Corneal flap complications in refractive surgery

Corneal flap complications in refractive surgery Part 2: Postoperative treatments of diffuse lamellar keratitis in an experimental animal model Mike P. Holzer, MD, Helga P. Sandoval, MD, Luis G. Vargas, MD, Terrance J. Kasper, MD, David T. Vroman, MD, David J. Apple, MD, Kerry D. Solomon, MD Purpose: To induce diffuse lamellar keratitis (DLK) and investigate a prophylactic treatment with pharmacological agents. Setting: Magill Research Center for Vision Correction, Storm Eye Institute, Charleston, South Carolina, USA. Methods: In 100 eyes of 50 Dutch Belted rabbits, a nasal corneal flap was cut and the interface inoculated with Pseudomonas aeruginosa lipopolysaccharide endotoxin (n ⫽ 50) or Palmolive® Ultra soap (n ⫽ 50). The eyes were randomly assigned to treatment with a mast-cell stabilizer, a nonsteroidal antiinflammatory drug (NSAID), a fluoroquinolone antibiotic agent, a corticosteroid, or left without treatment as a control. Slitlamp examinations and photographs were performed 1, 3, 5, and 7 days postoperatively, and DLK was graded by a masked observer from 0 (no DLK) to stage 4. Results: At the end of the study, 80 eyes were available for evaluation. Ninetyfour percent of the untreated eyes developed DLK compared to 56% of eyes treated with NSAIDs and 63% of eyes treated with steroids (P⬍.05, Fisher exact test). The DLK rates with the mast-cell stabilizer and fluoroquinolone antibiotic agent were 86% and 76%, respectively. The DLK incidence in the latter 2 groups was not significantly different from that in the control eyes (P⬎.05, Fisher exact test). Conclusions: Postoperative prophylactic treatment with NSAIDs and corticosteroids led to a statistically significantly lower incidence of postoperative DLK. The study demonstrated that corticosteroids and NSAIDs can be used to treat DLK after LASIK. While steroids are a generally accepted treatment for DLK, NSAIDS may offer an additional potent modality. J Cataract Refract Surg 2003; 29:803– 807 © 2003 ASCRS and ESCRS

L

aser in situ keratomileusis (LASIK) is currently the most popular keratorefractive procedure performed worldwide with generally excellent outcomes.1 However, as with all procedures, complications occasionally occur postoperatively. These include stromal interface inflammation, also known as diffuse lamellar keratitis Accepted for publication September 25, 2002. Reprint requests to Kerry D. Solomon, MD, Magill Research Center for Vision Correction, Medical University of South Carolina, Storm Eye Institute, 167 Ashley Avenue, Charleston, South Carolina 29425, USA. © 2003 ASCRS and ESCRS Published by Elsevier Science Inc.

(DLK). This inflammatory reaction was first described in 1998 when the total number of LASIK procedures was starting to rapidly increase.2 The disease starts with noninfectious diffuse granular infiltrates in the lamellar interface 1 to 5 days postoperatively.3,4 However, DLK has been found in conjunction with epithelial defects after several months.5– 8 The early stages of DLK are treated with frequent administration of topical corticosteroids; for more severe types of DLK, which may include loss of visual acuity, photophobia, pain, and flap melting, lifting the 0886-3350/03/$–see front matter doi:10.1016/S0886-3350(02)01915-6

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flap and irrigating the stromal bed are recommended.3,4,9 With immediate, adequate therapy, DLK can be treated with good success and no residual problems for the patients. This study evaluated various postoperative treatment options as potential alternatives or additions to corticosteroid treatment.

