CLINICAL SCIENCE
Effect of Diquafosol Tetrasodium Eye Drop for Persistent Dry Eye After Laser In Situ Keratomileusis Yosai Mori, MD,* Ryohei Nejima, MD,* Ayami Masuda, MD,* Yoko Maruyama,* Keiichiro Minami, PhD,* Kazunori Miyata, MD, PhD,* and Shiro Amano, MD, PhD†
Purpose: To evaluate the effect of diquafosol tetrasodium (DQS) for the treatment of persistent dry eye after laser in situ keratomileusis (LASIK).
Setting: Miyata Eye Hospital, Miyazaki, Japan. Design: Noncomparative case series. Methods: This prospective study included 30 eyes of 15 patients in whom dry eye had persisted for over 12 months after LASIK, and the symptoms had not improved with artificial tears and sodium hyaluronate treatment. In addition, treatment with DQS 3% eye drops, 6 times a day, was performed for 12 weeks. Best-corrected visual acuity, tear secretion with the Schirmer test, tear break-up time, and fluorescein and lissamine green staining scores on the cornea and conjunctiva were examined before and at 1, 4, and 12 weeks after the addition. A subjective questionnaire of 14 symptoms was also assessed before and 12 weeks after treatment. Results: The fluorescein and lissamine green staining scores significantly improved over 12 weeks; however, the best-corrected visual acuity and tear secretion did not change. The symptoms of fatigue, dryness, grittiness, discomfort, difficulty in reading, and discomfort within the area of dryness improved after the additional DQS treatment. Conclusions: The DQS treatment improved the subjective and objective symptoms of persistent dry eye after LASIK. Increased mucin production because of the addition of DQS probably improved the tear film stability and reduced the symptoms of dry eye in patients who had persistent dry eye after LASIK. Key Words: dry eye, LASIK, mucin, diquafosol tetrasodium (Cornea 2014;33:659–662)
toms or exacerbate a preexisting dry eye situation; this condition typically lasts until corneal sensation3–5 and corneal innervation6–8 return to preoperative levels. The recovery of corneal sensation and tear break-up time (BUT) require approximately 6 months after LASIK3,5,9; however, observation with a confocal microscope showed that recovery of the decreased corneal subbasal nerves because of LASIK requires more than 3 years.6–8 Normally, most cases of LASIKassociated dry eye syndrome are transient and last for 3 to 6 months. However, some chronic cases exhibit prolonged signs of dry eye syndrome which can result in negative effects on a patient’s visual outcome and satisfaction.2 The conventional treatment for LASIK-associated dry eye syndrome is temporary water supplement using artificial tears or sodium hyaluronate.10,11 This treatment effectively improves ocular surface disorders such as superficial punctate keratitis (SPK) in mild cases. For moderate-to-severe cases, punctal occlusion with silicone12 or collagen13 plugs can also be used to increase the tear volume. Because the stability of the tear film is maintained with hydrophilicity and the lubrication of mucin,14 using only water supplement and tear retention is insufficient. Diquafosol tetrasodium (DQS), a P2Y2 receptor agonist, facilitates mucin production and tear secretion15,16 and is expected to become an effective treatment for dry eye syndrome. For dry eyes, the use of a DQS eye drop significantly improved corneal and conjunctival staining, and many of the certain symptoms would be relieved.17,18 The additional DQS treatment was also effective in cases when sodium hyaluronate did not improve the patient’s subjective or objective symptoms.19 The additional DQS treatment is expected to be helpful in cases of persistent dry eye after LASIK not responding well to water supplement/retention treatment. The purpose of this prospective study was to evaluate the effect of treatment with DQS eye drops on persistent dry eye after LASIK.
D
ry eye is a major complication after laser in situ keratomileusis (LASIK).1–3 Corneal denervation because of the LASIK flap creation can trigger postoperative dry eye symp-
Received for publication September 19, 2013; revision received March 7, 2013; accepted March 23, 2014. Published online ahead of print May 22, 2014. From the *Miyata Eye Hospital, Miyakonojo, Japan; and †Department of Ophthalmology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Presented at the Annual Meeting of ARVO, May, 6, 2012, Fort Lauderdale, FL. The authors have no funding or conflicts of interest to disclose. Reprints: Yosai Mori, Miyata Eye Hospital, 6-3 Kurahara-cho, Miyakonojo, Miyazaki, 885-0051 Japan (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
Cornea Volume 33, Number 7, July 2014
PATIENTS AND METHODS Patients This prospective study contained 30 eyes of 15 patients who underwent myopic LASIK with a nasal-hinged flap and who had been diagnosed with mild-to-moderate dry eye syndrome for 12 months or longer after LASIK. All patients received both preservative-free artificial tears and sodium hyaluronate 0.1% solution (Hyalein; Santen Pharmaceuticals, Osaka, Japan), without punctual occlusion. This study excluded dry eyes that had improved with water supplement www.corneajrnl.com |
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and retention treatment. The severity of dry eye syndrome was measured by grading SPK in terms of the area (A) and the density (D).20 After fluorescein staining of the cornea, the area and the density of the SPK lesions were scored from 0 to 3 as described previously.13,20 The scores for the area and the density were presented as a combination such as A1D2. The SPK was evaluated by adding both scores. The cases in which the score did not improve by 2 or more during 3 consecutive visits were included in the study. This criterion was required to confirm that a case was not healing with the previous treatment of preservative-free artificial tears and sodium hyaluronate 0.1%. The SPK score before the addition of DQS had significantly deteriorated compared with the former SPK scores (P , 0.016) (Table 1). This study adhered to the tenets of the Declaration of Helsinki, and the Institutional Review Board of Miyata Eye Hospital approved the study. All patients provided informed consent before enrollment in the study.
