- Email: [email protected]
Graft detachment and rebubbling rate in Descemet membrane endothelial keratoplasty
Accepted Manuscript Graft detachment and re-bubbling rate in Descemet Membrane Endothelial Keratoplasty Mohit Parekh, Pia Leon, Alessandro Ruzza, Davide Borroni, Stefano Ferrari, Diego Ponzin, Vito Romano PII:
S0039-6257(16)30270-3
DOI:
10.1016/j.survophthal.2017.07.003
Reference:
SOP 6738
To appear in:
Survey of Ophthalmology
Received Date: 12 December 2016 Revised Date:
13 July 2017
Accepted Date: 17 July 2017
Please cite this article as: Parekh M, Leon P, Ruzza A, Borroni D, Ferrari S, Ponzin D, Romano V, Graft detachment and re-bubbling rate in Descemet Membrane Endothelial Keratoplasty, Survey of Ophthalmology (2017), doi: 10.1016/j.survophthal.2017.07.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Graft detachment and re-bubbling rate in Descemet Membrane Endothelial Keratoplasty Authors Mohit Parekh1,2, Pia Leon3,4,5, Alessandro Ruzza1, Davide Borroni6,7, Stefano Ferrari1, Diego Ponzin1 and Vito Romano8
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Affiliations 1 International Center for Ocular Physiopathology, The Veneto Eye Bank Foundation, Mestre, Venice, Italy 2 Department of Molecular Medicine, School of Biomedicine, University of Padova, Padova, Italy 3 Department of Ophthalmology, SS Giovanni and Paolo Hospital, Venice, Italy 4 Department of Ophthalmology, Villa Igea Hospital, Forli, Italy 5 Istituto Internazionale per la Ricerca e Formazione in Oftalmologia (IRFO), Forlì, Italy 6 Department of Ophthalmology, Riga Stradins University, Riga, Latvia 7 Department of Genetics, Riga Stradins University, Riga, Latvia 8 Moorfields Eye Hospital NHS Foundation Trust, London, UK
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Correspondence Mohit Parekh, PhD International Center for Ocular Physiopathology, The Veneto Eye Bank Foundation, Via Paccagnella 11, Padiglione Rama, 30174, Zelarino, Venice, Italy Tel: +390419656473 Fax: +390419656471 Email: [email protected]
Conflict of interest None of the authors have any potential conflict of interest
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Keywords DMEK, re-bubble rate, graft detachment
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Abstract Descemet Membrane Endothelial Keratoplasty (DMEK) is a selective replacement of dysfunctional endothelium with healthy donor Descemet’s membrane and endothelium. Although the donor preparation and surgical methods still remain a challenge, DMEK is gaining popularity in terms of early rehabilitation and visual outcomes. New and improved donor preparation techniques like prestripped DMEK tissues are taken up rapidly due to less manipulation that is required in the surgical theatre. Donor graft delivery in the recipient eye has also been improved due to new products like pre-stripped and pre-loaded membranes. As DMEK is at its budding stage, only early outcomes have been known so far. Early graft detachment, re-bubbling rates, primary failures are still being studied in DMEK. As there are different techniques that are currently used for preparation and injection of the graft, it becomes difficult to judge the results based on specific inclusion and exclusion criteria. Graft detachment and re-bubbling rates have been a huge challenge both during the surgery and also while reporting post-op data. This review highlights the importance of defining graft detachment and re-bubbling rates and therefore its surgical relevance, which may also have an impact on graft preparation and insertion techniques.
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Introduction Descemet Membrane Endothelial Keratoplasty (DMEK) has evolved over the years since Melles first introduced it in 2006 [30]. From the first studies published, DMEK has demonstrated excellent results in terms of visual recovery and a low rate of post-operative rejection [1]. Differently from Descemet's stripping automated endothelial keratoplasty (DSAEK), DMEK surgical procedure has highlighted significant difficulties due to the complexity of handling of the membrane, implanting the graft with the correct orientation and management of early post-operative complications that may occur such as the detachment of the graft. Various preparation and delivery techniques have been addressed so far, and there is still no standard technique available yet. At the Veneto Eye Bank Foundation (FBOV) in Italy, we have observed a constant increase in the requests of pre-cut DMEK tissues since 2014 [Figure 1]. DMEK is gaining popularity due to early rehabilitation and better visual outcome. Hence, its validation and standardization in terms of preparation, implantation and postoperative data collection and analysis becomes essential. In 2016 we published a ‘proof of concept’ paper for pre-loading DMEK tissues and introduced a modified design for a surgical device that could help to preserve, transport and transplant a DMEK graft with less manipulation [33]. Pre-loading DMEK, as we assume, will also be useful to standardize and validate DMEKs with advantages like reducing primary graft failure rates due to de-oriented grafts, lowering high surgical skills quotient, high rehabilitation rate with better visual acuity, low surgical time, costs and logistic requirements [33]. DMEK is also gaining popularity in the USA, as per the Eye Bank Association of America (EBAA) report of 2015, it was only performed in 748 cases in 2012, that increased to 1,522 cases in 2013 to 2,865 in 2014 and 4,694 cases in 2015A. With the new techniques in the field of DMEK preparation and shipment, it becomes essential to standardize the delivery technique followed by monitoring and reporting the post-op clinical data in a universally accepted format. This review describes the results achieved after DMEK highlighting the importance of determining, monitoring and reporting graft detachment and re-bubbling rates.
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Graft detachment It is important to monitor the behaviour during the course of visual rehabilitation and in the late post-operative period once the DMEK graft is implanted inside the recipient’s eye. The main and commonest post-operative complication following DMEK is the graft detachment. Usually DMEK complication rates have been reported separately by detachment rates. The graft detachment can be classified as complete or partial. ‘Complete’ - when all the donor tissue is completely detached from the recipient and floats in anterior chamber and, ‘Partial’ - when part of the donor is still attached to the recipient.
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Diagnosis It must be noted that all the reports that do not perform Anterior Segment Optical Coherence Tomography (AS-OCT) in the follow-up can mis-report a partial Descement membrane detachment (DMDs). If the cornea is relatively clear, the presence of DMDs can be easily detected by slit-lamp biomicroscopy. However, in the presence of severe corneal edema, AS-OCT remains the best imaging tool to determine the configuration (planar or scrolled) and location of DMD, which are vital for planning the surgical technique. Various classification systems have been proposed for DMD such as planar versus non-planar, scrolled versus non-scrolled, and peripheral versus peripheral with central involvement. Planar DMDs are those in which the separation between the stroma and DM is <1 mm, when the separation is >1 mm, the detachment is termed non-planar. DMDs that exhibit a 3
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Rate of graft detachment The initial reports of complete DMDs rate were 30% [1,31], partial graft detachment rates have been reported in around 62-63% cases [21,22,34]. However, with improved techniques and surgical experience, reported graft detachments have reduced to 34.6% in a multicentre study and as low as 4% in one case series [1]. Therefore, a learning curve for DMEK implantation including the postoperative care is highly relevant.
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Early management or prevention of primary graft failure Most lamellar keratoplasty complications that threaten graft survival occur in the earliest week or weeks post-transplant and in most cases are evident at the first post-operative clinical examination. The diagnosis and successful management of these early complications is crucial to long-term graft survival [18]. The size of descemetorhexis plays a role in order to reduce the peripheral postoperative oedema and to prevent DMDs. It has been reported that it should be slightly smaller compared to the diameter of the graft; the graft diameter (or chord length) in the eye differs from the diameter of the graft on the trephine block. This difference depends on the disparity between the radius of curvature of the trephine and that of the posterior cornea [40].
