Review
Surgical compensation of presbyopia with corneal inlays Expert Review of Medical Devices Downloaded from informahealthcare.com by Emory University on 08/14/15 For personal use only.
Expert Rev. Med. Devices 12(3), 341–352 (2015)
Aris Konstantopoulos*1,2 and Jodhbir S Mehta1–5 1 Tissue Engineering and Stem Cell Group, Singapore Eye Research Institute, 11 Third Hospital Avenue,169856, Singapore, Singapore 2 Singapore National Eye Centre, 11 Third Hospital Avenue, 168751, Singapore, Singapore 3 Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, 119228, Singapore, Singapore 4 Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore, Singapore 5 Department of Clinical Sciences, Duke-NUS Graduate Medical School, 8 College Road, 169857, Singapore, Singapore *Author for correspondence: Tel.: +65 632 245 65 Fax: +65 632 245 99 [email protected]
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Presbyopia, the physiological change in near vision that develops with ageing, gradually affects individuals older than 40 years and is a growing cause of visual disability due to ageing demographics of the global population. The routine use of computers and ‘smartphones’, combined with the affluence of the ‘baby boomers’ generation has set high standards for near vision correction. Corneal inlays are a relatively new treatment modality that is effective at compensating for presbyopia. The dimensions of these devices vary from 2 to 3.8 mm in diameter and 5 to 32 mm in thickness. They are implanted in the anterior corneal stroma of the non-dominant eye, most commonly, in a femtosecond laser created corneal pocket. They improve near vision by increasing the depth of focus, creating a hyper-prolate region of increased central cornea power or providing a refractive add power. This article reviews the literature on the efficacy and safety of corneal inlays. KEYWORDS: Flexivue microlens . Icolens . inlay . Kamra . presbyopia . Raindrop
Presbyopia is a physiological change in near vision that develops with ageing. It occurs due to a progressive reduction in the accommodative power of the crystalline lens and gradually affects individuals older than 40 years. [1]. Presbyopia is a growing cause of visual disability due to ageing of the population, especially in developed countries. [2]. It is expected that the global population with presbyopia will increase from 1.2 billion in 2010 to 1.8 billion by 2050 and in developed countries (Australia, New Zealand, North America, Europe and Japan) from 373 to 448 million [3]. The relatively good health and affluence of the ‘baby boomers’ generation, combined with high near vision requirements for use of computers and ‘smartphones’, are likely to place additional pressure on the ophthalmic community to provide solutions for spectacle independence. The vast majority of the population manages presbyopia by wearing spectacles with convex lenses. This has the disadvantage that objects are in sharp focus only at one predetermined distance, and the spectacles need to be removed for distance vision. Bifocal and varifocal spectacles can overcome this limitation, but emmetropic patients who have not used spectacles previously may be reluctant to wear
10.1586/17434440.2015.1007124
spectacles for near vision, especially socially. Ophthalmologists and the ophthalmic industry have, therefore, sought other solutions to overcome these limitations. Methods for spectacle-independent presbyopia correction include monovision, multifocal contact lenses, multifocal intraocular lenses, conductive keratoplasty and corneal laser surgery. Monovision, the state of the visual system where the one eye is rendered myopic, either with contact lenses or refractive surgery, and the other emmetropic, aims to provide good near vision in one eye while the fellow eye is used for distance activities. Disadvantages of monovision include reduced stereoacuity and binocular contrast sensitivity [4,5]. The main disadvantage of multifocal contact lenses is poor image quality of the focused image and simultaneous perception of a defocused ghost image that may be exacerbated by decentration of the contact lens or movement with blinking [6]. Multifocal intraocular lenses may also have similar dysphotopsia symptoms, including night glare and haloes, and reduced contrast sensitivity [7–9]. Conductive keratoplasty tends to regress postoperatively and can limit the quality of vision with induction of astigmatism and high-order aberrations [10,11].
2015 Informa UK Ltd
ISSN 1743-4440
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Flexivue Microlens (Presbia Cooperatief U.A., Amsterdam, Netherlands) and the Icolens (Neoptics AG, Huenenberg, Switzerland). All the four devices have received CE certification for use in Europe; the Kamra Vision has also been recommended for US FDA approval.
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Design & properties
Figure 1. Appearance of the implanted Kamra inlay.
Corneal laser presbyopic correction can also have similar side effects, such as loss of distance visual acuity, haloes and glare [12–14]. In addition, the laser-induced corneal changes tend to be irreversible. Corneal inlays are a relatively new treatment option for presbyopia that is gaining increasing popularity. They involve an external eye procedure and have the potential for reversibility and future proofing should the refractive status or requirements change. The evolution in design and understanding of the optics, combined with the precision and safety of femtosecond laser technology, make corneal inlays a viable alternative for presbyopia correction. They aim to provide a good range of unaided near and intermediate vision with minimal reduction in unaided distance vision. Discussion
Currently, there are four corneal inlays available: the Kamra Vision (Acufocus Inc., Irvine, CA, USA), the Raindrop (ReVision Optics Inc., Lake Forest, CA, USA), the Presbia
The Kamra Vision, a small-aperture inlay, has been available the longest and is the most widely used. The current version (ACI 7000 PDT) is made of polyvinylidene fluoride and is 5 mm thick. It has a 3.8 mm diameter with a central 1.6 mm aperture that allows only central collinear light to reach the retina. The central aperture has 8400 laser-etched perforations with a randomised hole pattern, 5–11 mm in diameter. [15]. An implanted Kamra inlay is shown in FIGURE 1. The Raindrop, a space-occupying inlay, was developed in 2007 and was formerly called Vue+ and PresbyLens (ReVision Optics Inc.). It is made of a proprietary biocompatible hydrogel material and is 80% water. The inlay is approximately 10 mm thick at the periphery and 32 mm at the centre. In its most recent design, the diameter has been enlarged to 2 mm in order to expand the near optical zone [16,17]. FIGURE 2 shows an implanted Raindrop inlay. The Flexivue Microlens, a refractive inlay, is composed of a hydrophilic acrylic polymer, measuring 3 mm in diameter and 15–20 mm in thickness, depending on the additional refractive power. The design features a central 0.15 mm hole that allows oxygen and nutrients to diffuse freely through the cornea [18,19]. The Icolens, also a refractive inlay, is the most recent inlay in development and was formerly called InVue (Biovision AG, Bruggs, Switzerland). It is composed of hydrophilic acrylic hydrogel and has a diameter of 3 mm with a peripheral edge thickness less than 15 mm that depends on the strength of the presbyopic correction. Similar to the Flexivue Microlens, a central 0.15 mm hole is present for nutrient diffusion [20]. The design of the inlays is summarised schematically in FIGURE 3. Mode of action
Figure 2. High magnification photo of Raindrop inlay.
342
The Kamra inlay improves near vision by increasing the depth of focus. It uses the principle of small-aperture optics, with which smaller apertures produce a longer depth of focus. This allows the perception of reasonably sharp images for different distances with no need for a change in the power of the lens [21,22,15]. The Raindrop inlay reshapes the central anterior corneal surface, creating a hyper-prolate region of increased power for focusing on near and intermediate objects. The inlay itself is of neutral refractive power [17]. The Flexivue Microlens inlay provides a refractive add power for near. It has a bifocal design that provides separate distance and near focal points. The central zone is free of refractive power and serves the distance vision. The peripheral zone has a higher index of refraction than the cornea, generating add power that ranges from +1.25 to +3.00 D and can be customised to the patient in 0.25 D steps [18,19]. Expert Rev. Med. Devices 12(3), (2015)
Surgical compensation of presbyopia with corneal inlays
A
Review
B
8400 holes, 5−11 µm in diameter, randomly arranged
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Central 1.6 mm aperture
The inlay has no intrinsic refractive power
2 mm 3.8 mm C
D
Peripheral zone for near vision correction; power range from +1.25 to +3.00 diopters
Peripheral zone for near vision correction; power range +1.5 to +3.0 diopters
Central hole allows nutrient flow through the cornea
Central hole allows nutrient flow through the cornea Central zone for distance vision; power range –1.0 to +1.5 diopters
Central plano zone for distance vision 3 mm
3 mm
Figure 3. Schematic diagrams explaining the design and dimensions of the inlays. (A) the Kamra, (B) the Raindrop, (C) the Flexivue Microlens and (D) the Icolens inlays.