FIGURE 1. Six areas on the conjunctiva for the scoring of lissamine green staining.
eyelash crusting/stickiness, epiphora, difficulty in reading, and discomfort within the area of dryness. Each symptom was graded from 1 (no symptoms) to 5 (constant symptoms).
Addition of DQS Treatment
Statistical Analysis
Before the addition of DQS, the best-corrected visual acuity (BCVA), BUT, tear secretion, SPK, and conjunctival staining were examined. The BUT was measured 3 times and averaged for the evaluation. Tear secretion was measured using the Schirmer test with anesthesia. SPK was examined using the AD scoring method. The conjunctival staining with lissamine green in 6 sections (Fig. 1) was scored, ranging from 0 (no staining) to 3 (the entire section).21 The demographic data of the subjects are shown in Table 1. DQS 3% solution (Diquas; Santen Pharmaceuticals, Osaka, Japan) was additionally instilled 6 times daily for 12 weeks in the same manner as noted in the previous studies.18,19 At 1, 4, and 12 weeks after the additional DQS treatment, the BCVA, BUT, and corneal and conjunctival staining were examined. The tear secretion was examined at 4 and 12 weeks. The subjective symptoms were assessed using a questionnaire before and at 12 weeks after the DQS treatment. The questionnaire, a modified version from the Ocular Surface Disease Index,22,23 included questions about the symptoms of fatigue, dryness, grittiness, heavy eyelids, pain, itchiness, discomfort, blurred vision, light sensitivity,
No complications or adverse events developed in association with DQS. The BCVA did not change throughout the follow-up period (20.24 to 20.23 logMAR, P = 0.96). Changes in the BUT are shown in Figure 2. The BUT improved significantly at 1, 4, and 12 weeks after the DQS treatment (P = 0.007, P , 0.001, and P , 0.001, respectively); however, this measurement had not recovered to normal levels ($10 seconds) in any eyes at 12 weeks. Tear secretion after the addition of the DQS treatment was 6.80 6 3.65 mm, which was not significantly different from that before the addition (P = 0.48, paired t test).
The changes in BUT and staining scores taken before and after the DQS treatment were examined using the Friedman test, after the Scheffe multiple comparison correction. The changes in tear secretion and each symptom in the questionnaire were compared using the Wilcoxon signedranks test. P , 0.05 was considered significant. The results were expressed as mean 6 standard deviation.
RESULTS
TABLE 1. Demographics of the Subjects Age, yrs Sex Duration after LASIK, mo SPK score
BCVA BUT, s Tear secretion, mm Conjunctival staining score
37.5 6 8.2 (range, 26–54) 14 females and 1 male 42.5 6 36.5 (range, 14–140) Before DQS treatment: 3.5 6 0.6 Previous visit (4.0 6 4.7 months ago) 3.0 6 0.8 (P = 0.016)* Previous but one (7.2 6 6.0 months ago) 2.5 6 1.3 (P , 0.001)* 20.24 6 0.06 logMAR (1.75 in decimal notation) 3.12 6 0.76 7.4 6 5.1 5.1 6 2.5
*Scheffe multiple comparison with “Before DQS treatment.”
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FIGURE 2. The changes in BUT after the additional DQS treatment. *Denotes a significant difference from before the addition. Pre: before the addition; 1W, 4W, and 12W: 1, 4, and 12 weeks after the addition, respectively. Ó 2014 Lippincott Williams & Wilkins
Cornea Volume 33, Number 7, July 2014
The SPK score changes are shown in Figure 3. The SPK score decreased significantly from 1 to 12 weeks (P , 0.001) after the additional DQS treatment. Table 2 shows the distribution of the AD scores before and 12 weeks after the start of the DQS treatment. The eyes that had mild SPK (score of 3) with the previous water supplementation treatment had improved only after the addition of DQS. Four and 9 of these 18 eyes recovered to a score of 0 (no SPK) and 2, respectively; the score in 5 eyes did not change. In the 10 eyes that had a score of four, 2 and 6 eyes recovered to a score of 0 and 2, respectively, and 2 eyes remained unchanged. Two eyes with a score of 5 did not improve after the addition of DQS eye drops. The total conjunctival staining score significantly decreased at 1, 4, and 12 weeks (P = 0.014, P , 0.001, and P , 0.001, respectively) (Fig. 3). There was significant improvement between the measurements taken before and 12 weeks after the additional treatment except for section 2 (P , 0.01, paired t test). The staining scores in the inferior cornea (sections 3 and 5) were 1.4 6 0.6 and 1.3 6 0.7, respectively, before the addition of DQS. These scores were higher compared with those of the other areas (mean, 0.4–0.8; P , 0.05). After 3 months of the DQS treatment, the noteworthy scores improved to 0.6 6 0.6 and 0.7 6 0.8, respectively (P , 0.001). Table 3 shows the symptom questionnaire score results. The additional DQS treatment resulted in a significant improvement in fatigue, dryness, grittiness, discomfort, difficulty in reading, and discomfort in the dry areas (P , 0.05, Wilcoxon signed-ranks test); there was a trend toward improvement in blurred vision (P = 0.063).
