Corneal transplantation
Corneal transplantation, also known as keratoplasty, is a surgical procedure that replaces a damaged or diseased portion of the cornea—the transparent front layer of the eye—with healthy corneal tissue from a deceased donor to restore vision impaired by conditions such as keratoconus, corneal scarring from infection or injury, Fuchs' endothelial dystrophy, or chemical burns.[1][2] The technique addresses corneal opacity or irregularity, which accounts for a significant portion of global blindness treatable through transplantation, with donor corneas preserved via methods like organ culture or hypothermic storage to maintain viability.[1][3] The first successful full-thickness human corneal transplant was performed on December 7, 1905, by Austrian ophthalmologist Eduard Zirm in Olomouc, then part of Austria-Hungary, using tissue from an 11-year-old donor split for bilateral grafts in a 45-year-old laborer blinded by lime burns; one graft remained clear for years, marking a milestone in ophthalmic surgery.[4][5] Early attempts dated to the 19th century but failed due to inadequate suture techniques and immune rejection, with modern advancements in microsurgery, immunosuppressive drugs like corticosteroids, and tissue matching improving outcomes.[1][3] Contemporary procedures include penetrating keratoplasty (PK), a full-thickness replacement still used for extensive damage, and selective lamellar techniques such as deep anterior lamellar keratoplasty (DALK) for stromal disorders or endothelial keratoplasty variants like Descemet's stripping automated endothelial keratoplasty (DSAEK) for endothelial dysfunction, which preserve the patient's epithelium or endothelium to minimize rejection and accelerate recovery.[6][2][3] Graft survival rates exceed 90% at one year for indications like keratoconus, though they decline to 70-80% at five years depending on factors including patient age, preoperative vascularization, and glaucoma history; complications encompass acute rejection (managed with steroids), infection, elevated intraocular pressure, and suture-related issues.[7][2][1] These procedures have restored sight to millions worldwide, with endothelial techniques reducing astigmatism and suture needs compared to PK, though challenges persist in high-risk cases with prior vascularization or repeated failures.[3][8]Indications and Patient Selection
Conditions Treated
Corneal transplantation, also known as keratoplasty, is primarily indicated for conditions causing significant corneal opacity, irregularity, or endothelial dysfunction that impair vision and cannot be adequately managed by conservative measures such as medications or spectacles.[1] The procedure aims to restore optical clarity, alleviate pain from decompensated endothelium, or structurally reinforce a thinned cornea.[9] In developed countries, endothelial diseases account for the majority of cases, comprising approximately 60% of transplants, while globally, infectious and traumatic etiologies predominate in resource-limited settings.[10][11] Keratoconus, a progressive noninflammatory ectatic disorder characterized by corneal thinning and protrusion, is a leading indication for anterior or full-thickness transplantation when advanced disease causes intolerable irregular astigmatism or hydrops.[1] It represents about 57% of deep anterior lamellar keratoplasty procedures in some series, often in younger patients where earlier interventions like cross-linking have failed.[12] Fuchs' endothelial dystrophy, the most common primary corneal endothelial disorder in older adults, leads to guttae formation, stromal edema, and eventual bullous keratopathy, necessitating endothelial keratoplasty in symptomatic cases with reduced visual acuity or pain from epithelial bullae.[13] It accounts for roughly 82% of Descemet membrane endothelial keratoplasty (DMEK) transplants and is the fourth most frequent reason for transplantation overall in the United States.[12][14] Pseudophakic or aphakic bullous keratopathy, resulting from endothelial cell loss following cataract surgery or intraocular lens complications, is the predominant indication in developed nations, driven by chronic stromal edema and epithelial breakdown unresponsive to hypertonic saline therapy.[1] Corneal scarring or opacity from trauma, infection (e.g., herpes simplex keratitis, bacterial ulcers), or chemical burns often requires transplantation when central involvement causes functional blindness, comprising 25-35% of cases in various registries and up to 80% of avoidable corneal blindness worldwide.[15][16][11] Less common indications include limbal stem cell deficiency with persistent epithelial defects, failed prior grafts, or tectonic support for perforated corneas, though success rates diminish with vascularization or repeated surgeries.[9]Selection Criteria and Contraindications
