Evaluation of a Thermosensitive Atelocollagen Punctal Plug Treatment for Dry Eye Disease TAKASHI KOJIMA, YUKIHIRO MATSUMOTO, OSAMA M.A. IBRAHIM, TAIS HITOMI WAKAMATSU, MURAT DOGRU, AND KAZUO TSUBOTA PURPOSE:
To evaluate the efficacy of a thermosensitive atelocollagen punctal plug in the treatment of dry eye disease. DESIGN: Prospective observational case series. METHODS: The thermosensitive atelocollagen punctal plug was warmed at 37 C, 39 C, 41 C, and 43 C to evaluate the appropriate temperature and time for solidification. Dry eye patients were divided into 2 groups according to the preparation method of the atelocollagen punctal plug. In the conventional implantation group, atelocollagen gel was kept at room temperature for 15 minutes before implantation (27 eyes of 14 patients). In the preheating group, atelocollagen was warmed at 41 C for 8 minutes before implantation (23 eyes of 13 dry eye patients). Strip meniscometry, vital stainings, tear film break-up time (BUT), and symptom scores were evaluated before and 1 month after plug implantation. RESULTS: In vitro experiments revealed that heating at 41 C for 8 minutes was sufficient to solidify the gel. The mean fluorescein score in the conventional implantation group significantly improved after treatment (before, 3.5 ± 2.3 points; after, 2.5 ± 0.9 points, P < .05). In the preheating group, the mean fluorescein score (before, 3.7 ± 1.7 points; after, 1.5 ± 1.2 points), strip meniscometry (before, 0.6 ± 0.7 mm; after, 1.1 ± 0.3 mm), BUT (before, 3.2 ± 0.7 seconds; after, 4.8 ± 1.0 seconds), and visual analog scale scores (before, 6.6 ± 1.5 points; after, 4.1 ± 0.9 points) significantly improved after treatment (P < .05). CONCLUSION: The thermosensitive atelocollagen punctal plug was effective for dry eye treatment. The preheating method was found to be useful to strengthen the efficacy of the thermosensitive atelocollagen punctal plug. (Am J Ophthalmol 2014;157:311–317. Ó 2014 by Elsevier Inc. All rights reserved.)
P
UNCTAL PLUG INSERTION HAS ALREADY BEEN
reported to be an effective treatment for aqueous tear-deficient dry eye diseases, such as StevensJohnson syndrome, contact lens–related dry eyes, and Accepted for publication Oct 30, 2013. From the Department of Ophthalmology, Keio University School of Medicine (T.K., Y.M., O.M.A.I., T.H.W., M.D., K.T.); and the Department of Ophthalmology, Tokyo Dental College (M.D.), Tokyo, Japan. Inquiries to Murat Dogru, Department of Ophthalmology, Tokyo Dental College, Sugano, Ichikawa-shi, Chiba, 272-8513, Japan; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.10.019
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neurogenic dry eyes occurring after laser in situ keratomileusis (LASIK) and photorefractive keratectomy.1–3 In 1961, Foulds reported the first punctal plug treatment with gelatin-type punctal plugs.4 In terms of materials, current punctal plugs are categorized as absorbable and nonabsorbable. Absorbable plugs are mainly used for evaluating the effect with nonabsorbable plugs or treatment of temporary dry eye disease such as post-LASIK dry eyes. The Freeman-style plug is among the most popular nonabsorbable punctal plug design. This plug consists of a cylindrical neck; a wider base that sits at the angle where the vertical and horizontal segments of the canaliculus meet, anchoring it in position; and a wider disc-shaped head or flange that sits on the surface of the punctal opening. The Freemanstyle punctal plug is available in various sizes and has been reported to fit most cases of dry eyes.5–8 It has been reported to have high stability and safety, with some inherent problems consisting of granulation formation, irritation of cornea and conjunctiva, epithelial laceration, and frequent extrusion.8–12 Surgical punctal occlusion by cautery or laser is another option for dry eyes not suitable for punctal plug treatment. However, such treatment options also possess several problems, such as deformation of the punctum, recanalization, and symblepharon formation. The collagen punctal plug is one of the absorbable plugs and is mainly used for temporary dry eye disease such as postsurgical dry eye or seasonal worsening of dry eye disease. A Cochrane database review concluded that temporary collagen plugs appear similarly effective to silicone plugs on a short-term basis.9 Recently, a new generation of thermosensitive atelocollagen punctum plug (Keeptear; Koken Bioscience Institutes, Tokyo, Japan) has been developed and is being widely used in Japan. Briefly, Keeptear is categorized as an absorbable collagen plug and possesses unique characteristics. Keeptear is available in a syringe. Keeptear is made of thermosensitive atelocollagen, which is liquid at room temperature but becomes a soft gel at body temperature. After insertion, as the Keeptear equilibrates to the body temperature, the material softens and fits the patient’s punctum. According to the manufacturer’s suggestions, Keeptear should be kept at room temperature for 15 minutes after being taken out of the refrigerator, after which it is then injected into the patient’s canaliculus from the punctum. We hypothesized that preheating atelocollagen gel could
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enhance the treatment effect, and thus we designed this study. In this study, we evaluated the efficacy of a new punctal plug (Keeptear) insertion method in patients with dry eye disease, comparing the preparation method with conventional methodology.