Materials and Methods In this experimental study, 100 eyes of 50 Dutch Belted rabbits weighing 1.5 to 2.0 kg were used. They were treated according to the guidelines of the Association for Research in Vision and Ophthalmology and the Division of Laboratory Animal Resources at the Medical University of South Carolina. The rabbits were anesthetized with an intramuscular injection of a 1:1 mixture of ketamine hydrochloride (Ketaset威) and xylazine (Rompum威). A nasal-hinged corneal flap was cut using the Automated Corneal Shaper威 microkeratome (Bausch & Lomb Surgical) and an 8.5 mm suction ring with a 160 ␮m plate. A new blade was used in each rabbit. The animal model and procedures are described in Part 1 of this article. The corneal interface of the rabbits was randomly exposed to Pseudomonas aeruginosa lipopolysaccharide (LPS) endotoxin or Palmolive Ultra soap, 2 substances found to cause DLK in a significant number of eyes.10 –12 Postoperatively, the rabbits were treated 4 times per day with 1 of the following topical medications or left without treatment as controls (n ⫽ 20): a mast-cell stabilizer (nedocromil sodium ophthalmic solution 2%) ([Alocril], Allergan Inc.) (n ⫽ 20); a nonsteroidal antiinflammatory drug (NSAID) (ketorolac tromethamine ophthalmic solution 0.5%) ([Acular威], Allergan Inc.) (n ⫽ 20); a fluoroquinolone antibiotic agent (ofloxacin ophthalmic solution 0.3% [Ocuflox威], Allergan Inc.) (n ⫽ 20); a corticosteroid (prednisolone acetate 1% [PredForte威], Allergan Inc.) (n ⫽ 20). The rabbits were examined on postoperative days 1, 3, 5, and 7 with a slitlamp microscope (Topcon slitlamp SL-7E); the corneal findings were documented and slitlamp photo-

graphs taken. One group of investigators was responsible for topical administration of the medications. A different investigator was responsible for slitlamp examination and DLK grading and was masked to the treatment group. The DLK findings in each eye were staged by the masked observer following the system of Linebarger and coauthors3,4 from 0 (no DLK) to stage 4. The rabbits received no topical or systemic medication except the study medication. On day 7, the rabbits were anesthetized with a 1:1 mixture of ketamine hydrochloride and xylazine and then killed with an intravenous injection of 2 mL pentobarbital (Sleepaway威). Statistical analysis was performed using the Fisher exact test and the Wilcoxon test (Statistica for Windows, StatSoft, Inc.). A P value less than 0.05 was considered statistically significant.

Results At the end of the study, 80 eyes were included for analysis. Twenty eyes were excluded because of a slipped (n ⫽ 12) or free (n ⫽ 5) flap, and 3 eyes had an epithelial abrasion because of insufficient suction by the microkeratome apparatus. The group sizes after exclusion of these 20 eyes are shown in Table 1. Throughout the 7-day follow-up, the highest DLK rate was in the control group: 94% (16 of 17). Eighty-six percent (12 of 14) of eyes treated with the mast-cell stabilizer and 76% (13 of 17) of those treated with the fluoroquinolone antibiotic agent developed DLK. The DLK rate in eyes treated with the NSAID and the corticosteroid was 56% and 63%, respectively. This was statistically significantly lower (P ⫽ .017 and P ⫽ .039, respectively, Fisher exact test) than the rate in the control group (Table 1). Figure 1 shows the DLK rates in each group during the follow-up. The rates in the NSAID and corticosteroid groups were significantly lower on days 5 and 7

Table 1. Number of eyes evaluated and DLK rates in each study group.

Group

Eyes Operated

Eyes Evaluated

Eyes with DLK

DLK Rate (%)

P Value

Mast-cell stabilizer

20

14

12

86

.576

NSAID

20

16

9

56

.017*

Fluoroquinolone antibiotic agent

20

17

13

76

.335

Corticosteroid

20

16

10

63

.039*

Control

20

17

16

94

—

NSAID ⫽ nonsteroidal antiinflammatory drug *Statistically significant difference compared with the control group

804

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than those in the control eyes (P⬍.05, Fisher exact test). The appearance of DLK varied from slightly granular with a faint haze to clumpy white granules within the entire interface. The mean severity scores are shown in Figure 2. On day 7, the mean score was significantly lower in the NSAID and corticosteroid groups than in the control group (P⬍.05, Wilcoxon test), and on day 5, the score in the NSAID group was significantly lower than in the control group (P⬍.05; Wilcoxon test). The DLK rate as well as the severity score generally increased during the first postoperative week in all groups. The increase was less dramatic in the eyes treated with NSAIDs or corticosteroids, and the severity score in these 2 groups decreased toward the end of the week.