DISCUSSION The DQS eye drop treatment was effective for persistent dry eye after LASIK that could not be improved with only artificial tears and sodium hyaluronate solution. In this
Diquafosol for Persistent Dry Eye After LASIK
TABLE 2. The Distribution of SPK Scores by the Area (A0–A3) and Density (D0–D3) Before and 12 weeks After the Additional DQS Treatment A0
A1
A2
A3
0 / 15 18 / 5 2/2
0/0 8/0 0/0
0/0 2/2 0/0
0/6
D0 D1 D2 D3
Before DQS treatment / 12 weeks after DQS treatment.
study, 14 of 15 patients enrolled were women. We surmised that the possible reasons for the skewed female enrollment were as follows: (1) chronic dry eye symptoms after LASIK were greater in women,24 and (2) patients who were approaching menopause had a higher risk of developing aqueous tear deficiency dry eye.25 In patients with dry eye syndrome, using only water supplementation and retention treatment is insufficient to improve the ocular surface staining scores.10 Yung et al26 reported that the lacrimal punctal occlusion with silicone plugs was effective for LASIK-associated dry eyes that were refractory to artificial tears; the BCVA, fluorescein staining, BUT, and symptoms improved significantly between 1 and 3 months. However, there were complications, such as infection, the loss of punctal plugs, and granuloma formation. During the assessment of cyclosporine ophthalmic solution (Restasis, cyclosporine ophthalmic emulsion; Allergan, Irvine, CA) that facilitates increased tear production, there was no substantial improvement in tear secretion, SPK, and the symptom questionnaire scores compared with artificial tears.27 In this study, the additional DQS treatment increased the BUT, but it did not change the tear secretion. These results suggested that the increase of mucins by the DQS treatment was effective for persistent dry eye after LASIK. Decreased secretion of mucins leads to a loss of hydrophilicity and lubrication and to reduced tear film
TABLE 3. Symptom Questionnaire Scores Symptom
FIGURE 3. The changes in the fluorescein staining scores for the cornea and in the lissamine green staining scores for the conjunctiva after the additional DQS treatment. *Denotes a significant difference from before the addition. Pre: before the addition; 1W, 4W, and 12W: 1, 4, and 12 weeks after the addition, respectively. Ó 2014 Lippincott Williams & Wilkins
Fatigue Dryness Grittiness Heavy eyelids Pain Itchiness Discomfort Blurred vision Light sensitivity Eyelash crusting/stickiness Epiphora Difficulty in reading Discomfort in dry area
Before DQS treatment 2.8 4.0 3.2 1.9 1.7 1.9 2.5 2.5 2.3 1.9 1.7 2.5 3.7
6 6 6 6 6 6 6 6 6 6 6 6 6
1.0 0.8 0.9 0.7 0.9 1.0 1.1 1.5 1.1 1.1 0.9 1.3 1.2
12 weeks after DQS treatment
P*
6 6 6 6 6 6 6 6 6 6 6 6 6
0.030 0.003 0.009 0.161 0.779 1.000 0.021 0.063 0.138 0.398 0.735 0.042 0.012
2.1 2.6 2.2 1.5 1.7 1.9 1.7 2.0 1.9 1.7 1.7 2.0 2.8
0.8 1.1 0.9 0.7 0.7 1.2 1.0 1.3 1.0 0.7 0.8 0.9 1.3
*Wilcoxon signed-ranks test.
