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There are numerous endothelial keratoplasty (EK) techniques used to treat disorders of the corneal endothelium. They include deep lamellar endothelial keratoplasty (DLEK), Descemet stripping endothelial keratoplasty (DSEK), Descemet stripping automated endothelial keratoplasty (DSAEK), Descemet membrane endothelial keratoplasty (DMEK), pre-Descemet endothelial keratoplasty (PDEK), Descemetorhexis without endothelial keratoplasty (DWEK), Descemet stripping only (DSO), and the proposed technique Descemet membrane endothelial transfer (DMET). The procedures involve the removal of the endothelium and Descemet membrane of the cornea through a corneal incision and possible placement of a circular graft from the inner lining of a donor cornea. The goal of these procedures is to restore corneal endothelial function, leading to improved vision and corneal clarity. This activity describes the evaluation and etiology of corneal endothelium disorders and reviews the role of the interprofessional team in managing patients who undergo treatment for endothelial dysfunction and its complications. Objectives: Review endothelial disorders and the relevant pathophysiology. Describe the various surgical techniques of endothelial transplantation and preparation of the transplanted tissue. Identify common complications of the different types of endothelial keratoplasties and their management. Explain the importance of communication among the interprofessional team workers for the appropriate selection of candidates for these procedures and the improvement of postoperative management. Access free multiple choice questions on this topic.

The cornea is a five-layered structure that provides the majority of the total refractive power of the eye (Fig. 1). In the past, penetrating keratoplasty (PK) had been the gold standard surgical treatment of corneal diseases for any layer, including diseases of the endothelium. With the improvement in technology and innovation over the last two decades, endothelial keratoplasty (EK) techniques involving transplantation of corneal components have been deployed to treat these diseases (Table 1). When compared to PK, EK introduces less foreign antigens, has improved visual recovery and outcomes, minimizes astigmatism, has less risk of dehiscence, and results in better globe stability.[1][2][3][4] History of Endothelial Keratoplasty Techniques The first endothelial transplant was developed by Dr. Tillett in 1956. The technique required a large incision and used a partial thickness graft created by the trephination of half of the posterior donor cornea.[5] During the 1960s, Dr. Barraquer developed a method of EK using a microkeratome for an anterior approach similar to a laser-assisted in situ keratomileusis (LASIK) flap followed by posterior trephination and suturing of the graft.[6] These techniques were complex, challenging to replicate, and unable to address the issues posed by PK. In 1998, Melles et al. made a significant advancement in the field by dissecting out a posterior stromal pocket using an intrastromal approach and securing the graft with air instead of the typical suturing that produced tension likely to pull the graft out of place.[7][8] Some refinements of this technique were made by Dr. Terry, who coined the term deep lamellar endothelial keratoplasty (DLEK) (Fig. 2A).[9] However, this procedure was technically challenging and not universally adopted.

The first endothelial transplant was developed by Dr. Tillett in 1956. The technique required a large incision and used a partial thickness graft created by the trephination of half of the posterior donor cornea.[5] During the 1960s, Dr. Barraquer developed a method of EK using a microkeratome for an anterior approach similar to a laser-assisted in situ keratomileusis (LASIK) flap followed by posterior trephination and suturing of the graft.[6] These techniques were complex, challenging to replicate, and unable to address the issues posed by PK. In 1998, Melles et al. made a significant advancement in the field by dissecting out a posterior stromal pocket using an intrastromal approach and securing the graft with air instead of the typical suturing that produced tension likely to pull the graft out of place.[7][8] Some refinements of this technique were made by Dr. Terry, who coined the term deep lamellar endothelial keratoplasty (DLEK) (Fig. 2A).[9] However, this procedure was technically challenging and not universally adopted. Next, in 2004, Melles et al. revolutionized the field with what is now called Descemet stripping endothelial keratoplasty (DSEK), after a few modifications made by Price et al.[10] DSEK utilizes a novel technique, "descemetorhexis," via an internal approach to remove the pathologic host Descemet membrane and endothelium. This procedure creates a smooth surface for graft application and removes the source of disease while sparing posterior stroma (Fig. 2B).[11] The use of a microkeratome to remove anterior stroma of the donor cornea was described by Dr. Gorovoy[12] and is now referred to as Descemet stripping automated endothelial keratoplasty (DSAEK). However, DSAEK is commonly referred to as DSEK as well. DSAEK has shown to have better visual outcomes compared to the original DSEK, and the technique continued to be refined, such as the addition of venting incisions in the cornea after graft application enhances graft adherence.[13]