Patient selection for corneal transplantation requires evaluation of visual potential, confirming functional retina and optic nerve via fundus examination or electroretinography where necessary, as transplantation addresses only anterior segment pathology and yields no benefit for posterior segment diseases like advanced glaucoma or macular degeneration.[1] Candidates must demonstrate adequate ocular surface stability, including sufficient tear production and lid apposition, to support graft survival, with preoperative Schirmer testing or tear breakup time assessment guiding suitability.[1] Systemic health permitting anesthesia and immunosuppression, along with patient compliance for intensive postoperative topical steroid and antibiotic regimens—typically hourly initially—are essential, as nonadherence elevates rejection risk by up to 20-30% in studies of graft failure.[1] Age alone does not preclude eligibility; successful outcomes occur in patients over 90 years with careful preoperative optimization, though pediatric cases demand consideration of amblyopia risk.[17] Contraindications prioritize cases where procedural risks, including infection or rejection, exceed potential gains. Absolute contraindications include no light perception vision without concurrent pain unresponsive to conservative measures, as transplantation offers no functional restoration and incurs unnecessary morbidity.[18] Severe ocular surface disorders, such as advanced dry eye, Stevens-Johnson syndrome, or toxic epidermal necrolysis, preclude surgery due to heightened epithelial failure and graft melt rates exceeding 50% in affected cohorts.[9] Active intraocular infection, uncontrolled glaucoma with decompensated endothelium, or anterior staphyloma represent further absolutes, as they foster postoperative complications like endophthalmitis or graft dislocation.[9] Relative contraindications encompass psychosocial factors, including unrealistic expectations or inability to attend follow-ups, which correlate with poorer visual outcomes in longitudinal analyses.[19] ABO blood type incompatibility, while not absolute, warrants caution as mismatches increase failure odds by 1.5-2 fold per registry data, favoring matched donors when feasible.[20]Donor Tissue Management
Procurement and Ethical Considerations
Corneal procurement typically begins upon notification of a potential donor's death to an accredited eye bank by hospitals, organ procurement organizations, or funeral homes, with recovery ideally occurring within 24 hours to optimize tissue viability. Eye bank technicians or trained recovery personnel then screen the donor's medical and social history for eligibility, excluding cases involving active systemic infections, certain malignancies, or high-risk behaviors for transmissible diseases as defined by FDA regulations under 21 CFR Part 1271. Serologic testing follows for HIV, hepatitis B and C, and syphilis, with additional FDA-required evaluations for donor risk assessment to prevent disease transmission.[21] Tissue recovery involves either whole globe enucleation or in-situ corneoscleral rim excision under sterile conditions, followed by immediate placement in preservation media such as Optisol-GS, which allows storage for up to 14 days per FDA guidelines.[22] In the United States, the Eye Bank Association of America (EBAA) oversees standards, reporting 65.1% of 2024 corneal donors registered on donor registries, with total corneas recovered increasing 2.9% from 2023 to meet rising transplant demands.[23] Globally, procurement volumes vary; for instance, India retrieved 47,676 corneas in 2023 but utilized only about 61%, highlighting inefficiencies in processing and distribution.[24] Regulations prohibit the sale of human tissue, permitting eye banks only to recover reasonable costs for procurement, processing, and distribution, as enforced by the National Organ Transplant Act.[25] Ethically, procurement hinges on consent models: explicit opt-in via registries, family authorization post-mortem, or presumed consent in jurisdictions like Wales (since 2015) and England/Scotland (implemented 2020), which presumes donation absent prior objection to increase supply without coercing donors.[26] Family consent overrides registered intent in many systems, contributing to refusal rates of 20-40% due to concerns over bodily disfigurement or inadequate respect for remains, despite corneectomy leaving no visible alteration when performed properly.[27] Living-related donation raises distinct issues, including non-therapeutic surgery risks without direct benefit to the donor and potential coercion within families, necessitating rigorous informed consent distinct from cadaveric procurement.[28] Cross-border export of corneas prompts ethical scrutiny over donor intent, as general consent may not specify international use; proposals advocate explicit "consent-for-export" to honor potential preferences against allocation to foreign recipients, particularly amid global disparities where high-income countries import tissue despite domestic capabilities.[29] Cultural and religious barriers persist, with lower donation rates in regions fearing mishandling of cadavers, underscoring the need for transparent processes to build trust without compromising safety standards.[30] Equity in allocation prioritizes medical need over non-clinical factors, guided by EBAA protocols to avoid commodification while maximizing utility from limited supply.[31]Preservation and Quality Control
