One-Year Clinical Outcomes of a Corneal Inlay for Presbyopia

CLINICAL SCIENCE

Sandra M. C. Beer, MD, Rodrigo Santos, MD, Eliane M. Nakano, MD, Flavio Hirai, MD, Enrico J. Nitschke, Claudia Francesconi, MD, and Mauro Campos, MD

phthalmologists have used a wide variety of procedures Purpose: To report the results of a 1-year follow-up analysis of the Oto correct for refractive errors. Corneal laser surgery safety and efficacy of the Flexivue Microlens corneal inlay. with multifocal patterns or monovision approaches have been Methods: The Flexivue Microlens corneal inlay was implanted in developed including laser-assisted in situ keratomileusis (LASIK),1,2 presbyLASIK,3 photorefractive keratectomy,4 the nondominant eye of patients with emmetropic presbyopia 5 2 laser epithelial keratomileusis thin-flap femto-LASIK, and (a spherical equivalent of 0.5 to 1.00 diopter) after the creation 6 7,8 of a 300-mm deep stromal pocket, using a femtosecond laser. The sub-Bowman keratomileusis. Conductive keratoplasty, patients were followed up according to a clinical protocol involving clear lens extraction, cataract surgery using multifocal, pseudoaccommodative intraocular lenses, or monovision refraction, anterior segment imaging analysis (Oculyzer), and optical 9–11 quality analysis (OPD-Scan). monofocal intraocular lenses have also been used to treat presbyopia. Results: Thirty-one patients were enrolled in this ongoing study. The necessity of a minimally invasive, removable, The mean age was 50.7 years (range 45–60 yrs), and 70% of the and safe surgical technique with a flat learning curve for patients were female. The mean uncorrected near visual acuity patients aged 45 to 60 years has led to the development of improved to Jaeger 1 in 87.1% of the eyes treated with the inlays. All refractive intracorneal lenses (inlays) such as the KAMRA, eyes improved 4 lines at all visits. The binocular uncorrected Raindrop, and Flexivue Microlens. These inlays are placed distance visual acuity was 20/20 in all patients. Ninety percent of inside a pocket in the corneal stroma, usually in the the patients reported that their near vision was good or excellent. nondominant eye. Some of the patients (16.1%) lost more than 3 lines of corrected In this prospective nonrandomized clinical study, we distance visual acuity. At the latest follow-up, induction of a corneal collected 1-year follow-up data on the safety and efficacy of spherical aberration to improve near visual acuity was statistically the Flexivue Microlens, which was implanted in 31 patients. significant. No other intraoperative or postoperative complication was noted.

Conclusions: The Flexivue Microlens provided patients with PATIENTS AND METHODS improved near vision, as a result of a negative spherical This clinical trial was performed at the Department aberration. A signiﬁcant loss of corrected distance visual acuity of Refractive Surgery, Federal University of São Paulo, São in the operated eyes was observed. Overall, this intracorneal inlay Paulo, Brazil. The study adhered to the tenets of the was an effective alternative to other procedures for the correction Declaration of Helsinki and obtained ethical approval from of presbyopia. the Institutional Ethics Committee (Hospital São Paulo). All participating patients provided informed consent before Key Words: bifocal refractive corneal inlay, intracorneal inlay, being studied. presbyopia, cornea Thirty-one patients were recruited from May 2012 to (Cornea 2017;36:816–820) June 2013. The inclusion criteria included were patients aged 45 to 60 years, uncorrected near visual acuity (UNVA) worse than J4, uncorrected distance visual acuity (UDVA) better than 20/40, corrected near visual acuity and corrected distance visual acuity (CDVA) better than 20/20, a spherical Received for publication September 4, 2016; revision received February 11, equivalent (SE) of 20.5 to 1.00 diopter (D), a refractive 2017; accepted February 14, 2017. Published online ahead of print April cylinder #20.75 D, the use of full-time reading glasses for 25, 2017. near visual tasks required for a minimum of 1 year, clearly From the Department of Ophthalmology and Visual Sciences, Federal University of Sao Paulo, São Paulo, Brazil. determined ocular dominance, central corneal thickness Sandra Beer is a consultant for Presbia. The remaining authors have no $500 mm, mesopic pupillary diameter $3 mm, and an funding or conﬂicts of interest to disclose. endothelial cell count (ECC) $2000 cells per millimeter Reprints: Sandra M. C. Beer, MD, Department of Ophthalmology, UNIFESP- square in the eye to be implanted. The exclusion criteria were Universidade Federal de São Paulo, Rua Vitor Meireles 523-Jardim São Caetano-São Caetano do Sul, São Paulo 9581-460, Brazil (e-mail: anterior or posterior segment pathology, previous intraocular [email protected]). or corneal surgery, chronic systemic or topical corticosteroid Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. treatment, the use of other immunosuppressive agents,