METHODS THE PROTOCOL OF THIS PROSPECTIVE RANDOMIZED CLIN-
ical study and informed consent were approved by the Institutional Review Board of the Keio University School of Medicine and the study was registered at UMIN-CTR (http://www.umin.ac.jp/ctr/index.htm) (UMIN000011574). The study procedures conformed to the ethical principles for research involving human subjects as outlined in the Declaration of Helsinki. Informed consents for both the treatment and participation in the research were obtained from all subjects after explanation of the nature and possible consequences of taking part in the study. IN
VITRO EXPERIMENTS: Keeptear punctal plugs (Figure 1, Top left) are made from bovine dermal tissue and prepared with 0.2% concentration by a manufacturing company for clinical use. To evaluate and understand the gel formation process of the Keeptear punctal plug, in vitro experiments were designed. The Keeptear atelocollagen punctal plug becomes a soft gel from liquid at 37 C (Figure 1, Top right). Initially, to determine the shortest time in which Keeptear reaches the gel form at 37 C, Keeptear was warmed using a thermoblock, which can adjust the temperature (Figure 1, Middle left). The timewise changes of collagen temperature were recorded using a thermometer (UV-1200; Shimadzu, Tokyo, Japan). In the in vitro experiments, the thermoblock was warmed to 37 C, 39 C, 41 C, and 43 C. To clarify when the Keeptear started to attain the soft gel form, spectrometry (digital multimeter PC5000a; Sanwa Electric Instrument Inc., Tokyo, Japan) was performed, and absorbance at 400 nm was measured after warming Keeptear at different temperatures. CLINICAL
plugs were STUDY: Subjects. Keeptear inserted in a total of 50 eyes of 27 dry eye patients (Sjo¨gren syndrome: 12 patients, non–Sjo¨gren syndrome: 15 patients). Before punctal plug insertion, irrigation of the canaliculus was performed for all patients, and it was confirmed that the tear drainage system was intact. Two preparation methods of Keeptear punctal plugs were randomly assigned to patients. In the conventional implantation group, atelocollagen gel was kept at room temperature for 15 minutes before implantation (27 eyes of 14 patients). In the preheating group, immediately after taking the atelocollagen punctal plug from the refrigerator,
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it was warmed at 41 C for 8 minutes before implantation (23 eyes of 13 dry eye patients). After plug insertion, patients were asked to use only preservative-free artificial tear eye drops (Softsantear; Santen Pharmaceutical Co Ltd, Osaka, Japan) 6 times a day. Tear functions and ocular surface examinations were performed before and 1 month after treatment. To minimize the effect of each examination on the following examinations, tear volume measurement using strip meniscometry was performed initially. Ten minutes later, tear film break-up time measurements and then vital stainings were performed. A single clinician (T.K.) performed injections of Keeptear punctal plugs and all examinations including tear functions and ocular surface vital stainings. Patient demographics and tear functions/ocular surface abnormalities before thermosensitive atelocollagen punctal plug treatment were shown in Table. Punctal plug procedure. A 26 G blunt-tip needle was used for insertion. A total of 150 mL of Keeptear was injected into each upper and lower punctum. If backflow of collagen was observed, injection was stopped. Immediately following insertion, a warm compress (hot eye mask, Kao Corporation, Tokyo, Japan) was placed onto the patients’ eyelids for 10 minutes. Plugs were inserted in both superior and inferior lacrimal puncta in all patients. Strip meniscometry testings. The tip of the meniscometry strip was inserted for 5 seconds into the lateral lower tear meniscus without touching the ocular surface. The duration of the test was measured strictly by a stopwatch chronometer at each testing. The length of the stained tear column in the central membrane ditch was regarded as the strip meniscometry value in that eye in millimeters. The SM testing has been reported to be useful in the evaluation of tear meniscus volume, as reported previously.13,14 Tear function tests. The standard tear film break-up time (BUT) measurement was performed after instillation of a 2-mL volume of a 0.5% fluorescein dye in the conjunctival sac with a micropipette. A cobalt blue filter was used to measure the BUT. The patients were then instructed to blink several times for a few seconds to ensure adequate mixing of the dye. The interval between the last complete blink and the appearance of the first corneal black spot in the stained tear film was measured 3 times and the mean value of the measurements was calculated. Vital stainings. Fluorescein stain scoring of the ocular surface was performed. The fluorescein staining scores of the ocular surface ranged from 0-9 points. In fluorescein and rose bengal staining, the ocular surface was divided into 3 parts: temporal conjunctiva, cornea, and nasal conjunctiva. Each zone had a staining score ranging from 0-3 points, with the minimum and maximum total staining scores ranging from 0-9 points.
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FIGURE 1. Overview of the in vitro experiment evaluating solidification process of Keeptear punctal plug. (Top left) Keeptear punctal plug is prepared in the syringe with 26 G blunt-tipped needle. (Top right) Twenty-four hours after heating at 37 C, Keeptear changes from liquid to soft gel. (Middle left) Syringe of Keeptear was placed in the thermoblock. (Middle right) Temperature changes were measured. (Bottom) Absorbance changes in Keeptear atelocollagen punctal plug was measured when it was heated with different temperature settings (37 C, 39 C, 41 C, and 43 C).
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TABLE. Patient Demographics and Tear Functions/Ocular Surface Abnormalities Before Thermosensitive Atelocollagen Punctal Plug Treatment for Dry Eye Disease Conventional Method
Preheating Method
Patients (eyes) Sex
After heating at different temperatures, absorbance at 400 nm was measured to evaluate the solidification process of atelocollagen. With 37 C, 39 C, 41 C, and 43 C warming, solidification was observed at, respectively, 12, 9, 7, and 6 minutes after heating (Figure 1, Bottom). With 43 C heating, absorbance reached a maximum and gradually decreased.
14 (27) 13 (23) Female:12, Female:10, Male: 2 Male:3 Age (y), mean 6 SD 61.3 6 17.2 62.4 6 14.5 Pretreatment tear functions and ocular surface abnormalities Schirmer I test (mm) 5.4 6 2.0 5.1 6 2.7 Tear film break-up time (seconds) 3.3 6 1.1 3.4 6 0.8 Fluorescein score (points) 3.6 6 2.4 3.8 6 1.7 Rose bengal score (points) 2.2 6 1.9 2.0 6 1.4
Strip meniscometry score changes. The mean strip meniscometry (SM) score showed an significant increase from 0.63 6 0.65 mm to 1.09 6 0.33 mm after atelocollagen punctal plug treatment in the preheating group (P ¼ .0171). The mean SM score showed an insignificant increase from 0.73 6 0.46 mm to 0.78 6 0.54 mm with atelocollagen punctal plug treatment in the conventional implantation group, as shown in Figure 2, Top left (P ¼ .8125).
Evaluation of dry eye symptoms. Symptoms of ‘‘dryness’’ were evaluated with visual analog scale (VAS) scores. Participants indicated scores on the VAS sheets before and 1 month after treatment. Lower scores on the VAS referred to a less severe degree of symptoms, whereas higher VAS scores indicated severe symptoms in this study (minimum: 0 point, maximum: 10 points).
Tear film break-up time changes. The mean BUT showed a statistically significant increase from 3.2 6 0.7 seconds to 4.8 6 1.0 seconds after atelocollagen punctal plug treatment in the preheating group (P ¼ .0425), whereas no statistically significant changes were observed before (3.5 6 1.3 seconds) and after (3.8 6 1.4 seconds) atelocollagen punctal plug treatment in the conventional implantation group, as shown in Figure 2, Top right (P ¼ .4922).
Dry eye diagnostic criteria. The diagnosis of dry eye disease was based on the diagnostic criteria of the Dry Eye Research Group in Japan.15 In brief, patients with (1) dry eye–related symptoms; (2) positive staining with fluorescein or rose bengal dyes; and (3) Schirmer I test results of less than 5 mm, or tear film BUT values of less than 5 seconds were diagnosed as having dry eyes. A fluorescein staining score above 3 points and a rose bengal staining score above 3 points was considered abnormal. Dry eye cases were categorized as Sjo¨gren syndrome (SS) and non-SS on the basis of the criteria proposed by Fox and associates.16
Vital staining score changes. The mean fluorescein staining score showed a significant decrease with atelocollagen punctal plug treatment both in preheating (from 3.8 6 1.7 points to 1.5 6 1.2 points, P ¼ .001) and conventional implantation groups (from 3.5 6 2.3 points to 2.5 6 0.9 points, P ¼ .0078), as shown in Figure 2, Middle left. The mean rose bengal scores did not change significantly before and after punctal plug treatment in both conventional (from 2.1 6 1.4 points to 1.9 6 0.9 points, P ¼ .6250) and preheating method groups (from 1.9 6 2.6 points to 1.5 6 1.7 points, P ¼ .2188) (Figure 2, Middle right).
