Fuchs Endothelial Dystrophy

Etiology

FED inheritance follows an autosomal dominant pattern with variable expressivity and incomplete penetrance.[19][20] However, nearly half of all cases are sporadic, and many patients are unaware of a family history of the disease.[21] Genetic factors play a significant role, particularly in early-onset FED, which is often familial and linked to autosomal dominant inheritance. Pathogenic mutations in COL8A, located at chromosomal position 1p34.3–p32.3 (FCD1), are associated with early-onset FED, as these mutations disrupt the structure of the Descemet membrane.

Late-onset FED exhibits greater genetic heterogeneity, with several mutations contributing to disease development. Repeat expansion mutations in TCF4, which encodes the E2-2 protein, are strongly associated with FED across diverse populations, with the highest prevalence in Caucasians, where the mutation exhibits 80% penetrance. Additionally, mutations in DMPK have been identified as potential genetic contributors to FED.

SLC4A11 encodes an ion channel that facilitates water resorption through the endothelial layer and plays a crucial role in maintaining corneal deturgescence. Mutations in this gene are associated with corneal edema and have been correlated with FED. Similarly, mutations in ZEB1, which encodes the transcription factor zinc finger E-box binding homeodomain 1, have been linked to late-onset FED and posterior polymorphous corneal dystrophy (PPCD).

AGBL1 encodes the deglutamylase enzyme adenosine triphosphate (ATP)/guanosine triphosphate (GTP) binding protein-like 1, and mutations in this gene are associated with FED. Missense mutations in LOXHD1 have been linked to progressive hearing loss and corneal endothelial cell dysfunction in FED. Additionally, KANK4, LAMC1, and ATP1B1 have been implicated in FED due to their effects on corneal deturgescence.[22] FED can coexist with other endothelial corneal dystrophies, particularly PPCD and congenital hereditary endothelial dystrophy (CHED), which share phenotypic similarities.

FED is a progressive corneal disorder characterized by endothelial cell loss, guttata formation, and stromal edema, resulting in visual impairment. The condition is multifactorial, involving genetic predisposition, environmental influences, and oxidative stress.

FED follows an autosomal dominant inheritance pattern with variable expressivity and incomplete penetrance, often demonstrating strong familial clustering. Genetic mutations play a significant role, with TCF4 mutations identified in approximately 70% of late-onset cases. Other genes, including ZEB1 and COL8A2, have been implicated, with COL8A2 mutations primarily associated with early-onset FED.[23] Given the hereditary nature of the disease, genetic screening in high-risk families can facilitate early detection and monitoring, potentially allowing for timely interventions to preserve visual function.

Endothelial cells in FED exhibit increased susceptibility to oxidative stress, leading to progressive endothelial apoptosis. Reduced antioxidant defense mechanisms further compromise cell survival, while mitochondrial dysfunction depletes energy reserves, impairing sodium-potassium pump activity and contributing to corneal edema.[24] Given these findings, antioxidant therapy, including vitamin C and N-acetylcysteine, is under investigation as a potential protective strategy.

Hormonal factors may also influence FED progression, as the condition is more prevalent in postmenopausal women, suggesting a link to estrogen deficiency. Estrogen plays a role in maintaining endothelial cell function, and its decline may contribute to disease onset or worsening. The disproportionately higher prevalence of FED in women, estimated at approximately 70%, supports the possibility of an endocrine influence.[25] Ongoing studies are exploring the potential effects of hormone replacement therapy (HRT) on FED progression.

Environmental and lifestyle factors further modulate disease risk. UV radiation exposure induces DNA damage in endothelial cells, accelerating guttata formation. The absence of protective measures, such as sunglasses and blue-light filtering lenses, represents a modifiable risk factor.[26] Additionally, smoking exacerbates oxidative stress, promoting endothelial degeneration, while systemic conditions such as diabetes, hypertension, and metabolic syndrome may contribute to corneal decompensation. Preventive strategies include UV protection, smoking cessation, and cardiovascular risk management, which may help slow disease progression.[27]

Postoperative endothelial stress following cataract surgery can accelerate FED progression, particularly in patients with borderline endothelial function. Phacoemulsification introduces mechanical and oxidative stress, increasing the risk of rapid corneal decompensation. Intraoperative trauma and the type of viscoelastic agents used during surgery further influence endothelial cell survival. Patients with preexisting guttata or early FED may experience a faster decline in endothelial function following cataract extraction.

To mitigate surgical risks, preoperative assessment of endothelial cell count is essential for identifying patients at higher risk of postoperative decompensation. Low-energy phacoemulsification techniques and strategies to protect the corneal endothelium, such as careful fluid management and the use of dispersive viscoelastics, can help preserve endothelial viability. In patients with significant endothelial dysfunction, concurrent or staged endothelial keratoplasty may be considered to optimize visual outcomes.

FED is a complex disorder influenced by genetic, oxidative, hormonal, and environmental factors. While early detection and lifestyle modifications may slow disease progression, surgical interventions remain necessary in advanced cases to restore corneal clarity and visual function.[28]

Epidemiology

Determining the incidence and prevalence of FED is challenging, as many individuals with corneal guttata never develop the disease, and symptoms often take decades to manifest. Corneal guttata typically appear in the 4th decade of life, but most patients do not require surgical intervention until their 6th or 7th decade. FED is the leading cause of corneal endothelial transplantation worldwide.[29]

Although corneal guttata may occur in up to 4% of adults older than 40 in the U.S., they are less frequently associated with corneal edema, and many individuals with guttata do not receive a diagnosis of FED. Several studies have documented the incidence and prevalence of central corneal guttata without edema. A 2005 study in Iceland found primary corneal guttata in 11% of women and 7% of men.[30] Another study reported prevalence rates of 6.7% in Chinese Singaporeans and 3.7% in Japanese individuals.[31]

Lorenzetti et al observed central corneal guttata in 31% of eyes among individuals aged 20 to 39 and in 70% of eyes in those older than 40. Goar et al found guttata in 9.6% of patients older than 40. In 1910, Ernst Fuchs estimated that FED affected fewer than 1% of his patients. Reported incidence and prevalence vary widely, likely due to differing clinical definitions of guttata. Evidence suggests that FED is more prevalent in Europe than in other regions, with a higher proportion of corneal transplants for FED in Europe and the U.S. compared to Asia, where FED rates are lower.