The Icolens also has a bifocal design with a central zone for distance correction that ranges from –1.0 to +1.5 D, and a peripheral refractive power add that ranges from +1.5 to +3.0 D in 0.5 D steps [23]. The inlay may potentially be replaced as the accommodative reserve and refractive status of the patient change with age.
placement of the inlay. Centration of the inlay is crucial for optimal function, and it is recommended that the inlay be aligned with the pupil centre or the visual axis (line of sight). At the end of the procedure, irrigation of the stromal bed should be avoided in order to avoid inlay movement and decentration. Kamra
Surgical implantation
Inlays are placed in the non-dominant eye of the patient. Initially, they were placed under a stromal flap, similar to that used for laser-assisted in situ keratomileusis (LASIK). More recently, the use of femtosecond lasers has facilitated the placement within a corneal pocket. The depth of the flap or pocket, usually between 150 and 200 mm, depends on the inlay and its mode of action. For example, the space-occupying Raindrop inlay needs to be placed relatively close to the corneal surface, as it exerts its refractive effect by increasing the curvature of the corneal surface and, thus, the refractive power. Most manufacturers have developed inlay-specific devices to facilitate the introduction and informahealthcare.com
Clinicians have used a variety of stromal pocket dimensions and depths for placement of the Kamra inlay. In a large study of 507 eyes, Waring reported placing the inlay in a lamellar dissection or pocket with a minimum depth of 180 mm that was created either with a femtosecond laser or with a microkeratome [21]. Tomita et al., in a study involving 223 eyes, placed the inlay in a femtosecond laser created pocket with a channel width of 5 mm and a depth of 200 or 250 mm [22]. In a similarly large study of 180 eyes, where Kamra inlay was combined with LASIK, the inlay was placed under a flap that was created with femtosecond laser at an intended depth of 200 mm [24]. A femtosecond laser was also used by Seyeddain et al. to create a 9.0 mm flap 343
344
39
32
24
64
Yilmaz et al. (2008)
Seyeddain et al. (2012)
Dexl et al. (2012)
Tomita et al. (2012)‡
16
20
From 20/132 to 20/21
Before surgery 95% read 0.6 logMAR (20/79.6) After surgery all eyes read 0.2 logMAR(20/31.7) or better
From J10 (20/77.3) to J4 (20/38.7)
From 0.90 (20/158.9) to 0.18 logMAR (20/30.3) in hyperopic group From 0.70 (20/100.2) to 0.10 logMAR (20/25.2) in emmetropic group From 0.31 (20/40.8) to 0.12 logMAR (20/26.4) in myopic group
From 0.33 (20/43) to 0.23 logMAR (20/34)
From J7/J8 (20/63) to J1 (20/25.7)
From J6 (20/51.7) to J1 (20/25.7)
From J8 (20/64.3) to J2 (20/32.3)
From J8 to J2–J3; that is, from 0.482 (20/64.3) to 0.139 logMAR (20/27.5)
Mean UNVA in inlay eye
20/107 to 20/26
NA
NA
NA
NA
From 20/40 to 20/25
NA
NA
From 20/35 to 20/26 From 0.239 to 0.139 logMAR
Mean UIVA in inlay eye
All patients satisfied or very satisfied with near vision 79% satisfied or very satisfied with intermediate vision
95% patients satisfied or very satisfied with near and intermediate vision
Satisfaction score increased for reading newspaper from 3 to approximately 5, for reading computer screen from 3 to 4.5†
Satisfaction score increased for reading newspaper from 1.6 to 5.2 in hyperopic group, from 2.0 to 5.6 in emmetropic group, from 4.9 to 5.2 in myopic group†
Satisfaction score increased for reading newspaper from 2 to 5, for reading computer screen from 3 to 5†
NA
NA
Satisfaction score for reading newspaper increased from 3.3 to 5.0, reading computer screen from 2.8 to 5.6†
NA
Questionnaire-based surveys
§
‡
1–7 scale. Combined with LASIK. InVue inlay. ¶ 1 never, 4 always. LASIK: Laser-assisted in situ keratomileusis; UNVA: Uncorrected near visual acuity; UIVA: Uncorrected intermediate visual acuity.
†
Chayet et al. (2013)‡
Garza et al. (2013)
Raindrop
13
223
Tomita et al. (2013)
Huseynova et al. (2014)
507
Eyes
Waring G (2011)
Kamra
Author (year)
Table 1. Efficacy summary table.
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12
12
3
6
24
36
12
6
18
Follow-up (months)
[28]
[16]
[33]
[24]
[32]
[25]
[27]
[22]
[21]
Ref.
Review Konstantopoulos & Mehta
Expert Rev. Med. Devices 12(3), (2015)
Follow-up (months)
12
Questionnaire-based surveys
81.25% patients reported near vision as excellent 93.75% independent of near spectacles
with a depth of 170 mm [25], whereas by Dexl et al. to create a pocket with a diameter of 4.4 mm at a depth of 230 mm [26]. In an older study involving 39 patients, a mechanical microkeratome was used to create a flap with a depth of 170 mm [27].
[31]
[30]
Review
12
Revision Optics Inc. recommends that the Raindrop inlay be placed at a minimum depth of 150 mm with a minimum residual stromal bed thickness of 300 mm. A preoperative central corneal thickness of 500–600 mm and a corneal flap thickness approximately one-third of the central corneal thickness are advised. It is recommended that a dry technique be used and the inlay be aligned over the centre of the light-constricted pupil [17]. Garza and colleagues placed the Raindrop inlay under a corneal flap; a femtosecond laser was used to create the flap with a diameter greater than 8 mm and a depth of 150 mm [16]. In a study that combined hyperopic LASIK with inlay implantation, a femtosecond laser flap with a diameter larger than 8 mm and a depth of 130–150 mm was used [28].
§
‡
1–7 scale. Combined with LASIK. InVue inlay. ¶ 1 never, 4 always. LASIK: Laser-assisted in situ keratomileusis; UNVA: Uncorrected near visual acuity; UIVA: Uncorrected intermediate visual acuity.
Flexivue Microlens
†
NA 52 Baily et al. (2014)
From 0.78 (20/120.5) to 0.44 (20/55.1) logMAR
Newspaper read well or very well by 57.5% of patients sms/email read well or very well by 65% of patients
12 Mean score for use of reading glasses 1.24¶ NA
Icolens
45
From 20/50 or worse in all eyes to 20/32 or better in 98%
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Bouzoukis et al. (2012)§
NA Limnopoulou et al. (2013)
Flexivue Microlens
47
From 0.68 (20/100) to 0.14 (20/25) logMAR
Mean UNVA in inlay eye
Mean UIVA in inlay eye
Raindrop
Eyes Author (year)
Table 1. Efficacy summary table (cont.).
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Ref.
[18]
Surgical compensation of presbyopia with corneal inlays
Malandrini and colleagues placed the Flexivue Microlens in a femtosecond laser created stromal pocket that had a diameter of 9–9.5 mm and depth of 300 mm [29]. Limnopoulou et al. used a femtosecond laser created stromal pocket with a width of 4.20 mm and depth of 280 mm for inlay placement [18]. Icolens
Bouzoukis et al. used a mechanical microkeratome to create a stromal pocket for implantation of the inlay, when it was marketed as InVue (Biovision AG). The pocket had a diameter of 3.5 mm and a depth of three-fifths of the total corneal thickness [30]. In a more recent study with the Icolens inlay, Baily and colleagues used femtosecond laser to create a pocket with a diameter of 3.6 mm and a depth of 290 mm [31]. Clinical efficacy
The near vision improvement achieved by each inlay is discussed below and the data are summarised in TABLE 1 & FIGURE 4. Kamra
In 2011, George Waring IV reported on the largest study to date on the use of the Kamra inlay; 507 naturally emmetropic eyes had implantation in 24 centres worldwide. At 12 months follow-up, 417 eyes were reviewed, but at 18 months only 99 eyes had follow-up. Mean uncorrected near visual acuity (UNVA) improved significantly from J8 (0.482 ± 0.925 logMAR; 20/64.3) before surgery to better than J3 (0.185 ± 0.848 logMAR; 20/30.6) at 1 month and between J2 and J3 (0.139 ± 0.851 logMAR; 20/27.5) at 18 months. Uncorrected intermediate visual acuity (UIVA) also improved significantly from 20/35 (0.239 ± 0.837 logMAR) before surgery to 20/26 (0.139 ± 0853 logMAR) at 18 months [21]. Tomita and colleagues investigated implantation of the latest Kamra inlay (ACI 7000 PDT) in 223 presbyopic eyes that were 345
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Pre-implantation Post-implantation
LogMAR unaided near visual acuity
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1.000
0.800
0.600
0.400
0.200
0.000 Kamra
Raindrop
Flexivue Inlay
Icolens
Figure 4. The graph summarises the unaided near visual acuity outcomes. The bars for Kamra represent the mean ± 1 standard deviation of six studies [21,22,25,27,32,33]. The bars for Raindrop, Flexivue and Icolens show the outcome of one study for each inlay [18,28,31] respectively.
