ARTICLE
Air reinjection and endothelial cell density in Descemet membrane endothelial keratoplasty: Five-year follow-up Matthew T. Feng, MD, Marianne O. Price, PhD, MBA, Jalee M. Miller, BS, Francis W. Price Jr, MD
PURPOSE: To evaluate 5-year endothelial cell loss after Descemet membrane endothelial keratoplasty (DMEK), compare it with reported rates for Descemet-stripping endothelial keratoplasty (DSEK) and penetrating keratoplasty (PKP), and investigate potential association between cell loss and air reinjection. SETTING: Price Vision Group, Indianapolis, Indiana, USA. DESIGN: Retrospective comparative case series. METHODS: Consecutive DMEK procedures performed between March 2008 and April 2013 were reviewed. The inclusion criterion was at least 6 months of follow-up. Endothelial cell density was recorded preoperatively and 1, 3, and 6 months and annually through 5 years postoperatively. Potential association between air reinjection and endothelial cell loss was evaluated by repeated measures analysis of variance. RESULTS: Of the 926 procedures performed, 673 eyes met the inclusion criterion. Indications for DMEK included Fuchs dystrophy (n Z 595), pseudophakic corneal edema (n Z 30), failed endothelial keratoplasty (n Z 39), and failed PKP (n Z 9). The median endothelial cell loss was 26% at 1 month, increasing to 39% at 5 years in cross-sectional and longitudinal analyses. Cell loss was similar in eyes with no (n Z 471) or 1 (n Z 155) air reinjection and significantly higher in eyes with 2 or more air reinjections (n Z 47, PZ.017). CONCLUSIONS: The median 5-year cell loss of 39% with DMEK compared favorably with prior reports of DSEK (53%) and PKP (70%) performed for similar indications. Similar to DSEK, most DMEK cell loss was associated with the surgical procedure itself; subsequent cell loss occurred at a slower rate than after PKP. Cell loss was not significantly increased in eyes with a single air reinjection. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2014; 40:1116–1121 Q 2014 ASCRS and ESCRS
Endothelial keratoplasty is the preferred treatment for endothelial dysfunction in the United States.1 Descemet-stripping automated endothelial keratoplasty (known as DSEK or DSAEK) is the most widely used method, but a growing number of surgeons are transitioning to Descemet membrane endothelial keratoplasty (DMEK). The key difference between DMEK and DSEK is the inclusion of supporting donor stromal tissue. The supporting tissue in DSEK facilitates handling for surgeons and improves adhesion at the expense of a larger incision size, increased higher-
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order aberrations, and a higher rejection rate in patients relative to DMEK.2–6 Most surgeons reinject air more frequently after DMEK than DSEK because DMEK does not adhere as readily and is more prone to partial edge detachments.1,7 We hypothesized that air reinjection could contribute to greater endothelial cell loss. The purpose of this study was threefold: to evaluate DMEK long-term (5-year) endothelial cell loss, to determine how it compares with what has been reported previously for DSEK and penetrating
0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2014.04.023
AIR REINJECTION AND ENDOTHELIAL CELL DENSITY IN DMEK
keratoplasty (PKP), and to assess the impact of air reinjection. PATIENTS AND METHODS In this study, data that were prospectively collected on a consecutive series of DMEK procedures performed between March 2008 and April 2013 were analyzed retrospectively. An independent review board approved the study, and all patients read and signed an informed consent document for the surgical procedure and for participation in the research. The criterion to be included in the study was having at least 6 months follow-up data available for analysis.
Surgical Technique The DMEK procedure was performed as previously described.8 In brief, a modified submerged cornea using a background-away technique was used to peel the endothelium and Descemet membrane from a donor cornea either the day of surgery or 1 to 2 days in advance.9,10 Patients received topical anesthesia and monitored intravenous sedation. Before an inferior peripheral iridotomy was made, dysfunctional endothelium and Descemet membrane were stripped from an area of the recipient cornea that approximately matched the planned graft diameter. An intraocular lens cartridge (ICL cartridge, Staar Surgical Co.; Softec, Lenstec Inc.; AT.Smart, Carl Zeiss Meditec AG; or Viscoject, Medicel AG) was used off-label to insert the donor tissue into the host anterior chamber. The donor tissue was uncurled with quick bursts of balanced salt solution; orientation was confirmed using a slit beam11 and the graft was secured in place with an 80% to 90% air fill. After the patient had remained supine for 1 hour, a slitlamp examination was performed and intraocular pressure (IOP) measured in the clinic to rule out pupil block before the patient was discharged. Patients were examined 1, 2, and 5 days after surgery for signs of graft detachment. If a partial graft detachment was affecting vision or appeared to be increasing in size, the patient was taken to a minor surgical procedure room and air was reinjected into the anterior chamber with a 30-gauge needle to achieve an 80% to 90% air fill. A slitlamp examination and IOP check were performed to ensure the peripheral iridotomy was patent before the patient was discharged.
Submitted: October 25, 2013. Final revision submitted: December 8, 2013. Accepted: December 9, 2013. From the Price Vision Group (Feng, F.W. Price) and the Cornea Research Foundation of America (M.O. Price, Miller), Indianapolis, Indiana, USA. Supported by the SCG Foundation, Thailand. Presented at the ASCRS Symposium on Cataract, IOL and Refractive Surgery, San Francisco, California, USA, April 2013. Corresponding author: Marianne O. Price, PhD, MBA, Cornea Research Foundation of America, 9002 North Meridian Street, Suite 212, Indianapolis, Indiana 46260, USA. E-mail: mprice@cornea. org.