Statistical analysis. For statistical analyses, paired t test was used for comparisons of tear functions and ocular surface tests before and after punctal plug insertion. A P value less than .05 was considered statistically significant. Data were processed using the IBM SPSS Statistics software (IBM, Armonk, New York, USA) for Macintosh OS X (Apple, Cupertino, California, USA).
CLINICAL STUDY:
Dryness visual analog scale symptom scores. The mean dryness VAS score showed a significant decrease from 6.6 6 1.5 points to 4.1 6 0.9 points in the preheating group (P ¼ .0078) and an insignificant decrease from 7.7 6 1.4 points to 6.6 6 2.3 points in the conventional implantation group upon Keeptear punctal plug treatment (P ¼ .125), as shown in Figure 2, Bottom. Complications. No complications related to Keeptear atelocollagen punctal plug insertion, including dacryocystitis, canaliculitis, granuloma formation, and conjunctival laceration, were observed in any of the eyes in this study.
RESULTS IN VITRO EXPERIMENTS:
Keeptear atelocollagen punctal plug was warmed at 4 different temperatures (37 C, 39 C, 41 C, and 43 C). At 37 C warming, atelocollagen did not reach 37 C. With 39 C, 41 C, and 43 C warming, atelocollagen reached 37 C at 10.5 minutes, 8.0 minutes, and 6.5 minutes, respectively (Figure 1, Middle right).
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DISCUSSION ALTHOUGH THE EFFICACY OF THE FREEMAN-STYLE PUNCTAL
plug treatment for dry eye patients has already been
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FIGURE 2. (Top left) Strip meniscometry was performed before and after Keeptear punctal plug implantation. In the preheating group, strip meniscometry value after treatment was significantly higher than that before treatment. (Top right) Tear film breakup time (BUT) was measured before and after Keeptear punctal plug implantation. In the preheating group, BUT was significantly improved after treatment. (Middle left) Fluorescein score was measured before and after Keeptear punctal plug implantation. In both conventional and preheating method groups, fluorescein score significantly improved after treatment. (Middle right) Rose bengal score was measured before and after Keeptear punctal plug implantation. In both conventional and preheating method groups, there were no significant differences between before and after treatment. (Bottom) Dryness visual analog scale (VAS) was analyzed before and after Keeptear punctal plug implantation. In the preheating method group, dryness VAS was significantly improved after treatment. * represents P < .05.
reported,5,6,9 these plugs are known to be associated with complications like granulation formation, irritation of cornea and conjunctiva, epithelial laceration, and frequent extrusion.10,17 A new type of cylindrical-shaped VOL. 157, NO. 2
punctal plug, called the SmartPlug, made of hydrophilic acryl, has also been employed in dry eye treatment, with good short-term efficacy and safety.18 However, several studies pointed out that SmartPlugs were associated with
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canaliculitis and dacryocystitis.19,20 A previous study showed that collagen punctal plug showed no statistically significant effects for dry eye disease after 5 days of occlusion.21 Other study showed that treatment with collagen punctal plugs improved tear meniscus height and tear stability in aqueous-deficient dry eyes after 12 days of treatment.22 Cochrane systematic review in relation to the punctal plug treatment concluded a relative lack of strong evidence supporting the efficacy of collagen punctal plugs as a treatment modality for dry eye.9 Since conventional collagen plug is dry and solid, it may be difficult to achieve ‘‘just-fit’’ for all sizes of puncta. In the current study, punctal occlusion with Keeptear was observed to be associated with improvements of tear stability and ocular surface vital staining scores. The extent of improvement with other types of punctal plugs should be assessed and compared with further prospective trials in the future. In vitro experiments were carried out to confirm the shortest time of heating for the Keeptear punctal plug to reach 37 C. With 43 C of heating, the time to reach 37 C was shortest among the tested temperatures. However, when atelocollagen was heated at 43 C, the absorbance at 400 nm decreased after reaching a maximum value. From these results, we speculated that atelocollagen started solidification with 43 C heating and then the 3-dimensional structure of collagen collapsed because of the high temperature. In fact, we confirmed that the atelocollagen gel turned to the liquid state 7 minutes after 43 C heating. Finally, from these results, 8 minutes of heating at 41 C was chosen as a suitable condition of preheating. We compared 2 preparation methods, conventional and preheating, in clinical settings. In the conventional method group, VAS symptom scores, tear functions, and rose bengal scores did not show significant improvements 1 month after treatment. Only fluorescein staining score showed a significant improvement after treatment. On the other hand, tear functions including strip meniscometry and BUT showed significant improvements after treatment in the preheating group. Similarly, fluorescein and rose bengal scores significantly improved after treatment in the preheating group. Since we found that the strip meniscometry value increased after treatment, we think that the Keeptear plug blocked the canaliculi and retained the tear volume at 1 month after treatment. Vital staining scores showed a statistically significant improvement after treatment, and these results suggest that increased tear volume improved the ocular surface abnormalities. Since BUT improved after treatment, pooling and qualitative improvement of tear fluid are suggestible changes attributable to the insertion of the plug. We assumed that the observed tear function and ocular surface differences between the 2 preparation methods occurred for the following reasons: In the conventional method group, the atelocollagen was still in liquid status when it was inserted. On the other hand, in the preheating group, the atelocollagen was already in a soft gel form at the time of insertion. In our experience, several patients in 316
the conventional method group complained that the subjective effects of the punctal plug could be sensed only for 1-2 weeks (data not shown). It is possible that the atelocollagen plug in liquid status was washed out through the tear drainage system before attaining soft gel form. One major disadvantage related to Keeptear is the inability to confirm the localization of the plug after insertion. However, the persistently low tear clearance rates were our key findings in confirming the existence of plugs. Thus, we recommend measurement of the tear clearance rate to evaluate whether the plugs are in place or not at busy clinical practices. Another disadvantage of Keeptear is the temporary effect in relation to punctal occlusion. Although the confirmation method of plug retention is not established, we believe this type of plug remains for at least 1 month after plug insertion, based on the current study. From these perspectives, temporary dry eye states such as postsurgical dry eye disease and seasonal worsening of dry eyes may be among the good indications for Keeptear plug implantation. During the follow-up period after Keeptear implantation, we did not find any complications such as dacryocystitis, canaliculitis, granuloma formation, and conjunctival laceration. However, some of these complications could occur several months later. Complication rates with a long-term follow-up period should be evaluated in future studies. The extrusion rate of this new generation of punctal plugs is still not clear and should be investigated in further trials. In the current study, we implemented a questionnaire using dryness VAS symptom scores. Although we found a statistically significant improvement in the preheating group after punctal plug treatment, detailed dryness feelings such as foreign body sensation, blurred vision, and pain were not investigated. Moreover, the effects for reading or driving a car would be important aspects in the treatment of dry eye disease. In a future study, a detailed questionnaire such as ocular surface disease index could be used for further symptom evaluation of Keeptear punctal plug treatment. In short, we found Keeptear to be effective and safe in the treatment of dry eye patients. It is our belief that further long-term investigations on a larger population of patients, comparing the results with other types of plugs, are absolutely essential. Further investigation for localization of the plug using high-frequency ultrasound or in vivo confocal microscopy, relationships between localization and clinical status, and long-term follow-up are also needed. One of the shortcomings of the current study was that the preparation method of Keeptear was not masked for the examiner. Since Keeptear becomes an opaque gel when it is heated, it was apparently obvious to the examiners which preparation methods were being applied in the patients. In summary, this study found thermosensitive atelocollagen punctal plug to be an effective treatment modality for dry eye disease. The preheating preparation of Keeptear is useful to strengthen the effect of atellocollagen punctal plug treatment.