816 | www.corneajrnl.com Cornea Volume 36, Number 7, July 2017

Copyright Ó 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Cornea Volume 36, Number 7, July 2017 Outcomes of a Corneal Inlay for Presbyopia patients who used telescopes or microscopes for professional was determined using noncontact corneal specular micros- reasons, and patients who had high vision requirements or copy (Florence, Italy). Visante anterior chamber optical expectations such as surgeons, architects, accountants, pro- coherence tomography (Carl Zeiss, Oberkochen, German) fessional athletes, and pilots. The patients were examined was used to analyze the depth of the pocket, and contrast before inlay implantation and postoperatively at 1 day, 1 sensitivity was determined using a contrast sensitivity test week, 1 month, 3 months, 6 months, 1 year, 3 years, and (Stereo Optical, Chicago, IL). 5 years.

Surgical Techniques Corneal Inlay Three experienced surgeons performed all surgeries The 3.2-mm Flexivue Microlens (Presbia, Irvine, CA) between August 2012 and June 2013. Centration was has a bifocal design with a central zone for distance vision, performed by identifying the line of sight (Purkinje line), with no refractive power and a peripheral positive refractive and the center of the pupil was marked with a pen using zone for near vision. The inlay comprises a biocompatible gentian violet. A pocket was created using an IntraLase hydrophilic acrylic material (Contaflex C126). The central femtosecond laser (60 kHz; Abbott Medical Optics, Milpitas, zone has a diameter of 1.6 mm and an edge thickness of CA). The pocket incision was always in the higher astigma- 15 mm. The available base power ranges from +1.50 D tism axis following the settings. The pocket tunnel entry and to +3.50 D in 0.25 D increments. There is a 0.5-mm diameter pocket bed had a diameter of 3.6 mm, and pockets were hole at the center of the disc that permits transfer of oxygen created at a depth of 300 mm. and nutrients through the lens. The lens power is determined Once the pocket was created, the inlay was loaded into by adding +0.25 D in the near power refraction in the an appropriate inserter. The instrument was then inserted into nondominant eye, according to the manufacturer’s instruc- the pocket, and the inlay was released at the centrally tions for inlay implantation. marked area. The postoperative topical medication regimen consisted of a combination of fourth-generation fluoroquinolone (Vigamox) Manifest Refraction and Visual Acuity for 7 days and a topical steroid such as 1.0% prednisolone (Pred Manifest refraction and visual acuity were measured Forte) eye drops given four times daily for 14 days, then tapered preoperatively and postoperatively from 1 week onward. All over 2 weeks. tests were performed monocularly and binocularly. All distance visual acuity measurements were performed using Snellen charts. Near visual acuity was tested using an Early Statistical Analyses Treatment Diabetic Retinopathy Study Chart (Precision Statistical analyses were performed using SPSS statis- Vision, Berkeley, CA) and a Jaeger chart at 16 inches under tical software for Windows, version 16 (SPSS, Inc., Chicago, a light source of 500 lux. All visual acuities are expressed in IL). A paired-sample t test was used to compare preoperative logMAR units and Jaeger. and postoperative data. P , 0.05 was considered statistically significant. The data are presented as mean 6 SD. Patient Satisfaction A subjective questionnaire was used to assess patient satisfaction during the clinical trial at 1, 3, 6, and 12 months RESULTS during the postoperative period. The result of the most recent The study cohort included 31 patients. The mean age questionnaire was used as the final result. Patients were asked was 50.7 years (range 45–60 years). The cohort included 9 to grade their overall satisfaction for near vision (excellent, males (29%) and 22 females (70.9%), and surgery was good, fair, or poor); satisfaction for binocular distance vision performed on 15 right eyes and 16 left eyes. The depth of (excellent, good, fair, or poor); satisfaction with distance the pocket varied from 266 to 311 mm (optical coherence vision in the operated eye (excellent, good, fair, or poor); tomography evaluation). frequency of glare and halos (never, sometimes, frequent, or At the slit-lamp, no signs of stromal reaction or always); dependence on reading glasses (never, ,50%, epithelial defects were noticed during the study period. The .50%, or always); and dependence on glasses for distance surgical interface was clear in all eyes with very subtle vision (never, ,50%, .50%, or always). opacities resembling an iLasik flap. Careful slit-lamp examination of the inlay area disclosed slight implant folds.