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Outcome Measures and Statistical Analysis The primary outcome measure was endothelial cell density (ECD). Baseline donor ECD was measured by the provider eye bank (usually the Indiana Lions Eye and Tissue Transplant Bank, Indianapolis, Indiana, USA) using specular microscopy (Keratoanalyser EKA-10, Konan Medical). Postoperative ECD was measured at 1, 3, and 6 months and at 1, 2, 3, 4, and 5 years with specular microscopy (manual centers method, Noncon Robo, Konan Medical, or automated analysis, EM-3500, Tomey Corp.; these methods have been shown to give comparable results12). The secondary outcome measure was air reinjection status. Descriptive statistics were reported as a proportion or mean G standard deviation, as appropriate. The ECD and endothelial cell loss were not normally distributed, so the median and interquartile range were reported. The potential effect of air reinjection on endothelial cell loss over time was assessed by repeated measures analysis of variance. The analysis was performed using Statistical Analysis Software (SAS version 9.3, SAS Institute, Inc.); a P value less than 0.05 was considered statistically significant.
RESULTS Between March 2008 and April 2013, 926 consecutive DMEK procedures were performed. Table 1 shows the demographics of the 673 cases (74%) that met the inclusion criterion of at least 6 months of follow-up. Follow-up data for cross-sectional analysis of endothelial cell loss was available to 1 year for 548 eyes, to 2 years for 254 eyes, to 3 years for 98 eyes, to 4 years for 41 eyes, and to 5 years for 28 eyes. Table 2 shows the ECD and endothelial cell loss at 1, 3, and 6 months and 1, 2, 3, 4, and 5 years after DMEK. A longitudinal analysis of endothelial cell loss in the 28 eyes that had a full 5 years of followup is also shown in Table 2. In both the cross-sectional and longitudinal analyses, most endothelial cell loss occurred early and was captured at the 1-month examination (Table 2). The median endothelial cell loss was 26% to 27% at 1 month and increased to 39% over the following 5-year period. Based on air reinjection status, more endothelial cell loss occurred in eyes that had 2 or more air reinjections than in those with none or 1 air reinjection (PZ.017, Figure 1). DISCUSSION In cross-sectional and longitudinal analyses, we found that median endothelial cell loss after DMEK was 26% to 27% at 1 month, increasing to 39% at 5 years. The cumulative 5-year cell loss of 39% was substantially lower than the 5-year cell loss of 70% measured after PKP in the Specular Microscopy Ancillary Study of the Cornea Donor Study.13 Cell loss after DSEK has ranged from 13% to 50% at 6 months,14,15 15% to 61% at 1 year,14,16 23% to 49% at 2 years,17–19 and 33% to 60% at 3 years.20,21 In the present study,
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Table 1. Demographics of 673 Descemet membrane endothelial keratoplasty eyes with follow-up of 6 months or longer. Age (Y) Median Range Sex Male:female Ethnicity European African, Hispanic, Asian Indication for graft Fuchs dystrophy Pseudophakic corneal edema Failed endothelial keratoplasty Failed penetrating keratoplasty Air re-injection status None One Two or more
65 22, 94 266:407 656 (97.5%) 17 (2.5%) 595 (88.4%) 30 (4.5%) 39 (5.8%) 9 (1.3%) 471 (70%) 155 (23%) 47 (7%)
DMEK cell loss fell within the ranges reported between 6 months and 2 years after DSEK and was slightly below the range reported at 3 years after DSEK. Other centers have also found that DMEK cell loss falls within the range reported between 3 months and 2 years after DSEK.6,22 Currently, only 1 other center has reported 5-year DMEK cell loss; their mean cell loss was 55% in 9 eyes.23 We found that the 5-year cell loss in our earliest DMEK cases was less than that reported in our earliest DSEK cases (39% versus 53%, Figure 2).24 Advances in techniques and instrumentation subsequently reduced the early cell loss with DSEK14 and that may ultimately happen with DMEK as well. From a historical perspective, when DSEK was first introduced, there were concerns that early
postoperative ECD was inferior to that after PKP. These fears were allayed when it was shown that DSEK ECD followed a slower rate of decline, such that ECD after DSEK and PKP was comparable at 3 years,21 and by 5 years, the median ECD was higher after DSEK than after PKP.24 The present study suggests that the trend in ECD after DMEK is similar to that after DSEK, with the biggest drop occurring early, in association with the surgical procedure, followed by a slower rate of decline than occurs after PKP. Because DMEK edge detachments are currently more common than DSEK detachments, we also investigated the potential association between air reinjection and endothelial cell loss. We found that median endothelial cell loss was similar in eyes with none or 1 air reinjection but higher in eyes that had 2 or more air reinjections. We hesitate to say that multiple air reinjections caused endothelial cell loss because grafts with lower ECD to begin with (because of perioperative trauma from other means) may be more likely to detach and require more air. The lower the ECD, the less innate endothelial function there is within the graft to suction itself onto the recipient cornea and the more likely that such a graft will require multiple air reinjections. These are probably grafts with multiple areas of detachment and slower resolution of edema. A single detachment, on the other hand, may receive and typically resolves after only 1 air reinjection. The etiology of detachment in that situation is frequently unrelated to graft health, such as, but not limited to, smaller initial bubble size or patient noncompliance with positioning or restrictions (usually an inferior detachment), localized corneal steepening due to a tight suture in the main incision (usually temporal), and retained recipient Descemet membrane
Table 2. Cross-sectional and longitudinal analyses of endothelial cell density and endothelial cell loss after Descemet membrane endothelial keratoplasty. Longitudinal Analysis (N Z 28 eyes)
Cross-sectional Analysis Postoperative Time Point Baseline donor 1 month 3 months 6 months 1 year 2 years 3 years 4 years 5 years
Endothelial Cell Density, cells/mm2 Median (Interquartile Range)
Cell Loss, % Median (Interquartile Range)
Cell Loss, % Median (Interquartile Range)
2924 (2778, 3049) 2170 (1896, 2415) 2162 (1876, 2389) 2147 (1842, 2400) 2127 (1812, 2423) 2141 (1761, 2398) 2077 (1600, 2304) 1880 (1536, 2200) 1926 (1443, 2220)
d 26 (18, 35) 27 (19, 35) 27 (18, 37) 27 (19, 38) 28 (18, 42) 31 (22, 47) 36 (26, 52) 39 (26, 54)
d 27 (17, 32) 24 (17, 34) 26 (14, 31) 25 (20, 33) 25 (20, 37) 27 (21, 46) 33 (25, 46) 39 (26, 54)
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Figure 1. Median endothelial cell survival plotted as a function of time after DMEK. Data from eyes with no air reinjections is compared with data from eyes with 1, 2, or more air reinjections.