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ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Tsubota Kazuo indicates consultancy (AcuFocus, Bausch Lomb Surgical, Pfizer, Santen, and SIFI), grants/grants pending (Allergan, Kissei, Kowa, Nidek, Opthecs, Otsuka, Santen, Suntory, and Wakasa Seikatsu), payment for lectures (Santen), patents (CEPT Company, Functional Visual Acuity Meter, JINS moisture glasses, and Rainbow Optical), and travel expenses (Santen). Murat Dogru indicates grants/grants pending (Otsuka and Santen). The authors indicate no funding support. Contributions of authors: design of the study (T.K., M.D., K.T.); conduct of the study (T.K., M.D., T.W., O.I., Y.M.); collection, management, analysis, and interpretation of the data (T.W., O.I., Y.M., M.D.); and preparation, review, or approval of manuscript (T.W., Y.M., M.D., K.T.).
REFERENCES 1. Sakamoto A, Kitagawa K, Tatami A. Efficacy and retention rate of two types of silicone punctal plugs in patients with and without Sjogren syndrome. Cornea 2004;23(3):249–254. 2. Giovagnoli D, Graham SJ. Inferior punctal occlusion with removable silicone punctal plugs in the treatment of dryeye related contact lens discomfort. J Am Optom Assoc 1992;63(7):481–485. 3. Kaido M, Goto E, Dogru M, Tsubota K. Punctal occlusion in the management of chronic Stevens-Johnson syndrome. Ophthalmology 2004;111(5):895–900. 4. Foulds WS. Intra-canalicular gelatin implants in the treatment of kerato-conjunctivitis sicca. Br J Ophthalmol 1961; 45(9):625–627. 5. Yung YH, Toda I, Sakai C, Yoshida A, Tsubota K. Punctal plugs for treatment of post-LASIK dry eye. Jpn J Ophthalmol 2012;56(3):208–213. 6. Kaido M, Ishida R, Dogru M, Tsubota K. Visual function changes after punctal occlusion with the treatment of short BUT type of dry eye. Cornea 2012;31(9):1009–1013. 7. Sabti S, Halter JP, Braun Frankl BC, Goldblum D. Punctal occlusion is safe and efficient for the treatment of keratoconjunctivitis sicca in patients with ocular GvHD. Bone Marrow Transplant 2012;47(7):981–984. 8. Mansour K, Leonhardt CJ, Kalk WW, Bootsma H, Bruin KJ, Blanksma LJ. Lacrimal punctum occlusion in the treatment of severe keratoconjunctivitis sicca caused by Sjogren syndrome: a uniocular evaluation. Cornea 2007;26(2):147–150. 9. Ervin AM, Wojciechowski R, Schein O. Punctal occlusion for dry eye syndrome. Cochrane Database Syst Rev 2010;9: CD006775. 10. Parikh NB, Francis JH, Latkany RA. Retention rate of silicone punctal plugs placed by residents in a general clinic setting. Ophthal Plast Reconstr Surg 2010;26(6):400–402. 11. Hsu HC. Ampullary pyogenic granuloma as a complication of lacrimal plug migration. Chang Gung Med J 2002;25(6): 415–418.
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12. Nava-Castaneda A, Tovilla-Canales JL, Rodriguez L, Tovilla YPJL, Jones CE. Effects of lacrimal occlusion with collagen and silicone plugs on patients with conjunctivitis associated with dry eye. Cornea 2003;22(1):10–14. 13. Ibrahim OM, Dogru M, Ward SK, et al. The efficacy, sensitivity, and specificity of strip meniscometry in conjunction with tear function tests in the assessment of tear meniscus. Invest Ophthalmol Vis Sci 2011;52(5):2194–2198. 14. Dogru M, Ishida K, Matsumoto Y, et al. Strip meniscometry: a new and simple method of tear meniscus evaluation. Invest Ophthalmol Vis Sci 2006;47(5):1895–1901. 15. Uchino Y, Uchino M, Dogru M, Ward S, Yokoi N, Tsubota K. Changes in dry eye diagnostic status following implementation of revised Japanese dry eye diagnostic criteria. Jpn J Ophthalmol 2012;56(1):8–13. 16. Fox RI, Robinson CA, Curd JG, Kozin F, Howell FV. Sjogren’s syndrome. Proposed criteria for classification. Arthritis Rheum 1986;29(5):577–585. 17. Toufeeq A, Mohammad-Ali FH. Peripheral corneal ulceration as a complication of silicon punctal plug: a case report. Eye (Lond) 2007;21(11):1437–1438. 18. Kojima T, Dogru M, Ishida R, Goto E, Matsumoto Y, Tsubota K. Clinical evaluation of the Smart Plug in the treatment of dry eyes. Am J Ophthalmol 2006;141(2):386–388. 19. Hill RH 3rd, Norton SW, Bersani TA. Prevalence of canaliculitis requiring removal of SmartPlugs. Ophthal Plast Reconstr Surg 2009;25(6):437–439. 20. SmartPlug Study Group. Management of complications after insertion of the SmartPlug punctal plug: a study of 28 patients. Ophthalmology 2006;113(10):1859.e1–e6. 21. Lowther GE, Semes L. Effect of absorbable intracanalicular collagen implants in hydrogel contact lens patients with symptoms of dryness. Int Contact Lens Clin 1995;22: 238–243. 22. Farrell J, Patel S, Grierson DG, Sturrock RD. A clinical procedure to predict the value of temporary occlusion therapy in keratoconjunctivitis sicca. Ophthalmic Physiol Opt 2003; 23(1):1–8.
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Biosketch Takashi Kojima received his medical degree at Nagoya University School of Medicine. He completed a research fellowship with Prof. Dimitri Azar at Massachusetts Eye and Ear Infirmary and received doctor’s degree with Prof. Kazuo Tsubota at Keio University School of Medicine. Dr Kojima’s research is focused on dry eye diseases and ocular surface.