Next, in 2004, Melles et al. revolutionized the field with what is now called Descemet stripping endothelial keratoplasty (DSEK), after a few modifications made by Price et al.[10] DSEK utilizes a novel technique, "descemetorhexis," via an internal approach to remove the pathologic host Descemet membrane and endothelium. This procedure creates a smooth surface for graft application and removes the source of disease while sparing posterior stroma (Fig. 2B).[11] The use of a microkeratome to remove anterior stroma of the donor cornea was described by Dr. Gorovoy[12] and is now referred to as Descemet stripping automated endothelial keratoplasty (DSAEK). However, DSAEK is commonly referred to as DSEK as well. DSAEK has shown to have better visual outcomes compared to the original DSEK, and the technique continued to be refined, such as the addition of venting incisions in the cornea after graft application enhances graft adherence.[13] DSAEK had become widely adopted, and eye bank produced precut tissue has proven to be reliable; thus, replacing the need for preparation by surgeons.[14][15][16] A study by Neff et al. found that thinner grafts, specifically those ≤ 131 μm, were associated with improved visual outcomes;[17] although the correlation between graft thickness and clinical outcomes has been disputed.[18][19] Another iteration using thinner grafts with less stroma, Ultrathin DSAEK (UT-DSAEK) developed by Busin et al. in 2013, was shown to have the same or better outcomes with faster recovery and similar complications as DSEK.[20][21] Comparing thicknesses, UT-DSAEK grafts are around 100 μm, whereas DSEK and DSAEK grafts are closer to 200 μm.[22] Melles et al., however, continued to innovate with the development of Descemet membrane endothelial keratoplasty (DMEK).

DSAEK had become widely adopted, and eye bank produced precut tissue has proven to be reliable; thus, replacing the need for preparation by surgeons.[14][15][16] A study by Neff et al. found that thinner grafts, specifically those ≤ 131 μm, were associated with improved visual outcomes;[17] although the correlation between graft thickness and clinical outcomes has been disputed.[18][19] Another iteration using thinner grafts with less stroma, Ultrathin DSAEK (UT-DSAEK) developed by Busin et al. in 2013, was shown to have the same or better outcomes with faster recovery and similar complications as DSEK.[20][21] Comparing thicknesses, UT-DSAEK grafts are around 100 μm, whereas DSEK and DSAEK grafts are closer to 200 μm.[22] Melles et al., however, continued to innovate with the development of Descemet membrane endothelial keratoplasty (DMEK). DMEK uses a graft consisting of endothelium and DM without any stroma (Fig. 2C). The graft is around 10-15 μm in thickness and prepared via a descemetorhexis performed on the donor eye.[22][23] A similar technique, pre-Descemet Endothelial Keratoplasty (PDEK), is prepared using pneumodissection to include the pre-Descemet layer in the graft, which helps with graft handling.[24] Compared to DSAEK, DMEK has better visual outcomes, faster recovery time, and lower immune rejection rate. However, it was not widely adopted due to the increased surgical skill required and higher rates of complications such as graft detachment and the need to rebubble.[25][26] Although short-lived, DMEK technique with a stromal rim (DMEK-S) was an attempt to hybridize the ease of handling inside the eye from DSEAK and retain visual benefits of DMEK developed by Studeny et al. (Fig. 2D).[27] Refinement of DMEK techniques continued, such as the development of pre- and intraoperative manipulations to better identify DMEK graft orientation, use of gas bubble tamponade that decreases chances of detachment, and eye bank technicians becoming proficient at producing preloaded DMEK grafts.[1][28][29][30]

DMEK uses a graft consisting of endothelium and DM without any stroma (Fig. 2C). The graft is around 10-15 μm in thickness and prepared via a descemetorhexis performed on the donor eye.[22][23] A similar technique, pre-Descemet Endothelial Keratoplasty (PDEK), is prepared using pneumodissection to include the pre-Descemet layer in the graft, which helps with graft handling.[24] Compared to DSAEK, DMEK has better visual outcomes, faster recovery time, and lower immune rejection rate. However, it was not widely adopted due to the increased surgical skill required and higher rates of complications such as graft detachment and the need to rebubble.[25][26] Although short-lived, DMEK technique with a stromal rim (DMEK-S) was an attempt to hybridize the ease of handling inside the eye from DSEAK and retain visual benefits of DMEK developed by Studeny et al. (Fig. 2D).[27] Refinement of DMEK techniques continued, such as the development of pre- and intraoperative manipulations to better identify DMEK graft orientation, use of gas bubble tamponade that decreases chances of detachment, and eye bank technicians becoming proficient at producing preloaded DMEK grafts.[1][28][29][30] The femtosecond laser has also been used to assist in EK procedures. Femtosecond laser-assisted DSEK (FS-DSEK) has been used to produce successful DSEK grafts consistently. However, a visual improvement from FS-DSEK appears limited when compared to DSAEK or PK.[31][32] Femtosecond and excimer laser-assisted EK (FELEK) uses a Femtosecond laser to dissect a thin graft that is smoothened with excimer photoablation. FELEK has shown some success on a small cohort of patients and may provide similar results to DMEK with less of a learning curve.[33] Femtosecond laser-enabled descemetorhexis DMEK (FE-DMEK) or Femtosecond laser-assisted DMEK (F-DMEK) has been used to perform the descemetorhexis for DMEK, resulting in fewer graft detachments and need for rebubbling when compared to manual descemetorhexis.[34][35][36]