METHODS All tests were performed in the operated eye by 2 Efficacy examiners. The tests included corneal topography, pachyme- The mean SE refractive error decreased significantly try, and keratometry using the Scheimpflug WaveLight from 0.33 6 0.38 D preoperatively to 21.78 D 6 0.80 D Oculyzer and Topolyzer system (Pentacam HR, Alcon, Fort (P , 0.05) at the last follow-up visit. The mean defocus Worth, TX). Optical quality analyses were performed using decreased from 0.48 6 0.38 D to 21.26 6 0.83 D the OPD-Scan III (Nidek, Gamagori, Japan), and the ECC (P = 0.0001). Mean preoperative refractive astigmatism

Copyright Ó 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Beer et al Cornea Volume 36, Number 7, July 2017 was 20.29 6 0.27 D, and mean postoperative astigmatism in the operated eye decreased significantly from 0.03 6 0.01 was 21.02 6 0.70 D (P = 0.0001). preoperatively to 0.01 6 0.01 postoperatively (P = 0.0001). The UNVA improved four lines in all patients. The mean UNVA in the surgical eye improved significantly from 0.17 6 0.56 preoperatively to 0.48 6 0.23 postoperatively Subjective Assessment (P , 0.05). In 87.1% of the patients, the UNVA was logMAR After 1 year of follow-up, 91% and 52% of the patients 0.3 or better (Jaeger 1-J1); in four patients, the UNVA was reported excellent/good UNVA and UDVA, respectively, in logMAR 0.4 (J2). the nondominant eye. Ninety-three percent of the patients In 83.9% of the patients, the best-corrected distance reported excellent/good binocular UDVA. The use of spec- visual acuity (BCDVA) of the operated eye decreased tacles for near vision decreased significantly after inlay significantly from 20/20 preoperatively to 20/30 postopera- implantation; 65% of the patients never used spectacles for tively. One patient lost four lines of the BCDVA. The UDVA near vision, whereas 32% of the patients used spectacles in the operated eye included 70.9% of the patients with 20/40 #50% of the time and only for computer work. Only 3% of or better. In the study, 16.1% of the patients lost more than the patients complained of frequent halos and glare (Table 1). three lines of BCDVA. During the follow-up period, glare and halos were described by 3.2% of the patients and only 1 patient DISCUSSION experienced a disturbing optical effect while driving. No Although corneal implants were developed more than corneal inlay had to be removed during the study period. 