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To evaluate the efficacy of a thermosensitive atelocollagen punctal plug in the treatment of dry eye disease. DESIGN: Prospective observational case series. METHODS: The thermosensitive atelocollagen punctal plug was warmed at 37 C, 39 C, 41 C, and 43 C to evaluate the appropriate temperature and time for solidification. Dry eye patients were divided into 2 groups according to the preparation method of the atelocollagen punctal plug. In the conventional implantation group, atelocollagen gel was kept at room temperature for 15 minutes before implantation (27 eyes of 14 patients). In the preheating group, atelocollagen was warmed at 41 C for 8 minutes before implantation (23 eyes of 13 dry eye patients). Strip meniscometry, vital stainings, tear film break-up time (BUT), and symptom scores were evaluated before and 1 month after plug implantation. RESULTS: In vitro experiments revealed that heating at 41 C for 8 minutes was sufficient to solidify the gel. The mean fluorescein score in the conventional implantation group significantly improved after treatment (before, 3.5 ± 2.3 points; after, 2.5 ± 0.9 points, P < .05). In the preheating group, the mean fluorescein score (before, 3.7 ± 1.7 points; after, 1.5 ± 1.2 points), strip meniscometry (before, 0.6 ± 0.7 mm; after, 1.1 ± 0.3 mm), BUT (before, 3.2 ± 0.7 seconds; after, 4.8 ± 1.0 seconds), and visual analog scale scores (before, 6.6 ± 1.5 points; after, 4.1 ± 0.9 points) significantly improved after treatment (P < .05). CONCLUSION: The thermosensitive atelocollagen punctal plug was effective for dry eye treatment. The preheating method was found to be useful to strengthen the efficacy of the thermosensitive atelocollagen punctal plug. (Am J Ophthalmol 2014;157:311–317. Ó 2014 by Elsevier Inc. All rights reserved.)
P
UNCTAL PLUG INSERTION HAS ALREADY BEEN
reported to be an effective treatment for aqueous tear-deficient dry eye diseases, such as StevensJohnson syndrome, contact lens–related dry eyes, and Accepted for publication Oct 30, 2013. From the Department of Ophthalmology, Keio University School of Medicine (T.K., Y.M., O.M.A.I., T.H.W., M.D., K.T.); and the Department of Ophthalmology, Tokyo Dental College (M.D.), Tokyo, Japan. Inquiries to Murat Dogru, Department of Ophthalmology, Tokyo Dental College, Sugano, Ichikawa-shi, Chiba, 272-8513, Japan; e-mail: [email protected] 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2013.10.019
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neurogenic dry eyes occurring after laser in situ keratomileusis (LASIK) and photorefractive keratectomy.1–3 In 1961, Foulds reported the first punctal plug treatment with gelatin-type punctal plugs.4 In terms of materials, current punctal plugs are categorized as absorbable and nonabsorbable. Absorbable plugs are mainly used for evaluating the effect with nonabsorbable plugs or treatment of temporary dry eye disease such as post-LASIK dry eyes. The Freeman-style plug is among the most popular nonabsorbable punctal plug design. This plug consists of a cylindrical neck; a wider base that sits at the angle where the vertical and horizontal segments of the canaliculus meet, anchoring it in position; and a wider disc-shaped head or flange that sits on the surface of the punctal opening. The Freemanstyle punctal plug is available in various sizes and has been reported to fit most cases of dry eyes.5–8 It has been reported to have high stability and safety, with some inherent problems consisting of granulation formation, irritation of cornea and conjunctiva, epithelial laceration, and frequent extrusion.8–12 Surgical punctal occlusion by cautery or laser is another option for dry eyes not suitable for punctal plug treatment. However, such treatment options also possess several problems, such as deformation of the punctum, recanalization, and symblepharon formation. The collagen punctal plug is one of the absorbable plugs and is mainly used for temporary dry eye disease such as postsurgical dry eye or seasonal worsening of dry eye disease. A Cochrane database review concluded that temporary collagen plugs appear similarly effective to silicone plugs on a short-term basis.9 Recently, a new generation of thermosensitive atelocollagen punctum plug (Keeptear; Koken Bioscience Institutes, Tokyo, Japan) has been developed and is being widely used in Japan. Briefly, Keeptear is categorized as an absorbable collagen plug and possesses unique characteristics. Keeptear is available in a syringe. Keeptear is made of thermosensitive atelocollagen, which is liquid at room temperature but becomes a soft gel at body temperature. After insertion, as the Keeptear equilibrates to the body temperature, the material softens and fits the patient’s punctum. According to the manufacturer’s suggestions, Keeptear should be kept at room temperature for 15 minutes after being taken out of the refrigerator, after which it is then injected into the patient’s canaliculus from the punctum. We hypothesized that preheating atelocollagen gel could
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enhance the treatment effect, and thus we designed this study. In this study, we evaluated the efficacy of a new punctal plug (Keeptear) insertion method in patients with dry eye disease, comparing the preparation method with conventional methodology.