emmetropic following myopic or hyperopic LASIK. Patients were followed up for 6 months. Mean UNVA in the inlayimplanted eyes improved significantly from J8 (20/64.3) before surgery to J2 (20/32.3) at 6 months. Mean binocular UNVA also improved from J6 (20/51.7) to J2 (20/32.3). Patient satisfaction and near activities were also assessed with a questionnaire and found to be significantly better following the inlay implantation [22]. Yilmaz et al. also reported a significant improvement in near vision 1 year following inlay implantation in emmetropic patients who had had previous LASIK for hyperopia. Mean UNVA improved from J6 (20/51.7) to J1(20/25.7). In this study, 27 of the 39 eyes had previous LASIK [27]. A smaller study of 32 naturally emmetropic presbyopes by Seyeddain et al., using the previous version Kamra inlay (ACI 7000), reported 3-year results. Mean UNVA improved from J7/J8 (20/63) before surgery to J1 (20/25.7) at 36 months. Mean binocular UNVA also improved significantly from J6 (20/51.7) to J1 (20/25.7). Eyes with an inlay had a significant improvement in mean UIVA from 20/40 preoperatively to 20/25 and mean binocular UIVA remained 20/20 throughout the follow-up [25]. In a study of 24 naturally emmetropic presbyopes by Dexl et al., the mean reading distance was shown to decrease significantly following inlay implantation from 46.7 cm before surgery to 39.5 cm at 24 months [32]. Patients reported significantly greater vision scores for near and intermediate tasks compared to before surgery, particularly when tasks were performed 346
in bright light. Mean reading acuity at best distance improved significantly from 0.33 logMAR (20/43) at baseline to 0.23 logMAR (approximately J3;20/34). An improvement of up to five lines occurred in 75.0% of patients, 20.8% had no gain in near vision and 4.2% had a loss of one line. Compared to the previous study by the same research group [25], near vision results appear worse. However, according to the authors, the previous study by Seyeddain et al. used a single optotype near reading chart, whereas the current study by Dexl et al. tested the ability to read sentences at a minimum reading speed. Tomita and colleagues evaluated the efficacy of Kamra inlay implantation with simultaneous LASIK in 64 patients. At 6 months, mean logMAR UNVA improved in the inlay eye by seven lines in hyperopic eyes, six lines in emmetropic eyes and two lines in myopic eyes [24]. In a small study of 13 eyes, the Kamra inlay was implanted in pseudophakic patients with an improvement in UNVA from J10 (20/77.3) to J4 (20/38.7). However, the follow-up period was limited to 3 months, and in 4 of the 13 patients, inlay implantation was combined with LASIK [33]. Raindrop
A smaller number of studies are available for the Raindrop inlay. In a study by Garza and colleagues, 20 emmetropic presbyopic patients had implantation of the Raindrop inlay and were investigated for 12 months following surgery. Before surgery, approximately 95% of eyes had UNVA of 0.6 logMAR (20/79.6) or better. All 19 inlay eyes that were available for examination at 12 months achieved UNVA of 0.2 logMAR (20/31.7) or better. Binocularly, mean UNVA was better than 0.10 logMAR (20/25.2 Snellen) at 12 months, and all patients achieved UNVA of 0.18 logMAR (20/30.3) or better. Patient satisfaction questionnaires showed that 95% of patients were satisfied or very satisfied with their near and intermediate vision, and all were satisfied or very satisfied with their distance vision. A slight increase in the ease of performing intermediate tasks and a substantial increase in the ability to perform near tasks compared to before surgery were reported [16]. In a second study on the Raindrop, Chayet et al. investigated combining inlay implantation with LASIK for hyperopic presbyopia in 16 eyes. LASIK treatment in the inlay eye was targeted for 0.00 to +0.50 D with zero cylinder, while the fellow eye for a 0.00 D outcome with zero cylinder. Mean Snellen UNVA improved significantly in the inlay eye from 20/132 preoperatively to 20/21 at 12 months; all eyes achieved 20/25 or better. Mean UIVA also improved significantly from 20/107 before surgery to 20/26 at 12 months. Binocular near and intermediate vision were also better; mean binocular UNVA and UIVA improved significantly from baseline and were 20/21 and 20/26, respectively, at 12 months. Patient satisfaction was high, as all patients reported being satisfied or very satisfied with their near, distance and overall vision. However, only 79% were satisfied or very satisfied with their intermediate vision. Patients also reported a substantial increase in the ease with which they performed near tasks after surgery and a smaller increase for intermediate tasks [28]. Expert Rev. Med. Devices 12(3), (2015)
Surgical compensation of presbyopia with corneal inlays
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Flexivue Microlens
Only one study has been published in the peer-review literature on the Flexivue Microlens. Limnopoulou et al. examined the 12-month visual outcomes in 47 emmetropic presbyopes who had the inlay implanted. Mean UNVA improved significantly from 0.68 logMAR (20/100) before surgery to 0.14 logMAR (20/25); UNVA was 20/32 or better in 75% of eyes. Binocular UNVA also improved significantly from 0.53 logMAR (20/60) to 0.13 logMAR (20/25). High patient satisfaction was reported, as at 12 months 81.25% of patients perceived their UNVA in the inlay eye as excellent and 93.75% were independent of near spectacles [18]. Icolens
Bouzoukis et al. investigated the outcomes of the InVue inlay, subsequently called Icolens, for the correction of emmetropic presbyopia in 45 patients. Twelve months after surgery, UNVA in the inlay eye and binocularly were 20/32 or better in 98% and 20/40 or better in 100% of patients. Using a scale of 1–4, patients graded the frequency of use of reading glasses with a mean score of 1.24, with 1 corresponding to never and 4 to always [30]. A more recent study by Baily et al. reported on the 12-month outcomes of the Icolens inlay in 52 emmetropic presbyopes. The mean UNVA in the surgical eye improved significantly from 0.78 logMAR (20/120.5) preoperatively to 0.44 logMAR (20/55.1) postoperatively, that is, from N18/N24 to N8. All patients achieved UNVA of N16 (20/103) or better. Mean binocular UNVA also improved significantly from N18 (20/116) preoperatively to N8 (20/51.7). The newspaper could be read well or very well without a reading aid by 57.5% of patients and sms/email by 65% of patients. All questioned patients responded yes or rather yes to whether they would have the procedure redone. However, the questionnaire results were based on 40 patients and may not include the 11 (21.1%) cases that had the inlay removed during the course of the study [31]. Safety
Cornea inlay implantation is overall a safe and reversible procedure. It is associated with a small loss of uncorrected distance visual acuity (UDVA) and, in some studies, corrected distance visual acuity (CDVA) in the implanted eyes, but the binocular vision tends to remain unaffected [16,18,22,25,26,30–33]. Reduction in contrast sensitivity [16,18,21,25,30], and haloes may develop following the procedure [16,18,22,29,31,33,34]. However, the vast majority of patients were happy with the improvement in near vision and outcome [16,18,22,28,30,31]. The data summarising the safety of the four inlays is presented in TABLE 2. Kamra
In the study of 507 eyes by Waring, UDVA decreased significantly in the implanted eye to 20/20 (0.011 ± 0.890 logMAR) at 18 months; although the author does not specify the exact preoperative UDVA, it was approximately 20/18 in the informahealthcare.com
Review
publication. There was also a significant reduction in mesopic and scotopic contrast sensitivity in the implanted eye, but the scores did remain within the range of the normal population. No explantation of inlays was reported [21]. In the Tomita et al. study on patients with previous LASIK, the mean UDVA decreased significantly from 20/16 to 20/20 following surgery. The mean binocular UDVA, however, did not change and remained stable at 20/12.5. The mean CDVA and corrected near visual acuity (CNVA) in the operated eye also remained unchanged at 20/12.5 and J1 (20/25.7) respectively. No patient lost two or more lines of CDVA and 14% lost one line; however, all eyes achieved a CDVA of 20/20 or better. No patient lost lines of CNVA. A small but significant increase in haloes and glare was reported following surgery, as the mean score of both increased from 0.4 to 1.4 with a score of 1 corresponding to very light symptoms and 7 to very heavy symptoms [22]. A further study also found that there was significant reduction in the mean UDVA from 20/16 to 20/20 in the implanted eyes [25]. At 36 months, all surgical eyes had UDVA of 20/32 or better, 87.5% achieved 20/25 or better and 66% 20/20 or better. A loss of two lines of UDVA compared to before surgery occurred in 12.5% of cases. The mean binocular UDVA, however, was not affected and remained 20/16. Similar to the above study by Waring [21], a significant reduction in mesopic and photopic contrast sensitivity was detected, although the values did remain within the normal range. No explantation was reported, but 6.25% of inlays had to be recentred 6 months after initial implantation [25]. Dexl et al. also found that the mean UDVA decreased significantly in the surgical eye from 20/16 to 20/20, with 8.3% of patients losing more than two lines of UDVA. However, the postoperative binocular UDVA and CDVA did not decrease and remained 20/16 at 24 months follow-up. Compared to before surgery, 12.5% of patients lost one line of CDVA in the surgical eye and 4.2% lost three lines of CDVA. No explantation or recentration was reported [32]. A study by Yilmaz et al., involving 39 patients, reported an explantation rate of 7.7%. The inlays were explanted due to extrusion associated with presumed herpetic keratitis and refractive shift. All three eyes returned to within 1 D of the preoperative refractive state for near and distance vision, with no loss of CDVA [27]. In a small study that was conducted in pseudophakic patients, 23.1% lost two lines and 7.7% one line of UDVA in the implanted eye. Loss of two and one lines of CDVA was reported in 15.4 and 7.7% of eyes, respectively. Mean UDVA, CDVA and CNVA remained stable and were 20/20, 20/16 and J1 (20/25.7), respectively, before and after Kamra implantation. Severe haloes, glare and night vision disturbances were reported by 15.4% of patients [33]. Experimental work suggests that the Kamra inlay may reduce retinal image brightness. In a modified Liou–Brennan schematic model eye, up to 60% of the light was blocked by the inlay, particularly in combinations of small pupil sizes and field angles of 20–40 [35]. Reduced retinal illumination can increase 347
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Table 2. Summary of safety data. Author (year)
Eyes Mean UDVA in inlay eye
Mean CDVA in inlay eye
Quality of vision in inlay eye
Reported complications
Ref.