50 years ago, it was only after recent improvements in the design and materials that they became an effective alternative for the treatment of presbyopia.12–14 Three main categories of Endothelial Cell Count corneal inlays are commercially available: small-aperture The mean ECC was 2,690 6 230 cells per square inlays, space occupying inlays, and refractive-addition inlays. millimeter preoperatively and 2,737 6 258 cells per The KAMRA inlay (AcuFocus, Irvine, CA) was the square millimeter postoperatively at the 12-month first inlay approved by the US Food and Drug Administration follow-up examination (P . 0.05). (FDA). It is a small-aperture opaque inlay that is positioned on the stromal bed, using a conventional flap or pocket. Seyeddain et al15 described implantation of the KAMRA Optical Quality Analysis inlay in the nondominant eyes of 32 patients. Of these The mean root mean square (m) in the operated eye patients, 97% had a UNVA of Jaeger (J) 3 or better and increased significantly from 0.40 6 0.11 preoperatively to a mean UDVA of 20/20, and all eyes achieved a UDVA of 0.88 6 0.33 postoperatively (P , 0.05). The mean corneal 20/32 or better at 3 years. Nine eyes (28.3%) lost 1 line of spherical aberration (C12) in the operated eye increased from CDVA, and no inlay was explanted. Dexl et al16 reported 0.11 6 0.11 preoperatively to 20.35 6 0.21 postoperatively implantation of the third-generation KAMRA corneal inlay (P = 0.0001), and the total coma increased from 0.20 6 0.09 (ACI 7000PDT; AcuFocus) in 24 eyes. After a mean follow- preoperatively to 20.34 6 0.20 postoperatively (P = 0.0003). up of 12 months, 92% of the patients had a UNVA of J3 or better, and the mean UDVA was 20/20 in the operated eye. Tomita et al17 reported a series of 180 cases of Contrast Sensitivity Testing KAMRA implantation, with a 6-month follow-up period. Contrast sensitivity decreased in all treated eyes The mean logMAR UNVA improved 7 lines in hyperopic (Figs. 1A, B), and 1-year contrast sensitivity was significantly eyes, 6 lines in emmetropic eyes, and 2 lines in myopic eyes reduced (P , 0.05) in the operated eyes. The photopic curve and the mean logMAR UDVA showed improvements of 3 decreased in both lower and higher spatial frequencies, but in lines, 1 line, and 10 lines, respectively. the scotopic curve, only the lower spatial analysis decreased The Raindrop inlay (Vue+; Revision Optics, Lake significantly (P , 0.05). Forest, CA) comprises a permeable hydrogel having the same The modulation transfer function in the operated eye refractive index as the cornea, making it almost invisible. The decreased significantly from 63.97 6 16.44 preoperatively to size ranges from 2- to 4-mm diameter with a positive 30.9 6 5.26 postoperatively (P = 0.0001), and the Strehl ratio meniscus shape, so the central part is thicker (32 mm thick)