Figure 2. Median endothelial cell survival plotted as a function of time after surgery. The DMEK data are compared with published data from an initial series of DSEK cases performed at the same center and with data on PKP performed for similar indications in the Specular Microscopy Ancillary Study of the Cornea Donor Study.
(anywhere). These otherwise healthy grafts are therefore more similar to grafts that are never rebubbled, explaining their comparable median endothelial cell losses. In fact, some single detachments or small edge detachments can be watched and those grafts can do well without air reinjection. However, while grafts are partially detached, corneal edema diminishes our ability to measure cell density accurately or at all. Therefore, we cannot rule out another possibilitydthat rebubbling (further) traumatizes donor endothelial cells. A plausible mechanism is via damage from cavitation energy as multiple small air bubbles coalesce against the endothelium. If so, damage would be dose-dependent. It follows that multiple air reinjections, multiplied by the number of individual bubbles injected at each attempt, will increase the chances of significant cell loss. Our data could be interpreted as supporting such a phenomenon. Until it is confirmed or refuted by further study, the prudent course is to perform air injections and reinjections in such a way that only a single bubble is injected or enlarged. “Fish eggs” should be avoided. Regarding other factors that might influence endothelial cell loss, we have found that cell loss is comparable whether DMEK is performed alone or in combination with cataract extraction and IOL implantation.25 Most centers, including ours, prepare DMEK grafts using a direct peeling technique, which is associated with less cell loss than big bubble
separation methods.26 The volume of the donor tissue is 75% to 90% less with DMEK than with DSEK. While squeezing a DSEK graft through a 3.2 mm incision results in significantly more cell loss than using a 5.0 mm incision,21 in the present study the cell loss after DMEK performed with a 2.8 mm incision was similar to that after DSEK performed with a 5.0 mm incision. The ability to safely use a smaller incision with DMEK reduces the chance of inducing astigmatism and minimizes patients' activity restriction after surgery. Study limitations included the nonrandomized retrospective nature and the limited number of eyes with 5-year follow-up. Despite these limitations, we believe the data provide reassurance that DMEK is not inferior to DSEK or PKP in terms of intermediate to long-term endothelial cell loss. Previous studies have shown DMEK to be superior in the speed of visual rehabilitation, the final visual acuity attained, and the remarkably low rate of immunologic rejection episodes.1 We find that visual rehabilitation is so rapid after DMEK that we are now treating some fellow eyes within a 1- to 2-week timeframe, with or without combined cataract extraction.27 In summary, we found that median endothelial cell loss was 39% at 5 years after DMEK. This compared favorably with previously reported median 5-year cell loss of 53% with DSEK and 70% with PKP performed for endothelial dysfunction. As previously shown with DSEK, most of the cell loss after DMEK
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occurred early, probably during the surgical procedure, and subsequent cell loss occurred at a more moderate rate than seen after PKP. Descemet membrane endothelial keratoplasty does not adhere as readily as DSEK, so air is typically reinjected more frequently after DMEK to promote attachment. We found that a single air reinjection was not associated with substantially increased endothelial cell loss. WHAT WAS KNOWN The rate of endothelial cell loss over time differs between DSEK and PKP. Descemet-stripping endothelial keratoplasty generally has higher initial cell loss associated with the surgical procedure, although newer insertion techniques have substantially reduced this initial cell loss. Subsequent cell loss occurs at a lower rate with DSEK than with PKP; by 3 years the cumulative cell loss is similar for the 2 procedures and by 5 years, cell loss seems to be less with DSEK. The rate of air reinjection to ensure attachment is generally higher with DMEK than with DSEK and the potential effect on endothelial cell loss had not been determined.
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WHAT THIS PAPER ADDS
15.
The endothelial cell loss in the first 5 years after DMEK compared favorably with the loss after both DSEK and PKP.
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A single air reinjection did not significantly increase endothelial cell loss after DMEK.
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REFERENCES 1. Price MO, Price FW Jr. Descemet’s membrane endothelial keratoplasty surgery: update on the evidence and hurdles to acceptance. Curr Opin Ophthalmol 2013; 24:329–335 2. Melles GRJ, Ong TS, Ververs B, van der Wees J. Descemet membrane endothelial keratoplasty (DMEK). Cornea 2006; 25:987–990 3. Ham L, Dapena I, van Luijk C, van der Wees J, Melles GR. Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial dystrophy: review of the first 50 consecutive cases. Eye 2009; 23:1990–1998. Available at: http://www.nature.com/ eye/journal/v23/n10/pdf/eye2008393a.pdf. Accessed April 9, 2014 4. Guerra FP, Anshu A, Price MO, Giebel AW, Price FW. Descemet’s membrane endothelial keratoplasty; prospective study of 1-year visual outcomes, graft survival, and endothelial cell loss. Ophthalmology 2011; 118:2368–2373 5. Anshu A, Price MO, Price FW Jr. Risk of corneal transplant rejection significantly reduced with Descemet’s membrane endothelial keratoplasty. Ophthalmology 2012; 119:536–540 6. Tourtas T, Laaser K, Bachmann BO, Cursiefen C, Kruse FE. Descemet membrane endothelial keratoplasty versus Descemet
19.