Several nonheritable risk factors are associated with FED. Age and gender significantly influence disease development, with adults older than 40 and women at higher risk.[32] Reported female-to-male ratios range from 2.5:1 to 3:1. Additional risk factors include smoking, UV light exposure, and diabetes, which can affect disease severity. A rare early-onset form of FED presents in the 1st decade of life and has an equal female-to-male ratio.

Pathophysiology

The endothelial barrier and pumps are essential for maintaining corneal deturgescence and transparency, and endothelial cell dysfunction is central to the pathogenesis of FED. The corneal endothelium consists of a monolayer of hexagonal cells that regulate water flow, balancing inflow and outflow to prevent corneal swelling. These cells originate from neural crest cells and remain in the G1 phase of the cell cycle. A functional endothelium typically contains 400 to 500 cells/mm2. The aqueous humor supplies the cornea with solutes and nutrients, which diffuse through the endothelial barrier via IOP gradients.[33]

Tight junctions between endothelial cells restrict paracellular water diffusion, making sodium-potassium ATPase pumps the primary drivers of fluid movement from the cornea into the aqueous humor. While the sodium-potassium pump is the main endothelial pump, it functions alongside aquaporins and the SLC4A11-encoded sodium-borate cotransporter. The high metabolic demands of endothelial cells require ATP, chloride ions, bicarbonate ions, and carbonic anhydrase to sustain active transport processes. Corneal transparency depends on maintaining stromal hydration below 3.5 mg of water per mg of dry tissue. When endothelial function is compromised, and the number of active pumps declines, the cornea absorbs excess water, leading to swelling, hazy vision, and reduced visual acuity. 

The pathophysiology of FED involves several proposed mechanisms, including channelopathies, oxidative stress, apoptosis, and epithelial-mesenchymal transition (EMT). Despite multiple hypotheses, the precise underlying mechanisms remain unclear. A key contributor to FED development is channelopathy in the corneal endothelium, characterized by ion channel dysfunction due to genetic mutations. For example, mutations in SLC4A11 disrupt normal endothelial function.

Mitochondrial dysfunction also appears to play a role. Endothelial cells in FED exhibit decreased cytochrome oxidase activity, particularly in areas of corneal edema. This deficiency suggests that impaired mitochondrial function leads to inadequate ATP production, compromising endothelial pump activity.

Oxidative stress is another significant pathogenetic factor. The cornea is continuously exposed to UV light, generating ROS that damages both mitochondrial and nuclear DNA. This oxidative damage triggers endothelial cell apoptosis, contributing to progressive cell loss.[34] Excessive apoptosis further accelerates endothelial degeneration.[35][36] The accumulation of oxidative DNA damage around guttata disrupts mitochondrial function, leading to ongoing endothelial loss and ocular tissue degeneration.[37]

FED may also be linked to the unfolded protein response (UPR) of the endoplasmic reticulum. When misfolded or abnormal proteins accumulate in the endoplasmic reticulum, cellular mechanisms are activated to halt translation, degrade misfolded proteins, and, if unresolved, trigger apoptosis. Studies have shown that the endoplasmic reticulum enlarges, and several unfolded protein response markers are overactivated in FED.[38][39]

EMT is another proposed mechanism in FED pathogenesis. Abnormal deposition of extracellular matrix proteins, such as collagen and basement membrane components, leads to the characteristic thickening of the Descemet membrane. Histopathological analysis of FED reveals endothelial cells that have transformed into a fibroblastic or epithelial phenotype, allowing them to secrete excess extracellular matrix proteins. Genes implicated in EMT include ZEB1 and TCF4.[40]

In FED, degenerating endothelial cells produce hyaline excrescences known as guttata, which accumulate on the Descemet membrane and correlate with its thickening. These excrescences are visible both histologically and clinically. In the early stages, guttata are isolated and generally not confluent, while endothelial cells compensate for cell loss by undergoing polymegathism.[41]

Progression occurs over 2 to 3 decades, with an increase in both the number and size of guttata. As the disease advances, guttata extend to the peripheral cornea and become confluent. In stage 2, endothelial loss over guttata impairs corneal deturgescence, leading to increased corneal thickness. As FED progresses further, corneal decompensation allows excessive fluid accumulation, resulting in corneal edema. Swelling becomes more likely when ECD falls below 1,000 cells/mm².

In stage 3, worsening stromal edema may lead to epithelial bullae formation, which can rupture and cause significant discomfort. The final stage is characterized by subepithelial scarring and corneal vascularization.[42]

Histopathology

Specular microscopy relies on a smooth, transparent cornea to generate specular reflection. The utility of this diagnostic tool is limited in cases of significant corneal edema, as seen in FED. When visible, corneal guttata appear as dark, oval-to-round areas, often with a small central point of reflection. Endothelial cell counts decrease, and gaps form between cells. While specular microscopy provides rapid imaging and is a well-established technique, its effectiveness is reduced in patients with FED due to impaired visualization of the corneal stroma.