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stability.14 The addition of DQS to the water supplementation treatment facilitated the production of the mucin type MUC5AC. MUC5AC is a secreted mucin type that retains water and lubricates the ocular surface.28,29 Increased mucins in the tear film probably improved the BUT, corneal and conjunctival staining scores, and symptoms. Although the additional DQS treatment was effective for mild-to-moderate SPK cases, no improvement was observed in cases with severe SPK (score of 5). DQS increased the secretion of mucin from conjunctival goblet cells. Tauber et al17 reported that the effect of DQS was not prolonged after termination of treatment. In cases with severe SPK, the conjunctival staining was also severe, which suggested severe damage to the conjunctiva and decreased goblet cell density. Thus, it was believed that the underlying conjunctival disorder could not be improved with only secreted mucins. More improvement may be obtained with the use of cell membrane-associated mucins. The symptoms of fatigue, dryness, grittiness, discomfort, difficulty in reading, and discomfort in the area of dryness improved during this trial. These symptoms are highly associated with tear film stability. The improvement of the tear film stability was demonstrated as an increase in the BUT, which was observed after the additional DQS treatment. It has been reported that the effect of DQS for dry eye was not prolonged after treatment termination.17 After LASIK, the corneal sensitivity deteriorates. Tear volume, goblet cell density, and the integrity of the corneal and conjunctival cells may be damaged because of surgical stress. This surgical stress changes the tear film stability and induces epithelial damage in the cornea and the conjunctiva. As a result, a vicious cycle of ocular surface and tear film deterioration may be initiated.30 The addition of DQS stabilizes the tear film and may break the vicious circle. However, it is not known if the improvements in the ocular surface are maintained after termination of the DQS treatment. Further investigations will be required to further explore this point. In conclusion, DQS treatment was effective for persistent dry eye after LASIK. This study demonstrated that this treatment that restored both mucins and tears in the tear film was more effective than the conventional therapy for LASIKassociated dry eye syndrome. REFERENCES 1. Toda I, Asano-Kato N, Komai-Hori Y, et al. Dry eye after laser in situ keratomileusis. Am J Ophthalmol. 2001;132:1–7. 2. Albietz JM, Lenton LM, McLennan SG. Chronic dry eye and regression after laser in situ keratomileusis for myopia. J Cataract Refract Surg. 2004;30:675–684. 3. Nejima R, Miyata K, Tanabe T, et al. Corneal barrier function, tear film stability, and corneal sensation after photorefractive keratectomy and laser in situ keratomileusis. Am J Ophthalmol. 2005;139:64–71. 4. Pérez-Santonja JJ, Sakla HF, Cardona C, et al. Corneal sensitivity after photorefractive keratectomy and laser in situ keratomileusis for low myopia. Am J Ophthalmol. 1999;127:497–504. 5. Benitez-del-Castillo JM, del Rio T, Iradier T, et al. Decrease in tear secretion and corneal sensitivity after laser in situ keratomileusis. Cornea. 2001;20:30–32. 6. Patel SV, McLaren JW, Kittleson KM, et al. Subbasal nerve density and corneal sensitivity after laser in situ keratomileusis: femtosecond laser vs mechanical microkeratome. Arch Ophthalmol. 2010;128:1413–1419.
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7. Erie JC, McLaren JW, Hodge DO, et al. Recovery of corneal subbasal nerve density after PRK and LASIK. Am J Ophthalmol. 2005;140:1059– 1064. 8. Calvillo MP, McLaren JW, Hodge DO, et al. Corneal reinnervation after LASIK: prospective 3-year longitudinal study. Invest Ophthalmol Vis Sci. 2004;45:3991–3996. 9. Linna TU, Vesaluoma MH, Pérez-Santonja JJ, et al. Effect of myopic LASIK on corneal sensitivity and morphology of subbasal nerves. Invest Ophthalmol Vis Sci. 2000;41:393–397. 10. Shimmura S, Ono M, Shinozaki K, et al. Sodium hyaluronate eyedrops in the treatment of dry eyes. Br J Ophthalmol. 1995;79: 1007–1011. 11. Nakamura M, Hikida M, Nakano T, et al. Characterization of water retentive properties of hyaluronan. Cornea. 1993;12:433–436. 12. Balaram M, Schaumberg DA, Dana MR. Efficacy and tolerability outcomes after punctal occlusion with silicone plugs in dry eye syndrome. Am J Ophthalmol. 2001;131:30–36. 13. Miyata K, Otani S, Miyai T, et al. Atelocollagen punctal occlusion in dry eye patients. Cornea. 2006;25:47–50. 14. Versura P, Maltarello MC, Cellini M, et al. Detection of mucus glycoconjugates in human conjunctiva by using the lectin-colloidal gold technique in TEM. II. A quantitative study in dry-eye patients. Acta Opthalmol (Copenh). 1986;64:451–455. 15. Fujihara T, Murakami T, Nagano T, et al. INS365 suppresses loss of corneal epithelial integrity by secretion of mucin-like glycoprotein in a rabbit short-term dry eye model. J Ocul Pharmacol Ther. 2002;18: 363–370. 16. Fujihara T, Murakami T, Fujita H, et al. Improvement of corneal barrier function by the P2Y(2) agonist INS365 in a rat dry eye model. Invest Ophthalmol Vis Sci. 2001;42:96–100. 17. Tauber J, Davitt WF, Bokosky JE, et al. Double-masked, placebocontrolled safety and efficacy trial of diquafosol tetrasodium (INS365) ophthalmic solution for the treatment of dry eye. Cornea. 2004;23:784– 792. Erratum in: Cornea 2007; 26:514. 18. Matsumoto Y, Ohashi Y, Watanabe H, et al; Diquafosol Ophthalmic Solution Phase 2 Study Group. Efficacy and safety of diquafosol ophthalmic solution in patients with dry eye syndrome: a Japanese phase 2 clinical trial. Ophthalmology. 2012;119:1954–1960. 