Waring G (2011)
507
Reduced from 20/18 to 20/20
NA
Reduction in mesopic and scotopic contrast sensitivity
NA
[21]
Tomita et al. (2011)†
223
From 20/16 to 20/20
Unchanged at 20/12.5;14% lost 1 line
Increase in haloes and glare scores from 0.4 to 1.4‡
0
[22]
Yilmaz et al. (2008)
39
Unchanged at 20/20
2.6% lost 1 line; 0% lost 2 lines
NA
7.7% explanted
[27]
Seyeddain et al. (2012)
32
From 20/16 to 20/20; 12.5% lost two lines
28.3% lost 1 line; 3.1% lost >2 lines; 9.3% gained 1 line
Reduction in mesopic and photopic contrast sensitivity
6.3% recentered
[25]
Dexl et al. (2012)
24
From 20/16 to 20/20; 8.3% lost >2 lines
12.5% lost 1 line, 4.2% lost 3 lines
NA
0
[32]
Dexl et al. (2011)
32
NA
NA
56% corneal iron deposits
[41]
Dexl et al. (2011)
24
NA
NA
4.2% corneal iron deposition
[42]
Huseynova et al. (2014)
13
Unchanged at 20/20; 23.1% lost 2 lines; 7.7% lost 1 line
Unchanged at 20/16; 15.4% lost 2 lines; 7.7% lost 1 line
Haloes and glare reported by 15.4%
0
[33]
Garza et al. (2013)
20
Remained better than 0.2 logMAR (20/31.7)
Mean loss of 0.02 logMAR (1 letter); 0% lost two lines
Reduction in photopic and mesopic contrast sensitivity; 5% reported haloes
5% explanted 5% decentered and replaced
[16]
Chayet et al. (2013)§
16
From 20/68 to 20/31
Mean loss of 0.03 logMAR (less than one line); 7.1% lost two lines
No change in reported haloes and glare; mean halo score 0.2¶
6.3% explanted
[28]
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Kamra
Raindrop
Flexivue Microlens Limnopoulou et al. (2013)
47
From 0.06 (20/23) to 0.38 logMAR (20/48)
37% lost 1 line; 0% lost 2 lines
Reduced mesopic and photopic contrast sensitivity; haloes and glare reported by 12.5%
0% explanted or recentered
[18]
Malandrini et al. (2014)
52
NA
NA
NA
11.5% explanted
[29]
Bouzoukis et al. (2012)#
45
From 20/25 or better in all eyes to 20/40 or better in 93% of eyes
6.7% lost one line; 0% lost two lines
Reduced contrast sensitivity; increased higher-order aberrations; glare reported by 18%
0% explanted or recentered
[30]
Baily et al. (2014)
52
From 0.05 (20/22.4) to 0.22 logMAR (20/33.2)
77% lost ‡1 lines
Drive impairing glare reported by 15%
21.1% explanted
[31]
Icolens
†
prior LASIK. 1 light symptoms, 7 heavy symptoms. § combined with LASIK. ¶ 0 absent, 4 severe. # InVue inlay. CDVA: Corrected distance visual acuity; LASIK: Laser-assisted in situ keratomileusis; UDVA: Uncorrected distance visual acuity. ‡
348
Expert Rev. Med. Devices 12(3), (2015)
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Surgical compensation of presbyopia with corneal inlays
the visual latency in the eye with the smaller pupil, potentially inducing distortion of the path of moving objects, known as Pulfrich effect [36]. A study that used a binocular adaptive optics vision analyser found that a simulated small-aperture corneal inlay increased the depth of focus to the same extent as traditional monovision; however, both methods experienced a comparable reduction in binocular summation with respect to natural vision [37]. A similar simulation study found that small-aperture optics did not compromise stereoacuity under photopic conditions, as values of stereoacuity were similar to those attained under normal binocular vision [38]. Kamra implantation has been found with in vivo confocal microscopy to induce apoptotic stromal cell death and increased inflammatory cell infiltration at 48 h following surgery. The apoptosis and inflammation regressed over time, as by 6 weeks there was no difference between controls and implanted eyes [39]. However, another confocal microscopy study found that stromal keratocytes were present at a reduced density and also in a low-grade activation state 6 months following implantation. Interestingly, increased keratocyte activation correlated with poorer distance and near vision [40]. Corneal iron deposits have been reported to occur following implantation of the original (ACI 7000) Kamra inlay [41]. These were detected in 56% of 32 eyes that were followed-up for 36 months. The deposits were diagnosed at a mean of 18 months post-implantation and most commonly had a ringshaped formation, complete or incomplete, at the outer border of the inlay. They did not affect vision adversely. In a followup study, the same research group investigated 24 patients who had had the new Kamra inlay (ACI 7000 PDT) and had completed 18 months follow-up [42]. Corneal iron deposition was observed in 4.2% of the 24 patients, whereas with the previous inlay design 31.3% of patients showed corneal iron deposition after 18 months. Good visual potential has been reported following the removal of the Kamra inlay. In a series of 10 cases, the most common reason for removal was subjective dissatisfaction in quality of vision with night glare, photophobia, haloes, starburst or blurry vision. Six months after inlay removal, mean CDVA was 0 logMAR (20/20); two eyes had gained one line of CDVA and five eyes had not experienced any change, whereas two eyes had lost one line and one eye had lost two lines of CDVA. In most cases, a trace of corneal haze was still detectable clinically by slit-lamp examination at 6 months [34]. Raindrop
In the study by Garza et al., involving 20 eyes, mean UDVA in the implanted eye remained better than 0.2 logMAR (20/31.7) at all postoperative visits; 85% of implanted eyes achieved UDVA of 0.22 logMAR (20/33.2) or better by the 1-week visit. Binocular UDVA was less affected, as it remained 0.01 logMAR (20/20.5) or better at all postoperative visits after the first month. At the 12-month visit, all patients achieved CDVA and CNVA of 0.05 logMAR (20/22.4) or better. On informahealthcare.com
Review
average, patients lost 0.02 logMAR (1 letter) CDVA and 0.02 logMAR CNVA. No eye lost two or more lines of CDVA or CNVA [16]. In the same study, a small reduction (
Surgical compensation of presbyopia with corneal inlays Expert Review of Medical Devices Downloaded from informahealthcare.com by Emory University on 08/14/15 For personal use only.