Confocal microscopy offers a superior view of the corneal endothelium compared to specular microscopy and is more effective for evaluating FED. However, this modality is not available in all clinical settings.[43] Confocal microscopy uses a gel to reduce light scattering at the corneal epithelium, making it particularly beneficial for patients with epithelial disorders or significant stromal edema. Confocal microscopy can reveal a characteristic “strawberry-like” endothelial pattern and in vivo microstructural changes. In advanced stages, findings may include fibrosis of the Descemet membrane, basal epithelial edema, and posterior stromal scarring.[44] Anterior stromal cell loss may also be detected through histology or confocal microscopy.

Light microscopy reveals intracellular epithelial edema, bullous separation, stromal thickening, endothelial loss, and Descemet membrane thickening with posterior nodules, a common finding in FED. Inflammatory cell infiltrates are not expected in patients with FED alone. Electron microscopy shows degenerating keratocytes in the corneal stroma and lipid keratopathy in most cases. Degenerating keratocytes exhibit vacuolization, cytoplasmic dissolution, loss of intracellular organelles, and nuclear chromatin clumping. The endothelium appears attenuated, particularly over posterior nodules.

Nonguttate forms of FED share many corneal changes with guttate forms, including endothelial cell pleomorphism, polymegethism, and reduced ECD, but lack guttata. Diagnosis of nonguttate FED often relies on specular or confocal microscopy.[45][46] Previous studies using phase contrast microscopy have demonstrated closely packed excrescences within thickened lamellae, even when absent on light microscopy. Additionally, oxytalan staining has revealed buried guttata on light microscopy. These findings suggest that nonguttate and guttate forms of FED may represent variations of the same disease.

Toxicokinetics

Toxicokinetics refers to the absorption, distribution, metabolism, and excretion of potentially toxic substances, including medications and surgical adjuncts used to treat FED. Understanding the toxicokinetics of various agents is crucial for optimizing the treatment of this condition while minimizing adverse effects.[47]

Hypertonic saline permeates topically with limited systemic absorption. This agent does not undergo systemic metabolism and is cleared locally via the tear film. Toxicity concerns include epithelial irritation and transient stinging. Topical corticosteroids, including prednisolone, fluorometholone, and loteprednol, rapidly penetrate the cornea and accumulate in the aqueous humor. These drugs are metabolized in the liver via CYP3A4 enzymes and excreted renally. Potential adverse effects include increased IOP, cataract formation, and corneal thinning.

Carbonic anhydrase inhibitors (CAIs) such as dorzolamide and brinzolamide are absorbed through the cornea into the aqueous humor, with minimal hepatic metabolism, and are primarily excreted through the kidneys. In individuals with endothelial dysfunction, these agents may contribute to corneal decompensation. β-Blockers, including timolol and betaxolol, are absorbed systemically via the conjunctiva, undergo hepatic metabolism, and are eliminated renally. Potential systemic side effects include bradycardia, bronchospasm, and hypotension.

ROCK inhibitors are absorbed locally in ocular tissues and metabolized in the liver, with excretion occurring through both fecal and renal pathways. Common adverse effects include conjunctival hyperemia and mild irritation. Mitomycin-C, used as an adjunct in glaucoma surgery, diffuses into ocular tissues but undergoes no metabolic transformation. This agent is slowly cleared via the aqueous humor, with toxicity concerns that include corneal toxicity and delayed wound healing.

Long-term steroid users require close IOP monitoring, and lower doses of β-blockers should be considered in patients with systemic comorbidities. Adjusting glaucoma medication regimens in patients with FED can help prevent corneal decompensation.

Toxicity Arising from Surgical Interventions

Toxicity may result from surgical interventions due to anesthesia and preservative use, endothelial keratoplasty-associated complications, and altered drug elimination in individuals with FED. Benzalkonium chloride (BAK), a common preservative in ophthalmic solutions, is known to cause endothelial toxicity in FED. Mitomycin-C, often used in glaucoma surgeries, can contribute to corneal thinning and delayed epithelial healing.[48] To mitigate these risks, preservative-free formulations should be prioritized for long-term therapy, and balanced salt solution (BSS) should be used intraoperatively to minimize exposure to toxic agents.

Endothelial keratoplasty, including DMEK and DSEK, introduces additional toxicity concerns. Donor endothelial cells are susceptible to stress from prolonged tissue manipulation, leading to apoptosis. Furthermore, preservatives in graft storage media may result in transient corneal haze postoperatively.[49] Minimizing surgical handling of donor tissue and thoroughly irrigating grafts before transplantation can help reduce these complications.

Elimination and clearance of ocular drugs may be altered in individuals with FED. Topical drugs can be systemically absorbed through nasolacrimal drainage, potentially leading to systemic side effects. Additionally, impaired endothelial function in FED may slow aqueous humor clearance, prolonging drug exposure.[50]

Long-term steroid users require close IOP monitoring, and lower doses of β-blockers should be considered in patients with systemic comorbidities. Adjusting glaucoma medication regimens in FED patients can help prevent corneal decompensation.

Understanding the toxicokinetics of commonly used drugs and surgical adjuncts in FED management is essential for optimizing therapy while preventing drug-induced complications. Minimizing exposure to cornea-toxic agents and monitoring drug clearance can help preserve long-term corneal health and improve graft survival.[51]

History and Physical

A detailed clinical history and thorough physical examination are essential for early diagnosis and appropriate FED management.[52] Assessing the progression of symptoms is essential when obtaining a clinical history, as they typically worsen over time due to endothelial dysfunction. Early symptoms in the mild stage include morning blurry vision that improves throughout the day, increased glare and halos around lights, particularly at night, and occasional fluctuating vision.[53] As endothelial dysfunction progresses to the moderate stage, patients may experience persistent blurry vision throughout the day, increased light sensitivity, contrast loss, and difficulty with night vision due to corneal edema.