Corneal tissues for transplantation are primarily preserved using hypothermic storage in intermediate-term media such as Optisol-GS, which maintains endothelial viability for up to 14 days at 2-6°C by inhibiting metabolic activity and reducing stromal swelling.[32] This method, dominant in North America, supports endothelial cell densities and graft clarity comparable to shorter storage times, with studies showing functional preservation beyond 21 days in some cases, though standard protocols limit release to 14 days to ensure reliability.[33] In contrast, organ culture—prevalent in Europe—involves incubation at 31-37°C in nutrient-rich media supplemented with antibiotics, allowing storage up to 4 weeks but requiring decontamination protocols to manage microbial growth and endothelial cell loss over time.[34] Cryopreservation, involving freezing at -196°C, preserves stromal structure indefinitely but destroys endothelial cells, limiting its use to non-endothelial grafts or research.[35] Quality control begins with procurement and extends through preservation, governed by standards from organizations like the Eye Bank Association of America (EBAA), which mandate donor screening for infectious risks via serologic testing for HIV, hepatitis B/C, syphilis, and other pathogens, alongside medical history review to exclude contraindications such as active malignancy or sepsis.[36] Tissue evaluation includes slit-lamp biomicroscopy to assess clarity, absence of epithelial defects, Descemet's membrane integrity, and sufficient rim size, followed by specular microscopy for endothelial cell density (ECD), with eye bank policies typically requiring a minimum of 2000 cells/mm² for endothelial-involving procedures to predict graft survival.[22] Sterility is verified through cultures of preservation media incubated for at least 48 hours, testing for bacteria and fungi, while EBAA protocols emphasize documentation of death-to-preservation intervals—ideally under 24 hours—to minimize ischemic damage.[31] Ongoing quality assurance in eye banks incorporates periodic audits, endothelial viability assays, and rejection rates tracking, with programs demonstrating increased tissue utilization by identifying and discarding substandard lots early, thereby reducing postoperative failure risks from poor preservation.[37] Advances in media formulation continue to refine these processes, prioritizing endothelial hexagonality and polymegathism metrics to better correlate storage duration with long-term graft outcomes.[38]Surgical Procedures
Preoperative Preparation
Preoperative preparation for corneal transplantation begins with a comprehensive evaluation of the patient's ocular and systemic health to ensure suitability for surgery and minimize risks. This includes a detailed medical history review to identify comorbidities such as diabetes mellitus, autoimmune disorders, or active infections that could impair healing or increase complication rates, alongside a thorough ocular examination involving slit-lamp biomicroscopy, tonometry, fundus evaluation, and assessment of tear film stability.[1] Specular microscopy is routinely performed to quantify endothelial cell density, typically requiring at least 1,000 to 2,000 cells/mm² for optimal graft viability, while anterior segment optical coherence tomography (AS-OCT) and corneal topography aid in planning the surgical approach, particularly for lamellar techniques.[1] [9] Systemic evaluation may involve consultation with primary care providers to optimize conditions like hypertension or coagulopathies, with laboratory tests such as complete blood count, coagulation profile, and blood glucose levels recommended if indicated by history.[2] Medication reconciliation is critical, often requiring discontinuation of anticoagulants (e.g., aspirin or warfarin) 7 to 10 days prior under medical supervision to reduce intraoperative bleeding risk, while continuing essential therapies like antihypertensives with sips of water on the day of surgery.[39] [1] Patients are instructed to cease contact lens wear at least 1 to 2 weeks beforehand to avoid corneal warping that could affect measurements, and any active ocular surface disease, such as dry eye or blepharitis, is treated preemptively to enhance postoperative epithelial healing.[1] Informed consent is obtained after discussing procedure-specific risks, including infection (incidence approximately 0.1-1%), graft rejection (up to 20-30% in high-risk cases), glaucoma, and astigmatism, with success rates varying by indication—e.g., over 90% graft survival at 1 year for Fuchs' dystrophy but lower for vascularized corneas.[2] [1] Preoperative counseling emphasizes realistic expectations, such as potential need for spectacles or contact lenses post-surgery due to induced refractive errors, and adherence to immunosuppression protocols. On the day of surgery, patients fast after midnight, arrive in loose clothing without facial makeup or jewelry, and may receive prophylactic topical antibiotics or mydriatics as per surgeon protocol.[39] [40]Full-Thickness Penetrating Keratoplasty