19. Kamiya K, Nakanishi M, Ishii R, et al. Clinical evaluation of the additive effect of diquafosol tetrasodium on sodium hyaluronate monotherapy in patients with dry eye syndrome: a prospective, randomized, multicenter study. Eye (Lond). 2012;26:1363–1368. 20. Miyata K, Amano S, Sawa M, et al. A novel grading method for superficial punctate keratopathy magnitude and its correlation with corneal epithelial permeability. Arch Ophthalmol. 2003;121:1537–1539. 21. Berntsen DA, Mitchell GL, Nichols JJ. Reliability of grading lissamine green conjunctival staining. Cornea. 2006;25:695–700. 22. Schiffman RM, Christianson MD, Jacobsen G, et al. Reliability and validity of the Ocular Surface Disease Index. Arch Ophthalmol. 2000; 118:615–621. 23. Dougherty BE, Nichols JJ, Nichols KK. Rasch analysis of the Ocular Surface Disease Index (OSDI). Invest Ophthalmol Vis Sci. 2011;52: 8630–8635. 24. Albietz JM, Lenton LM, McLennan SG. Effect of laser in situ keratomileusis for hyperopia on tear film and ocular surface. J Refract Surg. 2002; 18:113–123. 25. Albietz JM. Prevalence of dry eye subtypes in clinical optometry practice. Optom Vis Sci. 2000;77:357–363. 26. Yung YH, Toda I, Sakai C, et al. Punctal plugs for treatment of postLASIK dry eye. Jpn J Ophthalmol. 2012;56:208–213. 27. Salib GM, McDonald MB, Smolek M. Safety and efficacy of cyclosporine 0.05% drops versus unpreserved artificial tears in dry-eye patients having laser in situ keratomileusis. J Cataract Refract Surg. 2006;32: 772–778. 28. Inatomi T, Spurr-Michaud S, Tisdale AS, et al. Expression of secretory mucin genes by human conjunctival epithelia. Invest Ophthalmol Vis Sci. 1996;37:1684–1692. 29. Paz HB, Tisdale AS, Danjo Y, et al. The role of calcium in mucin packaging within goblet cells. Exp Eye Res. 2003;77:69–75. 30. Konomi K, Chen LL, Tarko RS, et al. Preoperative characteristics and a potential mechanism of chronic dry eye after LASIK. Invest Ophthalmol Vis Sci. 2008;49:168–174.
Ó 2014 Lippincott Williams & Wilkins
Effect of Diquafosol Tetrasodium Eye Drop for Persistent Dry Eye After Laser In Situ Keratomileusis Yosai Mori, MD,* Ryohei Nejima, MD,* Ayami Masuda, MD,* Yoko Maruyama,* Keiichiro Minami, PhD,* Kazunori Miyata, MD, PhD,* and Shiro Amano, MD, PhD†
Purpose: To evaluate the effect of diquafosol tetrasodium (DQS) for the treatment of persistent dry eye after laser in situ keratomileusis (LASIK).
Setting: Miyata Eye Hospital, Miyazaki, Japan. Design: Noncomparative case series. Methods: This prospective study included 30 eyes of 15 patients in whom dry eye had persisted for over 12 months after LASIK, and the symptoms had not improved with artificial tears and sodium hyaluronate treatment. In addition, treatment with DQS 3% eye drops, 6 times a day, was performed for 12 weeks. Best-corrected visual acuity, tear secretion with the Schirmer test, tear break-up time, and fluorescein and lissamine green staining scores on the cornea and conjunctiva were examined before and at 1, 4, and 12 weeks after the addition. A subjective questionnaire of 14 symptoms was also assessed before and 12 weeks after treatment. Results: The fluorescein and lissamine green staining scores significantly improved over 12 weeks; however, the best-corrected visual acuity and tear secretion did not change. The symptoms of fatigue, dryness, grittiness, discomfort, difficulty in reading, and discomfort within the area of dryness improved after the additional DQS treatment. Conclusions: The DQS treatment improved the subjective and objective symptoms of persistent dry eye after LASIK. Increased mucin production because of the addition of DQS probably improved the tear film stability and reduced the symptoms of dry eye in patients who had persistent dry eye after LASIK. Key Words: dry eye, LASIK, mucin, diquafosol tetrasodium (Cornea 2014;33:659–662)
toms or exacerbate a preexisting dry eye situation; this condition typically lasts until corneal sensation3–5 and corneal innervation6–8 return to preoperative levels. The recovery of corneal sensation and tear break-up time (BUT) require approximately 6 months after LASIK3,5,9; however, observation with a confocal microscope showed that recovery of the decreased corneal subbasal nerves because of LASIK requires more than 3 years.6–8 Normally, most cases of LASIKassociated dry eye syndrome are transient and last for 3 to 6 months. However, some chronic cases exhibit prolonged signs of dry eye syndrome which can result in negative effects on a patient’s visual outcome and satisfaction.2 The conventional treatment for LASIK-associated dry eye syndrome is temporary water supplement using artificial tears or sodium hyaluronate.10,11 This treatment effectively improves ocular surface disorders such as superficial punctate keratitis (SPK) in mild cases. For moderate-to-severe cases, punctal occlusion with silicone12 or collagen13 plugs can also be used to increase the tear volume. Because the stability of the tear film is maintained with hydrophilicity and the lubrication of mucin,14 using only water supplement and tear retention is insufficient. Diquafosol tetrasodium (DQS), a P2Y2 receptor agonist, facilitates mucin production and tear secretion15,16 and is expected to become an effective treatment for dry eye syndrome. For dry eyes, the use of a DQS eye drop significantly improved corneal and conjunctival staining, and many of the certain symptoms would be relieved.17,18 The additional DQS treatment was also effective in cases when sodium hyaluronate did not improve the patient’s subjective or objective symptoms.19 The additional DQS treatment is expected to be helpful in cases of persistent dry eye after LASIK not responding well to water supplement/retention treatment. The purpose of this prospective study was to evaluate the effect of treatment with DQS eye drops on persistent dry eye after LASIK.