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DMEK graft is highly transparent and unless marked on its Descemet’s side, it becomes difficult to understand the orientation of the graft. Intra-operative and at first post operative control checking the marks allows the graft to be implanted with correct orientation and reduces any upside down arrangement further avoiding graft failure due to inverted transplant. Veldman et al. stamped an S on DMEK donor graft [49]. Others suggested asymmetric marks on the edges of the graft [2,5]. All these marks ensured correct graft orientation, and help in the early post op to exclude an upside down grating. Melles group proposed an algorithm to predict if a detachment is likely to be transient or lasting. Performing AS-OCT at 1 hour and 1 week postop: if at one week the graft is completely attached, then it will be detachment-free, instead, if any detachment is detected, they recommend to check the scan made at 1 hour after surgery, and if this exam also shows the same detachment, then spontaneous re-attachment is unlikely, and re-bubbling is recommended [13,8]. Management of graft detachment Management and prognosis vary in two type of detachments, in addition, in case of partial detachment, the location or the site of detachment plays a significant role along with the conformation, timing in terms of when the detachment occurs (day 1, 3 or later) and percentage of the graft attached. Partial (larger than 33% of the DMEK-graft surface), central, scrolled or complete detachment affects the visual recovery and require an intervention, commonly re-bubbling that is usually successful. The reinjection of air promotes attachment, improving visual recovery and preventing fibrosis and shrinkage of Descemet membrane. Cases of free-floating DMEK graft associated with re-endothelialisation without any air injection have already been reported, however the visual recovery was delayed by months and the endothelial cell density was low [12,3,36]. However it is still not clear how, hypotheses includes endothelial transfer, migration or regeneration of donor or recipient cells.
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There are different techniques and algorithm for management of graft detachment. Although there is no literature comparing the efficacy of different gases, most surgeons would choose air or sulphur hexafluoride (15 – 20% SF6) or in some cases perfluoropropane (12 – 14% C3F8) because of its longer resorption time for cases failing reattachment with the other two gases or those detached for a prolonged period [28,26]. Complete detachments, instead, are the most straightforward regarding management. In these cases the graft has entirely peeled away from the posterior corneal surface and is usually free-floating in the anterior chamber. It is never likely to re-attach and the entire cornea will always remain oedematous. These eyes should therefore be re-operated immediately; most often a re-DMEK or DSAEK can be performed with a good clinical outcome. Ham L. et al recently determined the re-bubbling rate of 4.4% where all the cases were performed within 6 months post op with a graft detachment rate of 11.6% (>1/3rd graft detached). It was noted that the visual acuity levels achieved 6 months after DMEK may remain stable up to at least 4-7 years with complications occurring after the first 6 months in <5% cases. However, it was reported that minor detachments (<1/3rd) required secondary intervention, all of them remaining clear at all follow-ups. Of the major detachments (>1/3rd), 23% remained clear and 77% required a repeat transplantation. Major graft detachment rates decreased over time from 20.8% to 10.4% [22]. Re-bubbling the graft could be an option to overcome the detachment of partially detached grafts. However, a repeat surgery may be performed on the completely detached grafts.
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Re-bubbling indications, techniques, management and success rate Re-bubbling (also called anterior chamber re-bubbling) is a procedure to manage graft detachment after DMEK if the graft is correctly oriented, various techniques for re-bubbling has been described with different rate of success that are listed further. The re-bubbling rates of 73.8% can be found if graft detachment and re-bubbling rates are recorded as one unit [24]. However, 3-6% of re-bubbling has been observed after partial detachment of 15-50% [38,39]. This further highlights the variation in the preferences of the surgeons where some would observe graft detachments for months before intervention [6,10] while others may repeat air injections for almost all within 1-2 weeks [14]. In general, graft detachment rates and time of re-bubble have been dissimilar with different methods to rescue the graft. Area of descemetorhexis may be an important factor for DMEK survival Further to what is described earlier in the management of graft detachment, Tourtas T et al. reported that graft detachment rate is related to the extent of descemetorhexis. Out of two groups, descemetorhexis of 10mm was performed in group A whereas group B consisted of 6mm. 33.3% graft detachment was found after 4 days in group A whereas 78.3% was found in group B. The rebubbling rate was found to be 6.7% in group A and 30.4% in Group B which was statistically significant. A larger descemetorhexis in DMEK was found to be correlated with better graft adhesion and lower re-bubbling rates where patients with a larger descemetorhexis require less intensive follow-up [47].
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Late intervention resulting in corneal scarring It has been observed by Baydoun L et al. that late intervention may allow the cornea to clear spontaneously however visual recovery is longer, while the delayed healing may lead to potential corneal scarring, poorer final visual outcome and lower endothelial cell count [4]. In a recent study, Muller et al. showed that re-bubbling procedures may be performed within 4 to 6 weeks, before 5
ACCEPTED MANUSCRIPT portions of the detached graft scar and that graft detachments may reattach with interface scarring [32].
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New and improved techniques for re-bubbling Some techniques and algorithms for management of graft detachment have been reported. Sharma et al [42,43] propose intracameral injection of air in cases of planar DMDs in the superior half of the cornea, and 14% perfluoropropane C3F8 in all the other cases, reporting a mean time of resolution of corneal oedema in 16 days. It is versatile that it can be performed at the slit lamp or in theatre. A three year comparative clinical study using 20% sulphur hexafluoride (SF6) versus 100% air tamponade to overcome graft detachment in DMEK showed a requirement of re-bubble in 2.38% from SF6 group compared to 12.8% from air tamponade group where the detachments were larger than 60%. Re-bubbling was performed sooner if more than 50% detachment was observed [17]. New techniques for DMEK strategies like S-Stamp have shown a higher re-bubbling rate (13%), as compared to a non-stamped graft, which comprised of 3% within first 6 months post-op [20]. Bimanual technique for insertion and positioning of the endothelium-Descemet membrane graft in DMEK study has reported 6.6% re-bubbling rate [41]. Busin et al. recently reported a new technique for delivery of tri-folded DMEK grafts where the only complication observed after surgery was graft detachment (10 of 42 eyes [23.8%]), which was successfully managed in all cases by single rebubbling within 6 days from surgery [7].
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Re-bubbling of the DMEK grafts using eye bank prepared tissues New techniques from the surgeons and the eye banks have also been evaluated on the basis of rebubbling rates. Eye bank prepared tissues for DMEK have reported 27.5% re-bubbling rate. The reported rates of partial detachment of DMEK tissues prepared by surgeons requiring air injection instead range from 9-82% [10,34,44,48]. However, Deng et al. noticed that the most common complication after DMEK was partial detachment of the DM graft at the periphery after the use of eye bank prepared tissues. Air injection for partial detachment was performed in 27.5% cases. No total detachment was observed, however, single air injection was sufficient for reattachment in 90.9% cases [9]. Liarakos et al. reported the effects of preservation medium on re-bubbling rate. This study showed that tissues preserved in hypothermic media show higher detachment rates (35%) compared to 27% with organ culture (OC). However, re-bubbling rates from corneas previously stored in cold storage was 24% with 29% in OC and 18% when the tissues were excised from fresh globes [25].