FIGURE 1. A and B, Contrast sensitivity in operated eyes at 1-year follow-up.

Copyright Ó 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Cornea Volume 36, Number 7, July 2017 Outcomes of a Corneal Inlay for Presbyopia

vision and one for near vision. The pocket of the cornea is TABLE 1. Results of the Patient Satisfaction Questionnaire (n = 31) created using a femtosecond laser. The Icolens and Flexivue Microlens are examples of this type of inlay. Question Reply(%) Bouzoukis et al19 recently reported the results of 1. Perception of uncorrected near vision in the implantation of the Invue Lens (BioVision, Hanover, Ger- nondominant eye? many), which was a precursor to the Icolens in 45 eyes. In Excellent 23 their study, the UNVA was 20/30 or better in 98% of the Good 68 operated eyes, and the UDVA was 20/40 or better in 93% of Fair 6 the operated eyes at the 12-month follow-up examination. Poor 3 Only three patients lost 1 line of CDVA in the operated eye. 2. Perception of the uncorrected (without glasses) The bifocal design of the Icolens inlay is similar to its distance in the nondominant eye? precursor lens; however, it also comes with a pocket-cutting Excellent 29 algorithm for the femtosecond laser, a preloaded deployment Good 23 device, and specially designed surgical instruments. Baily Fair 13 et al20 reported that after implantation involving 51 Icolens Poor 35 inlays, the UNVA improved from N18/N24 preoperatively to 3. Perception of the uncorrected (without glasses) binocular distance in the nondominant eye? N8 postoperatively. All patients had a UNVA of N16 or better, and 9 patients (17%) had a UNVA of N5 or better. Excellent 45 6 Good 48 There was mean loss of 1.67 1.77 lines of UDVA, and there was mean binocular gain of 0.48 6 1.16 lines of Fair 7 6 Poor 0 UDVA. The mean postoperative loss of CDVA was 1.78 4. How frequently does the patient use glasses for near 1.04 lines. Eleven implants were explanted because vision? of minimal improvement in the UNVA. No significant Never 65 adverse event was reported throughout the study. 21 Use glasses less than 50% 32 Limnopoulou et al reported follow-up results 1 year Use glasses more than 50% 3 after implantation of the Flexivue Microlens. The UNVA was Use glasses almost always 0 20/32 or better in 75% of the operated eyes, and there was 5. How frequently does the patient use glasses for far statistically significant worsening in the mean UDVA from 20/ vision? 20 preoperatively to 20/50 postoperatively. In this study, 17 Never 100 patients lost 1 line of CDVA, and no patient lost 2 lines of Use glasses less than 50% 0 CDVA in the operated eye. The inlay had physical properties Use glasses more than 50% 0 and a mechanism of action similar to that of the Icolens inlay. Use glasses almost always 0 Malandrini et al22 recently reported the results of 6. Does the patient complain about halos? implantation of the Flexivue Microlens in 81 eyes. After 36 Never 68 months of follow-up, 26 patients showed a mean preoperative Sometimes 29 UNVA and UDVA of 0.76 logMAR and 0.00 logMAR, Very frequently 3 respectively, compared with a postoperative UNVA and Always 0 UDVA of 0.10 logMAR and 0.15 logMAR, respectively. In 7. Does the patient complain about glare? total, 16 (62%) of the 26 implanted eyes lost more than 1 line Never 74 of UDVA, and 5 (19%) implanted eyes lost more than 2 lines Sometimes 23 of UDVA. Two implanted eyes (8%) lost more than 1 line of Very frequently 3 CDVA at 36 months. Explantation was performed in 6 treated Always 0 eyes because of halos, glare, and a reduced UDVA. In this study, there was significant improvement in the UNVA (87.1%) with significant loss in the monocular with no refractive power. The addition power varies from UDVA. The UNVA improved as a function of a myopic +1.50 to +2.50 based on an increasing central corneal radius shift in SEs and negative spherical aberrations. There was of curvature. The inlay was recently approved by the FDA. significant loss of CDVA, and 5 patients (16.1%) lost more Garza et al18 reported 1-year follow-up data for 20 patients than three lines. Corneal opacity was not seen in any patient, implanted with this inlay after showing that 100% of the but there was a slight haze in all patients. Possible mecha- patients had near vision equal to or better than logMAR 0.3 nisms for the decreased UDVA include centering of the inlay (20/40). One case was explanted, and 16 patients reported that and the association of higher-order aberration and decreased they rarely or never wore glasses for near vision contrast sensitivities. after implantation. Corneal inlay insertion involves a technical procedure Another type of inlay is based on a refractive addition with a considerable learning curve. We acknowledged deficits and has a central zone free of refractive power and a peripheral during the course of our study that should be addressed in the zone with a standard positive refractive power. The inlay is future. These include the development of a new insertion device inserted inside a pocket in the corneal stroma of the that eliminates some of the complexities of the earlier model. In nondominant eye, with 2 different focal points—one for far addition, we found centration to be critical for optimum