Discussion Laser in situ keratomileusis is the most common keratorefractive procedure worldwide.1 Diffuse lamellar keratitis is a postoperative condition that most LASIK surgeons have seen and requires immediate, appropriate treatment to avoid further complications such as the loss of visual acuity, photophobia, pain, an inflammatory reaction in the eye itself, or flap melting. Currently, the recommended treatment is frequent administration of topical corticosteroids and in more severe cases, lifting the flap and irrigating the stromal bed.3,4,9,13,14 Long-term treatment with corticosteroids, however, increases the risk for an intraocular pressure (IOP) rise and especially after LASIK, IOP might be inaccurately

measured as too low.15 Fogla and coauthors16 report a case of DLK that was treated frequently with corticosteroids and resulted in interface fluid accumulation and inaccurate low IOP measurements with Goldmann tonometry. Therefore, treatment alternatives or combinations with corticosteroids might be advantageous to avoid a corticosteroid-induced IOP rise or other complications. In previous studies, we show that various agents can cause DLK in rabbit eyes; P aeruginosa LPS endotoxin and Palmolive Ultra cause the disease in a significant number of eyes.10 –12 Holland et al.17 were the first to describe the possible relationship between bacterial endotoxins and DLK outbreaks. Peters et al.18 also demonstrated the potential of P aeruginosa endotoxin as a causative factor in the development of DLK in rabbit eyes. The results of this experimental animal study demonstrated that postoperative prophylactic treatment with an NSAID or a corticosteroid can lower the incidence and severity of DLK. This is an important finding since it demonstrates in a randomized, prospective, and observer-masked study that the recommended treatment with corticosteroids is an appropriate management of this complication. The NSAID, which has not been the first choice in the treatment of DLK, had the same potency in lowering the DLK rate and severity in rabbit eyes. This might be a promising treatment alternative or addition to the widely used corticosteroids in clinical practice. Further positive features of NSAIDs are their

Figure 1. (Holzer) Diffuse lamellar keratitis rates during the 7-day follow-up. The NSAID and corticosteroid groups had a significantly lower rate on days 5 and 7 than the untreated eyes in the control group (P⬍.05, Fisher exact test). J CATARACT REFRACT SURG—VOL 29, APRIL 2003

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Figure 2. (Holzer) Severity DLK score in all study groups. Diffuse lamellar keratitis was graded from 0 (no DLK) to stage 4, and the mean values were calculated. The severity was significantly lower on days 5 and 7 in the NSAID group (P⬍.05, Wilcoxon test) and on day 7 in the corticosteroid group (P⬍.05, Wilcoxon test) than in the control group.

analgesic effect to minimize postoperative discomfort and pain; they may also promote better wound healing than corticosteroids.19 –21 The study might be criticized because the rabbits were treated only 4 times per day with corticosteroids or 1 of the other drops despite the clinical recommendation of frequent administration of topical steroids. However, the aim of the study was to show the possibility of a prophylactic treatment for DLK in comparison to untreated eyes. This might be why the DLK rates even in the corticosteroid and NSAID groups were between 50% and 65% and not lower. It is also important to note that the stromal interface was exposed to a high concentration of the Pseudomonas endotoxin and Palmolive Ultra, concentrations much higher than found in normal clinical settings. This high dose was intentionally and uniformly placed in the interface to standardize the treatment settings and ensure the development of DLK. The findings with the fluoroquinolone antibiotic agent and the mast-cell stabilizer were similar to those in the untreated group and did not indicate that a postoperative prophylactic treatment with these substances would make a difference in the probability of DLK development. However, prophylactic treatment with a mast-cell stabilizer might be helpful if started before surgery instead of postoperatively. Boorstein reported lower DLK rates in patients treated with anti-allergy and/or asthma medication than in untreated patients (S.M. Boorstein, MD, “Atopy Is a Patient-Specific Risk Factor 806