The femtosecond laser has also been used to assist in EK procedures. Femtosecond laser-assisted DSEK (FS-DSEK) has been used to produce successful DSEK grafts consistently. However, a visual improvement from FS-DSEK appears limited when compared to DSAEK or PK.[31][32] Femtosecond and excimer laser-assisted EK (FELEK) uses a Femtosecond laser to dissect a thin graft that is smoothened with excimer photoablation. FELEK has shown some success on a small cohort of patients and may provide similar results to DMEK with less of a learning curve.[33] Femtosecond laser-enabled descemetorhexis DMEK (FE-DMEK) or Femtosecond laser-assisted DMEK (F-DMEK) has been used to perform the descemetorhexis for DMEK, resulting in fewer graft detachments and need for rebubbling when compared to manual descemetorhexis.[34][35][36] In settings with a scarcity of donor tissue, some modified or newer techniques may offer a solution. Hemi-DMEK and quarter-DMEK are variations involving grafts with smaller, modified shapes prepared by surgeons, and they appear to have similar visual outcomes, although with lower endothelial cell density.[30][37][38] Mini-DMEK is another technique where a graft is shaped and sized to fit a patient's particular endothelial defect. It has been used to treat acute corneal hydrops secondary to keratoconus in a small cohort of patients.[39] The observation of corneal clearing despite nonattachment of grafts in some cases has led to investigating techniques that do not use transplants, and instead, rely on primary intention healing of the endothelium (Fig. 2E).[40][41] These techniques have been termed Descemetorhexis without endothelial keratoplasty (DWEK) coined by Kaufman et al. or, increasingly becoming the norm, Descemet stripping only (DSO) proposed by Dr. Gorovoy.[40][42] ROCK inhibitors have also been used with DSO to salvage failing cases, speed up the recovery, and improve endothelial cell density in patients with Fuchs endothelial dystrophy.[43][44]

The observation of corneal clearing despite nonattachment of grafts in some cases has led to investigating techniques that do not use transplants, and instead, rely on primary intention healing of the endothelium (Fig. 2E).[40][41] These techniques have been termed Descemetorhexis without endothelial keratoplasty (DWEK) coined by Kaufman et al. or, increasingly becoming the norm, Descemet stripping only (DSO) proposed by Dr. Gorovoy.[40][42] ROCK inhibitors have also been used with DSO to salvage failing cases, speed up the recovery, and improve endothelial cell density in patients with Fuchs endothelial dystrophy.[43][44] Further comparison studies are warranted, but DSO may provide similar visual outcomes to DMEK after a longer recovery time without the risk of rejection, detachment, or need for immunosuppression.[45] Corneal clearance, despite subtotal detachment of grafts, has also inspired a purposed technique, Descemet membrane endothelial transfer (DMET), involving a focally attached free-floating graft to serve as a source of endothelial cells (Fig. 2F).[46][47] However, retrospective studies of DMEK cases with subtotal detachment do not always have satisfying results[48], and it is not entirely clear whether corneal clearance is due to endothelial cell transfer or simply primary intention healing of host endothelium.

Graft Detachment The most common early post-op complication in DSAEK and DMEK is graft detachment. DSEK graft detachments often resolve spontaneously, and rebubbling is reserved for complete detachments. Strategies to prevent DSEK detachment include ensuring the recipient site as larger or greater than graft size, counseling patients to avoid eye rubbing, using a long-acting gas (20% sulfur hexafluoride) bubble tamponade, and using intraoperative OCT to appreciate fluid in the graft-host interface that may be massaged out or drained via venting incisions.[1][13][81] The incidence of DMEK detachment varies, but some reports rate it as high as 74%. DMEK detachment is less likely to resolve spontaneously due to the graft's tendency to roll up. Detachments of the central cornea or involving more than one-third of the graft may require rebubbling, which is often successful but may result in a decreased endothelial cell density. If there is total detachment or the graft has rolled up, the patient may need regrafting.[1][26][82] Primary Graft Failure Primary graft failure is defined as the lack of improvement of corneal edema requiring regrafting. Primary graft failure may be attributed, in part, to the quality of donor tissue; however, the complexity of these techniques and potential for graft trauma may mean a surgeon's skill is a significant factor. The difference in surgeon familiarity and skill with these procedures may cause a "center effect" seen when comparing graft failure rates by low volume surgeons in the midst of a learning curve versus those performed at high-volume transplant centers.[83] After overcoming an apparent learning curve, the rate of rebubbling and regrafting is similar between DSEK and DMEK along with improved survival of DMEK grafts.[84][85] A 2018 report by the American Academy of Ophthalmology reviewing the safety and outcomes of DMEK and DSEK in the literature found that the primary graft failure rate for DMEK ranges from 0-12.5% with a mean of 1.7% and ranges from 0-29% with a mean of 5% for DSEK.[84] Pupillary Block and Increasing IOP