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Grading system for re-bubbling An interesting study by Maier AK et al. showed graft detachment with required re-bubbling rate of 38.1%. This study showed a grading system for unfolding and attaching of the graft lamella with regards to its difficulty in four grading groups: a) Graft lamella primarily oriented correctly in the anterior chamber, straight and direct unfolding and centring which showed 37% re-bubbling rate due to less manipulations; b) slightly complicated, indirect unfolding and centring (duration less than five min) which showed 44.7% re-bubbling rate; c) difficult indirect unfolding and centring (duration longer than 5 minutes), repeat air injection with BSS exchange necessary which showed 43.8% rebubbling rate and; d) direct manipulation of the graft lamella for unfolding and centring by cannula or forceps which showed 50% re-bubbling rate [27]. This shows that the degree of manipulation may lead to higher re-bubbling rates. 6
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Possible crucial factors in graft detachment includes -air/gas -previous glaucoma surgery/anterior chamber dysgenesis -anterior chamber depth -biomechanical behaviour of the graft -recipient surface – graft diameter and descemetorhexis -pre-stripped in eye bank and preservation media
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Conclusion and future aspects To increase the efficiency and post-op care, it would be appropriate to re-bubble a tissue irrelevant of the size of the graft detachment at the earliest and report any graft detachment as a re-bubble rate and combine them as one unit. There is a high chance of obtaining true-negative data where detachment rate may not reflect the re-bubbling rate and vice versa. This may also promote a DMEK technique that may be better but due to the re-bubbling rate (highlighted same as detachment rate) the efficiency of a particular DMEK technique may not be considered good, although its clinical efficiency is higher. As different studies have provided different DMEK graft detachment and re-bubbling rates at various time points, we believe that if the re-bubbling rate is defined, it would be easier to develop and standardize surgical procedures in the future based on the precise clinical data. Moreover, it has already been reported earlier that a graft, which is re-bubbled sooner, allows earlier rehabilitation and better visual outcome without compromising ECD and, in addition, it reduces the chances of potential corneal scarring [1,4]. So far we have only found one report in the literature by Terry et al., which has defined the re-bubbling rate as “Any tissue that had an injection of air into the anterior chamber in the postoperative period was recorded as a re-bubble”. This study showed 6% rebubbling rate between 1 and 3 weeks after the DMEK surgery [45].
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Other long and short term studies In a one-year study by Price et al., re-bubbling rate of 5% has been observed [35]. Whereas, Rodriguez-Calvo-de-Mora et al. reported re-bubbling rate (just once) for 13% and twice in 2% grafts where the median duration of follow-up was 18 months (range, 3-61 months) [39]. Tourtas T et al. reported graft detachment rate of 15.8% with 3% re-bubbling rate at 6 months post-op [46]. In another study by Fernández López E et al., re-bubbling was performed on average 26 (±21) days (range: 7-92 days) after DMEK, the air cannula was introduced in the area of graft attachment (attached area approach) (n = 25) or detachment (detached area approach) (n = 16). After excluding upside-down grafts (n = 3), the rebubbling success rate in total was 87% (33/38 eyes); in the attached area approach, it was 92% (22/24 eyes); and in the detached area approach, it was 79% (11/14). Of 14 eyes that had been re-bubbled later than 1 month postoperatively, 11 were successful; in 8 eyes, the graft seemed too stiff and/or immobile to allow complete unfolding [15]. However, a recent study by Gerber-Hollbach N et al. [16] showed that rebubbling a DMEK graft may result in similar visual outcomes as in uncomplicated DMEK, when performed within the first 6-8 weeks post op. Rebubbled eyes may have lower ECD, which may be attributed to additional air bubble trauma and or selection bias through more extensive manipulation during initial DMEK or higher risk of graft detachment in more complicated eyes.
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It has already been suggested by Muller et al. that re-bubbling is a feasible procedure to manage graft detachment after DMEK if the graft is correctly oriented. Proper preoperative planning may aid in minimizing intraoperative complications and may increase the success rate. Late interventions (>1 month postoperatively) may still produce graft reattachment, but increased graft stiffness and/or fibrosis may complicate complete graft unfolding. Incomplete host DM removal may relate to postoperative DMEK graft detachment and wound instability. Graft detachments may reattach with interface scarring. Re-bubbling procedures may be performed within 4 to 6 weeks, before portions of the detached graft scar [32]. We believe that to achieve early rehabilitation rate and a visual acuity accounting 20/20, an early rebubbling of the graft is necessary. The seriousness of re-bubbling for small peripheral detachments has not been identified yet. It is also recommended to report graft detachment rates along with rebubbling rates to broaden the knowledge of graft activity in vivo. The definition can be further modified from Terry et al’s report and may be re-defined as ‘Graft Detachment and Re-Bubbling (GDRB) - Any tissue that has been detached regardless of the amount of detachment and has an injection of air or other gases into the anterior chamber for reattachment of the graft in the postoperative period’. As early re-bubbling of the graft has already shown its benefits in terms of visual outcomes and limited corneal scarring [1,4], reporting of re-bubbling rates will also provide a standardised method for surgery and reporting the post-op data, which will further enhance the DMEK surgery.
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Method of literature search All the papers were searched in PubMed with words ‘DMEK; Descemet Membrane Endothelial Keratoplasty; Re-bubbling rate; detachment rate; clinical outcomes’. The year of publication was not considered in the inclusion criteria as DMEK is relatively recently developed.
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1. Ang M, Wilkins MR, Mehta JS, Tan D. Descemet membrane endothelial keratoplasty. Br J Ophthalmol. 2016;100(1):15-21. 2. Bachmann Bo, Laaser K, Cursiefen C, et al. A method to confirm correct orientation of descemet membrane during descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2010;149(6):922-925. 3. Balachandran C, Ham L, Verschoor CA, et al. Spontaneous corneal clearance despite graft detachment in descemet membrane endothelial keratoplasty. Am J Ophthalmol 2009;148(2):227-34. 4. Baydoun L, van Dijk K, Dapena I, et al. Repeat descemet membrane endothelial keratoplasty after complicated primary descemet membrane endothelial keratoplasty. Ophthalmology. 2015;122(1):8–16. 5. Bhogal M, Maurino V, Allan BD. Use of a single peripheral triangular mark to ensure correct graft orientation in Descemet membrane endothelial keratoplasty. J Cataract Refract Surg. 2015;41(9):2022-2024. 6. Bucher F, Hos D, Muller-Schwefe S, et al. Spontaneous long-term course of persistent peripheral graft detachments after Descemet’s membrane endothelial keratoplasty. Br. J Ophthalmol. 2015; 99(6):768-72. 7. Busin M, Leon P, Scorcia V, Ponzin D. Contact Lens-Assisted Pull-Through Technique for Delivery of Tri-Folded (Endothelium in) DMEK Grafts Minimizes Surgical Time and Cell Loss. Ophthalmology. 2016;123(3):476-83. 8. Dapena I, Moutsouris K, Ham L, Melles GR. Graft detachment rate. Ophthalmology 2010;117(4):847-847.e1. 9. Deng SX, Sanchez PJ, Chen L. Clinical outcomes of Descemet membrane endothelial keratoplasty using eye bank-prepared tissues. Am J Ophthalmol. 2015;159(3):590-6. 10. Dirisamer M, Ham L, Dapena I, et al. Efficacy of descemet membrane endothelial keratoplasty: clinical outcome of 200 consecutive cases after a learning curve of 25 cases. Arch Ophthalmol, 2011;129(11):1435–1443. 11. Dirisamer M, Dapena I, Ham L, et al. Patterns of corneal endothelialization and corneal clearance after descemet membrane endothelial keratoplasty for fuchs endothelial dystrophy. Am J Ophthalmol. 2011;152(4):543–55. e1. 12. Dirisamer M, Ham L, Dapena I, et al. Descemet membrane endothelial transfer: "freefloating" donor Descemet implantation as a potential alternative to "keratoplasty". Cornea 2012;31(2):194-7. 13. Dirisamer M, van Dijk K, Dapena I, et al. Prevention and management of graft detachment in descemet membrane endothelial keratoplasty. Arch Ophthalmol 2012;130(3):280-91. 14. Feng MT, Price MO, Miller JM, et al. Air reinjection and endothelial cell density in Descemet membrane endothelial keratoplasty: five-year follow-up. J Cataract Refract Surg. 2014;40(7):1116–21. 15. Fernández López E, Baydoun L, Gerber-Hollbach N, et al. Rebubbling Techniques for Graft Detachment After Descemet Membrane Endothelial Keratoplasty. Cornea. 2016;35(6):75964. 16. Gerber-Hollbach N, Baydoun L, López EF, et al. Clinical Outcome of Rebubbling for Graft Detachment After Descemet Membrane Endothelial Keratoplasty. Cornea. 2017 Apr 21. doi: 10.1097/ICO.0000000000001220. 17. Gorovoy IR and Gorovoy MS. Descemet Membrane Endothelial Keratoplasty Postoperative year 1 endothelial cell counts. Am J Ophthalmol. 2015;159(3):597-600.