20.
21.
22.
23.
stripping automated endothelial keratoplasty. Am J Ophthalmol 2012; 153:1082–1090 Dirisamer M, Dapena I, Ham L, van Dijk K, Oganes O, Frank LE, van der Wees J, Melles GR. Patterns of corneal endothelialization and corneal clearance after Descemet membrane endothelial keratoplasty for Fuchs endothelial dystrophy. Am J Ophthalmol 2011; 152:543–555 Price MO, Giebel AW, Fairchild KM, Price FW Jr. Descemet’s membrane endothelial keratoplasty; prospective multicenter study of visual and refractive outcomes and endothelial survival. Ophthalmology 2009; 116:2361–2368 Feng MT, Burkhart ZN, Price FW Jr, Price MO. Effect of donor preparation-to-use times on Descemet membrane endothelial keratoplasty outcomes. Cornea 2013; 32:1080–1082 Tenkman LR, Price FW, Price MO. Descemet membrane endothelial keratoplasty donor preparation: navigating challenges and improving efficiency. Cornea 2014; 33:319–325 Burkhart ZN, Feng MT, Price MO, Price FW. Handheld slit beam techniques to facilitate DMEK and DALK. Cornea 2013; 32:722–724 Price MO, Fairchild KM, Price FW Jr. Comparison of manual and automated endothelial cell density analysis in normal eyes and DSEK eyes. Cornea 2013; 32:567–573 Cornea Donor Study Investigator Group. Donor age and corneal endothelial cell loss 5 years after successful corneal transplantation; specular microscopy ancillary study results. Ophthalmology 2008; 115:627–632.e8 Khor W-B, Han S-B, Mehta JS, Tan DT. Descemet stripping automated endothelial keratoplasty with a donor insertion device: clinical results and complications in 100 eyes. Am J Ophthalmol 2013; 156:773–779 Koenig SB, Covert DJ. Early results of small-incision Descemet’s stripping and automated endothelial keratoplasty. Ophthalmology 2007; 114:221–226 Mearza AA, Qureshi MA, Rostron CK. Experience and 12-month results of Descemet-stripping endothelial keratoplasty (DSEK) with a small-incision technique. Cornea 2007; 26:279–283 Terry MA, Li J, Goshe J, Davis-Boozer D. Endothelial keratoplasty: the relationship between donor tissue size and donor endothelial survival. Ophthalmology 2011; 118:1944–1949 Busin M, Madi S, Santorum P, Scoria V, Beltz J. Ultrathin Descement’s stripping automated endothelial keratoplasty with the microkeratome double-pass technique; two-year outcomes. Ophthalmology 2013; 120:1186–1194 Bertelmann E, Pleyer U, Rieck P. Risk factors for endothelial cell loss post-keratoplasty. Acta Ophthalmol Scand 2006; 84:766–770. Available at: http://onlinelibrary.wiley.com/doi/10. 1111/j.1600-0420.2006.00726.x/pdf. Accessed April 9, 2014 Ang M, Mehta JS, Lim F, Bose S, Htoon HM, Tan D. Endothelial cell loss and graft survival after Descemet’s stripping automated endothelial keratoplasty and penetrating keratoplasty. Ophthalmology 2012; 119:2239–2244 Price MO, Gorovoy M, Price FW Jr, Benetz BA, Menegay HJ, Lass JH. Descemet’s stripping automated endothelial keratoplasty; three-year graft and endothelial cell survival compared with penetrating keratoplasty. Ophthalmology 2013; 120:246– 251 Ham L, van Luijk C, Dapena I, Wong TH, Birbal R, van der Wees J, Melles GR. Endothelial cell density after Descemet membrane endothelial keratoplasty: 1- to 2-year follow-up. Am J Ophthalmol 2009; 148:521–527 Baydoun L, Tong CN, Tse WW, Chi H, Parker J, Ham L, Melles GRJ. Endothelial cell density after Descemet membrane endothelial keratoplasty; 1- to 5-year follow-up. Am J Opthalmol 2012; 154:762–763
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24. Price MO, Fairchild KM, Price DA, Price FW Jr. Descemet’s stripping endothelial keratoplasty; five-year graft survival and endothelial cell loss. Ophthalmology 2011; 118:725–729 25. Chaurasia S, Price FW Jr, Gunderson L, Price MO. Descemet’s membrane endothelial keratoplasty; clinical results of single versus triple procedures (combined with cataract surgery). Ophthalmology 2014; 121:454–458 26. Yoeruek E, Bayyoud T, Hofmann J, Szurman P, BartzSchmidt K-U. Comparison of pneumatic dissection and forceps dissection in Descemet membrane endothelial keratoplasty: histological and ultrastructural findings. Cornea 2012; 31:920–925
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27. McKee Y, Price MO, Gunderson L, Price FW Jr. Rapid sequential endothelial keratoplasty with and without combined cataract extraction. J Cataract Refract Surg 2013; 39:1372–1376
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First author: Matthew T. Feng, MD Price Vision Group, Indianapolis, Indiana, USA
Air reinjection and endothelial cell density in Descemet membrane endothelial keratoplasty: Five-year follow-up Matthew T. Feng, MD, Marianne O. Price, PhD, MBA, Jalee M. Miller, BS, Francis W. Price Jr, MD