Expert Rev. Med. Devices 12(3), 341–352 (2015)
Aris Konstantopoulos*1,2 and Jodhbir S Mehta1–5 1 Tissue Engineering and Stem Cell Group, Singapore Eye Research Institute, 11 Third Hospital Avenue,169856, Singapore, Singapore 2 Singapore National Eye Centre, 11 Third Hospital Avenue, 168751, Singapore, Singapore 3 Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, 119228, Singapore, Singapore 4 Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore, Singapore 5 Department of Clinical Sciences, Duke-NUS Graduate Medical School, 8 College Road, 169857, Singapore, Singapore *Author for correspondence: Tel.: +65 632 245 65 Fax: +65 632 245 99 [email protected]
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Presbyopia, the physiological change in near vision that develops with ageing, gradually affects individuals older than 40 years and is a growing cause of visual disability due to ageing demographics of the global population. The routine use of computers and ‘smartphones’, combined with the affluence of the ‘baby boomers’ generation has set high standards for near vision correction. Corneal inlays are a relatively new treatment modality that is effective at compensating for presbyopia. The dimensions of these devices vary from 2 to 3.8 mm in diameter and 5 to 32 mm in thickness. They are implanted in the anterior corneal stroma of the non-dominant eye, most commonly, in a femtosecond laser created corneal pocket. They improve near vision by increasing the depth of focus, creating a hyper-prolate region of increased central cornea power or providing a refractive add power. This article reviews the literature on the efficacy and safety of corneal inlays. KEYWORDS: Flexivue microlens . Icolens . inlay . Kamra . presbyopia . Raindrop
Presbyopia is a physiological change in near vision that develops with ageing. It occurs due to a progressive reduction in the accommodative power of the crystalline lens and gradually affects individuals older than 40 years. [1]. Presbyopia is a growing cause of visual disability due to ageing of the population, especially in developed countries. [2]. It is expected that the global population with presbyopia will increase from 1.2 billion in 2010 to 1.8 billion by 2050 and in developed countries (Australia, New Zealand, North America, Europe and Japan) from 373 to 448 million [3]. The relatively good health and affluence of the ‘baby boomers’ generation, combined with high near vision requirements for use of computers and ‘smartphones’, are likely to place additional pressure on the ophthalmic community to provide solutions for spectacle independence. The vast majority of the population manages presbyopia by wearing spectacles with convex lenses. This has the disadvantage that objects are in sharp focus only at one predetermined distance, and the spectacles need to be removed for distance vision. Bifocal and varifocal spectacles can overcome this limitation, but emmetropic patients who have not used spectacles previously may be reluctant to wear
10.1586/17434440.2015.1007124
spectacles for near vision, especially socially. Ophthalmologists and the ophthalmic industry have, therefore, sought other solutions to overcome these limitations. Methods for spectacle-independent presbyopia correction include monovision, multifocal contact lenses, multifocal intraocular lenses, conductive keratoplasty and corneal laser surgery. Monovision, the state of the visual system where the one eye is rendered myopic, either with contact lenses or refractive surgery, and the other emmetropic, aims to provide good near vision in one eye while the fellow eye is used for distance activities. Disadvantages of monovision include reduced stereoacuity and binocular contrast sensitivity [4,5]. The main disadvantage of multifocal contact lenses is poor image quality of the focused image and simultaneous perception of a defocused ghost image that may be exacerbated by decentration of the contact lens or movement with blinking [6]. Multifocal intraocular lenses may also have similar dysphotopsia symptoms, including night glare and haloes, and reduced contrast sensitivity [7–9]. Conductive keratoplasty tends to regress postoperatively and can limit the quality of vision with induction of astigmatism and high-order aberrations [10,11].
2015 Informa UK Ltd
ISSN 1743-4440
341
Review
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Flexivue Microlens (Presbia Cooperatief U.A., Amsterdam, Netherlands) and the Icolens (Neoptics AG, Huenenberg, Switzerland). All the four devices have received CE certification for use in Europe; the Kamra Vision has also been recommended for US FDA approval.
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Design & properties
Figure 1. Appearance of the implanted Kamra inlay.
Corneal laser presbyopic correction can also have similar side effects, such as loss of distance visual acuity, haloes and glare [12–14]. In addition, the laser-induced corneal changes tend to be irreversible. Corneal inlays are a relatively new treatment option for presbyopia that is gaining increasing popularity. They involve an external eye procedure and have the potential for reversibility and future proofing should the refractive status or requirements change. The evolution in design and understanding of the optics, combined with the precision and safety of femtosecond laser technology, make corneal inlays a viable alternative for presbyopia correction. They aim to provide a good range of unaided near and intermediate vision with minimal reduction in unaided distance vision. Discussion
Currently, there are four corneal inlays available: the Kamra Vision (Acufocus Inc., Irvine, CA, USA), the Raindrop (ReVision Optics Inc., Lake Forest, CA, USA), the Presbia
The Kamra Vision, a small-aperture inlay, has been available the longest and is the most widely used. The current version (ACI 7000 PDT) is made of polyvinylidene fluoride and is 5 mm thick. It has a 3.8 mm diameter with a central 1.6 mm aperture that allows only central collinear light to reach the retina. The central aperture has 8400 laser-etched perforations with a randomised hole pattern, 5–11 mm in diameter. [15]. An implanted Kamra inlay is shown in FIGURE 1. The Raindrop, a space-occupying inlay, was developed in 2007 and was formerly called Vue+ and PresbyLens (ReVision Optics Inc.). It is made of a proprietary biocompatible hydrogel material and is 80% water. The inlay is approximately 10 mm thick at the periphery and 32 mm at the centre. In its most recent design, the diameter has been enlarged to 2 mm in order to expand the near optical zone [16,17]. FIGURE 2 shows an implanted Raindrop inlay. The Flexivue Microlens, a refractive inlay, is composed of a hydrophilic acrylic polymer, measuring 3 mm in diameter and 15–20 mm in thickness, depending on the additional refractive power. The design features a central 0.15 mm hole that allows oxygen and nutrients to diffuse freely through the cornea [18,19]. The Icolens, also a refractive inlay, is the most recent inlay in development and was formerly called InVue (Biovision AG, Bruggs, Switzerland). It is composed of hydrophilic acrylic hydrogel and has a diameter of 3 mm with a peripheral edge thickness less than 15 mm that depends on the strength of the presbyopic correction. Similar to the Flexivue Microlens, a central 0.15 mm hole is present for nutrient diffusion [20]. The design of the inlays is summarised schematically in FIGURE 3. Mode of action
Figure 2. High magnification photo of Raindrop inlay.
342
The Kamra inlay improves near vision by increasing the depth of focus. It uses the principle of small-aperture optics, with which smaller apertures produce a longer depth of focus. This allows the perception of reasonably sharp images for different distances with no need for a change in the power of the lens [21,22,15]. The Raindrop inlay reshapes the central anterior corneal surface, creating a hyper-prolate region of increased power for focusing on near and intermediate objects. The inlay itself is of neutral refractive power [17]. The Flexivue Microlens inlay provides a refractive add power for near. It has a bifocal design that provides separate distance and near focal points. The central zone is free of refractive power and serves the distance vision. The peripheral zone has a higher index of refraction than the cornea, generating add power that ranges from +1.25 to +3.00 D and can be customised to the patient in 0.25 D steps [18,19]. Expert Rev. Med. Devices 12(3), (2015)
Surgical compensation of presbyopia with corneal inlays
A
Review
B
8400 holes, 5−11 µm in diameter, randomly arranged
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Central 1.6 mm aperture
The inlay has no intrinsic refractive power
2 mm 3.8 mm C
D
Peripheral zone for near vision correction; power range from +1.25 to +3.00 diopters
Peripheral zone for near vision correction; power range +1.5 to +3.0 diopters
Central hole allows nutrient flow through the cornea
Central hole allows nutrient flow through the cornea Central zone for distance vision; power range –1.0 to +1.5 diopters
Central plano zone for distance vision 3 mm
3 mm
Figure 3. Schematic diagrams explaining the design and dimensions of the inlays. (A) the Kamra, (B) the Raindrop, (C) the Flexivue Microlens and (D) the Icolens inlays.