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ACCEPTED MANUSCRIPT 37. Potter J, Zalatimo N. Descemet’s membrane detachment after cataract extraction. Optometry. 2005;76(12):720–24. 38. Reid RA, Craig EA, Suleman H. Descemet’s membrane endothelial keratoplasty (DMEK): first UK prospective study of 1-year visual outcomes, graft survival and endothelial cell count. Br J Ophthalmol. 2015;99(2):166–9. 39. Rodriguez-Calvo-de-Mora M, Quilendrino R, Ham L, et al. Clinical outcome of 500 consecutive cases undergoing Descemet’s membrane endothelial keratoplasty. Ophthalmology. 2015;122(3):464–70. 40. Romano V, Tey A, Hill NM, et al. Influence of graft size on graft survival following Descemet stripping automated endothelial keratoplasty. Br J Ophthalmol. 2015;99(6):784-8. 41. Sáles CS, Straiko MD, Terry MA. Novel Technique for Rebubbling DMEK Grafts at the Slit Lamp Using Intravenous Extension Tubing. Cornea. 2016;35(4):582-5. 42. Sharma A, Singh SK, Bhutia PL, Pant R. Perfluoropropane (C3F8) injection for Descemet's membrane detachment in cataract surgery. Nepal J Ophthalmol. 2015;7(1):74-8. 43. Sharma N, Gupta S, Maharana P, et al. Anterior Segment Optical Coherence TomographyGuided Management Algorithm for Descemet Membrane Detachment After Intraocular Surgery. Cornea 2015;34(9):1170-4. 44. Sophie X. Deng, P.James Sanchez, and Luxia Chen. Clinical outcomes of Descemet Membrane Endothelial Keratoplasty using Eye Bank-Prepared Tissues. American Journal of Ophthalmology. 2015;159(3):590-596. 45. Terry MA, Straiko MD, Veldman PB, Talajic JC, VanZyl C, Sales CS, Mayko ZM. Standardized DMEK Technique: Reducing Complications Using Prestripped Tissue, Novel Glas s Injector, and Sulfur Hexafluoride (SF6) Gas. Cornea. 2015;34(8):845-52. 46. Tourtas T, Laaser K, Bachmann BO, Cursiefen C, Kruse FE. Descemet membrane endothelial keratoplasty versus descemet stripping automated endothelial keratoplasty. Am J Ophthalmol. 2012;153(6):1082–1090.e1082. 47. Tourtas T, Schlomberg J, Wessel JM, Bachmann BO, Schlötzer-Schrehardt U, Kruse FE. Graft adhesion in descemet membrane endothelial keratoplasty dependent on size of remov al of host's descemet membrane. JAMA Ophthalmol. 2014;132(2):155-61. 48. Veldman PB, Dye PK, Holiman JD, et al. The Sstamp in Descemet Membrane Endothelial Keratoplasty Safely Eliminates Upside-down Graft Implantation. Ophthalmology. 2016;123(1):161-4. 49. Veldman PB, Dye PK, Holiman JD, et al. Stamping an S on DMEK donor tissue to prevent upside-down grafts: laboratory validation and detailed preparation technique description. Cornea. 2015;34(9):1175-78.
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A. Eye Bank Association of America. 2015 Eye Banking Statistical Report. Washington DC, Eye Bank Association of America, 2016.
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ACCEPTED MANUSCRIPT Figure and figure legends
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Figure 1: Number of corneal tissues prepared for specific keratoplasties between 2012 and 2015 at FBOV, Venice, Italy. A consistent decrease in the request for PK has been noticed since 2012 where as tissues for DSAEK and DMEK prepared in the eye banks have shown increased popularity.
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S0039-6257(16)30270-3
DOI:
10.1016/j.survophthal.2017.07.003
Reference:
SOP 6738
To appear in:
Survey of Ophthalmology
Received Date: 12 December 2016 Revised Date:
13 July 2017
Accepted Date: 17 July 2017
Please cite this article as: Parekh M, Leon P, Ruzza A, Borroni D, Ferrari S, Ponzin D, Romano V, Graft detachment and re-bubbling rate in Descemet Membrane Endothelial Keratoplasty, Survey of Ophthalmology (2017), doi: 10.1016/j.survophthal.2017.07.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Graft detachment and re-bubbling rate in Descemet Membrane Endothelial Keratoplasty Authors Mohit Parekh1,2, Pia Leon3,4,5, Alessandro Ruzza1, Davide Borroni6,7, Stefano Ferrari1, Diego Ponzin1 and Vito Romano8
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Affiliations 1 International Center for Ocular Physiopathology, The Veneto Eye Bank Foundation, Mestre, Venice, Italy 2 Department of Molecular Medicine, School of Biomedicine, University of Padova, Padova, Italy 3 Department of Ophthalmology, SS Giovanni and Paolo Hospital, Venice, Italy 4 Department of Ophthalmology, Villa Igea Hospital, Forli, Italy 5 Istituto Internazionale per la Ricerca e Formazione in Oftalmologia (IRFO), Forlì, Italy 6 Department of Ophthalmology, Riga Stradins University, Riga, Latvia 7 Department of Genetics, Riga Stradins University, Riga, Latvia 8 Moorfields Eye Hospital NHS Foundation Trust, London, UK
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Correspondence Mohit Parekh, PhD International Center for Ocular Physiopathology, The Veneto Eye Bank Foundation, Via Paccagnella 11, Padiglione Rama, 30174, Zelarino, Venice, Italy Tel: +390419656473 Fax: +390419656471 Email: [email protected]
Conflict of interest None of the authors have any potential conflict of interest
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Keywords DMEK, re-bubble rate, graft detachment
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Abstract Descemet Membrane Endothelial Keratoplasty (DMEK) is a selective replacement of dysfunctional endothelium with healthy donor Descemet’s membrane and endothelium. Although the donor preparation and surgical methods still remain a challenge, DMEK is gaining popularity in terms of early rehabilitation and visual outcomes. New and improved donor preparation techniques like prestripped DMEK tissues are taken up rapidly due to less manipulation that is required in the surgical theatre. Donor graft delivery in the recipient eye has also been improved due to new products like pre-stripped and pre-loaded membranes. As DMEK is at its budding stage, only early outcomes have been known so far. Early graft detachment, re-bubbling rates, primary failures are still being studied in DMEK. As there are different techniques that are currently used for preparation and injection of the graft, it becomes difficult to judge the results based on specific inclusion and exclusion criteria. Graft detachment and re-bubbling rates have been a huge challenge both during the surgery and also while reporting post-op data. This review highlights the importance of defining graft detachment and re-bubbling rates and therefore its surgical relevance, which may also have an impact on graft preparation and insertion techniques.