for the Development of DLK,” presented at the ASCRS Symposium on Cataract, IOL and Refractive Surgery, San Diego, California, USA, April 2001). This might indicate that long-term treatment with these medications could have a DLK-lowering effect. The fluoroquinolone antibiotic agent also might require preoperative treatment for DLK prophylaxis. These issues will be addressed in another study to specifically investigate a preoperative treatment for DLK prophylaxis. In conclusion, the results of this study showed that the incidence and severity of DLK after LASIK could be significantly lowered with the help of topical prophylactic corticosteroid and NSAID therapy. These findings confirm the recommendation of treating DLK with frequent administration of corticosteroids and offer an additional treatment option with NSAIDs, which might be combined with corticosteroids. The most important way to minimize DLK rates after LASIK is to avoid the potential factors that cause DLK during surgery. Special attention should be paid to meticulous lid hygiene and to the ocular surface and epithelium; endotoxin contamination of surgical instruments and fluidics should be carefully avoided; and the stromal interface should be thoroughly irrigated during surgery. Studies are underway to investigate the use of preoperative topical administration of antiinflammatory agents (corticosteroids and NSAIDs) and mast-cell stabilizers and the effect on the incidence and severity of DLK.

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References 1. Solomon KD, Holzer MP, Sandoval HP, et al. Refractive surgery survey 2001. J Cataract Refract Surg 2002; 28: 346 –355 2. Smith RJ, Maloney RK. Diffuse lamellar keratitis; a new syndrome in lamellar refractive surgery. Ophthalmology 1998; 105:1721–1726 3. Linebarger EJ, Hardten DR, Lindstrom RL. Diffuse lamellar keratitis: diagnosis and management. J Cataract Refract Surg 2000; 26:1072–1077 4. Linebarger EJ, Hardten DR, Lindstrom RL. Diffuse lamellar keratitis: identification and management. Int Ophthalmol Clin 2000; 40(3):77–86 5. Haw WW, Manche EE. Late onset diffuse lamellar keratitis associated with an epithelial defect in six eyes. J Refract Surg 2000; 16:744 –748 6. Harrison DA, Periman LM. Diffuse lamellar keratitis associated with recurrent corneal erosions after laser in situ keratomileusis. J Refract Surg 2001; 17:463–465 7. Weisenthal RW. Diffuse lamellar keratitis induced by trauma 6 months after laser in situ keratomileusis. J Refract Surg 2000; 16:749 –751 8. Schwartz GS, Park DH, Schloff S, Lane SS. Traumatic flap displacement and subsequent diffuse lamellar keratitis after laser in situ keratomileusis. J Cataract Refract Surg 2001; 27:781–783 9. Ambro´ sio R Jr, Wilson SE. Complications of laser in situ keratomileusis: etiology, prevention, and treatment. J Refract Surg 2001; 17:350 –379 10. Holzer MP, Solomon KD, Vroman DT, et al. Diffuse lamellar Keratitis (DLK) nach LASIK: Ein experimentelles Tiermodell im Kaninchenauge. In: Demeler U, Voelcker HE, Auffarth GU, eds, 15. Kongress der Deutschsprachigen Gesellschaft fu¨ r Intraokularlinsen-Implantation und Refraktive Chirurgie. Koeln, Biermann Verlag 2001; 305–308 11. Holzer MP, Solomon KD, Vargas LG, et al. Diffuse Lamella¨re Keratitis: Tierexperimentelle Studie zur Evaluierung einer postoperativen Kortikosteroidprophylaxe. Ophthalmologe 2002; 99:849 – 853 12. Holzer MP, Solomon KD, Vroman DT, et al. Diffuse lamellar keratitis: Evaluation of etiology, histopathologic findings, and clinical implications in an experimental animal model. J Cataract Refract Surg 2003; 29:542–549 13. Dick HB, Frisch L, Augustin AJ. Diagnose und Therapie

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From the Magill Research Center for Vision Correction, Storm Eye Institute, Medical University of South Carolina, Charleston, South Carolina, USA. Presented in part at the annual meeting of the German Speaking Society of Intraocular Lens Implantation and Refractive Surgery (DGII), Heidelberg, Germany, February 2002, and the ASCRS Symposium on Cataract, IOL and Refractive Surgery, Philadelphia, Pennsylvania, USA, June 2002. Supported in part by an unrestricted grant from Research to Prevent Blindness, New York, New York, USA. None of the authors has a financial or proprietary interest in any product mentioned.

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