PURPOSE: To evaluate 5-year endothelial cell loss after Descemet membrane endothelial keratoplasty (DMEK), compare it with reported rates for Descemet-stripping endothelial keratoplasty (DSEK) and penetrating keratoplasty (PKP), and investigate potential association between cell loss and air reinjection. SETTING: Price Vision Group, Indianapolis, Indiana, USA. DESIGN: Retrospective comparative case series. METHODS: Consecutive DMEK procedures performed between March 2008 and April 2013 were reviewed. The inclusion criterion was at least 6 months of follow-up. Endothelial cell density was recorded preoperatively and 1, 3, and 6 months and annually through 5 years postoperatively. Potential association between air reinjection and endothelial cell loss was evaluated by repeated measures analysis of variance. RESULTS: Of the 926 procedures performed, 673 eyes met the inclusion criterion. Indications for DMEK included Fuchs dystrophy (n Z 595), pseudophakic corneal edema (n Z 30), failed endothelial keratoplasty (n Z 39), and failed PKP (n Z 9). The median endothelial cell loss was 26% at 1 month, increasing to 39% at 5 years in cross-sectional and longitudinal analyses. Cell loss was similar in eyes with no (n Z 471) or 1 (n Z 155) air reinjection and significantly higher in eyes with 2 or more air reinjections (n Z 47, PZ.017). CONCLUSIONS: The median 5-year cell loss of 39% with DMEK compared favorably with prior reports of DSEK (53%) and PKP (70%) performed for similar indications. Similar to DSEK, most DMEK cell loss was associated with the surgical procedure itself; subsequent cell loss occurred at a slower rate than after PKP. Cell loss was not significantly increased in eyes with a single air reinjection. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2014; 40:1116–1121 Q 2014 ASCRS and ESCRS
Endothelial keratoplasty is the preferred treatment for endothelial dysfunction in the United States.1 Descemet-stripping automated endothelial keratoplasty (known as DSEK or DSAEK) is the most widely used method, but a growing number of surgeons are transitioning to Descemet membrane endothelial keratoplasty (DMEK). The key difference between DMEK and DSEK is the inclusion of supporting donor stromal tissue. The supporting tissue in DSEK facilitates handling for surgeons and improves adhesion at the expense of a larger incision size, increased higher-
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order aberrations, and a higher rejection rate in patients relative to DMEK.2–6 Most surgeons reinject air more frequently after DMEK than DSEK because DMEK does not adhere as readily and is more prone to partial edge detachments.1,7 We hypothesized that air reinjection could contribute to greater endothelial cell loss. The purpose of this study was threefold: to evaluate DMEK long-term (5-year) endothelial cell loss, to determine how it compares with what has been reported previously for DSEK and penetrating
0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2014.04.023
AIR REINJECTION AND ENDOTHELIAL CELL DENSITY IN DMEK
keratoplasty (PKP), and to assess the impact of air reinjection. PATIENTS AND METHODS In this study, data that were prospectively collected on a consecutive series of DMEK procedures performed between March 2008 and April 2013 were analyzed retrospectively. An independent review board approved the study, and all patients read and signed an informed consent document for the surgical procedure and for participation in the research. The criterion to be included in the study was having at least 6 months follow-up data available for analysis.
Surgical Technique The DMEK procedure was performed as previously described.8 In brief, a modified submerged cornea using a background-away technique was used to peel the endothelium and Descemet membrane from a donor cornea either the day of surgery or 1 to 2 days in advance.9,10 Patients received topical anesthesia and monitored intravenous sedation. Before an inferior peripheral iridotomy was made, dysfunctional endothelium and Descemet membrane were stripped from an area of the recipient cornea that approximately matched the planned graft diameter. An intraocular lens cartridge (ICL cartridge, Staar Surgical Co.; Softec, Lenstec Inc.; AT.Smart, Carl Zeiss Meditec AG; or Viscoject, Medicel AG) was used off-label to insert the donor tissue into the host anterior chamber. The donor tissue was uncurled with quick bursts of balanced salt solution; orientation was confirmed using a slit beam11 and the graft was secured in place with an 80% to 90% air fill. After the patient had remained supine for 1 hour, a slitlamp examination was performed and intraocular pressure (IOP) measured in the clinic to rule out pupil block before the patient was discharged. Patients were examined 1, 2, and 5 days after surgery for signs of graft detachment. If a partial graft detachment was affecting vision or appeared to be increasing in size, the patient was taken to a minor surgical procedure room and air was reinjected into the anterior chamber with a 30-gauge needle to achieve an 80% to 90% air fill. A slitlamp examination and IOP check were performed to ensure the peripheral iridotomy was patent before the patient was discharged.
Submitted: October 25, 2013. Final revision submitted: December 8, 2013. Accepted: December 9, 2013. From the Price Vision Group (Feng, F.W. Price) and the Cornea Research Foundation of America (M.O. Price, Miller), Indianapolis, Indiana, USA. Supported by the SCG Foundation, Thailand. Presented at the ASCRS Symposium on Cataract, IOL and Refractive Surgery, San Francisco, California, USA, April 2013. Corresponding author: Marianne O. Price, PhD, MBA, Cornea Research Foundation of America, 9002 North Meridian Street, Suite 212, Indianapolis, Indiana 46260, USA. E-mail: mprice@cornea. org.