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Introduction Descemet Membrane Endothelial Keratoplasty (DMEK) has evolved over the years since Melles first introduced it in 2006 [30]. From the first studies published, DMEK has demonstrated excellent results in terms of visual recovery and a low rate of post-operative rejection [1]. Differently from Descemet's stripping automated endothelial keratoplasty (DSAEK), DMEK surgical procedure has highlighted significant difficulties due to the complexity of handling of the membrane, implanting the graft with the correct orientation and management of early post-operative complications that may occur such as the detachment of the graft. Various preparation and delivery techniques have been addressed so far, and there is still no standard technique available yet. At the Veneto Eye Bank Foundation (FBOV) in Italy, we have observed a constant increase in the requests of pre-cut DMEK tissues since 2014 [Figure 1]. DMEK is gaining popularity due to early rehabilitation and better visual outcome. Hence, its validation and standardization in terms of preparation, implantation and postoperative data collection and analysis becomes essential. In 2016 we published a ‘proof of concept’ paper for pre-loading DMEK tissues and introduced a modified design for a surgical device that could help to preserve, transport and transplant a DMEK graft with less manipulation [33]. Pre-loading DMEK, as we assume, will also be useful to standardize and validate DMEKs with advantages like reducing primary graft failure rates due to de-oriented grafts, lowering high surgical skills quotient, high rehabilitation rate with better visual acuity, low surgical time, costs and logistic requirements [33]. DMEK is also gaining popularity in the USA, as per the Eye Bank Association of America (EBAA) report of 2015, it was only performed in 748 cases in 2012, that increased to 1,522 cases in 2013 to 2,865 in 2014 and 4,694 cases in 2015A. With the new techniques in the field of DMEK preparation and shipment, it becomes essential to standardize the delivery technique followed by monitoring and reporting the post-op clinical data in a universally accepted format. This review describes the results achieved after DMEK highlighting the importance of determining, monitoring and reporting graft detachment and re-bubbling rates.
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Graft detachment It is important to monitor the behaviour during the course of visual rehabilitation and in the late post-operative period once the DMEK graft is implanted inside the recipient’s eye. The main and commonest post-operative complication following DMEK is the graft detachment. Usually DMEK complication rates have been reported separately by detachment rates. The graft detachment can be classified as complete or partial. ‘Complete’ - when all the donor tissue is completely detached from the recipient and floats in anterior chamber and, ‘Partial’ - when part of the donor is still attached to the recipient.
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Diagnosis It must be noted that all the reports that do not perform Anterior Segment Optical Coherence Tomography (AS-OCT) in the follow-up can mis-report a partial Descement membrane detachment (DMDs). If the cornea is relatively clear, the presence of DMDs can be easily detected by slit-lamp biomicroscopy. However, in the presence of severe corneal edema, AS-OCT remains the best imaging tool to determine the configuration (planar or scrolled) and location of DMD, which are vital for planning the surgical technique. Various classification systems have been proposed for DMD such as planar versus non-planar, scrolled versus non-scrolled, and peripheral versus peripheral with central involvement. Planar DMDs are those in which the separation between the stroma and DM is <1 mm, when the separation is >1 mm, the detachment is termed non-planar. DMDs that exhibit a 3
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Rate of graft detachment The initial reports of complete DMDs rate were 30% [1,31], partial graft detachment rates have been reported in around 62-63% cases [21,22,34]. However, with improved techniques and surgical experience, reported graft detachments have reduced to 34.6% in a multicentre study and as low as 4% in one case series [1]. Therefore, a learning curve for DMEK implantation including the postoperative care is highly relevant.
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Early management or prevention of primary graft failure Most lamellar keratoplasty complications that threaten graft survival occur in the earliest week or weeks post-transplant and in most cases are evident at the first post-operative clinical examination. The diagnosis and successful management of these early complications is crucial to long-term graft survival [18]. The size of descemetorhexis plays a role in order to reduce the peripheral postoperative oedema and to prevent DMDs. It has been reported that it should be slightly smaller compared to the diameter of the graft; the graft diameter (or chord length) in the eye differs from the diameter of the graft on the trephine block. This difference depends on the disparity between the radius of curvature of the trephine and that of the posterior cornea [40].
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DMEK graft is highly transparent and unless marked on its Descemet’s side, it becomes difficult to understand the orientation of the graft. Intra-operative and at first post operative control checking the marks allows the graft to be implanted with correct orientation and reduces any upside down arrangement further avoiding graft failure due to inverted transplant. Veldman et al. stamped an S on DMEK donor graft [49]. Others suggested asymmetric marks on the edges of the graft [2,5]. All these marks ensured correct graft orientation, and help in the early post op to exclude an upside down grating. Melles group proposed an algorithm to predict if a detachment is likely to be transient or lasting. Performing AS-OCT at 1 hour and 1 week postop: if at one week the graft is completely attached, then it will be detachment-free, instead, if any detachment is detected, they recommend to check the scan made at 1 hour after surgery, and if this exam also shows the same detachment, then spontaneous re-attachment is unlikely, and re-bubbling is recommended [13,8]. Management of graft detachment Management and prognosis vary in two type of detachments, in addition, in case of partial detachment, the location or the site of detachment plays a significant role along with the conformation, timing in terms of when the detachment occurs (day 1, 3 or later) and percentage of the graft attached. Partial (larger than 33% of the DMEK-graft surface), central, scrolled or complete detachment affects the visual recovery and require an intervention, commonly re-bubbling that is usually successful. The reinjection of air promotes attachment, improving visual recovery and preventing fibrosis and shrinkage of Descemet membrane. Cases of free-floating DMEK graft associated with re-endothelialisation without any air injection have already been reported, however the visual recovery was delayed by months and the endothelial cell density was low [12,3,36]. However it is still not clear how, hypotheses includes endothelial transfer, migration or regeneration of donor or recipient cells.