D
ry eye is a major complication after laser in situ keratomileusis (LASIK).1–3 Corneal denervation because of the LASIK flap creation can trigger postoperative dry eye symp-
Received for publication September 19, 2013; revision received March 7, 2013; accepted March 23, 2014. Published online ahead of print May 22, 2014. From the *Miyata Eye Hospital, Miyakonojo, Japan; and †Department of Ophthalmology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan. Presented at the Annual Meeting of ARVO, May, 6, 2012, Fort Lauderdale, FL. The authors have no funding or conflicts of interest to disclose. Reprints: Yosai Mori, Miyata Eye Hospital, 6-3 Kurahara-cho, Miyakonojo, Miyazaki, 885-0051 Japan (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
Cornea Volume 33, Number 7, July 2014
PATIENTS AND METHODS Patients This prospective study contained 30 eyes of 15 patients who underwent myopic LASIK with a nasal-hinged flap and who had been diagnosed with mild-to-moderate dry eye syndrome for 12 months or longer after LASIK. All patients received both preservative-free artificial tears and sodium hyaluronate 0.1% solution (Hyalein; Santen Pharmaceuticals, Osaka, Japan), without punctual occlusion. This study excluded dry eyes that had improved with water supplement www.corneajrnl.com |
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and retention treatment. The severity of dry eye syndrome was measured by grading SPK in terms of the area (A) and the density (D).20 After fluorescein staining of the cornea, the area and the density of the SPK lesions were scored from 0 to 3 as described previously.13,20 The scores for the area and the density were presented as a combination such as A1D2. The SPK was evaluated by adding both scores. The cases in which the score did not improve by 2 or more during 3 consecutive visits were included in the study. This criterion was required to confirm that a case was not healing with the previous treatment of preservative-free artificial tears and sodium hyaluronate 0.1%. The SPK score before the addition of DQS had significantly deteriorated compared with the former SPK scores (P , 0.016) (Table 1). This study adhered to the tenets of the Declaration of Helsinki, and the Institutional Review Board of Miyata Eye Hospital approved the study. All patients provided informed consent before enrollment in the study.
FIGURE 1. Six areas on the conjunctiva for the scoring of lissamine green staining.
eyelash crusting/stickiness, epiphora, difficulty in reading, and discomfort within the area of dryness. Each symptom was graded from 1 (no symptoms) to 5 (constant symptoms).
Addition of DQS Treatment
Statistical Analysis
Before the addition of DQS, the best-corrected visual acuity (BCVA), BUT, tear secretion, SPK, and conjunctival staining were examined. The BUT was measured 3 times and averaged for the evaluation. Tear secretion was measured using the Schirmer test with anesthesia. SPK was examined using the AD scoring method. The conjunctival staining with lissamine green in 6 sections (Fig. 1) was scored, ranging from 0 (no staining) to 3 (the entire section).21 The demographic data of the subjects are shown in Table 1. DQS 3% solution (Diquas; Santen Pharmaceuticals, Osaka, Japan) was additionally instilled 6 times daily for 12 weeks in the same manner as noted in the previous studies.18,19 At 1, 4, and 12 weeks after the additional DQS treatment, the BCVA, BUT, and corneal and conjunctival staining were examined. The tear secretion was examined at 4 and 12 weeks. The subjective symptoms were assessed using a questionnaire before and at 12 weeks after the DQS treatment. The questionnaire, a modified version from the Ocular Surface Disease Index,22,23 included questions about the symptoms of fatigue, dryness, grittiness, heavy eyelids, pain, itchiness, discomfort, blurred vision, light sensitivity,
No complications or adverse events developed in association with DQS. The BCVA did not change throughout the follow-up period (20.24 to 20.23 logMAR, P = 0.96). Changes in the BUT are shown in Figure 2. The BUT improved significantly at 1, 4, and 12 weeks after the DQS treatment (P = 0.007, P , 0.001, and P , 0.001, respectively); however, this measurement had not recovered to normal levels ($10 seconds) in any eyes at 12 weeks. Tear secretion after the addition of the DQS treatment was 6.80 6 3.65 mm, which was not significantly different from that before the addition (P = 0.48, paired t test).