The Icolens also has a bifocal design with a central zone for distance correction that ranges from –1.0 to +1.5 D, and a peripheral refractive power add that ranges from +1.5 to +3.0 D in 0.5 D steps [23]. The inlay may potentially be replaced as the accommodative reserve and refractive status of the patient change with age.
placement of the inlay. Centration of the inlay is crucial for optimal function, and it is recommended that the inlay be aligned with the pupil centre or the visual axis (line of sight). At the end of the procedure, irrigation of the stromal bed should be avoided in order to avoid inlay movement and decentration. Kamra
Surgical implantation
Inlays are placed in the non-dominant eye of the patient. Initially, they were placed under a stromal flap, similar to that used for laser-assisted in situ keratomileusis (LASIK). More recently, the use of femtosecond lasers has facilitated the placement within a corneal pocket. The depth of the flap or pocket, usually between 150 and 200 mm, depends on the inlay and its mode of action. For example, the space-occupying Raindrop inlay needs to be placed relatively close to the corneal surface, as it exerts its refractive effect by increasing the curvature of the corneal surface and, thus, the refractive power. Most manufacturers have developed inlay-specific devices to facilitate the introduction and informahealthcare.com
Clinicians have used a variety of stromal pocket dimensions and depths for placement of the Kamra inlay. In a large study of 507 eyes, Waring reported placing the inlay in a lamellar dissection or pocket with a minimum depth of 180 mm that was created either with a femtosecond laser or with a microkeratome [21]. Tomita et al., in a study involving 223 eyes, placed the inlay in a femtosecond laser created pocket with a channel width of 5 mm and a depth of 200 or 250 mm [22]. In a similarly large study of 180 eyes, where Kamra inlay was combined with LASIK, the inlay was placed under a flap that was created with femtosecond laser at an intended depth of 200 mm [24]. A femtosecond laser was also used by Seyeddain et al. to create a 9.0 mm flap 343
344
39
32
24
64
Yilmaz et al. (2008)
Seyeddain et al. (2012)
Dexl et al. (2012)
Tomita et al. (2012)‡
16
20
From 20/132 to 20/21
Before surgery 95% read 0.6 logMAR (20/79.6) After surgery all eyes read 0.2 logMAR(20/31.7) or better
From J10 (20/77.3) to J4 (20/38.7)
From 0.90 (20/158.9) to 0.18 logMAR (20/30.3) in hyperopic group From 0.70 (20/100.2) to 0.10 logMAR (20/25.2) in emmetropic group From 0.31 (20/40.8) to 0.12 logMAR (20/26.4) in myopic group
From 0.33 (20/43) to 0.23 logMAR (20/34)
From J7/J8 (20/63) to J1 (20/25.7)
From J6 (20/51.7) to J1 (20/25.7)
From J8 (20/64.3) to J2 (20/32.3)
From J8 to J2–J3; that is, from 0.482 (20/64.3) to 0.139 logMAR (20/27.5)
Mean UNVA in inlay eye
20/107 to 20/26
NA
NA
NA
NA
From 20/40 to 20/25
NA
NA
From 20/35 to 20/26 From 0.239 to 0.139 logMAR
Mean UIVA in inlay eye
All patients satisfied or very satisfied with near vision 79% satisfied or very satisfied with intermediate vision
95% patients satisfied or very satisfied with near and intermediate vision
Satisfaction score increased for reading newspaper from 3 to approximately 5, for reading computer screen from 3 to 4.5†
Satisfaction score increased for reading newspaper from 1.6 to 5.2 in hyperopic group, from 2.0 to 5.6 in emmetropic group, from 4.9 to 5.2 in myopic group†
Satisfaction score increased for reading newspaper from 2 to 5, for reading computer screen from 3 to 5†
NA
NA
Satisfaction score for reading newspaper increased from 3.3 to 5.0, reading computer screen from 2.8 to 5.6†
NA
Questionnaire-based surveys
§
‡
1–7 scale. Combined with LASIK. InVue inlay. ¶ 1 never, 4 always. LASIK: Laser-assisted in situ keratomileusis; UNVA: Uncorrected near visual acuity; UIVA: Uncorrected intermediate visual acuity.
†
Chayet et al. (2013)‡
Garza et al. (2013)
Raindrop
13
223
Tomita et al. (2013)
Huseynova et al. (2014)
507
Eyes
Waring G (2011)
Kamra
Author (year)
Table 1. Efficacy summary table.
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12
12
3
6
24
36
12
6
18
Follow-up (months)
[28]
[16]
[33]
[24]
[32]
[25]
[27]
[22]
[21]
Ref.
Review Konstantopoulos & Mehta
Expert Rev. Med. Devices 12(3), (2015)
Follow-up (months)
12
Questionnaire-based surveys
81.25% patients reported near vision as excellent 93.75% independent of near spectacles
with a depth of 170 mm [25], whereas by Dexl et al. to create a pocket with a diameter of 4.4 mm at a depth of 230 mm [26]. In an older study involving 39 patients, a mechanical microkeratome was used to create a flap with a depth of 170 mm [27].
[31]
[30]
Review
12
Revision Optics Inc. recommends that the Raindrop inlay be placed at a minimum depth of 150 mm with a minimum residual stromal bed thickness of 300 mm. A preoperative central corneal thickness of 500–600 mm and a corneal flap thickness approximately one-third of the central corneal thickness are advised. It is recommended that a dry technique be used and the inlay be aligned over the centre of the light-constricted pupil [17]. Garza and colleagues placed the Raindrop inlay under a corneal flap; a femtosecond laser was used to create the flap with a diameter greater than 8 mm and a depth of 150 mm [16]. In a study that combined hyperopic LASIK with inlay implantation, a femtosecond laser flap with a diameter larger than 8 mm and a depth of 130–150 mm was used [28].
§
‡
1–7 scale. Combined with LASIK. InVue inlay. ¶ 1 never, 4 always. LASIK: Laser-assisted in situ keratomileusis; UNVA: Uncorrected near visual acuity; UIVA: Uncorrected intermediate visual acuity.
Flexivue Microlens
†
NA 52 Baily et al. (2014)
From 0.78 (20/120.5) to 0.44 (20/55.1) logMAR
Newspaper read well or very well by 57.5% of patients sms/email read well or very well by 65% of patients
12 Mean score for use of reading glasses 1.24¶ NA
Icolens
45
From 20/50 or worse in all eyes to 20/32 or better in 98%
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Bouzoukis et al. (2012)§
NA Limnopoulou et al. (2013)
Flexivue Microlens
47
From 0.68 (20/100) to 0.14 (20/25) logMAR
Mean UNVA in inlay eye
Mean UIVA in inlay eye
Raindrop
Eyes Author (year)
Table 1. Efficacy summary table (cont.).
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Ref.
[18]
Surgical compensation of presbyopia with corneal inlays
Malandrini and colleagues placed the Flexivue Microlens in a femtosecond laser created stromal pocket that had a diameter of 9–9.5 mm and depth of 300 mm [29]. Limnopoulou et al. used a femtosecond laser created stromal pocket with a width of 4.20 mm and depth of 280 mm for inlay placement [18]. Icolens
Bouzoukis et al. used a mechanical microkeratome to create a stromal pocket for implantation of the inlay, when it was marketed as InVue (Biovision AG). The pocket had a diameter of 3.5 mm and a depth of three-fifths of the total corneal thickness [30]. In a more recent study with the Icolens inlay, Baily and colleagues used femtosecond laser to create a pocket with a diameter of 3.6 mm and a depth of 290 mm [31]. Clinical efficacy
The near vision improvement achieved by each inlay is discussed below and the data are summarised in TABLE 1 & FIGURE 4. Kamra
In 2011, George Waring IV reported on the largest study to date on the use of the Kamra inlay; 507 naturally emmetropic eyes had implantation in 24 centres worldwide. At 12 months follow-up, 417 eyes were reviewed, but at 18 months only 99 eyes had follow-up. Mean uncorrected near visual acuity (UNVA) improved significantly from J8 (0.482 ± 0.925 logMAR; 20/64.3) before surgery to better than J3 (0.185 ± 0.848 logMAR; 20/30.6) at 1 month and between J2 and J3 (0.139 ± 0.851 logMAR; 20/27.5) at 18 months. Uncorrected intermediate visual acuity (UIVA) also improved significantly from 20/35 (0.239 ± 0.837 logMAR) before surgery to 20/26 (0.139 ± 0853 logMAR) at 18 months [21]. Tomita and colleagues investigated implantation of the latest Kamra inlay (ACI 7000 PDT) in 223 presbyopic eyes that were 345
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Konstantopoulos & Mehta
Pre-implantation Post-implantation
LogMAR unaided near visual acuity
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1.000
0.800
0.600
0.400
0.200
0.000 Kamra
Raindrop
Flexivue Inlay
Icolens
Figure 4. The graph summarises the unaided near visual acuity outcomes. The bars for Kamra represent the mean ± 1 standard deviation of six studies [21,22,25,27,32,33]. The bars for Raindrop, Flexivue and Icolens show the outcome of one study for each inlay [18,28,31] respectively.
