S200-S201.

  22. Rezende RA, Uchoa UC, Cohen EJ, Laibson PR, Rapuano CJ. Complications associated with anterior basement membrane dystrophy after laser in situ keratomileusis. J Cataract Refract Surg. 2004;30:2328-2331.

  23. Asano-Kato N, Toda I, Hori-Komai Y, Takano Y, Tsubota K. Epithelial ingrowth after laser in situ keratomileusis: clinical features and possible mechanisms. Am J Ophthalmol. 2002;134:801-807.

  24. Knorz MC. Flap and interface complications in LASIK. Curr Opinion Ophthalmol. 2002;13:242-245.

  25. Mulhern MG, Condon PI, O'Keefe M. Myopic and hyperopic laser in situ keratomileusis retreatments: Indications, techniques, limitations, and results. J Cataract Refract Surg. 2001;27:1278-1287.

  26. Hardten DR, Chittcharus A, Lindstrom RL. Long-term analysis of LASIK for the correction of refractive errors after penetrating keratoplasty. Trans Am Ophthalmol Soc. 2002;100:143-150; discussion, 150-152.

  27. Asano-Kato N, Toda I, Hori-Komai Y, Takano Y, Dogru M, Tsubota K. Histopathological findings of epithelial ingrowth after laser in situ keratomileusis. Cornea. 2005;24:130-134.

  28. Naoumidi I, Papadaki T, Zacharopoulos I, Siganos C, Pallikaris I. Epithelial ingrowth after laser in situ keratomileusis: A histopathologic study in human corneas. Arch Ophthalmol. 2003;121:950-955.

  29. Wilson SE, Mohan RR, Hutcheon AE, et al. Effect of ectopic epithelial tissue within the stroma on keratocyte apoptosis, mitosis, and myofibroblast transformation. Exp Eye Res. 2003;76:193-201.

  30. Waring GO III. Epithelial ingrowth after laser in situ keratomileusis. Am J Ophthalmol. 2001;131:402-403.

  31. Vroman DT, Karp CL. Complication from use of alcohol to treat epithelial ingrowth after laser-assisted in situ keratomileusis. Arch Ophthalmol. 2001;119:1378-1379.

  32. Rojas MC, Lumba JD, Manche EE. Treatment of epithelial ingrowth after laser in situ keratomileusis with mechanical debridement and flap suturing. Arch Ophthalmol. 2004;122:997-1001.

  33. Rousou J, Levitsky S, Gonzalez-Lavin L, et al. Randomized clinical trial of fibrin sealant in patients undergoing resternotomy or reoperation after cardiac operations: A multicenter study. J Thorac Cardiovasc Surg. 1989;97:194-203.

  34. Olsen TW, Sternberg P Jr, Capone A Jr, et al. Macular hole surgery using thrombin-activated fibrinogen and selective removal of the internal limiting membrane. Retina. 1998;18:322-329.

  35. Grewing R, Mester U. Fibrin sealant in the management of complicated hypotony after trabeculectomy. Ophthalmic Surg Lasers. 1997;28:124-127.

  36. Cohen RA, McDonald MB. Fixation of conjunctival autografts with an organic tissue adhesive. Arch Ophthalmol. 1993;111:1167-1168.

  37. Grewing R, Mester U. Radial suture stabilized by fibrin glue to correct preoperative against-the-rule astigmatism during cataract surgery. Ophthalmic Surg. 1994;25:446-448.

  38. Henrick A, Kalpakian B, Gaster RN, Vanley C. Organic tissue glue in the closure of cataract incisions in rabbit eyes. J Cataract Refract Surg. 1991;17:551-555.

  39. Duchesne B, Tahi H, Galand A. Use of human fibrin glue and amniotic membrane transplant in corneal perforation. Cornea. 2001;20:230-232.

  40. Meskin SW, Ritterband DC, Shapiro DE, et al. Liquid bandage (2-octyl cyanoacrylate) as a temporary wound barrier in clear corneal cataract surgery. Ophthalmology. 2005;112:2015-2021.