In the advanced stage, characterized by corneal edema and bullous keratopathy, vision loss becomes persistent and does not improve throughout the day. Patients may also develop pain and a foreign body sensation due to epithelial bullae formation, along with progressive photophobia and discomfort.[54]

A family history of FED, which follows an autosomal dominant inheritance pattern, is a significant risk factor. Additionally, a history of cataract surgery or other intraocular procedures may exacerbate corneal decompensation. Comorbid conditions such as diabetes and glaucoma, as well as previous eye trauma, can further accelerate endothelial cell loss.[55]

A thorough ophthalmic examination, particularly with slit-lamp biomicroscopy and specular microscopy, helps identify characteristic features of FED and assess disease severity. Slit-lamp biomicroscopy reveals corneal guttata, the hallmark sign, which appear as dark drop-like structures on the endothelium, creating a "beaten metal" appearance. As the disease progresses, the Descemet membrane thickens due to endothelial decompensation, leading to stromal edema. Corneal edema and stromal haze result in a blurry reflex on retroillumination and increased light scatter (see Image. Fuchs Endothelial Dystrophy Findings).

In advanced disease, fluid-filled microcysts or blisters, known as epithelial bullae, develop, causing pain and discomfort. Specular microscopy shows a progressive decline in ECD. Normal ECD ranges from 2,500 to 3,000 cells/mm², while early-stage FED presents with counts below 1,500 cells/mm². In advanced disease, ECD drops below 500 cells/mm², often accompanied by polymegathism and pleomorphism.[56]

Several diagnostic tests can aid in assessing corneal health and detecting complications in FED. Pachymetry measures corneal thickness and helps identify edema, with advanced cases often showing an increase beyond 640 µm. Fluorescein staining evaluates epithelial integrity and highlights features such as bullous keratopathy and microerosions. Gonioscopy and IOP measurements are used to rule out secondary glaucoma. While primary angle closure is not typically observed in FED, steroid-induced glaucoma is a possible risk.

Additional Information

FED typically manifests during the 4th decade of life and progresses through 4 stages over 20 to 30 years (see Staging). In stage 1, most individuals remain asymptomatic as endothelial cells compensate for cell loss. A routine ophthalmologic examination may reveal central corneal guttata incidentally, with biomicroscopy showing guttata, pigment on the posterior corneal surface, and a thickened Descemet membrane. Stage 1 is indistinguishable from central corneal guttata without FED and is only recognized once the disease progresses.

In stage 2, corneal decompensation leads to edema. Patients may report painless blurry vision and glare, worsening in the morning due to overnight corneal hydration from closed eyelids. Many describe using multiple pairs of glasses throughout the day as relative corneal dehydration causes a hyperopic shift. Additional findings include a hazy cornea, poor night vision, and discomfort while blinking.

In stage 3, epithelial bullae develop, further impairing vision. These bullae may rupture, leading to episodic pain. The 4th stage is marked by subepithelial scarring and significant vision loss, sometimes reducing visual acuity to the level of hand motion. Pain may be absent. In developed regions, this stage is rare due to the availability of corneal transplantation.

Slit-lamp examination may be used to assess the extent and confluence of guttata, which indicates disease progression, as well as the severity of corneal edema in advanced stages. In early disease, guttata appear centrally and expand peripherally in a predominantly horizontal pattern. Under direct illumination, guttata present as pinpoint indentations, while retroillumination reveals them as small droplets, reflecting the term's origin from the Latin word gutta. Differentiating guttata in the central cornea from Hassall-Henle bodies in the peripheral cornea is essential, as the latter represent an age-related normal finding.

As the disease advances, the Descemet membrane thickens, best visualized with broad tangential illumination, and guttata become confluent. Stromal edema initially appears as a gray haze anterior to the Descemet membrane. With increasing edema, the inelastic Descemet membrane is pushed posteriorly, forming wrinkles and folds. Full-thickness stromal edema presents with a ground-glass appearance.

Slit-lamp examination in FED may also reveal anterior corneal epithelial changes that correspond with disease progression. In stage 2, microcysts appear on the corneal surface and may be visualized using topical fluorescein and cobalt blue lighting. In stage 3, epithelial defects become evident as extracellular fluid accumulates beneath the epithelium. Stage 4 is characterized by subepithelial scarring and the formation of a connective tissue pannus. Over time, peripheral corneal vascularization develops while stromal and epithelial edema diminish. In rare cases of nonguttate FED, guttata are absent on slit-lamp examination. However, marked corneal edema and bullous keratopathy may still be present.

Pachymetry is often used to assess central corneal thickness (CCT) and guide clinical decision-making, as a CCT greater than 640 µm typically indicates corneal edema. However, some patients with inherently thinner corneas may exhibit advanced FED with a CCT of less than 600 µm. Serial CCT measurements are valuable for monitoring disease progression. The corneal central-to-peripheral thickness ratio (CPTR) has been proposed as a more objective and reproducible metric of FED severity, though it is not routinely used in clinical practice. 

The differential diagnosis of FED includes several conditions with overlapping clinical features. Pseudophakic bullous keratopathy (PBK) presents as endothelial loss following cataract surgery. PPCD is typically bilateral but often asymmetric. Iridocorneal endothelial (ICE) syndrome is characterized by unilateral corneal edema with abnormal iris findings. CHED manifests as early-onset, diffuse bilateral corneal haze.