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There are different techniques and algorithm for management of graft detachment. Although there is no literature comparing the efficacy of different gases, most surgeons would choose air or sulphur hexafluoride (15 – 20% SF6) or in some cases perfluoropropane (12 – 14% C3F8) because of its longer resorption time for cases failing reattachment with the other two gases or those detached for a prolonged period [28,26]. Complete detachments, instead, are the most straightforward regarding management. In these cases the graft has entirely peeled away from the posterior corneal surface and is usually free-floating in the anterior chamber. It is never likely to re-attach and the entire cornea will always remain oedematous. These eyes should therefore be re-operated immediately; most often a re-DMEK or DSAEK can be performed with a good clinical outcome. Ham L. et al recently determined the re-bubbling rate of 4.4% where all the cases were performed within 6 months post op with a graft detachment rate of 11.6% (>1/3rd graft detached). It was noted that the visual acuity levels achieved 6 months after DMEK may remain stable up to at least 4-7 years with complications occurring after the first 6 months in <5% cases. However, it was reported that minor detachments (<1/3rd) required secondary intervention, all of them remaining clear at all follow-ups. Of the major detachments (>1/3rd), 23% remained clear and 77% required a repeat transplantation. Major graft detachment rates decreased over time from 20.8% to 10.4% [22]. Re-bubbling the graft could be an option to overcome the detachment of partially detached grafts. However, a repeat surgery may be performed on the completely detached grafts.
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Re-bubbling indications, techniques, management and success rate Re-bubbling (also called anterior chamber re-bubbling) is a procedure to manage graft detachment after DMEK if the graft is correctly oriented, various techniques for re-bubbling has been described with different rate of success that are listed further. The re-bubbling rates of 73.8% can be found if graft detachment and re-bubbling rates are recorded as one unit [24]. However, 3-6% of re-bubbling has been observed after partial detachment of 15-50% [38,39]. This further highlights the variation in the preferences of the surgeons where some would observe graft detachments for months before intervention [6,10] while others may repeat air injections for almost all within 1-2 weeks [14]. In general, graft detachment rates and time of re-bubble have been dissimilar with different methods to rescue the graft. Area of descemetorhexis may be an important factor for DMEK survival Further to what is described earlier in the management of graft detachment, Tourtas T et al. reported that graft detachment rate is related to the extent of descemetorhexis. Out of two groups, descemetorhexis of 10mm was performed in group A whereas group B consisted of 6mm. 33.3% graft detachment was found after 4 days in group A whereas 78.3% was found in group B. The rebubbling rate was found to be 6.7% in group A and 30.4% in Group B which was statistically significant. A larger descemetorhexis in DMEK was found to be correlated with better graft adhesion and lower re-bubbling rates where patients with a larger descemetorhexis require less intensive follow-up [47].
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Late intervention resulting in corneal scarring It has been observed by Baydoun L et al. that late intervention may allow the cornea to clear spontaneously however visual recovery is longer, while the delayed healing may lead to potential corneal scarring, poorer final visual outcome and lower endothelial cell count [4]. In a recent study, Muller et al. showed that re-bubbling procedures may be performed within 4 to 6 weeks, before 5
ACCEPTED MANUSCRIPT portions of the detached graft scar and that graft detachments may reattach with interface scarring [32].
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New and improved techniques for re-bubbling Some techniques and algorithms for management of graft detachment have been reported. Sharma et al [42,43] propose intracameral injection of air in cases of planar DMDs in the superior half of the cornea, and 14% perfluoropropane C3F8 in all the other cases, reporting a mean time of resolution of corneal oedema in 16 days. It is versatile that it can be performed at the slit lamp or in theatre. A three year comparative clinical study using 20% sulphur hexafluoride (SF6) versus 100% air tamponade to overcome graft detachment in DMEK showed a requirement of re-bubble in 2.38% from SF6 group compared to 12.8% from air tamponade group where the detachments were larger than 60%. Re-bubbling was performed sooner if more than 50% detachment was observed [17]. New techniques for DMEK strategies like S-Stamp have shown a higher re-bubbling rate (13%), as compared to a non-stamped graft, which comprised of 3% within first 6 months post-op [20]. Bimanual technique for insertion and positioning of the endothelium-Descemet membrane graft in DMEK study has reported 6.6% re-bubbling rate [41]. Busin et al. recently reported a new technique for delivery of tri-folded DMEK grafts where the only complication observed after surgery was graft detachment (10 of 42 eyes [23.8%]), which was successfully managed in all cases by single rebubbling within 6 days from surgery [7].
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Re-bubbling of the DMEK grafts using eye bank prepared tissues New techniques from the surgeons and the eye banks have also been evaluated on the basis of rebubbling rates. Eye bank prepared tissues for DMEK have reported 27.5% re-bubbling rate. The reported rates of partial detachment of DMEK tissues prepared by surgeons requiring air injection instead range from 9-82% [10,34,44,48]. However, Deng et al. noticed that the most common complication after DMEK was partial detachment of the DM graft at the periphery after the use of eye bank prepared tissues. Air injection for partial detachment was performed in 27.5% cases. No total detachment was observed, however, single air injection was sufficient for reattachment in 90.9% cases [9]. Liarakos et al. reported the effects of preservation medium on re-bubbling rate. This study showed that tissues preserved in hypothermic media show higher detachment rates (35%) compared to 27% with organ culture (OC). However, re-bubbling rates from corneas previously stored in cold storage was 24% with 29% in OC and 18% when the tissues were excised from fresh globes [25].
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Grading system for re-bubbling An interesting study by Maier AK et al. showed graft detachment with required re-bubbling rate of 38.1%. This study showed a grading system for unfolding and attaching of the graft lamella with regards to its difficulty in four grading groups: a) Graft lamella primarily oriented correctly in the anterior chamber, straight and direct unfolding and centring which showed 37% re-bubbling rate due to less manipulations; b) slightly complicated, indirect unfolding and centring (duration less than five min) which showed 44.7% re-bubbling rate; c) difficult indirect unfolding and centring (duration longer than 5 minutes), repeat air injection with BSS exchange necessary which showed 43.8% rebubbling rate and; d) direct manipulation of the graft lamella for unfolding and centring by cannula or forceps which showed 50% re-bubbling rate [27]. This shows that the degree of manipulation may lead to higher re-bubbling rates. 6
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Possible crucial factors in graft detachment includes -air/gas -previous glaucoma surgery/anterior chamber dysgenesis -anterior chamber depth -biomechanical behaviour of the graft -recipient surface – graft diameter and descemetorhexis -pre-stripped in eye bank and preservation media
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Conclusion and future aspects To increase the efficiency and post-op care, it would be appropriate to re-bubble a tissue irrelevant of the size of the graft detachment at the earliest and report any graft detachment as a re-bubble rate and combine them as one unit. There is a high chance of obtaining true-negative data where detachment rate may not reflect the re-bubbling rate and vice versa. This may also promote a DMEK technique that may be better but due to the re-bubbling rate (highlighted same as detachment rate) the efficiency of a particular DMEK technique may not be considered good, although its clinical efficiency is higher. As different studies have provided different DMEK graft detachment and re-bubbling rates at various time points, we believe that if the re-bubbling rate is defined, it would be easier to develop and standardize surgical procedures in the future based on the precise clinical data. Moreover, it has already been reported earlier that a graft, which is re-bubbled sooner, allows earlier rehabilitation and better visual outcome without compromising ECD and, in addition, it reduces the chances of potential corneal scarring [1,4]. So far we have only found one report in the literature by Terry et al., which has defined the re-bubbling rate as “Any tissue that had an injection of air into the anterior chamber in the postoperative period was recorded as a re-bubble”. This study showed 6% rebubbling rate between 1 and 3 weeks after the DMEK surgery [45].