The changes in BUT and staining scores taken before and after the DQS treatment were examined using the Friedman test, after the Scheffe multiple comparison correction. The changes in tear secretion and each symptom in the questionnaire were compared using the Wilcoxon signedranks test. P , 0.05 was considered significant. The results were expressed as mean 6 standard deviation.
RESULTS
TABLE 1. Demographics of the Subjects Age, yrs Sex Duration after LASIK, mo SPK score
BCVA BUT, s Tear secretion, mm Conjunctival staining score
37.5 6 8.2 (range, 26–54) 14 females and 1 male 42.5 6 36.5 (range, 14–140) Before DQS treatment: 3.5 6 0.6 Previous visit (4.0 6 4.7 months ago) 3.0 6 0.8 (P = 0.016)* Previous but one (7.2 6 6.0 months ago) 2.5 6 1.3 (P , 0.001)* 20.24 6 0.06 logMAR (1.75 in decimal notation) 3.12 6 0.76 7.4 6 5.1 5.1 6 2.5
*Scheffe multiple comparison with “Before DQS treatment.”
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FIGURE 2. The changes in BUT after the additional DQS treatment. *Denotes a significant difference from before the addition. Pre: before the addition; 1W, 4W, and 12W: 1, 4, and 12 weeks after the addition, respectively. Ó 2014 Lippincott Williams & Wilkins
Cornea Volume 33, Number 7, July 2014
The SPK score changes are shown in Figure 3. The SPK score decreased significantly from 1 to 12 weeks (P , 0.001) after the additional DQS treatment. Table 2 shows the distribution of the AD scores before and 12 weeks after the start of the DQS treatment. The eyes that had mild SPK (score of 3) with the previous water supplementation treatment had improved only after the addition of DQS. Four and 9 of these 18 eyes recovered to a score of 0 (no SPK) and 2, respectively; the score in 5 eyes did not change. In the 10 eyes that had a score of four, 2 and 6 eyes recovered to a score of 0 and 2, respectively, and 2 eyes remained unchanged. Two eyes with a score of 5 did not improve after the addition of DQS eye drops. The total conjunctival staining score significantly decreased at 1, 4, and 12 weeks (P = 0.014, P , 0.001, and P , 0.001, respectively) (Fig. 3). There was significant improvement between the measurements taken before and 12 weeks after the additional treatment except for section 2 (P , 0.01, paired t test). The staining scores in the inferior cornea (sections 3 and 5) were 1.4 6 0.6 and 1.3 6 0.7, respectively, before the addition of DQS. These scores were higher compared with those of the other areas (mean, 0.4–0.8; P , 0.05). After 3 months of the DQS treatment, the noteworthy scores improved to 0.6 6 0.6 and 0.7 6 0.8, respectively (P , 0.001). Table 3 shows the symptom questionnaire score results. The additional DQS treatment resulted in a significant improvement in fatigue, dryness, grittiness, discomfort, difficulty in reading, and discomfort in the dry areas (P , 0.05, Wilcoxon signed-ranks test); there was a trend toward improvement in blurred vision (P = 0.063).
DISCUSSION The DQS eye drop treatment was effective for persistent dry eye after LASIK that could not be improved with only artificial tears and sodium hyaluronate solution. In this
Diquafosol for Persistent Dry Eye After LASIK
TABLE 2. The Distribution of SPK Scores by the Area (A0–A3) and Density (D0–D3) Before and 12 weeks After the Additional DQS Treatment A0
A1
A2
A3
0 / 15 18 / 5 2/2
0/0 8/0 0/0
0/0 2/2 0/0
0/6
D0 D1 D2 D3
Before DQS treatment / 12 weeks after DQS treatment.