emmetropic following myopic or hyperopic LASIK. Patients were followed up for 6 months. Mean UNVA in the inlayimplanted eyes improved significantly from J8 (20/64.3) before surgery to J2 (20/32.3) at 6 months. Mean binocular UNVA also improved from J6 (20/51.7) to J2 (20/32.3). Patient satisfaction and near activities were also assessed with a questionnaire and found to be significantly better following the inlay implantation [22]. Yilmaz et al. also reported a significant improvement in near vision 1 year following inlay implantation in emmetropic patients who had had previous LASIK for hyperopia. Mean UNVA improved from J6 (20/51.7) to J1(20/25.7). In this study, 27 of the 39 eyes had previous LASIK [27]. A smaller study of 32 naturally emmetropic presbyopes by Seyeddain et al., using the previous version Kamra inlay (ACI 7000), reported 3-year results. Mean UNVA improved from J7/J8 (20/63) before surgery to J1 (20/25.7) at 36 months. Mean binocular UNVA also improved significantly from J6 (20/51.7) to J1 (20/25.7). Eyes with an inlay had a significant improvement in mean UIVA from 20/40 preoperatively to 20/25 and mean binocular UIVA remained 20/20 throughout the follow-up [25]. In a study of 24 naturally emmetropic presbyopes by Dexl et al., the mean reading distance was shown to decrease significantly following inlay implantation from 46.7 cm before surgery to 39.5 cm at 24 months [32]. Patients reported significantly greater vision scores for near and intermediate tasks compared to before surgery, particularly when tasks were performed 346
in bright light. Mean reading acuity at best distance improved significantly from 0.33 logMAR (20/43) at baseline to 0.23 logMAR (approximately J3;20/34). An improvement of up to five lines occurred in 75.0% of patients, 20.8% had no gain in near vision and 4.2% had a loss of one line. Compared to the previous study by the same research group [25], near vision results appear worse. However, according to the authors, the previous study by Seyeddain et al. used a single optotype near reading chart, whereas the current study by Dexl et al. tested the ability to read sentences at a minimum reading speed. Tomita and colleagues evaluated the efficacy of Kamra inlay implantation with simultaneous LASIK in 64 patients. At 6 months, mean logMAR UNVA improved in the inlay eye by seven lines in hyperopic eyes, six lines in emmetropic eyes and two lines in myopic eyes [24]. In a small study of 13 eyes, the Kamra inlay was implanted in pseudophakic patients with an improvement in UNVA from J10 (20/77.3) to J4 (20/38.7). However, the follow-up period was limited to 3 months, and in 4 of the 13 patients, inlay implantation was combined with LASIK [33]. Raindrop
A smaller number of studies are available for the Raindrop inlay. In a study by Garza and colleagues, 20 emmetropic presbyopic patients had implantation of the Raindrop inlay and were investigated for 12 months following surgery. Before surgery, approximately 95% of eyes had UNVA of 0.6 logMAR (20/79.6) or better. All 19 inlay eyes that were available for examination at 12 months achieved UNVA of 0.2 logMAR (20/31.7) or better. Binocularly, mean UNVA was better than 0.10 logMAR (20/25.2 Snellen) at 12 months, and all patients achieved UNVA of 0.18 logMAR (20/30.3) or better. Patient satisfaction questionnaires showed that 95% of patients were satisfied or very satisfied with their near and intermediate vision, and all were satisfied or very satisfied with their distance vision. A slight increase in the ease of performing intermediate tasks and a substantial increase in the ability to perform near tasks compared to before surgery were reported [16]. In a second study on the Raindrop, Chayet et al. investigated combining inlay implantation with LASIK for hyperopic presbyopia in 16 eyes. LASIK treatment in the inlay eye was targeted for 0.00 to +0.50 D with zero cylinder, while the fellow eye for a 0.00 D outcome with zero cylinder. Mean Snellen UNVA improved significantly in the inlay eye from 20/132 preoperatively to 20/21 at 12 months; all eyes achieved 20/25 or better. Mean UIVA also improved significantly from 20/107 before surgery to 20/26 at 12 months. Binocular near and intermediate vision were also better; mean binocular UNVA and UIVA improved significantly from baseline and were 20/21 and 20/26, respectively, at 12 months. Patient satisfaction was high, as all patients reported being satisfied or very satisfied with their near, distance and overall vision. However, only 79% were satisfied or very satisfied with their intermediate vision. Patients also reported a substantial increase in the ease with which they performed near tasks after surgery and a smaller increase for intermediate tasks [28]. Expert Rev. Med. Devices 12(3), (2015)
Surgical compensation of presbyopia with corneal inlays
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Flexivue Microlens
Only one study has been published in the peer-review literature on the Flexivue Microlens. Limnopoulou et al. examined the 12-month visual outcomes in 47 emmetropic presbyopes who had the inlay implanted. Mean UNVA improved significantly from 0.68 logMAR (20/100) before surgery to 0.14 logMAR (20/25); UNVA was 20/32 or better in 75% of eyes. Binocular UNVA also improved significantly from 0.53 logMAR (20/60) to 0.13 logMAR (20/25). High patient satisfaction was reported, as at 12 months 81.25% of patients perceived their UNVA in the inlay eye as excellent and 93.75% were independent of near spectacles [18]. Icolens
Bouzoukis et al. investigated the outcomes of the InVue inlay, subsequently called Icolens, for the correction of emmetropic presbyopia in 45 patients. Twelve months after surgery, UNVA in the inlay eye and binocularly were 20/32 or better in 98% and 20/40 or better in 100% of patients. Using a scale of 1–4, patients graded the frequency of use of reading glasses with a mean score of 1.24, with 1 corresponding to never and 4 to always [30]. A more recent study by Baily et al. reported on the 12-month outcomes of the Icolens inlay in 52 emmetropic presbyopes. The mean UNVA in the surgical eye improved significantly from 0.78 logMAR (20/120.5) preoperatively to 0.44 logMAR (20/55.1) postoperatively, that is, from N18/N24 to N8. All patients achieved UNVA of N16 (20/103) or better. Mean binocular UNVA also improved significantly from N18 (20/116) preoperatively to N8 (20/51.7). The newspaper could be read well or very well without a reading aid by 57.5% of patients and sms/email by 65% of patients. All questioned patients responded yes or rather yes to whether they would have the procedure redone. However, the questionnaire results were based on 40 patients and may not include the 11 (21.1%) cases that had the inlay removed during the course of the study [31]. Safety
Cornea inlay implantation is overall a safe and reversible procedure. It is associated with a small loss of uncorrected distance visual acuity (UDVA) and, in some studies, corrected distance visual acuity (CDVA) in the implanted eyes, but the binocular vision tends to remain unaffected [16,18,22,25,26,30–33]. Reduction in contrast sensitivity [16,18,21,25,30], and haloes may develop following the procedure [16,18,22,29,31,33,34]. However, the vast majority of patients were happy with the improvement in near vision and outcome [16,18,22,28,30,31]. The data summarising the safety of the four inlays is presented in TABLE 2. Kamra
In the study of 507 eyes by Waring, UDVA decreased significantly in the implanted eye to 20/20 (0.011 ± 0.890 logMAR) at 18 months; although the author does not specify the exact preoperative UDVA, it was approximately 20/18 in the informahealthcare.com
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publication. There was also a significant reduction in mesopic and scotopic contrast sensitivity in the implanted eye, but the scores did remain within the range of the normal population. No explantation of inlays was reported [21]. In the Tomita et al. study on patients with previous LASIK, the mean UDVA decreased significantly from 20/16 to 20/20 following surgery. The mean binocular UDVA, however, did not change and remained stable at 20/12.5. The mean CDVA and corrected near visual acuity (CNVA) in the operated eye also remained unchanged at 20/12.5 and J1 (20/25.7) respectively. No patient lost two or more lines of CDVA and 14% lost one line; however, all eyes achieved a CDVA of 20/20 or better. No patient lost lines of CNVA. A small but significant increase in haloes and glare was reported following surgery, as the mean score of both increased from 0.4 to 1.4 with a score of 1 corresponding to very light symptoms and 7 to very heavy symptoms [22]. A further study also found that there was significant reduction in the mean UDVA from 20/16 to 20/20 in the implanted eyes [25]. At 36 months, all surgical eyes had UDVA of 20/32 or better, 87.5% achieved 20/25 or better and 66% 20/20 or better. A loss of two lines of UDVA compared to before surgery occurred in 12.5% of cases. The mean binocular UDVA, however, was not affected and remained 20/16. Similar to the above study by Waring [21], a significant reduction in mesopic and photopic contrast sensitivity was detected, although the values did remain within the normal range. No explantation was reported, but 6.25% of inlays had to be recentred 6 months after initial implantation [25]. Dexl et al. also found that the mean UDVA decreased significantly in the surgical eye from 20/16 to 20/20, with 8.3% of patients losing more than two lines of UDVA. However, the postoperative binocular UDVA and CDVA did not decrease and remained 20/16 at 24 months follow-up. Compared to before surgery, 12.5% of patients lost one line of CDVA in the surgical eye and 4.2% lost three lines of CDVA. No explantation or recentration was reported [32]. A study by Yilmaz et al., involving 39 patients, reported an explantation rate of 7.7%. The inlays were explanted due to extrusion associated with presumed herpetic keratitis and refractive shift. All three eyes returned to within 1 D of the preoperative refractive state for near and distance vision, with no loss of CDVA [27]. In a small study that was conducted in pseudophakic patients, 23.1% lost two lines and 7.7% one line of UDVA in the implanted eye. Loss of two and one lines of CDVA was reported in 15.4 and 7.7% of eyes, respectively. Mean UDVA, CDVA and CNVA remained stable and were 20/20, 20/16 and J1 (20/25.7), respectively, before and after Kamra implantation. Severe haloes, glare and night vision disturbances were reported by 15.4% of patients [33]. Experimental work suggests that the Kamra inlay may reduce retinal image brightness. In a modified Liou–Brennan schematic model eye, up to 60% of the light was blocked by the inlay, particularly in combinations of small pupil sizes and field angles of 20–40 [35]. Reduced retinal illumination can increase 347
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Table 2. Summary of safety data. Author (year)
Eyes Mean UDVA in inlay eye
Mean CDVA in inlay eye
Quality of vision in inlay eye
Reported complications
Ref.