Penetrating keratoplasty (PK), also known as full-thickness corneal transplantation, involves the excision of the patient's central cornea through its entire thickness and replacement with a full-thickness donor corneal graft.[9] This procedure addresses severe corneal opacities, decompensations, or structural defects that impair vision or ocular integrity, serving as the traditional standard before the advent of selective lamellar techniques.[3] First successfully performed by Eduard Zirm on a human patient in 1905, PK marked a milestone in ophthalmic surgery, with early success attributed to precise suturing and tissue matching.[9][41] The surgical technique requires operating under a surgical microscope with the patient under local or general anesthesia. The host cornea is centered and marked with a circular marker, followed by partial-depth trephination using a handheld or motorized trephine to a depth of approximately 80% to avoid perforation.[9] Completion of the host button excision is achieved with a sharp blade or scissors, such as Vannas scissors. The donor cornea, typically oversized by 0.25 to 0.5 mm in diameter (common sizes 7.0 to 7.5 mm for host), is prepared by punching with a corresponding trephine on an artificial anterior chamber.[9][3] Suturing secures the donor graft to the recipient bed, beginning with four cardinal sutures at the 12, 3, 6, and 9 o'clock positions using 10-0 nylon monofilament to ensure alignment and minimize astigmatism.[42] Common techniques include interrupted sutures (typically 16 to 24 bites), single continuous running suture (10-0 nylon with 16 bites), or combined interrupted and continuous methods, with the choice influencing postoperative astigmatism and suture adjustment ease.[9][43] Femtosecond laser-assisted trephination has been employed in some cases to enhance wound edge configuration and reduce irregular astigmatism, though its routine use remains debated due to cost and availability.[3] Postoperatively, graft survival varies by indication, exceeding 90% at five years for keratoconus but lower (50-80%) for inflammatory conditions like keratitis, reflecting risks of rejection and endothelial failure.[9][3] Despite these outcomes, PK provides a robust optical result without lamellar interfaces, though it carries higher complication rates compared to endothelial keratoplasty, including suture-related issues and elevated intraocular pressure.[3]Lamellar Techniques
Lamellar keratoplasty encompasses surgical procedures that selectively replace diseased corneal layers while preserving healthy recipient tissue, in contrast to full-thickness penetrating keratoplasty (PK), which excises the entire cornea.[44] These techniques divide into anterior approaches, targeting the stroma for conditions like keratoconus or scarring, and posterior or endothelial approaches, addressing endothelial dysfunction such as in Fuchs' dystrophy.[44][45] The primary advantages of lamellar methods over PK include a substantially reduced risk of endothelial graft rejection—reported at 34% to 68% in PK cases—and maintenance of globe integrity, which lowers intraoperative risks like expulsive hemorrhage and postoperative complications such as endophthalmitis.[45][44] Preservation of the recipient's healthy endothelium in anterior techniques or stroma in endothelial techniques also permits less stringent donor tissue criteria and enhances tectonic stability, with studies indicating burst pressures of 500-700 mmHg in deep anterior lamellar keratoplasty compared to PK.[45] Despite these benefits, lamellar techniques present limitations, including potential interface opacity or haze that may impair visual quality, technical demands such as achieving precise lamellar dissection, and procedure-specific risks like Descemet's membrane rupture in anterior methods or graft dislocation in endothelial ones.[44] Outcomes vary by subtype, but overall, lamellar procedures facilitate faster visual rehabilitation and minimal induced astigmatism due to suture-free or limited-suture designs in many variants.[45] Modern advancements, including the big-bubble technique introduced in 2002 for deep anterior dissection and automated preparation for endothelial grafts, have improved feasibility and success rates since the early 2000s.[45]Anterior Lamellar Keratoplasty
Anterior lamellar keratoplasty (ALK) refers to a group of partial-thickness corneal transplant procedures that replace diseased or opaque anterior stromal layers while preserving the recipient's healthy Descemet's membrane and endothelium.[45] This approach minimizes risks associated with full-thickness penetrating keratoplasty (PK), such as endothelial cell loss and intraocular complications, by avoiding entry into the anterior chamber.[46] ALK techniques are classified by depth: superficial anterior lamellar keratoplasty (SALK) for very anterior opacities, automated lamellar therapeutic keratoplasty (ALTK) or hemi-automated variants for mid-stromal pathology using microkeratomes, and deep anterior lamellar keratoplasty (DALK) for near-full stromal replacement.