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Outcome Measures and Statistical Analysis The primary outcome measure was endothelial cell density (ECD). Baseline donor ECD was measured by the provider eye bank (usually the Indiana Lions Eye and Tissue Transplant Bank, Indianapolis, Indiana, USA) using specular microscopy (Keratoanalyser EKA-10, Konan Medical). Postoperative ECD was measured at 1, 3, and 6 months and at 1, 2, 3, 4, and 5 years with specular microscopy (manual centers method, Noncon Robo, Konan Medical, or automated analysis, EM-3500, Tomey Corp.; these methods have been shown to give comparable results12). The secondary outcome measure was air reinjection status. Descriptive statistics were reported as a proportion or mean G standard deviation, as appropriate. The ECD and endothelial cell loss were not normally distributed, so the median and interquartile range were reported. The potential effect of air reinjection on endothelial cell loss over time was assessed by repeated measures analysis of variance. The analysis was performed using Statistical Analysis Software (SAS version 9.3, SAS Institute, Inc.); a P value less than 0.05 was considered statistically significant.
RESULTS Between March 2008 and April 2013, 926 consecutive DMEK procedures were performed. Table 1 shows the demographics of the 673 cases (74%) that met the inclusion criterion of at least 6 months of follow-up. Follow-up data for cross-sectional analysis of endothelial cell loss was available to 1 year for 548 eyes, to 2 years for 254 eyes, to 3 years for 98 eyes, to 4 years for 41 eyes, and to 5 years for 28 eyes. Table 2 shows the ECD and endothelial cell loss at 1, 3, and 6 months and 1, 2, 3, 4, and 5 years after DMEK. A longitudinal analysis of endothelial cell loss in the 28 eyes that had a full 5 years of followup is also shown in Table 2. In both the cross-sectional and longitudinal analyses, most endothelial cell loss occurred early and was captured at the 1-month examination (Table 2). The median endothelial cell loss was 26% to 27% at 1 month and increased to 39% over the following 5-year period. Based on air reinjection status, more endothelial cell loss occurred in eyes that had 2 or more air reinjections than in those with none or 1 air reinjection (PZ.017, Figure 1). DISCUSSION In cross-sectional and longitudinal analyses, we found that median endothelial cell loss after DMEK was 26% to 27% at 1 month, increasing to 39% at 5 years. The cumulative 5-year cell loss of 39% was substantially lower than the 5-year cell loss of 70% measured after PKP in the Specular Microscopy Ancillary Study of the Cornea Donor Study.13 Cell loss after DSEK has ranged from 13% to 50% at 6 months,14,15 15% to 61% at 1 year,14,16 23% to 49% at 2 years,17–19 and 33% to 60% at 3 years.20,21 In the present study,
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Table 1. Demographics of 673 Descemet membrane endothelial keratoplasty eyes with follow-up of 6 months or longer. Age (Y) Median Range Sex Male:female Ethnicity European African, Hispanic, Asian Indication for graft Fuchs dystrophy Pseudophakic corneal edema Failed endothelial keratoplasty Failed penetrating keratoplasty Air re-injection status None One Two or more
65 22, 94 266:407 656 (97.5%) 17 (2.5%) 595 (88.4%) 30 (4.5%) 39 (5.8%) 9 (1.3%) 471 (70%) 155 (23%) 47 (7%)
DMEK cell loss fell within the ranges reported between 6 months and 2 years after DSEK and was slightly below the range reported at 3 years after DSEK. Other centers have also found that DMEK cell loss falls within the range reported between 3 months and 2 years after DSEK.6,22 Currently, only 1 other center has reported 5-year DMEK cell loss; their mean cell loss was 55% in 9 eyes.23 We found that the 5-year cell loss in our earliest DMEK cases was less than that reported in our earliest DSEK cases (39% versus 53%, Figure 2).24 Advances in techniques and instrumentation subsequently reduced the early cell loss with DSEK14 and that may ultimately happen with DMEK as well. From a historical perspective, when DSEK was first introduced, there were concerns that early
postoperative ECD was inferior to that after PKP. These fears were allayed when it was shown that DSEK ECD followed a slower rate of decline, such that ECD after DSEK and PKP was comparable at 3 years,21 and by 5 years, the median ECD was higher after DSEK than after PKP.24 The present study suggests that the trend in ECD after DMEK is similar to that after DSEK, with the biggest drop occurring early, in association with the surgical procedure, followed by a slower rate of decline than occurs after PKP. Because DMEK edge detachments are currently more common than DSEK detachments, we also investigated the potential association between air reinjection and endothelial cell loss. We found that median endothelial cell loss was similar in eyes with none or 1 air reinjection but higher in eyes that had 2 or more air reinjections. We hesitate to say that multiple air reinjections caused endothelial cell loss because grafts with lower ECD to begin with (because of perioperative trauma from other means) may be more likely to detach and require more air. The lower the ECD, the less innate endothelial function there is within the graft to suction itself onto the recipient cornea and the more likely that such a graft will require multiple air reinjections. These are probably grafts with multiple areas of detachment and slower resolution of edema. A single detachment, on the other hand, may receive and typically resolves after only 1 air reinjection. The etiology of detachment in that situation is frequently unrelated to graft health, such as, but not limited to, smaller initial bubble size or patient noncompliance with positioning or restrictions (usually an inferior detachment), localized corneal steepening due to a tight suture in the main incision (usually temporal), and retained recipient Descemet membrane
Table 2. Cross-sectional and longitudinal analyses of endothelial cell density and endothelial cell loss after Descemet membrane endothelial keratoplasty. Longitudinal Analysis (N Z 28 eyes)
Cross-sectional Analysis Postoperative Time Point Baseline donor 1 month 3 months 6 months 1 year 2 years 3 years 4 years 5 years
Endothelial Cell Density, cells/mm2 Median (Interquartile Range)
Cell Loss, % Median (Interquartile Range)
Cell Loss, % Median (Interquartile Range)
2924 (2778, 3049) 2170 (1896, 2415) 2162 (1876, 2389) 2147 (1842, 2400) 2127 (1812, 2423) 2141 (1761, 2398) 2077 (1600, 2304) 1880 (1536, 2200) 1926 (1443, 2220)
d 26 (18, 35) 27 (19, 35) 27 (18, 37) 27 (19, 38) 28 (18, 42) 31 (22, 47) 36 (26, 52) 39 (26, 54)
d 27 (17, 32) 24 (17, 34) 26 (14, 31) 25 (20, 33) 25 (20, 37) 27 (21, 46) 33 (25, 46) 39 (26, 54)
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Figure 1. Median endothelial cell survival plotted as a function of time after DMEK. Data from eyes with no air reinjections is compared with data from eyes with 1, 2, or more air reinjections.