METHODS THE PROTOCOL OF THIS PROSPECTIVE RANDOMIZED CLIN-
ical study and informed consent were approved by the Institutional Review Board of the Keio University School of Medicine and the study was registered at UMIN-CTR (http://www.umin.ac.jp/ctr/index.htm) (UMIN000011574). The study procedures conformed to the ethical principles for research involving human subjects as outlined in the Declaration of Helsinki. Informed consents for both the treatment and participation in the research were obtained from all subjects after explanation of the nature and possible consequences of taking part in the study. IN
VITRO EXPERIMENTS: Keeptear punctal plugs (Figure 1, Top left) are made from bovine dermal tissue and prepared with 0.2% concentration by a manufacturing company for clinical use. To evaluate and understand the gel formation process of the Keeptear punctal plug, in vitro experiments were designed. The Keeptear atelocollagen punctal plug becomes a soft gel from liquid at 37 C (Figure 1, Top right). Initially, to determine the shortest time in which Keeptear reaches the gel form at 37 C, Keeptear was warmed using a thermoblock, which can adjust the temperature (Figure 1, Middle left). The timewise changes of collagen temperature were recorded using a thermometer (UV-1200; Shimadzu, Tokyo, Japan). In the in vitro experiments, the thermoblock was warmed to 37 C, 39 C, 41 C, and 43 C. To clarify when the Keeptear started to attain the soft gel form, spectrometry (digital multimeter PC5000a; Sanwa Electric Instrument Inc., Tokyo, Japan) was performed, and absorbance at 400 nm was measured after warming Keeptear at different temperatures. CLINICAL
plugs were STUDY: Subjects. Keeptear inserted in a total of 50 eyes of 27 dry eye patients (Sjo¨gren syndrome: 12 patients, non–Sjo¨gren syndrome: 15 patients). Before punctal plug insertion, irrigation of the canaliculus was performed for all patients, and it was confirmed that the tear drainage system was intact. Two preparation methods of Keeptear punctal plugs were randomly assigned to patients. In the conventional implantation group, atelocollagen gel was kept at room temperature for 15 minutes before implantation (27 eyes of 14 patients). In the preheating group, immediately after taking the atelocollagen punctal plug from the refrigerator,
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it was warmed at 41 C for 8 minutes before implantation (23 eyes of 13 dry eye patients). After plug insertion, patients were asked to use only preservative-free artificial tear eye drops (Softsantear; Santen Pharmaceutical Co Ltd, Osaka, Japan) 6 times a day. Tear functions and ocular surface examinations were performed before and 1 month after treatment. To minimize the effect of each examination on the following examinations, tear volume measurement using strip meniscometry was performed initially. Ten minutes later, tear film break-up time measurements and then vital stainings were performed. A single clinician (T.K.) performed injections of Keeptear punctal plugs and all examinations including tear functions and ocular surface vital stainings. Patient demographics and tear functions/ocular surface abnormalities before thermosensitive atelocollagen punctal plug treatment were shown in Table. Punctal plug procedure. A 26 G blunt-tip needle was used for insertion. A total of 150 mL of Keeptear was injected into each upper and lower punctum. If backflow of collagen was observed, injection was stopped. Immediately following insertion, a warm compress (hot eye mask, Kao Corporation, Tokyo, Japan) was placed onto the patients’ eyelids for 10 minutes. Plugs were inserted in both superior and inferior lacrimal puncta in all patients. Strip meniscometry testings. The tip of the meniscometry strip was inserted for 5 seconds into the lateral lower tear meniscus without touching the ocular surface. The duration of the test was measured strictly by a stopwatch chronometer at each testing. The length of the stained tear column in the central membrane ditch was regarded as the strip meniscometry value in that eye in millimeters. The SM testing has been reported to be useful in the evaluation of tear meniscus volume, as reported previously.13,14 Tear function tests. The standard tear film break-up time (BUT) measurement was performed after instillation of a 2-mL volume of a 0.5% fluorescein dye in the conjunctival sac with a micropipette. A cobalt blue filter was used to measure the BUT. The patients were then instructed to blink several times for a few seconds to ensure adequate mixing of the dye. The interval between the last complete blink and the appearance of the first corneal black spot in the stained tear film was measured 3 times and the mean value of the measurements was calculated. Vital stainings. Fluorescein stain scoring of the ocular surface was performed. The fluorescein staining scores of the ocular surface ranged from 0-9 points. In fluorescein and rose bengal staining, the ocular surface was divided into 3 parts: temporal conjunctiva, cornea, and nasal conjunctiva. Each zone had a staining score ranging from 0-3 points, with the minimum and maximum total staining scores ranging from 0-9 points.
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FIGURE 1. Overview of the in vitro experiment evaluating solidification process of Keeptear punctal plug. (Top left) Keeptear punctal plug is prepared in the syringe with 26 G blunt-tipped needle. (Top right) Twenty-four hours after heating at 37 C, Keeptear changes from liquid to soft gel. (Middle left) Syringe of Keeptear was placed in the thermoblock. (Middle right) Temperature changes were measured. (Bottom) Absorbance changes in Keeptear atelocollagen punctal plug was measured when it was heated with different temperature settings (37 C, 39 C, 41 C, and 43 C).
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TABLE. Patient Demographics and Tear Functions/Ocular Surface Abnormalities Before Thermosensitive Atelocollagen Punctal Plug Treatment for Dry Eye Disease Conventional Method
Preheating Method
Patients (eyes) Sex
After heating at different temperatures, absorbance at 400 nm was measured to evaluate the solidification process of atelocollagen. With 37 C, 39 C, 41 C, and 43 C warming, solidification was observed at, respectively, 12, 9, 7, and 6 minutes after heating (Figure 1, Bottom). With 43 C heating, absorbance reached a maximum and gradually decreased.
14 (27) 13 (23) Female:12, Female:10, Male: 2 Male:3 Age (y), mean 6 SD 61.3 6 17.2 62.4 6 14.5 Pretreatment tear functions and ocular surface abnormalities Schirmer I test (mm) 5.4 6 2.0 5.1 6 2.7 Tear film break-up time (seconds) 3.3 6 1.1 3.4 6 0.8 Fluorescein score (points) 3.6 6 2.4 3.8 6 1.7 Rose bengal score (points) 2.2 6 1.9 2.0 6 1.4
Strip meniscometry score changes. The mean strip meniscometry (SM) score showed an significant increase from 0.63 6 0.65 mm to 1.09 6 0.33 mm after atelocollagen punctal plug treatment in the preheating group (P ¼ .0171). The mean SM score showed an insignificant increase from 0.73 6 0.46 mm to 0.78 6 0.54 mm with atelocollagen punctal plug treatment in the conventional implantation group, as shown in Figure 2, Top left (P ¼ .8125).
Evaluation of dry eye symptoms. Symptoms of ‘‘dryness’’ were evaluated with visual analog scale (VAS) scores. Participants indicated scores on the VAS sheets before and 1 month after treatment. Lower scores on the VAS referred to a less severe degree of symptoms, whereas higher VAS scores indicated severe symptoms in this study (minimum: 0 point, maximum: 10 points).
Tear film break-up time changes. The mean BUT showed a statistically significant increase from 3.2 6 0.7 seconds to 4.8 6 1.0 seconds after atelocollagen punctal plug treatment in the preheating group (P ¼ .0425), whereas no statistically significant changes were observed before (3.5 6 1.3 seconds) and after (3.8 6 1.4 seconds) atelocollagen punctal plug treatment in the conventional implantation group, as shown in Figure 2, Top right (P ¼ .4922).
Dry eye diagnostic criteria. The diagnosis of dry eye disease was based on the diagnostic criteria of the Dry Eye Research Group in Japan.15 In brief, patients with (1) dry eye–related symptoms; (2) positive staining with fluorescein or rose bengal dyes; and (3) Schirmer I test results of less than 5 mm, or tear film BUT values of less than 5 seconds were diagnosed as having dry eyes. A fluorescein staining score above 3 points and a rose bengal staining score above 3 points was considered abnormal. Dry eye cases were categorized as Sjo¨gren syndrome (SS) and non-SS on the basis of the criteria proposed by Fox and associates.16
Vital staining score changes. The mean fluorescein staining score showed a significant decrease with atelocollagen punctal plug treatment both in preheating (from 3.8 6 1.7 points to 1.5 6 1.2 points, P ¼ .001) and conventional implantation groups (from 3.5 6 2.3 points to 2.5 6 0.9 points, P ¼ .0078), as shown in Figure 2, Middle left. The mean rose bengal scores did not change significantly before and after punctal plug treatment in both conventional (from 2.1 6 1.4 points to 1.9 6 0.9 points, P ¼ .6250) and preheating method groups (from 1.9 6 2.6 points to 1.5 6 1.7 points, P ¼ .2188) (Figure 2, Middle right).