[47][48] Indications for ALK primarily include conditions confined to the anterior or mid-stroma, such as post-traumatic scars, infectious keratitis sequelae, anterior dystrophies (e.g., granular or lattice), and early-stage keratoconus without endothelial involvement.[49] It is contraindicated in cases with endothelial decompensation, deep stromal vascularization risking rejection, or active infection extending beyond the targeted layers.[50] Patient selection favors those with adequate endothelial reserve, confirmed via specular microscopy showing cell density above 2000-2500 cells/mm² preoperatively.[49] Surgical techniques vary by depth and tools. SALK involves manual lamellar dissection to remove superficial opacities, followed by suturing an overlay graft, suitable for nebulomacular scars from refractive surgery complications.[47] ALTK employs a microkeratome to create planar donor and host beds for anterior-to-mid stromal replacement, improving predictability over manual methods but limited to non-perforating depths.[51] DALK, the most common variant, uses methods like Anwar's big-bubble technique—injecting air or viscoelastic to separate Descemet's from stroma—or femtosecond laser-assisted dissection for precise, sutureless interfaces in select cases.[52] Intraoperative challenges include achieving bare Descemet's without perforation (success rates 70-90% with experienced surgeons) and managing incomplete baring via manual completion.[49] Postoperative outcomes demonstrate high efficacy, particularly for DALK in keratoconus, with 10-year graft survival rates of 96.7% and median survival projected at 49 years versus 17 years for PK.[53][54] Visual recovery is faster than PK, achieving best-corrected acuity of 20/40 or better in 70-90% of cases by 12 months, though interface haze may initially limit spectacle-corrected vision.[55] Rejection rates are markedly lower (2-5% endothelial rejection versus 10-20% in PK) due to preserved host endothelium, but stromal rejection can occur in 10-15% of vascularized cases.[50][56] Complications specific to ALK include intraoperative microperforations (5-10% in DALK, managed with stromal patching), postoperative interface irregularities causing astigmatism (reducing with suture adjustment), and Descemet's folds from incomplete adherence (resolving in 80% without intervention).[52] Long-term risks encompass suture-related infections or loosening (up to 36% in some series) and recurrent ectasia if dissection is insufficiently deep, though overall failure rates remain below 5% at 5 years.[57] Compared to PK, ALK reduces cataract formation and glaucoma risks by 50-70%, supporting its preference for anterior pathology in phakic eyes.[58]Endothelial Keratoplasty
Endothelial keratoplasty (EK) selectively replaces the dysfunctional corneal endothelium and Descemet membrane with donor tissue, preserving the recipient's stromal and epithelial layers to minimize surgical trauma and promote rapid recovery. Introduced as an evolution from earlier deep lamellar endothelial keratoplasty (DLEK) in the late 1990s, EK techniques gained prominence with Descemet's stripping endothelial keratoplasty (DSEK) in 2004, which involves manual or automated preparation of a donor graft including endothelium, Descemet membrane, and a thin stromal layer (typically 100-200 μm thick).[59][60] A further refinement, Descemet membrane endothelial keratoplasty (DMEK), developed subsequently by Melles and colleagues, uses an ultrathin graft comprising only the endothelium and Descemet membrane (10-15 μm thick), excluding stromal tissue for potentially superior optical outcomes.[59] Indications for EK primarily include endothelial decompensation from conditions such as Fuchs endothelial corneal dystrophy and pseudophakic or aphakic bullous keratopathy, where the procedure restores pump function to deturgesce the cornea without addressing anterior pathology.[59] Surgical technique begins with topical anesthesia and a 2- to 3-mm temporal clear corneal incision, followed by descemetorhexis—a controlled stripping of the host's diseased endothelium and Descemet membrane using a reversed Sinskey hook under air or viscoelastic to maintain anterior chamber depth. For DSEK or Descemet stripping automated endothelial keratoplasty (DSAEK), the donor graft is prepared by punching an 8-mm trephination and microkeratome dissection (in DSAEK) or manual stromal cleavage (in DSEK), then folded into a "taco" configuration with trypan blue staining for visibility, inserted via forceps or a glide sheet, and unfolded in the anterior chamber.[59] An air or sulfur hexafluoride bubble is injected to appose the graft to the host stroma, with partial venting after 5-10 minutes to prevent pupillary block; the patient is positioned supine for 30-60 minutes to facilitate adhesion.[59] DMEK preparation involves scoring and stripping the donor Descemet membrane in an eye bank setting for standardization, followed by "pizza roll" folding of the stain-marked scroll, insertion through an injector, and unfolding using specialized maneuvers like taps or fluid currents before air tamponade.