Figure 2. Median endothelial cell survival plotted as a function of time after surgery. The DMEK data are compared with published data from an initial series of DSEK cases performed at the same center and with data on PKP performed for similar indications in the Specular Microscopy Ancillary Study of the Cornea Donor Study.
(anywhere). These otherwise healthy grafts are therefore more similar to grafts that are never rebubbled, explaining their comparable median endothelial cell losses. In fact, some single detachments or small edge detachments can be watched and those grafts can do well without air reinjection. However, while grafts are partially detached, corneal edema diminishes our ability to measure cell density accurately or at all. Therefore, we cannot rule out another possibilitydthat rebubbling (further) traumatizes donor endothelial cells. A plausible mechanism is via damage from cavitation energy as multiple small air bubbles coalesce against the endothelium. If so, damage would be dose-dependent. It follows that multiple air reinjections, multiplied by the number of individual bubbles injected at each attempt, will increase the chances of significant cell loss. Our data could be interpreted as supporting such a phenomenon. Until it is confirmed or refuted by further study, the prudent course is to perform air injections and reinjections in such a way that only a single bubble is injected or enlarged. “Fish eggs” should be avoided. Regarding other factors that might influence endothelial cell loss, we have found that cell loss is comparable whether DMEK is performed alone or in combination with cataract extraction and IOL implantation.25 Most centers, including ours, prepare DMEK grafts using a direct peeling technique, which is associated with less cell loss than big bubble
separation methods.26 The volume of the donor tissue is 75% to 90% less with DMEK than with DSEK. While squeezing a DSEK graft through a 3.2 mm incision results in significantly more cell loss than using a 5.0 mm incision,21 in the present study the cell loss after DMEK performed with a 2.8 mm incision was similar to that after DSEK performed with a 5.0 mm incision. The ability to safely use a smaller incision with DMEK reduces the chance of inducing astigmatism and minimizes patients' activity restriction after surgery. Study limitations included the nonrandomized retrospective nature and the limited number of eyes with 5-year follow-up. Despite these limitations, we believe the data provide reassurance that DMEK is not inferior to DSEK or PKP in terms of intermediate to long-term endothelial cell loss. Previous studies have shown DMEK to be superior in the speed of visual rehabilitation, the final visual acuity attained, and the remarkably low rate of immunologic rejection episodes.1 We find that visual rehabilitation is so rapid after DMEK that we are now treating some fellow eyes within a 1- to 2-week timeframe, with or without combined cataract extraction.27 In summary, we found that median endothelial cell loss was 39% at 5 years after DMEK. This compared favorably with previously reported median 5-year cell loss of 53% with DSEK and 70% with PKP performed for endothelial dysfunction. As previously shown with DSEK, most of the cell loss after DMEK
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occurred early, probably during the surgical procedure, and subsequent cell loss occurred at a more moderate rate than seen after PKP. Descemet membrane endothelial keratoplasty does not adhere as readily as DSEK, so air is typically reinjected more frequently after DMEK to promote attachment. We found that a single air reinjection was not associated with substantially increased endothelial cell loss. WHAT WAS KNOWN The rate of endothelial cell loss over time differs between DSEK and PKP. Descemet-stripping endothelial keratoplasty generally has higher initial cell loss associated with the surgical procedure, although newer insertion techniques have substantially reduced this initial cell loss. Subsequent cell loss occurs at a lower rate with DSEK than with PKP; by 3 years the cumulative cell loss is similar for the 2 procedures and by 5 years, cell loss seems to be less with DSEK. The rate of air reinjection to ensure attachment is generally higher with DMEK than with DSEK and the potential effect on endothelial cell loss had not been determined.
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WHAT THIS PAPER ADDS
15.
The endothelial cell loss in the first 5 years after DMEK compared favorably with the loss after both DSEK and PKP.
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A single air reinjection did not significantly increase endothelial cell loss after DMEK.
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REFERENCES 1. Price MO, Price FW Jr. Descemet’s membrane endothelial keratoplasty surgery: update on the evidence and hurdles to acceptance. Curr Opin Ophthalmol 2013; 24:329–335 2. Melles GRJ, Ong TS, Ververs B, van der Wees J. Descemet membrane endothelial keratoplasty (DMEK). Cornea 2006; 25:987–990 3. Ham L, Dapena I, van Luijk C, van der Wees J, Melles GR. Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial dystrophy: review of the first 50 consecutive cases. Eye 2009; 23:1990–1998. Available at: http://www.nature.com/ eye/journal/v23/n10/pdf/eye2008393a.pdf. Accessed April 9, 2014 4. Guerra FP, Anshu A, Price MO, Giebel AW, Price FW. Descemet’s membrane endothelial keratoplasty; prospective study of 1-year visual outcomes, graft survival, and endothelial cell loss. Ophthalmology 2011; 118:2368–2373 5. Anshu A, Price MO, Price FW Jr. Risk of corneal transplant rejection significantly reduced with Descemet’s membrane endothelial keratoplasty. Ophthalmology 2012; 119:536–540 6. Tourtas T, Laaser K, Bachmann BO, Cursiefen C, Kruse FE. Descemet membrane endothelial keratoplasty versus Descemet
19.