Primary graft failure is defined as the lack of improvement of corneal edema requiring regrafting. Primary graft failure may be attributed, in part, to the quality of donor tissue; however, the complexity of these techniques and potential for graft trauma may mean a surgeon's skill is a significant factor. The difference in surgeon familiarity and skill with these procedures may cause a "center effect" seen when comparing graft failure rates by low volume surgeons in the midst of a learning curve versus those performed at high-volume transplant centers.[83] After overcoming an apparent learning curve, the rate of rebubbling and regrafting is similar between DSEK and DMEK along with improved survival of DMEK grafts.[84][85] A 2018 report by the American Academy of Ophthalmology reviewing the safety and outcomes of DMEK and DSEK in the literature found that the primary graft failure rate for DMEK ranges from 0-12.5% with a mean of 1.7% and ranges from 0-29% with a mean of 5% for DSEK.[84] Pupillary Block and Increasing IOP Pupillary block by air may lead to serious glaucomatous damage to the eye. This risk is highest in DMEK as more air is used, and the associated risk is greater still with DMEK triple procedures. It should be suspected if there is increasing intraocular pressure (IOP), obscured iridotomy, or presence of pain or loss of vision. Prevention of pupillary block includes peripheral iridotomy and removal of some air to avoid complete filling of the anterior chamber after graft adhesion.[26][80] Post-keratoplasty glaucoma and increasing IOP is another common complication after DSEK and DMEK that is usually due to steroid responsiveness. Risk factors include a previous diagnosis of glaucoma or elevated IOP, and treatment may include tapering the steroid dose.[86][87] Rejection

Pupillary block by air may lead to serious glaucomatous damage to the eye. This risk is highest in DMEK as more air is used, and the associated risk is greater still with DMEK triple procedures. It should be suspected if there is increasing intraocular pressure (IOP), obscured iridotomy, or presence of pain or loss of vision. Prevention of pupillary block includes peripheral iridotomy and removal of some air to avoid complete filling of the anterior chamber after graft adhesion.[26][80] Post-keratoplasty glaucoma and increasing IOP is another common complication after DSEK and DMEK that is usually due to steroid responsiveness. Risk factors include a previous diagnosis of glaucoma or elevated IOP, and treatment may include tapering the steroid dose.[86][87] Rejection The presentation of immune rejection in DSEK is more subtle than after PK and often diagnosed incidentally. A study by Price et al. found that 35% of diagnosed patients were asymptomatic. Signs include diffuse or focal precipitates on slit-lamp examination, corneal edema, anterior chamber cells, and rarely Khodadoust Line. The risk of rejection is higher for African Americans, preexisting glaucoma, and steroid responders. A retrospective analysis by Price et al. found in 1312 DSEK cases for FECD, there was a 5-year rejection rate of 7.9%. DSEK rejection is typically treated with tapering doses of topical steroids.[88][89][90] Of note, a case of an autologous DSEK procedure was used to treat a patient with previous endothelial graft rejection.[91] DMEK rejection is diagnosed by the presence of retrocorneal precipitates on the graft on the slit-lamp examination. A retrospective analysis of 905 eyes found a very low rejection incidence of 2.4% over four years. Local steroid therapy resolves most cases, and some authors recommend prophylactic topical steroid therapy for the first 1-2 years postoperatively.[90][92] Intraoperative Hyphema Intraoperative hyphema may occur with DMEK, and this risk was shown to be higher in cases with combined cataract surgery. However, hyphema was not shown to significantly affect endothelium cell loss, visual acuity outcomes, or rebubbling rates.[93]

EK procedures have the potential to significantly improve patients' visual outcomes while avoiding the complications associated with previous techniques. Rapid development has led to a variety of techniques that may be more appropriate than others in particular situations, so healthcare teams need to refer and treat appropriate candidates with procedures that are suited to a surgeon's skills and patients' particular risk factors. The healthcare team should also be aware of the potential complications that need to be prevented, monitored, and treated should they occur.