[59][60] Compared to penetrating keratoplasty, EK reduces suture-related astigmatism (<1 diopter typically), shortens recovery to weeks rather than months, and lowers rejection risk due to less antigenic stromal exposure—DMEK rejection rates average 1.5-2.4% at 4 years versus 5-7.9% for DSEK/DSAEK and up to 20% for full-thickness grafts.[59][60] Graft survival reaches 93% at 5 years for both DSEK and DMEK, with DMEK extending to 90-96% at 5 years and showing 10% rejection at 10 years in some cohorts, though primary graft failure is higher in DMEK (mean 1.7%, range 0-12.5%) due to handling fragility.[59][61][62] Visual outcomes favor DMEK, with best spectacle-corrected acuity improving to 20/25 or better in 70-80% of cases within 3-6 months, attributed to minimal interface haze from the thinner graft.[60] Intraoperative challenges include incomplete descemetorhexis or graft inversion, while postoperative risks encompass partial detachment (up to 74% in early DMEK series, often managed by rebubbling in 20-30% of cases) and endothelial cell loss (35-80% at 5 years, higher initially).[59][60] Donor tissue selection emphasizes endothelial cell density >2,300 cells/mm² and viability >90% to optimize long-term function.[59] Despite a steeper learning curve for DMEK (approximately 25-50 cases to proficiency), its adoption has increased for its refractive stability and reduced higher-order aberrations.[60]Intraoperative and Postoperative Protocols
Intraoperative protocols for corneal transplantation are conducted under strict aseptic conditions, typically using local or general anesthesia, with povidone-iodine preparation and draping to minimize infection risk.[9] In penetrating keratoplasty (PK), the central host cornea is marked at 7-7.5 mm diameter and trephined to 80% depth using a handheld or motorized trephine, followed by completion of the excision with an MVR blade and scissors to enter the anterior chamber; a donor button, punched 0.25-0.5 mm larger than the host bed on a Teflon block, is then placed under viscoelastic protection and secured with 10-0 nylon sutures—either 4 cardinal interrupted sutures initially, followed by 16-24 additional interrupted or a continuous running configuration—to achieve watertight closure and minimize astigmatism.[9] For lamellar procedures like deep anterior lamellar keratoplasty (DALK), stromal dissection employs techniques such as the big-bubble method to bare Descemet's membrane while preserving the endothelium, with the donor graft sutured to the host rim.[1] In endothelial keratoplasty (e.g., DSAEK or DMEK), the host endothelium and Descemet's membrane are stripped manually or with automated assistance, the donor lenticule (including partial stroma in DSAEK or isolated membrane in DMEK) is folded or scrolled for insertion via a small incision, unfolded, and apposed to the host using an air or sulfur hexafluoride bubble to promote adhesion, often with trypan blue staining for visualization in DMEK.[1] Intraoperative considerations include avoiding iris or lens trauma during open-sky phases in PK, using viscoelastic to maintain anterior chamber depth, and performing peripheral iridectomy if indicated to prevent pupillary block.[9] Postoperative protocols prioritize immunosuppression, infection prevention, and graft stabilization, with variations by procedure type and patient risk factors such as vascularization or prior rejection.[63] Topical corticosteroids, such as 1% prednisolone acetate or 0.1% dexamethasone, are initiated hourly for the first 1-2 days post-PK, then tapered gradually over 6-12 months to once-daily indefinite use in high-risk cases, while lower-intensity regimens (e.g., fluorometholone once daily) suffice for DMEK in pseudophakic eyes; systemic steroids like intravenous methylprednisolone (1 g twice daily for 3 days) followed by oral prednisone taper may supplement high-risk PK.[9][63] Broad-spectrum topical antibiotics (e.g., fluoroquinolones) are administered 4-6 times daily for 2 weeks to avert endophthalmitis, with cycloplegics like homatropine for pain and antiglaucoma agents (e.g., timolol) if intraocular pressure rises.[9] For endothelial keratoplasty, patients maintain a supine position (face-up) for several hours to days to ensure bubble-mediated graft attachment, avoiding vigorous activity; protective eye shields are worn at night, and eye rubbing or pressure is prohibited to prevent dislocation or suture issues in PK.[2][1] Follow-up begins within 24-48 hours, with frequent visits in the first year to assess visual acuity, intraocular pressure, suture integrity (selective removal in PK after 6-12 months to reduce astigmatism), and rejection signs like ciliary flush or keratic precipitates, continuing annually lifelong due to rejection risks persisting beyond 10% even after initial healing.[2][63] Lubricants and avoidance of alcohol or water exposure to the eye aid comfort, while full visual rehabilitation, including spectacles or contact lenses, is delayed 3-12 months pending stromal clarity.[2][9]Complications and Risks
Intraoperative and Early Postoperative Risks