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Other long and short term studies In a one-year study by Price et al., re-bubbling rate of 5% has been observed [35]. Whereas, Rodriguez-Calvo-de-Mora et al. reported re-bubbling rate (just once) for 13% and twice in 2% grafts where the median duration of follow-up was 18 months (range, 3-61 months) [39]. Tourtas T et al. reported graft detachment rate of 15.8% with 3% re-bubbling rate at 6 months post-op [46]. In another study by Fernández López E et al., re-bubbling was performed on average 26 (±21) days (range: 7-92 days) after DMEK, the air cannula was introduced in the area of graft attachment (attached area approach) (n = 25) or detachment (detached area approach) (n = 16). After excluding upside-down grafts (n = 3), the rebubbling success rate in total was 87% (33/38 eyes); in the attached area approach, it was 92% (22/24 eyes); and in the detached area approach, it was 79% (11/14). Of 14 eyes that had been re-bubbled later than 1 month postoperatively, 11 were successful; in 8 eyes, the graft seemed too stiff and/or immobile to allow complete unfolding [15]. However, a recent study by Gerber-Hollbach N et al. [16] showed that rebubbling a DMEK graft may result in similar visual outcomes as in uncomplicated DMEK, when performed within the first 6-8 weeks post op. Rebubbled eyes may have lower ECD, which may be attributed to additional air bubble trauma and or selection bias through more extensive manipulation during initial DMEK or higher risk of graft detachment in more complicated eyes.
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It has already been suggested by Muller et al. that re-bubbling is a feasible procedure to manage graft detachment after DMEK if the graft is correctly oriented. Proper preoperative planning may aid in minimizing intraoperative complications and may increase the success rate. Late interventions (>1 month postoperatively) may still produce graft reattachment, but increased graft stiffness and/or fibrosis may complicate complete graft unfolding. Incomplete host DM removal may relate to postoperative DMEK graft detachment and wound instability. Graft detachments may reattach with interface scarring. Re-bubbling procedures may be performed within 4 to 6 weeks, before portions of the detached graft scar [32]. We believe that to achieve early rehabilitation rate and a visual acuity accounting 20/20, an early rebubbling of the graft is necessary. The seriousness of re-bubbling for small peripheral detachments has not been identified yet. It is also recommended to report graft detachment rates along with rebubbling rates to broaden the knowledge of graft activity in vivo. The definition can be further modified from Terry et al’s report and may be re-defined as ‘Graft Detachment and Re-Bubbling (GDRB) - Any tissue that has been detached regardless of the amount of detachment and has an injection of air or other gases into the anterior chamber for reattachment of the graft in the postoperative period’. As early re-bubbling of the graft has already shown its benefits in terms of visual outcomes and limited corneal scarring [1,4], reporting of re-bubbling rates will also provide a standardised method for surgery and reporting the post-op data, which will further enhance the DMEK surgery.
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Method of literature search All the papers were searched in PubMed with words ‘DMEK; Descemet Membrane Endothelial Keratoplasty; Re-bubbling rate; detachment rate; clinical outcomes’. The year of publication was not considered in the inclusion criteria as DMEK is relatively recently developed.
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1. Ang M, Wilkins MR, Mehta JS, Tan D. Descemet membrane endothelial keratoplasty. Br J Ophthalmol. 2016;100(1):15-21. 2. Bachmann Bo, Laaser K, Cursiefen C, et al. A method to confirm correct orientation of descemet membrane during descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2010;149(6):922-925. 3. Balachandran C, Ham L, Verschoor CA, et al. Spontaneous corneal clearance despite graft detachment in descemet membrane endothelial keratoplasty. Am J Ophthalmol 2009;148(2):227-34. 4. Baydoun L, van Dijk K, Dapena I, et al. Repeat descemet membrane endothelial keratoplasty after complicated primary descemet membrane endothelial keratoplasty. Ophthalmology. 2015;122(1):8–16. 5. Bhogal M, Maurino V, Allan BD. Use of a single peripheral triangular mark to ensure correct graft orientation in Descemet membrane endothelial keratoplasty. J Cataract Refract Surg. 2015;41(9):2022-2024. 6. Bucher F, Hos D, Muller-Schwefe S, et al. Spontaneous long-term course of persistent peripheral graft detachments after Descemet’s membrane endothelial keratoplasty. Br. J Ophthalmol. 2015; 99(6):768-72. 7. Busin M, Leon P, Scorcia V, Ponzin D. Contact Lens-Assisted Pull-Through Technique for Delivery of Tri-Folded (Endothelium in) DMEK Grafts Minimizes Surgical Time and Cell Loss. Ophthalmology. 2016;123(3):476-83. 8. Dapena I, Moutsouris K, Ham L, Melles GR. Graft detachment rate. Ophthalmology 2010;117(4):847-847.e1. 9. Deng SX, Sanchez PJ, Chen L. Clinical outcomes of Descemet membrane endothelial keratoplasty using eye bank-prepared tissues. Am J Ophthalmol. 2015;159(3):590-6. 10. Dirisamer M, Ham L, Dapena I, et al. Efficacy of descemet membrane endothelial keratoplasty: clinical outcome of 200 consecutive cases after a learning curve of 25 cases. Arch Ophthalmol, 2011;129(11):1435–1443. 11. Dirisamer M, Dapena I, Ham L, et al. Patterns of corneal endothelialization and corneal clearance after descemet membrane endothelial keratoplasty for fuchs endothelial dystrophy. Am J Ophthalmol. 2011;152(4):543–55. e1. 12. Dirisamer M, Ham L, Dapena I, et al. Descemet membrane endothelial transfer: "freefloating" donor Descemet implantation as a potential alternative to "keratoplasty". Cornea 2012;31(2):194-7. 13. Dirisamer M, van Dijk K, Dapena I, et al. Prevention and management of graft detachment in descemet membrane endothelial keratoplasty. Arch Ophthalmol 2012;130(3):280-91. 14. Feng MT, Price MO, Miller JM, et al. Air reinjection and endothelial cell density in Descemet membrane endothelial keratoplasty: five-year follow-up. J Cataract Refract Surg. 2014;40(7):1116–21. 15. Fernández López E, Baydoun L, Gerber-Hollbach N, et al. Rebubbling Techniques for Graft Detachment After Descemet Membrane Endothelial Keratoplasty. Cornea. 2016;35(6):75964. 16. Gerber-Hollbach N, Baydoun L, López EF, et al. Clinical Outcome of Rebubbling for Graft Detachment After Descemet Membrane Endothelial Keratoplasty. Cornea. 2017 Apr 21. doi: 10.1097/ICO.0000000000001220. 17. Gorovoy IR and Gorovoy MS. Descemet Membrane Endothelial Keratoplasty Postoperative year 1 endothelial cell counts. Am J Ophthalmol. 2015;159(3):597-600.