A detailed history and focused ophthalmic examination are essential for the early diagnosis and monitoring of FED. Slit-lamp findings and specular microscopy play a critical role in staging the disease and guiding treatment decisions.[57]

Evaluation

Evaluating FED requires a comprehensive ophthalmic examination with specialized imaging and functional tests. Early detection enables timely intervention to preserve vision.

History, physical examination, pachymetry, and microscopy are key evaluation tools. Additional modalities aid in staging and monitoring disease progression. Specular or confocal microscopy can assess endothelial cell loss, while CCT measurement helps monitor corneal edema and disease progression. AS-OCT has recently demonstrated utility in documenting guttata in FED, though its resolution limits quantitative analysis to a small central corneal region. Routine eye exams every 6 months are recommended to track FED progression.

Specular microscopy evaluates ECD, revealing a low ECD (<1,000 cells/mm²) along with pleomorphism and polymegathism. Pachymetry, whether ultrasound or optical, measures corneal thickness, with advanced cases often exceeding 640 μm. AS-OCT provides detailed imaging of corneal layers, showing a thickened Descemet membrane and stromal hyperreflectivity. Gonioscopy and IOP measurements help rule out secondary causes of corneal edema, confirming the absence of glaucoma-related pathology. Fluorescein staining assesses epithelial integrity, highlighting bullous keratopathy and microerosions.

Additional considerations in FED evaluation include genetic testing, which may be warranted in suspected early-onset cases associated with SLC4A11 mutations. A thorough differential diagnosis is essential to distinguish FED from PPCD, ICE syndrome, and PBK. Comprehensive assessment relies on clinical evaluation, imaging, and endothelial function testing, enabling early detection, effective monitoring, and timely surgical intervention when necessary.

Treatment / Management

FED management depends on disease stage, corneal edema severity, and visual impact, with treatment ranging from conservative measures in early cases to surgical intervention in advanced stages.[58] Early FED can be managed medically, but vision is often worse in the morning than in the afternoon. Several treatments address FED symptoms, including blurry vision and ocular pain. Medical options such as hyperosmotic saline drops or ointment help dehydrate the cornea. Patients experiencing blurry vision in the morning may benefit from gently warming the cornea with dry air from a hairdryer.

Supportive treatments and surgical interventions, including phototherapeutic keratectomy, amniotic membrane transplant, anterior stromal puncture, and conjunctival flaps, can relieve pain, particularly in cases involving ruptured bullae in later stages. Surgical intervention may be considered for advanced disease affecting function and quality of life. The decision to perform cataract surgery alone or a combined DSEK and phacoemulsification procedure depends on CCT and ECD. Older adults with FED often have comorbid conditions such as cataracts, age-related macular degeneration, and cardiovascular disease, which can complicate surgical planning.

Nonsurgical Interventions

Hypertonic saline serves as a first-line therapy for early-to-moderate FED by dehydrating the cornea and reducing morning swelling. Hypertonic saline is typically instilled 4 to 6 times daily, especially upon waking. However, the effects of this fluid are temporary and do not halt disease progression. Lubricating eye drops, particularly preservative-free artificial tears, help minimize ocular surface irritation and discomfort caused by corneal edema.

Topical steroids such as fluorometholone and loteprednol have a mild anti-inflammatory role and may reduce endothelial oxidative stress, leading to transient improvements in corneal clarity. However, long-term use requires monitoring due to the risk of increased IOP.[59] Scleral contact lenses create a fluid-filled reservoir over the cornea, enhancing visual clarity and are often used in moderate FED cases with significant visual distortion.[60] (A1)

Surgical Treatments

FED is the leading indication for corneal transplantation in the U.S., accounting for 36% of nearly 47,000 corneal transplants performed in 2016. Several surgical procedures have demonstrated utility in managing the disease. PKP, Descemet stripping automated endothelial keratoplasty (DSAEK), and DMEK are definitive treatments for restoring vision.[61](B3)

PKP has been used since the 1950s to replace endothelial cells but carries risks such as high postoperative astigmatism, prolonged visual recovery, suture trauma, persistent epithelial defects, and refractive surgery complications. Due to these limitations, newer techniques such as DSAEK, DMEK, posterior lamellar keratoplasty (PLK), and deep lamellar endothelial keratoplasty (DLEK) have gained favor. DSAEK is currently the most common treatment for endothelial dysfunction, offering better visual outcomes than PKP with minimal astigmatic changes. DMEK, which transplants only the endothelial layer and the Descemet membrane, provides the fastest visual rehabilitation among keratoplasty techniques. PLK and DLEK are used less frequently due to their thick graft-host stromal interface.[62]

DMEK is the preferred surgical procedure for advanced FED, offering the best visual outcomes. This procedure involves transplanting an ultrathin donor Descemet membrane with a healthy endothelium. DMEK has a graft rejection rate of less than 2% and allows for rapid visual recovery within approximately 3 months. However, graft detachment requiring rebubbling occurs in 10% to 20% of cases.[63] DSEK is an alternative for patients with prior ocular surgery or glaucoma. The graft is slightly thicker than in DMEK, making handling easier. Visual recovery is slower, taking approximately 6 months, with a rejection rate of 5% to 10%.[64] PKP is reserved for severe corneal scarring or multiple graft failures. This procedure has a higher rejection risk of approximately 20% and requires a longer healing period of up to a year.[65](A1)

Combined phacoemulsification and DMEK or DSEK may be considered for patients with visually significant cataracts. Preoperative specular microscopy is useful in assessing endothelial function before cataract surgery.