Intraoperative complications during corneal transplantation, particularly in full-thickness penetrating keratoplasty (PK), include expulsive choroidal hemorrhage (ECH), a rare but potentially devastating event resulting from rupture of short posterior ciliary arteries under elevated episcleral venous pressure during the open-sky phase.[64] Risk factors for choroidal hemorrhage encompass preoperative hypertension, glaucoma, and high myopia, with incidence rates reported as low as 0.67% in large series but associated with poor visual outcomes when occurring.[65] Other PK-specific risks involve iris prolapse, vitreous loss, lens capsule damage, and irregular trephination leading to astigmatism or poor centration, often mitigated by manual or femtosecond laser-assisted techniques.[66] In endothelial keratoplasty procedures such as Descemet membrane endothelial keratoplasty (DMEK) or Descemet stripping automated endothelial keratoplasty (DSAEK), intraoperative challenges primarily consist of difficulties in graft insertion, unfolding, positioning, or manipulation, occurring in approximately 5% of cases for DMEK.[67] Intraoperative fibrin formation, though uncommon (affecting <5% in reported series), can complicate graft adherence and increase endothelial cell trauma.[68] Donor tissue damage or air tamponade-related issues, such as pupil block, represent additional hazards, with overall intraoperative complication rates decreasing with surgeon experience to below 10%.[69] Early postoperative risks, within the first weeks following surgery, frequently involve elevated intraocular pressure (IOP), reported in up to 20.7% of PK cases and linked to steroid use or incomplete air removal in endothelial procedures.[70] Graft detachment or dislocation is prevalent in lamellar techniques, affecting 23% of DSAEK grafts and necessitating re-bubbling in 10-20% of DMEK cases due to incomplete adhesion or pupillary block.[71] Wound-related issues, including dehiscence and suture loosening in PK (incidence ~5-10% in early period), heighten vulnerability to trauma and infection.[72] Infectious keratitis emerges as a critical early threat, with rates around 1-5% across procedures, often bacterial or fungal, exacerbated by epithelial defects or suture exposure.[73] Acute inflammation or sclerokeratitis, alongside double anterior chamber formation in lamellar grafts, can precipitate graft failure if unmanaged, underscoring the need for vigilant monitoring and topical prophylaxis.[74] Overall early complication rates hover at 20-33%, with prompt intervention preserving graft survival in most instances.[75]Immune Rejection and Graft Failure
Immune rejection occurs when the recipient's immune system recognizes donor corneal antigens as foreign, triggering an alloimmune response that damages the graft endothelium, stroma, or epithelium, potentially leading to irreversible opacification and vision loss.[76] This process is primarily T-cell mediated, involving CD4+ and CD8+ T lymphocytes that infiltrate the graft, release cytokines, and induce apoptosis of donor cells, with B cells and antibodies playing secondary roles in some cases.[77] Despite the cornea's relative immune privilege—due to its avascularity, anterior chamber-associated immune deviation, and lack of lymphatic drainage—rejection remains the leading cause of graft failure, accounting for approximately 34% of failures in penetrating keratoplasty (PK) across multicentric studies.[78] Risk factors for rejection include recipient corneal neovascularization exceeding two quadrants, which facilitates immune cell trafficking; young recipient age under 40 years, associated with more robust immune responses; HLA incompatibility; large graft diameters over 8 mm; prior graft failure; preoperative glaucoma or uveitis; and intraoperative issues like loose sutures or exposed knots that promote antigen exposure.[79][80] Vascularization and inflammation breach the cornea's immune barriers, increasing rejection risk by up to threefold in high-risk eyes compared to avascular low-risk cases.[8] Rejection episodes manifest acutely within the first year post-transplant in 70-80% of cases, presenting as endothelial rejection with keratic precipitates and corneal edema (Khodadoust line), stromal rejection with haze and infiltrates, or epithelial rejection with linear lesions; chronic rejection develops insidiously over years via ongoing low-grade inflammation.[81] In low-risk PK, rejection episodes occur in 10-30% of grafts, with actual failure in only 5-15% due to successful reversal; high-risk PK sees 30-60% rejection rates, culminating in 70% failure within 10 years without intensified immunosuppression.[82][83] Overall graft survival post-PK declines from 91% at 1 year to 44% at 20 years, with rejection contributing disproportionately in vascularized or regrafted corneas.[84] Diagnosis relies on clinical signs such as reduced visual acuity, sectoral or diffuse edema, and specific patterns like mutton-fat precipitates on the endothelium, confirmed by slit-lamp biomicroscopy and anterior segment optical coherence tomography; confocal microscopy can detect subclinical dendritic cells indicating early alloimmunity.