20.
21.
22.
23.
stripping automated endothelial keratoplasty. Am J Ophthalmol 2012; 153:1082–1090 Dirisamer M, Dapena I, Ham L, van Dijk K, Oganes O, Frank LE, van der Wees J, Melles GR. Patterns of corneal endothelialization and corneal clearance after Descemet membrane endothelial keratoplasty for Fuchs endothelial dystrophy. Am J Ophthalmol 2011; 152:543–555 Price MO, Giebel AW, Fairchild KM, Price FW Jr. Descemet’s membrane endothelial keratoplasty; prospective multicenter study of visual and refractive outcomes and endothelial survival. Ophthalmology 2009; 116:2361–2368 Feng MT, Burkhart ZN, Price FW Jr, Price MO. Effect of donor preparation-to-use times on Descemet membrane endothelial keratoplasty outcomes. Cornea 2013; 32:1080–1082 Tenkman LR, Price FW, Price MO. Descemet membrane endothelial keratoplasty donor preparation: navigating challenges and improving efficiency. Cornea 2014; 33:319–325 Burkhart ZN, Feng MT, Price MO, Price FW. Handheld slit beam techniques to facilitate DMEK and DALK. Cornea 2013; 32:722–724 Price MO, Fairchild KM, Price FW Jr. Comparison of manual and automated endothelial cell density analysis in normal eyes and DSEK eyes. Cornea 2013; 32:567–573 Cornea Donor Study Investigator Group. Donor age and corneal endothelial cell loss 5 years after successful corneal transplantation; specular microscopy ancillary study results. Ophthalmology 2008; 115:627–632.e8 Khor W-B, Han S-B, Mehta JS, Tan DT. Descemet stripping automated endothelial keratoplasty with a donor insertion device: clinical results and complications in 100 eyes. Am J Ophthalmol 2013; 156:773–779 Koenig SB, Covert DJ. Early results of small-incision Descemet’s stripping and automated endothelial keratoplasty. Ophthalmology 2007; 114:221–226 Mearza AA, Qureshi MA, Rostron CK. Experience and 12-month results of Descemet-stripping endothelial keratoplasty (DSEK) with a small-incision technique. Cornea 2007; 26:279–283 Terry MA, Li J, Goshe J, Davis-Boozer D. Endothelial keratoplasty: the relationship between donor tissue size and donor endothelial survival. Ophthalmology 2011; 118:1944–1949 Busin M, Madi S, Santorum P, Scoria V, Beltz J. Ultrathin Descement’s stripping automated endothelial keratoplasty with the microkeratome double-pass technique; two-year outcomes. Ophthalmology 2013; 120:1186–1194 Bertelmann E, Pleyer U, Rieck P. Risk factors for endothelial cell loss post-keratoplasty. Acta Ophthalmol Scand 2006; 84:766–770. Available at: http://onlinelibrary.wiley.com/doi/10. 1111/j.1600-0420.2006.00726.x/pdf. Accessed April 9, 2014 Ang M, Mehta JS, Lim F, Bose S, Htoon HM, Tan D. Endothelial cell loss and graft survival after Descemet’s stripping automated endothelial keratoplasty and penetrating keratoplasty. Ophthalmology 2012; 119:2239–2244 Price MO, Gorovoy M, Price FW Jr, Benetz BA, Menegay HJ, Lass JH. Descemet’s stripping automated endothelial keratoplasty; three-year graft and endothelial cell survival compared with penetrating keratoplasty. Ophthalmology 2013; 120:246– 251 Ham L, van Luijk C, Dapena I, Wong TH, Birbal R, van der Wees J, Melles GR. Endothelial cell density after Descemet membrane endothelial keratoplasty: 1- to 2-year follow-up. Am J Ophthalmol 2009; 148:521–527 Baydoun L, Tong CN, Tse WW, Chi H, Parker J, Ham L, Melles GRJ. Endothelial cell density after Descemet membrane endothelial keratoplasty; 1- to 5-year follow-up. Am J Opthalmol 2012; 154:762–763
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24. Price MO, Fairchild KM, Price DA, Price FW Jr. Descemet’s stripping endothelial keratoplasty; five-year graft survival and endothelial cell loss. Ophthalmology 2011; 118:725–729 25. Chaurasia S, Price FW Jr, Gunderson L, Price MO. Descemet’s membrane endothelial keratoplasty; clinical results of single versus triple procedures (combined with cataract surgery). Ophthalmology 2014; 121:454–458 26. Yoeruek E, Bayyoud T, Hofmann J, Szurman P, BartzSchmidt K-U. Comparison of pneumatic dissection and forceps dissection in Descemet membrane endothelial keratoplasty: histological and ultrastructural findings. Cornea 2012; 31:920–925
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27. McKee Y, Price MO, Gunderson L, Price FW Jr. Rapid sequential endothelial keratoplasty with and without combined cataract extraction. J Cataract Refract Surg 2013; 39:1372–1376
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First author: Matthew T. Feng, MD Price Vision Group, Indianapolis, Indiana, USA