Postoperative management includes steroid tapering, with low-dose topical steroids (eg, prednisolone 1%) maintained for at least 6 to 12 months to prevent rejection. Regular IOP monitoring is necessary to detect steroid-induced glaucoma. Lifelong UV protection and adequate corneal hydration can help reduce oxidative stress on the corneal endothelium. 

Emerging Therapies

Novel modalities targeting corneal endothelial cell dysfunction include ROCK inhibitors. Y-27632, primarily used in research, has shown potential in promoting endothelial cell adhesion and proliferation. Clinically available ROCK inhibitors, such as netarsudil and ripasudil, may increase endothelial cell survival and migration and are being investigated for their ability to delay surgical intervention.[66][67][68](B3)

Other experimental approaches include corneal collagen cross-linking (CXL), which has shown mixed results in reducing corneal edema, improving visual acuity, and alleviating ocular discomfort. Preliminary research suggests that lithium, N-acetylcysteine, and sulforaphane may have therapeutic benefits in FED. Gene therapies, including adenovirus vector therapy and CRISPR gene editing, are also being explored, though their efficacy remains uncertain.

Differential Diagnosis

FED can present with corneal edema, endothelial dysfunction, and progressive visual impairment, overlapping with other ocular conditions. A thorough clinical examination, imaging, and endothelial cell analysis are crucial in distinguishing FED from other causes of corneal edema and endothelial pathology.

PBK typically occurs following cataract surgery due to endothelial cell loss from intraocular lens implantation. A history of recent intraocular surgery and specular microscopy findings of a low endothelial cell count help differentiate this condition from FED. PPCD presents with bilateral corneal edema and vesicular endothelial changes, often asymmetrical. Slit-lamp examination reveals characteristic "railroad track" endothelial bands, while specular microscopy shows polymorphic endothelial cells.

CHED manifests early in life, with diffuse bilateral corneal haze appearing in infancy or childhood. A neonatal history and genetic testing for SLC4A11 mutations confirm the diagnosis. ICE syndrome is characterized by unilateral corneal edema, abnormal iris changes, and peripheral anterior synechiae. A slit-lamp examination may show a beaten-metal appearance of the endothelium, and gonioscopy reveals peripheral angle abnormalities.

Corneal graft failure should be considered in individuals with a history of corneal transplantation who develop recurrent corneal edema. Graft clarity assessment and specular microscopy help assess endothelial function. Herpetic endotheliitis, caused by herpes simplex virus or varicella-zoster virus, typically presents with unilateral corneal edema, keratic precipitates, and a history of uveitis. Diagnosis is supported by serology, anterior chamber inflammation, and response to antiviral therapy.

Chronic angle-closure glaucoma can mimic FED, presenting with corneal edema and elevated IOP. Gonioscopy findings of closed angles, IOP exceeding 30 mm Hg, and glaucomatous optic neuropathy confirm the diagnosis. Acute endothelial toxicity results in rapid-onset corneal edema following intraocular surgery or chemical exposure. A history of recent intraocular procedures or exposure to toxic agents such as mitomycin-C or BAK is key to identifying this cause.

Other diagnoses that must be considered include the following:

• Primary central corneal guttata
• Aphakic bullous keratopathy, especially with a history of cataract surgery
• Recurrent corneal erosions
• Chandler syndrome
• Posterior polymorphous dystrophy
• Congenital hereditary stromal dystrophy
• Toxic anterior segment syndrome
• Hassall-Henle bodies
• Herpetic disciform keratitis
• Pigment dispersion syndrome
• Anterior uveitis
• Interstitial keratitis
• Herpetic stromal keratitis 

Differentiating FED from other corneal endothelial disorders is essential for appropriate treatment planning. A detailed history, slit-lamp examination, and specular microscopy provide critical diagnostic insights, while additional testing helps exclude alternative causes of corneal edema.

Pertinent Studies and Ongoing Trials

Recent research and clinical trials are investigating innovative treatments for FED to enhance patient outcomes and potentially reduce reliance on traditional corneal transplantation.[69] An emerging approach is Descemetorhexis Without Endothelial Keratoplasty (DWEK) or Descemet Stripping Only (DSO), which involves removing a small section of diseased endothelium without implanting donor tissue. This technique encourages endogenous endothelial cell migration and repopulation. A study conducted by the Royal Victorian Eye and Ear Hospital demonstrated improved vision in FED patients using this method without requiring a corneal transplant.[70]

ROCK inhibitors are being investigated for their potential to promote corneal endothelial healing. The Descemet Endothelial Thickness Comparison Trial II (DETECT II) is a multicenter, placebo-controlled clinical trial comparing DMEK to DSO with adjunctive ripasudil in patients with FED. STN1010904 ophthalmic suspension is currently in a Phase IIa trial that assesses its efficacy and safety in FED management without surgical intervention. Similarly, a Phase III clinical trial is investigating the role of K-321 eye drops in promoting corneal healing and improving visual outcomes following descemetorhexis.

Further research also examines the broader impact of FED on visual function. The Mayo Clinic is conducting studies to evaluate how the disease affects vision and quality of life, aiming to clarify the progression of visual impairment and corneal transparency loss over time.[71] These ongoing investigations represent significant advancements in FED research, offering promising prospects for less invasive treatments and improved patient outcomes.

Treatment Planning

The primary goals of FED treatment are to manage corneal edema, slow disease progression, and restore vision through surgical intervention when necessary. Treatment strategies are typically stage-based, with interventions tailored to disease severity.

In the early stage, when symptoms are mild and vision remains unaffected, management focuses on symptom relief and disease monitoring. Hypertonic saline can help reduce morning corneal edema while lubricating artificial tears support corneal hydration. UV protection using sunglasses with a UV400 filter may minimize oxidative damage. ECD should be monitored every 6 to 12 months, with annual eye exams unless symptoms worsen.