[80] Prompt treatment with high-dose topical corticosteroids (e.g., prednisolone acetate 1% hourly or difluprednate 0.05% every 2 hours) reverses 50-90% of acute episodes if initiated within days, often augmented by oral prednisone (1 mg/kg tapering over weeks) or subconjunctival steroids for severe cases.[85][80] In steroid-resistant or high-risk scenarios, adjunctive topical cyclosporine (0.05-2%) or tacrolimus (0.03%) inhibits T-cell activation, with systemic mycophenolate mofetil or tacrolimus reserved for recurrent rejection, achieving graft salvage in up to 80% of treated high-risk patients.[83] Prevention involves perioperative topical steroids for 6-12 months, HLA matching in high-risk cases, and anterior chamber irrigation with corticosteroids during surgery to suppress early inflammation.[86] Graft failure from unchecked rejection results in endothelial decompensation, stromal scarring, and secondary glaucoma, necessitating regrafting with lower success rates (e.g., 52-78% survival at 5-10 years for repeat PK).[87] Non-immune contributors to failure, such as primary endothelial insufficiency or infection, compound risks but are distinct from rejection; endothelial keratoplasty variants like DMEK exhibit lower rejection rates (under 5% at 5 years) due to minimal stromal exposure, highlighting surgical technique's role in mitigating immune triggers.[79] Long-term monitoring with specular microscopy tracks endothelial cell density loss, a precursor to failure exceeding 20-30% from baseline.[78]Long-Term Complications
Late endothelial failure represents a primary long-term complication following corneal transplantation, particularly in penetrating keratoplasty (PK), where graft survival declines to approximately 44% at 20 years due to progressive endothelial cell loss independent of rejection.[88] In endothelial keratoplasty techniques such as Descemet's stripping endothelial keratoplasty (DSEK), 10-year graft survival reaches 79%, but endothelial cell loss averages 73%, with higher risks in eyes with prior glaucoma surgery.[89] [90] Secondary glaucoma emerges frequently, affecting up to 26.4% of cases in certain cohorts, often exacerbated by steroid use or surgical trauma, and correlates with elevated graft failure rates; treatments for glaucoma further increase failure risk by up to fivefold over five years post-PK.[91] [92] Persistent astigmatism, exceeding 5 diopters in some PK patients long-term, stems from wound healing irregularities and suture-related distortions, necessitating ongoing refractive interventions.[93] Recurrence of the underlying pathology, such as keratoconus or herpetic disease, occurs in a minority but contributes to late graft decompensation, with probabilities rising over decades despite initial low rates.[94] Ocular surface disorders, including chronic epithelial defects in 22.6% of high-risk cases, arise from limbal stem cell deficiency or persistent inflammation, heightening vulnerability to ulceration and perforation.[91] Allograft rejection, though more acute, can manifest chronically, remaining the leading cause of irreversible failure across techniques due to immune privilege breakdown.[79]Outcomes and Prognostic Factors
Graft Survival Rates
Graft survival in corneal transplantation is defined as the time from surgery until graft failure, typically requiring regrafting due to opacity, rejection, or endothelial decompensation. Rates vary significantly by surgical technique, underlying indication (e.g., keratoconus versus bullous keratopathy), recipient factors like vascularization or prior grafts, and follow-up duration. Penetrating keratoplasty (PK) historically shows 90% survival at 5 years and 82% at 10 years for first-time grafts across indications, declining to 44% at 20 years due to cumulative endothelial loss and rejection.[95][96][97] For PK, survival is highest in keratoconus (95% at 10 years) and lower in dystrophies (55% at 10 years) or regrafts (53% at 5 years, 41% at 10 years), reflecting reduced endothelial reserve and increased rejection risk in compromised beds.[98][96] In bullous keratopathy, PK survival is approximately 43% at 10 years, inferior to endothelial keratoplasty alternatives.[99] Endothelial keratoplasty techniques, such as Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK), demonstrate superior short- to medium-term survival for endothelial dysfunction, with 93% at 5 years overall and lower rejection rates (7% for DSAEK, 1.5% for DMEK) compared to PK's 20%.[60][100] DMEK achieves 97.4% survival at 5 years in Fuchs dystrophy cohorts, outperforming DSAEK (78.4%) and PK (54.6%) in national registries, attributed to selective endothelial replacement minimizing stromal exposure to immune triggers.[92] However, long-term data (beyond 5 years) suggest PK may retain an edge in cumulative survival for certain high-risk cases, though endothelial techniques reduce early failure from suture-related issues.[62]| Technique | Indication Example | 5-Year Survival | 10-Year Survival | Key Reference |
|---|---|---|---|---|
| PK | Keratoconus | ~90-95% | 95% | [98] |
| PK | Dystrophies/BK | ~70-82% | 43-55% | [99] [98] |
| DSAEK | Endothelial failure | 78-93% | ~57% (BK) | [92] [100] |
| DMEK | Fuchs dystrophy | 97% | Limited data | [92] |