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.

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).

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]

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]

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.

The cornea protects internal structures of the eye and provides 40-44 D of refractive power, which is approximately 70% of total refraction. The layers of the cornea, from anterior to posterior, include the epithelium, Bowman layer, stroma, Descemet membrane, and endothelium (Fig. 1). The epithelium is a protective layer and provides a smooth surface for the tear film-cornea interface that contributes to refractive power. Bowman layer is the most anterior portion of the stroma and assists in maintaining corneal shape. The stroma is the primary refracting medium of the cornea and source of mechanical strength. The stromal collagen fibers are organized in parallel bundles called fibrils that are arranged in layers at right angles to one another called lamellae. The lamellae are highly interlaced anteriorly but become less so posteriorly. This puts the posterior stroma at risk of becoming swollen when hydrated. The cornea is highly innervated with subepithelial and stromal plexuses supplied by the ophthalmic nerve. Descemet membrane is secreted by endothelial cells and serves as an attachment for endothelium to the stroma via numerous hemidesmosomes.[49] Although somewhat controversial, a strong pre-Descemet layer (also referred to as "Dua Layer") has been discovered on the posterior stroma using pneumodissection and may have clinical and surgical significance.[50]

The endothelium is a monolayer of hexagonal cells with extensive lateral interdigitations and incomplete belt of tight junctions. According to the pump-and-leak hypothesis, anterior chamber contents gradually leak into the corneal stroma supplying it with nutrients.[51] The activity of the endothelial cells creates a net flux of ions out of the stroma into the aqueous humor, ensuring the removal of water from the stroma. Dehydration of the stroma is essential for corneal clarity. Endothelial cell density gradually decreases with age. To compensate for cell loss, endothelial cells migrate, increase in size, and lose their hexagonal morphology. Unfortunately, once cell density falls below a 500-700 cell/mm threshold due to aging or disease, the endothelial capacity to pump may become insufficient, and corneal stromal edema will follow. It was believed that endothelial cells do not undergo mitosis in adults. The cells have shown to exhibit contact inhibition, and there is a scarcity of positive growth factors and abundancy of negative growth factors in the anterior chamber. However, ex vivo and in vitro growth of endothelial cells has been demonstrated, and progenitor-like endothelial cells have been identified at the endothelium-trabecular meshwork transition zone.[41][49][52]

Endothelial Diseases

Diseases affecting the corneal endothelium leading to the surgical intervention will be briefly described.

Fuchs Endothelial Corneal Dystrophy (FECD)

FECD is the most common corneal dystrophy. It presents bilaterally in the second to third decade of life, but there is also a rare early-onset subtype. It displays autosomal dominant inheritance, but sporadic cases are most common. The characteristic features of FECD are the formation of excrescences from the Descemet membrane called guttae, loss of corneal endothelial cell density, and progressive corneal edema. The guttae are visible upon slit-lamp examination, and they develop centrally then coalesce and begin appearing peripherally over the years. Evaluating the distribution of guttae serves as the basis for clinical staging. The endothelial cells in FECD have less antioxidant gene expression and more apoptosis-related factors leading to decreased endothelial cell density. The chronic corneal edema that results causes progressive blurry vision and may lead to painful epithelial bullae.[53][54]

Pseudophakic and Aphakic Bullous Keratopathy

This disease is a complication of cataract surgery after an artificial intraocular lens is placed (pseudophakic) or not (aphakic). Incidence is 1-2% of cataract surgeries, and risk factors include advanced age or concurrent endothelial disease. The loss of endothelial cells in this disease is a consequence of surgical trauma such as heat from phacoemulsification or high irrigation and aspiration rates, causing turbulence and rapidly moving lens particles. The loss of endothelial cells results in corneal stromal edema, subepithelial bullae, tearing, decreased vision, and pain.[55]

Iridocorneal Endothelial Syndrome (ICE)

ICE is a rare syndrome made up of three clinical variants that include Chandler syndrome, progressive essential iris atrophy, and Cogan-Reese syndrome. Common to all variants is the pathologic proliferation of corneal endothelial cells that migrate to the iridocorneal angle and iris, possibly due to a viral trigger. Pathognomonic to ICE syndrome are endothelial "ICE cells" that have a dark-light reversed pattern on specular microscopy found in areas of the cornea with a hammered silver appearance. Hallmarks of the disease include irregular endothelium structure, blockage of the iridocorneal angle, and iris abnormalities (e.g., atrophy, corectopia, or polycoria). These changes lead to secondary glaucoma and corneal edema and decompensation.[56][57]

Posterior Polymorphous Dystrophy (PPCD):

PPCD is a rare, autosomal-dominant, bilateral disease affecting the Descemet membrane and corneal endothelium. This disease has variable expressivity, and presentations range from asymptomatic irregularities of the endothelium to symptomatic corneal edema or glaucoma. It typically presents asymptomatically in the first decade of life then progresses at varying rates. Findings on specular microscopy include asymmetric patches of geographic gray hazy lesions, grouped vesicles, and broad bands with scalloped margins as well as stratified epithelium-like endothelium. Other common findings are anterior synechiae and glaucoma.[58][59]

Congenital Hereditary Endothelial Dystrophy (CHED):

CHED is a rare inherited disease affecting the corneal endothelium characterized by ground glass-like corneal opacification due to endothelium failure and corneal edema as well as and nystagmus. It presents at or shortly after birth. Two genetic forms exist, namely, CHED1, which is autosomal dominant, and CHED2, which is autosomal recessive. CHED2 is more common than CHED1 and share similarities with PPCD, e.g., similar specular microscopy findings.[58][59]

Patients with endothelial dysfunction and visual disability are appropriate candidates. Fuchs endothelial corneal dystrophy, aphakic or pseudophakic bullous keratopathy, and previous penetrating or endothelial graft failures are the most common indications. Less common indications include endothelial failure secondary to trauma, iridocorneal endothelial syndrome, posterior polymorphous dystrophy, and congenital hereditary endothelial dysfunction.[1][60] DMEK has also been used to salvage a failed PK with better visual outcomes and similar four-year survival as repeat PK and DSEK.[26][61]

In extensive disease resulting in full-thickness stromal scarring such as advanced bullous keratopathy, a PK may be more appropriate. The stromal scaring and opacities lead to failure to improve patient vision as well as limit the surgeon's view.[26] Some relative contraindications for DMEK include cases where patients have glaucoma tubes, aphakia, or iris defects because the thin grafts may be lost; therefore, DSAEK or a hybrid DMEK may be preferred.[60] Ocular pressurization may be necessary for graft attachment, so pre-phthisic or hypotonic eyes are contraindicated to avoid the progression of bulbar atrophy.[26]

Along with basic ophthalmologic operating room equipment, a microkeratome may be required depending on the technique. Donor tissue used for DSEK and DMEK may be prepared by the surgeon, usually on the day of surgery or obtained from an eye bank. Glide or mechanical injection devices for the insertion of grafts will be needed for DSEK. An intraocular lens injector may be used for DMEK graft insertion. A viscoelastic substance or air injection may be used for better visualization, and anterior chamber irrigation may be used to maintain anterior chamber depth.