As FED progresses to the moderate stage, characterized by persistent corneal edema and visual disturbances, treatment aims to reduce swelling and improve functional vision. Hypertonic saline and topical steroids can aid in edema management. Scleral contact lenses may be beneficial for patients with significant irregular astigmatism. Cataract status should be evaluated, as endothelial function assessment is crucial before surgery. ROCK inhibitors are under investigation for their potential to delay disease progression.[72] Follow-up is recommended every 3 to 6 months to monitor corneal thickness and visual function.

In the advanced stage, severe edema, vision loss, and corneal opacification necessitate surgical intervention for visual rehabilitation. DMEK is the preferred procedure for optimal visual outcomes, while DSEK is an alternative for patients with prior ocular surgery or glaucoma. PKP is reserved for cases with significant corneal scarring. When cataracts are present, combined phacoemulsification with DMEK or DSEK may be performed.[73] Postoperative follow-up should occur every 1 to 3 months, transitioning to annual evaluations once recovery stabilizes. 

Surgical decision-making in FED is guided by patient-specific factors, including the severity of corneal edema, presence of cataracts, history of prior ocular surgeries, and overall corneal health. The choice of intervention aims to optimize visual outcomes while minimizing surgical risks.

For patients with mild corneal edema and no significant vision loss, medical therapy remains the preferred approach, as surgery is unnecessary. When FED is accompanied by a visually significant cataract, phacoemulsification with DMEK is the preferred option, though DSEK may also be considered. Performing a combined procedure helps prevent the need for multiple surgeries. In patients who have a history of glaucoma surgery or a filtering bleb, DSEK is favored over DMEK due to its lower risk of graft detachment. For individuals with severe corneal scarring or multiple graft failures, PKP is required, as a full-thickness transplant is necessary for vision restoration.

Long-term management of FED focuses on monitoring graft survival, optimizing postoperative care, and supporting corneal health to prevent disease progression. Annual specular microscopy and corneal thickness measurements help assess endothelial function and detect early signs of graft failure. Steroid therapy should be carefully tapered to prevent rejection while minimizing IOP elevation. Recognizing early signs of graft rejection—redness, sensitivity to light, vision loss, and pain (the RSVP mnemonic)—is essential for prompt intervention. Lifestyle and nutritional support, including adequate hydration, antioxidants, and UV protection, further contribute to corneal health.

While early-stage FED can be managed conservatively, advanced cases require timely keratoplasty, with surgical decisions tailored to patient-specific factors. Postoperative monitoring remains critical for long-term graft survival.[74]

Toxicity and Adverse Effect Management

Adverse effects associated with topical medications used in FED management vary based on the drug class, requiring careful monitoring and individualized treatment adjustments to minimize complications. Hypertonic saline often causes ocular irritation and a transient burning sensation upon application. Using preservative-free formulations can help mitigate discomfort, and applying lubricating artificial tears 10 minutes after instillation may further reduce irritation.

Corticosteroids present risks such as steroid-induced ocular hypertension and glaucoma, which can lead to optic nerve damage. Long-term use may also accelerate posterior subcapsular cataract formation and impair wound healing, increasing susceptibility to infections.[75] Regular IOP monitoring every 4 to 6 weeks is essential, particularly in patients at risk for glaucoma. Steroid-sparing agents like cyclosporine 0.05% may be considered for prolonged therapy, while weaker corticosteroids such as fluorometholone or loteprednol may be recommended for patients with a history of steroid-induced IOP elevation. Gradual tapering is necessary to prevent rebound inflammation.

IOP-lowering agents are often required for steroid-induced glaucoma but must be selected cautiously. β-Blockers can cause systemic side effects such as bradycardia, hypotension, and bronchospasm, making them unsuitable for patients with asthma or chronic obstructive pulmonary disease (COPD). Additionally, these agents may contribute to dry eye and delay corneal epithelial healing.[76] Preservative-free formulations can help reduce ocular surface irritation. CAIs are another option, but these medications may worsen corneal decompensation in patients with preexisting endothelial dysfunction, making them less suitable for individuals with advanced FED.[77]

For ROCK inhibitors, conjunctival hyperemia is a common adverse effect. These agents may be beneficial for patients experiencing steroid-induced IOP elevation who also require endothelial protection.[78]

Anesthetic and surgical agents used in FED management can pose risks to the corneal endothelium, necessitating careful selection and monitoring to prevent toxicity-related complications. Preservatives in anesthetic drops, such as BAK, may contribute to endothelial toxicity, particularly in patients undergoing keratoplasty. When possible, preservative-free anesthetics should be used to minimize damage. Additionally, mitomycin-C, sometimes utilized in conjunction with glaucoma surgery, has been associated with corneal thinning and delayed epithelial healing. Limiting mitomycin-C exposure is essential to prevent corneal toxicity.[79]

Graft-related toxicities also present challenges in posttransplant management. Some patients may develop inflammatory reactions to donor corneal endothelium, even in the absence of overt rejection. Low-grade inflammation should be monitored closely and managed with short courses of corticosteroids as needed.[80] Furthermore, despite successful outcomes following DMEK or DSEK, gradual endothelial cell loss occurs over time. To ensure long-term graft viability, annual specular microscopy assessments are necessary to track ECD and detect early signs of dysfunction.[81]

Managing toxicity and adverse effects in FED requires a comprehensive approach that includes regular monitoring, medication adjustments, and patient-specific modifications. Reducing drug-related toxicity, maintaining IOP control, and optimizing posttransplant care are essential for improving long-term outcomes and ensuring graft survival.[82]