Copyright Ó 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Beer et al Cornea Volume 36, Number 7, July 2017 functioning of the inlay and postulated that inadequate centra- 10. Cummings JS, Colvard DM, Dell SJ, et al. Usage evaluation of the tion in certain cases might have contributed to inferior refractive Crystalens AT-45 accommodating interocular lens Results of the U.S. fi Food and Drug Administration clinical trial. J Cataract Refract Surg. outcomes. A signi cant advantage of the corneal inlay pro- 2006;32:812–825. cedure is that the inlay can be removed. This is an advantage 11. Macsai MS, Padnick-Silver L, Fontes BM, et al. Visual outcomes after over procedures involving corneal ablation or creation of rings accommodating intraocular lens implantation. J Cataract Refract Surg. for intrastromal treatments; however, additional studies and 2006;32:628–633. longer follow-up periods are necessary. In this study, the 12. Barraquer JL. Queratoplastia refractiva. Estudos e informaciones. Oftalnologicas. 1949;2:10. Flexivue Microlens provided patients with improved near 13. Choyce P. The present status of intracorneal implants. J Cataract Ophth. vision as a function of a myopic shift and negative spherical 1968;3:295. aberrations. A significant loss of CDVA in the operated eyes 14. Dohlman CH, Refojo MF, Rose J. Synthetic polymers in corneal surgery: was observed. Overall, this intracorneal inlay was an effective glyceryl methacylate. Arch Ophthalmol. 1967;177:52–58. 15. Seyeddain O, Hohensinn M, Riha W, et al. Small-aperture corneal inlay alternative to other procedures for the correction of presbyopia. for the correction of presbyopia: 3-year follow-up. J Cataract Refract Surg. 2012;38:35–45. REFERENCES 16. Dexl AK, Seyeddain O, Riha W, et al. One-year visual outcomes and 1. Pallikaris IG, Papatzanaki ME, Siganos DS, et al. A corneal flap patient satisfaction after surgical correction of presbyopia with an technique for laser in situ keratomileusis. Human studies. Arch intracorneal inlay of a new design. J Cataract Refract Surg. 2012;38: Ophthalmol. 1991;109:1604–1617. 262–269. 2. Pallikaris IG, Papatzanaki ME, Stathi EZ, et al. Laser in situ keratomi- 17. Tomita M, Kanamori T, Waring GO IV, et al. Simultaneous corneal leusis. Lasers Surg Med. 1990;10:463–468. inlay implantation and laser in situ keratomileusis for presbyopia in 3. Ortiz D, Illueca C, Alió JL. PresbyLASIK versus multifocal refractive patients with hyperopia, myopia, or emmetropia: six-month results. J IOLs. Ophth Times Europe. 2008;4:1. Cataract Refract Surg. 2012;38:495–506. 4. Seiler T, McDonnell PJ. Excimer laser photorefractive keratectomy. Surv 18. Garza EB, Gomez S, Chayet A, et al. One-Year safety and efficacy Ophthalmol. 1995;40:89–118. results of a hydrogel inlay to improve near vision in patients with 5. Taneri S, Zieske JD, Azar DT. Evolution, techniques, clinical outcomes, emmetropic presbyopia. J Refract Surg. 2013;29:166–172. and pathophysiology of LASEK: review of the literature. Surv Oph- 19. Bouzoukis DI, Kymionis GD, Panagopoulou SI, et al. Visual outcomes thalmol. 2004;49:576–602. and safety of a small diameter intraestromal refractive inlay for the 6. Slade SG. Thin-flap laser-assisted in situ keratomileusis. Curr Opin corneal compensation of presbyopia. J Refract Surg. 2012;28:168–173. Ophthalmol. 2008;19:325–329. 20. Baily C, Kohner T, O’Keefer M. Preloaded refractive-addition corneal 7. Pallikaris IG, Naoumidi TL, Astyrakakis NJ. Long term results of inlay to compensate for presbyopia implanted using a femtosecond laser: conductive keratoplasty for low to moderate hyperopia. J Cataract one-year visual outcomes and safety. J Cataract Refract Surg. 2014;40: Refract Surg. 2005;31:1520–1529. 1341–1348. 8. McDonald MB, Durrie D, Asbell P, et al. Treatment of presbyopia with 21. Limnopoulou AN, Bouzoukis DI, Kymionis GD, et al. Visual outcomes conductive keratoplasty: six-month results of the 1-year United States and safety of a refractive corneal inlay for presbyopia using femtosecond FDA clinical trial. Cornea. 2004;23:661–668. laser. J Refract Surg. 2013;29:12–18. 9. Pepose JS, Qazi MA, Davies J, et al. Visual performance of patients with 22. Malandrini A, Martone G, Menabuoni L, et al. Bifocal refractive corneal bilateral vs combination Crystalens, ReZoom, and ReSTOR intraocular inlay implantation to improve near vision in emmetropic presbyopic lens implants. Am J Ophthalmol. 2007;144:347–357. patients. J Cataract Refract Surg. 2015;41:1962–1972.