Waring G (2011)
507
Reduced from 20/18 to 20/20
NA
Reduction in mesopic and scotopic contrast sensitivity
NA
[21]
Tomita et al. (2011)†
223
From 20/16 to 20/20
Unchanged at 20/12.5;14% lost 1 line
Increase in haloes and glare scores from 0.4 to 1.4‡
0
[22]
Yilmaz et al. (2008)
39
Unchanged at 20/20
2.6% lost 1 line; 0% lost 2 lines
NA
7.7% explanted
[27]
Seyeddain et al. (2012)
32
From 20/16 to 20/20; 12.5% lost two lines
28.3% lost 1 line; 3.1% lost >2 lines; 9.3% gained 1 line
Reduction in mesopic and photopic contrast sensitivity
6.3% recentered
[25]
Dexl et al. (2012)
24
From 20/16 to 20/20; 8.3% lost >2 lines
12.5% lost 1 line, 4.2% lost 3 lines
NA
0
[32]
Dexl et al. (2011)
32
NA
NA
56% corneal iron deposits
[41]
Dexl et al. (2011)
24
NA
NA
4.2% corneal iron deposition
[42]
Huseynova et al. (2014)
13
Unchanged at 20/20; 23.1% lost 2 lines; 7.7% lost 1 line
Unchanged at 20/16; 15.4% lost 2 lines; 7.7% lost 1 line
Haloes and glare reported by 15.4%
0
[33]
Garza et al. (2013)
20
Remained better than 0.2 logMAR (20/31.7)
Mean loss of 0.02 logMAR (1 letter); 0% lost two lines
Reduction in photopic and mesopic contrast sensitivity; 5% reported haloes
5% explanted 5% decentered and replaced
[16]
Chayet et al. (2013)§
16
From 20/68 to 20/31
Mean loss of 0.03 logMAR (less than one line); 7.1% lost two lines
No change in reported haloes and glare; mean halo score 0.2¶
6.3% explanted
[28]
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Kamra
Raindrop
Flexivue Microlens Limnopoulou et al. (2013)
47
From 0.06 (20/23) to 0.38 logMAR (20/48)
37% lost 1 line; 0% lost 2 lines
Reduced mesopic and photopic contrast sensitivity; haloes and glare reported by 12.5%
0% explanted or recentered
[18]
Malandrini et al. (2014)
52
NA
NA
NA
11.5% explanted
[29]
Bouzoukis et al. (2012)#
45
From 20/25 or better in all eyes to 20/40 or better in 93% of eyes
6.7% lost one line; 0% lost two lines
Reduced contrast sensitivity; increased higher-order aberrations; glare reported by 18%
0% explanted or recentered
[30]
Baily et al. (2014)
52
From 0.05 (20/22.4) to 0.22 logMAR (20/33.2)
77% lost ‡1 lines
Drive impairing glare reported by 15%
21.1% explanted
[31]
Icolens
†
prior LASIK. 1 light symptoms, 7 heavy symptoms. § combined with LASIK. ¶ 0 absent, 4 severe. # InVue inlay. CDVA: Corrected distance visual acuity; LASIK: Laser-assisted in situ keratomileusis; UDVA: Uncorrected distance visual acuity. ‡
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Surgical compensation of presbyopia with corneal inlays
the visual latency in the eye with the smaller pupil, potentially inducing distortion of the path of moving objects, known as Pulfrich effect [36]. A study that used a binocular adaptive optics vision analyser found that a simulated small-aperture corneal inlay increased the depth of focus to the same extent as traditional monovision; however, both methods experienced a comparable reduction in binocular summation with respect to natural vision [37]. A similar simulation study found that small-aperture optics did not compromise stereoacuity under photopic conditions, as values of stereoacuity were similar to those attained under normal binocular vision [38]. Kamra implantation has been found with in vivo confocal microscopy to induce apoptotic stromal cell death and increased inflammatory cell infiltration at 48 h following surgery. The apoptosis and inflammation regressed over time, as by 6 weeks there was no difference between controls and implanted eyes [39]. However, another confocal microscopy study found that stromal keratocytes were present at a reduced density and also in a low-grade activation state 6 months following implantation. Interestingly, increased keratocyte activation correlated with poorer distance and near vision [40]. Corneal iron deposits have been reported to occur following implantation of the original (ACI 7000) Kamra inlay [41]. These were detected in 56% of 32 eyes that were followed-up for 36 months. The deposits were diagnosed at a mean of 18 months post-implantation and most commonly had a ringshaped formation, complete or incomplete, at the outer border of the inlay. They did not affect vision adversely. In a followup study, the same research group investigated 24 patients who had had the new Kamra inlay (ACI 7000 PDT) and had completed 18 months follow-up [42]. Corneal iron deposition was observed in 4.2% of the 24 patients, whereas with the previous inlay design 31.3% of patients showed corneal iron deposition after 18 months. Good visual potential has been reported following the removal of the Kamra inlay. In a series of 10 cases, the most common reason for removal was subjective dissatisfaction in quality of vision with night glare, photophobia, haloes, starburst or blurry vision. Six months after inlay removal, mean CDVA was 0 logMAR (20/20); two eyes had gained one line of CDVA and five eyes had not experienced any change, whereas two eyes had lost one line and one eye had lost two lines of CDVA. In most cases, a trace of corneal haze was still detectable clinically by slit-lamp examination at 6 months [34]. Raindrop
In the study by Garza et al., involving 20 eyes, mean UDVA in the implanted eye remained better than 0.2 logMAR (20/31.7) at all postoperative visits; 85% of implanted eyes achieved UDVA of 0.22 logMAR (20/33.2) or better by the 1-week visit. Binocular UDVA was less affected, as it remained 0.01 logMAR (20/20.5) or better at all postoperative visits after the first month. At the 12-month visit, all patients achieved CDVA and CNVA of 0.05 logMAR (20/22.4) or better. On informahealthcare.com
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average, patients lost 0.02 logMAR (1 letter) CDVA and 0.02 logMAR CNVA. No eye lost two or more lines of CDVA or CNVA [16]. In the same study, a small reduction (