Statistical analysis. For statistical analyses, paired t test was used for comparisons of tear functions and ocular surface tests before and after punctal plug insertion. A P value less than .05 was considered statistically significant. Data were processed using the IBM SPSS Statistics software (IBM, Armonk, New York, USA) for Macintosh OS X (Apple, Cupertino, California, USA).
CLINICAL STUDY:
Dryness visual analog scale symptom scores. The mean dryness VAS score showed a significant decrease from 6.6 6 1.5 points to 4.1 6 0.9 points in the preheating group (P ¼ .0078) and an insignificant decrease from 7.7 6 1.4 points to 6.6 6 2.3 points in the conventional implantation group upon Keeptear punctal plug treatment (P ¼ .125), as shown in Figure 2, Bottom. Complications. No complications related to Keeptear atelocollagen punctal plug insertion, including dacryocystitis, canaliculitis, granuloma formation, and conjunctival laceration, were observed in any of the eyes in this study.
RESULTS IN VITRO EXPERIMENTS:
Keeptear atelocollagen punctal plug was warmed at 4 different temperatures (37 C, 39 C, 41 C, and 43 C). At 37 C warming, atelocollagen did not reach 37 C. With 39 C, 41 C, and 43 C warming, atelocollagen reached 37 C at 10.5 minutes, 8.0 minutes, and 6.5 minutes, respectively (Figure 1, Middle right).
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DISCUSSION ALTHOUGH THE EFFICACY OF THE FREEMAN-STYLE PUNCTAL
plug treatment for dry eye patients has already been
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FIGURE 2. (Top left) Strip meniscometry was performed before and after Keeptear punctal plug implantation. In the preheating group, strip meniscometry value after treatment was significantly higher than that before treatment. (Top right) Tear film breakup time (BUT) was measured before and after Keeptear punctal plug implantation. In the preheating group, BUT was significantly improved after treatment. (Middle left) Fluorescein score was measured before and after Keeptear punctal plug implantation. In both conventional and preheating method groups, fluorescein score significantly improved after treatment. (Middle right) Rose bengal score was measured before and after Keeptear punctal plug implantation. In both conventional and preheating method groups, there were no significant differences between before and after treatment. (Bottom) Dryness visual analog scale (VAS) was analyzed before and after Keeptear punctal plug implantation. In the preheating method group, dryness VAS was significantly improved after treatment. * represents P < .05.
reported,5,6,9 these plugs are known to be associated with complications like granulation formation, irritation of cornea and conjunctiva, epithelial laceration, and frequent extrusion.10,17 A new type of cylindrical-shaped VOL. 157, NO. 2
punctal plug, called the SmartPlug, made of hydrophilic acryl, has also been employed in dry eye treatment, with good short-term efficacy and safety.18 However, several studies pointed out that SmartPlugs were associated with
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canaliculitis and dacryocystitis.19,20 A previous study showed that collagen punctal plug showed no statistically significant effects for dry eye disease after 5 days of occlusion.21 Other study showed that treatment with collagen punctal plugs improved tear meniscus height and tear stability in aqueous-deficient dry eyes after 12 days of treatment.22 Cochrane systematic review in relation to the punctal plug treatment concluded a relative lack of strong evidence supporting the efficacy of collagen punctal plugs as a treatment modality for dry eye.9 Since conventional collagen plug is dry and solid, it may be difficult to achieve ‘‘just-fit’’ for all sizes of puncta. In the current study, punctal occlusion with Keeptear was observed to be associated with improvements of tear stability and ocular surface vital staining scores. The extent of improvement with other types of punctal plugs should be assessed and compared with further prospective trials in the future. In vitro experiments were carried out to confirm the shortest time of heating for the Keeptear punctal plug to reach 37 C. With 43 C of heating, the time to reach 37 C was shortest among the tested temperatures. However, when atelocollagen was heated at 43 C, the absorbance at 400 nm decreased after reaching a maximum value. From these results, we speculated that atelocollagen started solidification with 43 C heating and then the 3-dimensional structure of collagen collapsed because of the high temperature. In fact, we confirmed that the atelocollagen gel turned to the liquid state 7 minutes after 43 C heating. Finally, from these results, 8 minutes of heating at 41 C was chosen as a suitable condition of preheating. We compared 2 preparation methods, conventional and preheating, in clinical settings. In the conventional method group, VAS symptom scores, tear functions, and rose bengal scores did not show significant improvements 1 month after treatment. Only fluorescein staining score showed a significant improvement after treatment. On the other hand, tear functions including strip meniscometry and BUT showed significant improvements after treatment in the preheating group. Similarly, fluorescein and rose bengal scores significantly improved after treatment in the preheating group. Since we found that the strip meniscometry value increased after treatment, we think that the Keeptear plug blocked the canaliculi and retained the tear volume at 1 month after treatment. Vital staining scores showed a statistically significant improvement after treatment, and these results suggest that increased tear volume improved the ocular surface abnormalities. Since BUT improved after treatment, pooling and qualitative improvement of tear fluid are suggestible changes attributable to the insertion of the plug. We assumed that the observed tear function and ocular surface differences between the 2 preparation methods occurred for the following reasons: In the conventional method group, the atelocollagen was still in liquid status when it was inserted. On the other hand, in the preheating group, the atelocollagen was already in a soft gel form at the time of insertion. In our experience, several patients in 316
the conventional method group complained that the subjective effects of the punctal plug could be sensed only for 1-2 weeks (data not shown). It is possible that the atelocollagen plug in liquid status was washed out through the tear drainage system before attaining soft gel form. One major disadvantage related to Keeptear is the inability to confirm the localization of the plug after insertion. However, the persistently low tear clearance rates were our key findings in confirming the existence of plugs. Thus, we recommend measurement of the tear clearance rate to evaluate whether the plugs are in place or not at busy clinical practices. Another disadvantage of Keeptear is the temporary effect in relation to punctal occlusion. Although the confirmation method of plug retention is not established, we believe this type of plug remains for at least 1 month after plug insertion, based on the current study. From these perspectives, temporary dry eye states such as postsurgical dry eye disease and seasonal worsening of dry eyes may be among the good indications for Keeptear plug implantation. During the follow-up period after Keeptear implantation, we did not find any complications such as dacryocystitis, canaliculitis, granuloma formation, and conjunctival laceration. However, some of these complications could occur several months later. Complication rates with a long-term follow-up period should be evaluated in future studies. The extrusion rate of this new generation of punctal plugs is still not clear and should be investigated in further trials. In the current study, we implemented a questionnaire using dryness VAS symptom scores. Although we found a statistically significant improvement in the preheating group after punctal plug treatment, detailed dryness feelings such as foreign body sensation, blurred vision, and pain were not investigated. Moreover, the effects for reading or driving a car would be important aspects in the treatment of dry eye disease. In a future study, a detailed questionnaire such as ocular surface disease index could be used for further symptom evaluation of Keeptear punctal plug treatment. In short, we found Keeptear to be effective and safe in the treatment of dry eye patients. It is our belief that further long-term investigations on a larger population of patients, comparing the results with other types of plugs, are absolutely essential. Further investigation for localization of the plug using high-frequency ultrasound or in vivo confocal microscopy, relationships between localization and clinical status, and long-term follow-up are also needed. One of the shortcomings of the current study was that the preparation method of Keeptear was not masked for the examiner. Since Keeptear becomes an opaque gel when it is heated, it was apparently obvious to the examiners which preparation methods were being applied in the patients. In summary, this study found thermosensitive atelocollagen punctal plug to be an effective treatment modality for dry eye disease. The preheating preparation of Keeptear is useful to strengthen the effect of atellocollagen punctal plug treatment.