study, 14 of 15 patients enrolled were women. We surmised that the possible reasons for the skewed female enrollment were as follows: (1) chronic dry eye symptoms after LASIK were greater in women,24 and (2) patients who were approaching menopause had a higher risk of developing aqueous tear deficiency dry eye.25 In patients with dry eye syndrome, using only water supplementation and retention treatment is insufficient to improve the ocular surface staining scores.10 Yung et al26 reported that the lacrimal punctal occlusion with silicone plugs was effective for LASIK-associated dry eyes that were refractory to artificial tears; the BCVA, fluorescein staining, BUT, and symptoms improved significantly between 1 and 3 months. However, there were complications, such as infection, the loss of punctal plugs, and granuloma formation. During the assessment of cyclosporine ophthalmic solution (Restasis, cyclosporine ophthalmic emulsion; Allergan, Irvine, CA) that facilitates increased tear production, there was no substantial improvement in tear secretion, SPK, and the symptom questionnaire scores compared with artificial tears.27 In this study, the additional DQS treatment increased the BUT, but it did not change the tear secretion. These results suggested that the increase of mucins by the DQS treatment was effective for persistent dry eye after LASIK. Decreased secretion of mucins leads to a loss of hydrophilicity and lubrication and to reduced tear film
TABLE 3. Symptom Questionnaire Scores Symptom
FIGURE 3. The changes in the fluorescein staining scores for the cornea and in the lissamine green staining scores for the conjunctiva after the additional DQS treatment. *Denotes a significant difference from before the addition. Pre: before the addition; 1W, 4W, and 12W: 1, 4, and 12 weeks after the addition, respectively. Ó 2014 Lippincott Williams & Wilkins
Fatigue Dryness Grittiness Heavy eyelids Pain Itchiness Discomfort Blurred vision Light sensitivity Eyelash crusting/stickiness Epiphora Difficulty in reading Discomfort in dry area
Before DQS treatment 2.8 4.0 3.2 1.9 1.7 1.9 2.5 2.5 2.3 1.9 1.7 2.5 3.7
6 6 6 6 6 6 6 6 6 6 6 6 6
1.0 0.8 0.9 0.7 0.9 1.0 1.1 1.5 1.1 1.1 0.9 1.3 1.2
12 weeks after DQS treatment
P*
6 6 6 6 6 6 6 6 6 6 6 6 6
0.030 0.003 0.009 0.161 0.779 1.000 0.021 0.063 0.138 0.398 0.735 0.042 0.012
2.1 2.6 2.2 1.5 1.7 1.9 1.7 2.0 1.9 1.7 1.7 2.0 2.8
0.8 1.1 0.9 0.7 0.7 1.2 1.0 1.3 1.0 0.7 0.8 0.9 1.3
*Wilcoxon signed-ranks test.
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Mori et al
stability.14 The addition of DQS to the water supplementation treatment facilitated the production of the mucin type MUC5AC. MUC5AC is a secreted mucin type that retains water and lubricates the ocular surface.28,29 Increased mucins in the tear film probably improved the BUT, corneal and conjunctival staining scores, and symptoms. Although the additional DQS treatment was effective for mild-to-moderate SPK cases, no improvement was observed in cases with severe SPK (score of 5). DQS increased the secretion of mucin from conjunctival goblet cells. Tauber et al17 reported that the effect of DQS was not prolonged after termination of treatment. In cases with severe SPK, the conjunctival staining was also severe, which suggested severe damage to the conjunctiva and decreased goblet cell density. Thus, it was believed that the underlying conjunctival disorder could not be improved with only secreted mucins. More improvement may be obtained with the use of cell membrane-associated mucins. The symptoms of fatigue, dryness, grittiness, discomfort, difficulty in reading, and discomfort in the area of dryness improved during this trial. These symptoms are highly associated with tear film stability. The improvement of the tear film stability was demonstrated as an increase in the BUT, which was observed after the additional DQS treatment. It has been reported that the effect of DQS for dry eye was not prolonged after treatment termination.17 After LASIK, the corneal sensitivity deteriorates. Tear volume, goblet cell density, and the integrity of the corneal and conjunctival cells may be damaged because of surgical stress. This surgical stress changes the tear film stability and induces epithelial damage in the cornea and the conjunctiva. As a result, a vicious cycle of ocular surface and tear film deterioration may be initiated.30 The addition of DQS stabilizes the tear film and may break the vicious circle. However, it is not known if the improvements in the ocular surface are maintained after termination of the DQS treatment. Further investigations will be required to further explore this point. In conclusion, DQS treatment was effective for persistent dry eye after LASIK. This study demonstrated that this treatment that restored both mucins and tears in the tear film was more effective than the conventional therapy for LASIKassociated dry eye syndrome. REFERENCES 1. Toda I, Asano-Kato N, Komai-Hori Y, et al. Dry eye after laser in situ keratomileusis. Am J Ophthalmol. 2001;132:1–7. 2. Albietz JM, Lenton LM, McLennan SG. Chronic dry eye and regression after laser in situ keratomileusis for myopia. J Cataract Refract Surg. 2004;30:675–684. 3. Nejima R, Miyata K, Tanabe T, et al. Corneal barrier function, tear film stability, and corneal sensation after photorefractive keratectomy and laser in situ keratomileusis. Am J Ophthalmol. 2005;139:64–71. 4. Pérez-Santonja JJ, Sakla HF, Cardona C, et al. Corneal sensitivity after photorefractive keratectomy and laser in situ keratomileusis for low myopia. Am J Ophthalmol. 1999;127:497–504. 5. Benitez-del-Castillo JM, del Rio T, Iradier T, et al. Decrease in tear secretion and corneal sensitivity after laser in situ keratomileusis. Cornea. 2001;20:30–32. 6. Patel SV, McLaren JW, Kittleson KM, et al. Subbasal nerve density and corneal sensitivity after laser in situ keratomileusis: femtosecond laser vs mechanical microkeratome. Arch Ophthalmol. 2010;128:1413–1419.
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