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18. Greenrod EB, Jones MN, Kaye S, Larkin DF. Center and surgeon effect on outcomes of endothelial keratoplasty versus penetrating keratoplasty in the United Kingdom. Am J Ophthalmol. 2014;158(5):957-66. 19. Güell JL, Morral M, Gris O, Elies D, Manero F. Comparison of Sulfur Hexafluoride 20% versus Air Tamponade in Descemet Membrane Endothelial Keratoplasty. Ophthalmology. 2015;122(9):1757-64. 20. Guell JL, Morral M, Gris O, Elies D, Manero F. Bimanual technique for insertion and positioning of endothelium-Descemet membrane graft in Descemet membrane endothelial keratoplasty. Cornea. 2013;32(12):1521-6. 21. Guerra FP, Anshu A, Price MO, et al. Endothelial keratoplasty: fellow eyes comparison of Descemet stripping automated endothelial keratoplasty and Descemet membrane endothelial keratoplasty. Cornea. 2011;30(12):1382–6. 22. Guerra FP, Anshu A, Price MO, et al. Descemet’s membrane endothelial keratoplasty: prospective study of 1-year visual outcomes, graft survival, and endothelial cell loss. Ophthalmology. 2011;118(12):2368–73. 23. Ham L, Dapena I, Liarakos VS, et al. Midterm results of Descemet membrane endothelial keratoplasty (DMEK): 4 to 7 years clinic al outcome. Am J Ophthalmol. 2016;171:113-121. 24. Laaser K, Bachmann BO, Horn FK, et al. Descemet membrane endothelial keratoplasty combined with phacoemulsification and intraocular lens implantation: advanced triple procedure. Am J Ophthalmol. 2012;154(1):47–55 e2. 25. Liarakos VS, Monnereau C, Dapena I and Melles GRJ. Learning curve of Descemet membrane endothelial keratoplasty (DMEK) worldwide-Multicenter trial on DMEK. Panoptis. 2013;25(2):68-75. 26. Mahmood MA, Teichmann KD, Tomey KF, al-Rashed D. Detachment of Descemet's membrane. J Cataract Refract Surg. 1998;24(6):827-33. 27. Maier AK, Gundlach E, Schroeter J, et al. Influence of the difficulty of graft unfolding and attachment on the outcome in Descemet membrane endothelial keratoplasty. Graefes Arch Clin Exp Ophthalmol. 2015;253(6):895-900. 28. Marcon AS, Rapuano CJ, Jones MR, et al. Descemet's membrane detachment after cataract surgery: management and outcome. Ophthalmology 2002;109(12):2325-30. 29. Minkovitz JB, Schrenk LC, Pepose JS. Spontaneous resolution of an extensive detachment of Descemet’s membrane following phacoemulsification. Arch Ophthalmol. 1994;112(4):551–2. 30. Melles GR, Ong TS, Ververs B, van der Wees J. Descemet membrane endothelial keratoplasty (DMEK). Cornea. 2006;25(8):987-90. 31. Melles GR, Ong TS, Ververs B, et al. Preliminary clinical results of Descemet membrane endothelial keratoplasty. Am J Ophthalmol. 2008;145(2):222–7. 32. Müller TM, Verdijk RM, Lavy I, et al. Histopathologic Features of Descemet Membrane Endothelial Keratoplasty Graft Remnants, Folds, and Detachments. Ophthalmology. 2016;123(12):2489-2497. 33. Parekh M, Ruzza A, Ferrari S, Busin M and Ponzin D. Pre-loaded tissues for Descemet Membrane Endothelial Keratoplasty. Am J Ophthalmol. 2016;166:120-125. 34. Price MO, Giebel AW, Fairchild KM, et al. Descemet’s membrane endothelial keratoplasty: prospective multicenter study of visual and refractive outcomes and endothelial survival. Ophthalmol. 2009;116(12):2361–8. 35. Price MO, Feng MT, McKee Y, Price FW Jr. Repeat Descemet Membrane Endothelial Keratoplasty: Secondary Grafts with Early Intervention Are Comparable with Fellow-Eye Primary Grafts. Ophthalmology. 2015;122(8):1639-44. 36. Price FW, Jr., Price MO. Spontaneous corneal clearance despite graft detachment after descemet membrane endothelial keratoplasty. Am J Ophthalmol 2010;149(1):173-4; author reply 4-5.
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ACCEPTED MANUSCRIPT 37. Potter J, Zalatimo N. Descemet’s membrane detachment after cataract extraction. Optometry. 2005;76(12):720–24. 38. Reid RA, Craig EA, Suleman H. Descemet’s membrane endothelial keratoplasty (DMEK): first UK prospective study of 1-year visual outcomes, graft survival and endothelial cell count. Br J Ophthalmol. 2015;99(2):166–9. 39. Rodriguez-Calvo-de-Mora M, Quilendrino R, Ham L, et al. Clinical outcome of 500 consecutive cases undergoing Descemet’s membrane endothelial keratoplasty. Ophthalmology. 2015;122(3):464–70. 40. Romano V, Tey A, Hill NM, et al. Influence of graft size on graft survival following Descemet stripping automated endothelial keratoplasty. Br J Ophthalmol. 2015;99(6):784-8. 41. Sáles CS, Straiko MD, Terry MA. Novel Technique for Rebubbling DMEK Grafts at the Slit Lamp Using Intravenous Extension Tubing. Cornea. 2016;35(4):582-5. 42. Sharma A, Singh SK, Bhutia PL, Pant R. Perfluoropropane (C3F8) injection for Descemet's membrane detachment in cataract surgery. Nepal J Ophthalmol. 2015;7(1):74-8. 43. Sharma N, Gupta S, Maharana P, et al. Anterior Segment Optical Coherence TomographyGuided Management Algorithm for Descemet Membrane Detachment After Intraocular Surgery. Cornea 2015;34(9):1170-4. 44. Sophie X. Deng, P.James Sanchez, and Luxia Chen. Clinical outcomes of Descemet Membrane Endothelial Keratoplasty using Eye Bank-Prepared Tissues. American Journal of Ophthalmology. 2015;159(3):590-596. 45. Terry MA, Straiko MD, Veldman PB, Talajic JC, VanZyl C, Sales CS, Mayko ZM. Standardized DMEK Technique: Reducing Complications Using Prestripped Tissue, Novel Glas s Injector, and Sulfur Hexafluoride (SF6) Gas. Cornea. 2015;34(8):845-52. 46. Tourtas T, Laaser K, Bachmann BO, Cursiefen C, Kruse FE. Descemet membrane endothelial keratoplasty versus descemet stripping automated endothelial keratoplasty. Am J Ophthalmol. 2012;153(6):1082–1090.e1082. 47. Tourtas T, Schlomberg J, Wessel JM, Bachmann BO, Schlötzer-Schrehardt U, Kruse FE. Graft adhesion in descemet membrane endothelial keratoplasty dependent on size of remov al of host's descemet membrane. JAMA Ophthalmol. 2014;132(2):155-61. 48. Veldman PB, Dye PK, Holiman JD, et al. The Sstamp in Descemet Membrane Endothelial Keratoplasty Safely Eliminates Upside-down Graft Implantation. Ophthalmology. 2016;123(1):161-4. 49. Veldman PB, Dye PK, Holiman JD, et al. Stamping an S on DMEK donor tissue to prevent upside-down grafts: laboratory validation and detailed preparation technique description. Cornea. 2015;34(9):1175-78.
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A. Eye Bank Association of America. 2015 Eye Banking Statistical Report. Washington DC, Eye Bank Association of America, 2016.
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ACCEPTED MANUSCRIPT Figure and figure legends
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Figure 1: Number of corneal tissues prepared for specific keratoplasties between 2012 and 2015 at FBOV, Venice, Italy. A consistent decrease in the request for PK has been noticed since 2012 where as tissues for DSAEK and DMEK prepared in the eye banks have shown increased popularity.
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