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ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Tsubota Kazuo indicates consultancy (AcuFocus, Bausch Lomb Surgical, Pfizer, Santen, and SIFI), grants/grants pending (Allergan, Kissei, Kowa, Nidek, Opthecs, Otsuka, Santen, Suntory, and Wakasa Seikatsu), payment for lectures (Santen), patents (CEPT Company, Functional Visual Acuity Meter, JINS moisture glasses, and Rainbow Optical), and travel expenses (Santen). Murat Dogru indicates grants/grants pending (Otsuka and Santen). The authors indicate no funding support. Contributions of authors: design of the study (T.K., M.D., K.T.); conduct of the study (T.K., M.D., T.W., O.I., Y.M.); collection, management, analysis, and interpretation of the data (T.W., O.I., Y.M., M.D.); and preparation, review, or approval of manuscript (T.W., Y.M., M.D., K.T.).
REFERENCES 1. Sakamoto A, Kitagawa K, Tatami A. Efficacy and retention rate of two types of silicone punctal plugs in patients with and without Sjogren syndrome. Cornea 2004;23(3):249–254. 2. Giovagnoli D, Graham SJ. Inferior punctal occlusion with removable silicone punctal plugs in the treatment of dryeye related contact lens discomfort. J Am Optom Assoc 1992;63(7):481–485. 3. Kaido M, Goto E, Dogru M, Tsubota K. Punctal occlusion in the management of chronic Stevens-Johnson syndrome. Ophthalmology 2004;111(5):895–900. 4. Foulds WS. Intra-canalicular gelatin implants in the treatment of kerato-conjunctivitis sicca. Br J Ophthalmol 1961; 45(9):625–627. 5. Yung YH, Toda I, Sakai C, Yoshida A, Tsubota K. Punctal plugs for treatment of post-LASIK dry eye. Jpn J Ophthalmol 2012;56(3):208–213. 6. Kaido M, Ishida R, Dogru M, Tsubota K. Visual function changes after punctal occlusion with the treatment of short BUT type of dry eye. Cornea 2012;31(9):1009–1013. 7. Sabti S, Halter JP, Braun Frankl BC, Goldblum D. Punctal occlusion is safe and efficient for the treatment of keratoconjunctivitis sicca in patients with ocular GvHD. Bone Marrow Transplant 2012;47(7):981–984. 8. Mansour K, Leonhardt CJ, Kalk WW, Bootsma H, Bruin KJ, Blanksma LJ. Lacrimal punctum occlusion in the treatment of severe keratoconjunctivitis sicca caused by Sjogren syndrome: a uniocular evaluation. Cornea 2007;26(2):147–150. 9. Ervin AM, Wojciechowski R, Schein O. Punctal occlusion for dry eye syndrome. Cochrane Database Syst Rev 2010;9: CD006775. 10. Parikh NB, Francis JH, Latkany RA. Retention rate of silicone punctal plugs placed by residents in a general clinic setting. Ophthal Plast Reconstr Surg 2010;26(6):400–402. 11. Hsu HC. Ampullary pyogenic granuloma as a complication of lacrimal plug migration. Chang Gung Med J 2002;25(6): 415–418.
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12. Nava-Castaneda A, Tovilla-Canales JL, Rodriguez L, Tovilla YPJL, Jones CE. Effects of lacrimal occlusion with collagen and silicone plugs on patients with conjunctivitis associated with dry eye. Cornea 2003;22(1):10–14. 13. Ibrahim OM, Dogru M, Ward SK, et al. The efficacy, sensitivity, and specificity of strip meniscometry in conjunction with tear function tests in the assessment of tear meniscus. Invest Ophthalmol Vis Sci 2011;52(5):2194–2198. 14. Dogru M, Ishida K, Matsumoto Y, et al. Strip meniscometry: a new and simple method of tear meniscus evaluation. Invest Ophthalmol Vis Sci 2006;47(5):1895–1901. 15. Uchino Y, Uchino M, Dogru M, Ward S, Yokoi N, Tsubota K. Changes in dry eye diagnostic status following implementation of revised Japanese dry eye diagnostic criteria. Jpn J Ophthalmol 2012;56(1):8–13. 16. Fox RI, Robinson CA, Curd JG, Kozin F, Howell FV. Sjogren’s syndrome. Proposed criteria for classification. Arthritis Rheum 1986;29(5):577–585. 17. Toufeeq A, Mohammad-Ali FH. Peripheral corneal ulceration as a complication of silicon punctal plug: a case report. Eye (Lond) 2007;21(11):1437–1438. 18. Kojima T, Dogru M, Ishida R, Goto E, Matsumoto Y, Tsubota K. Clinical evaluation of the Smart Plug in the treatment of dry eyes. Am J Ophthalmol 2006;141(2):386–388. 19. Hill RH 3rd, Norton SW, Bersani TA. Prevalence of canaliculitis requiring removal of SmartPlugs. Ophthal Plast Reconstr Surg 2009;25(6):437–439. 20. SmartPlug Study Group. Management of complications after insertion of the SmartPlug punctal plug: a study of 28 patients. Ophthalmology 2006;113(10):1859.e1–e6. 21. Lowther GE, Semes L. Effect of absorbable intracanalicular collagen implants in hydrogel contact lens patients with symptoms of dryness. Int Contact Lens Clin 1995;22: 238–243. 22. Farrell J, Patel S, Grierson DG, Sturrock RD. A clinical procedure to predict the value of temporary occlusion therapy in keratoconjunctivitis sicca. Ophthalmic Physiol Opt 2003; 23(1):1–8.
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Biosketch Takashi Kojima received his medical degree at Nagoya University School of Medicine. He completed a research fellowship with Prof. Dimitri Azar at Massachusetts Eye and Ear Infirmary and received doctor’s degree with Prof. Kazuo Tsubota at Keio University School of Medicine. Dr Kojima’s research is focused on dry eye diseases and ocular surface.
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