Staging

Staging of FED is traditionally based on the extent of guttata and corneal edema. Early stages are characterized by endothelial cell loss and guttata formation on the Descemet membrane, while later stages involve all corneal layers. In 1978, Dr. Jay Krachmer and his team introduced a clinical grading scale to assess disease progression subjectively. This scale is outlined as follows:

• Grade 0 (G0): No apparent disease
• Grade 1 (G1): 0 to 12 central, nonconfluent guttata in at least 1 eye; typically asymptomatic
• Grade 2 (G2): More than 12 central, nonconfluent guttata in at least 1 eye
• Grade 3 (G3): 1- to 2-mm zone of central confluent guttata in the horizontal plane
• Grade 4 (G4): 2- to 5-mm zone of central confluent guttata in the horizontal plane
• Grade 5 (G5): Zone of central confluent guttata larger than 5 mm, with or without corneal stromal or epithelial edema [83]

Another staging system categorizes FED progression into 4 distinct stages spanning 2 to 3 decades, as follows:

• Stage 1: Asymptomatic slit-lamp examination revealing central nonconfluent guttata and thickening of the Descemet membrane
• Stage 2: Coalescence of guttata with endothelial cell polymegathism, pleomorphism, and loss; symptoms include blurry vision and glare, especially upon awakening
• Stage 3: Endothelial pump dysfunction leading to bullae formation in the epithelial and subepithelial layers, with corneal edema
• Stage 4: Corneal edema resulting in haziness, scarring, and significant vision loss

A 3rd classification further stratifies FED based on clinical features and diagnostic indicators, as follows:

• Mild: Mild guttata without corneal edema; normal pachymetry and ECD (1,500 cells/mm²)
• Moderate: Corneal edema with morning blur; increased pachymetry (>600 µm) and reduced ECD (<1,000 cells/mm²)
• Advanced: Persistent edema, bullous keratopathy, and vision loss; severe corneal thickening and critically low ECD (<500 cells/mm²)

However, with advancements in nonsurgical treatments and earlier surgical interventions, these traditional staging classifications may be losing clinical relevance.

Prognosis

FED is a progressive condition, with significant visual impairment often emerging in the 6th or 7th decade of life, necessitating surgical intervention. Prognosis depends on the stage at diagnosis, rate of endothelial cell loss, and timeliness of treatment. Early-stage cases may be managed conservatively, while advanced disease typically requires corneal transplantation (eg, DMEK or DSEK) for visual rehabilitation.[84]

Without treatment, FED follows a predictable progression, with endothelial cell loss gradually leading to worsening corneal edema and vision impairment. In the early stage, patients remain asymptomatic or experience mild morning blurring due to transient corneal edema. Vision remains functional for years with minimal interventions, such as hypertonic saline drops. However, if endothelial decompensation occurs, persistent corneal edema may develop.[85]

As the disease advances to the moderate stage, patients experience increased glare, halos, and fluctuating vision, which can interfere with activities like night driving and reading. Without intervention, corneal thickening progresses, and bullous keratopathy becomes inevitable. Corneal scarring further increases the likelihood of requiring surgical treatment.

In the advanced stage, severe endothelial failure results in chronic stromal edema, epithelial bullae, and persistent visual deterioration. Without surgery, functional vision is lost, significantly impacting daily life. Left untreated, bullous keratopathy can lead to recurrent erosions, pain, and permanent corneal scarring, making corneal transplantation the only viable option for visual rehabilitation.

DMEK offers the best visual outcomes among all surgical options, with a 90% to 95% graft survival rate at 5 years. Compared to other procedures, DMEK has the lowest rejection rates (<2%), but graft detachment requiring rebubbling occurs in 10% to 20% of cases (see Image. Long-Term Graft Survival Rates of Corneal Transplants in Fuchs Endothelial Dystrophy).[86]

DSEK has an 85% to 90% graft survival rate at 5 years and is more suitable for patients with prior ocular surgery or glaucoma. However, this approach has a higher rejection rate (5% to 10%) than DMEK, and visual recovery is slightly longer due to interface haze.[87]

PKP is reserved for cases with severe corneal scarring when DMEK or DSEK is not viable. Recovery is prolonged, taking approximately 1 year, and rejection rates are higher (~20%) compared to lamellar keratoplasty (see Image. Prognosis of Fuchs Endothelial Dystrophy After Surgery).[88]

If endothelial cells remain functional, DMEK and DSEK can provide stable vision for over a decade. Long-term graft survival depends on appropriate steroid tapering and rejection monitoring. Late graft failure occurring more than 10 years postoperatively may necessitate repeat keratoplasty in some cases. Patients with FED can maintain functional vision for decades with early diagnosis, proper medical management, and timely surgical intervention. Advances in DMEK and DSEK have significantly improved long-term visual rehabilitation with lower complication rates. Regular follow-up and adherence to postoperative care remain essential for sustained success.

Most patients who undergo keratoplasty for FED experience significant visual improvement.[89][90] A Cochrane review by Nanavaty et al in 2014 found no difference in final visual outcomes between patients who received endothelial keratoplasty (DSEK, DSAEK, DMEK, or femtosecond laser-assisted endothelial keratoplasty) and those who underwent PKP.[91] However, endothelial keratoplasty provides faster and more reliable visual recovery than PKP while preserving the structural integrity of the eye.[92] Additionally, PKP is associated with a higher risk of complications. By 2013, DMEK had surpassed PKP as the preferred treatment for endothelial disorders, and endothelial keratoplasty techniques, eg, DSAEK and DMEK, have since become the standard of care for FED.[93] Patients generally achieve good visual outcomes.

Long-term visual outcomes following keratoplasty depend on endothelial cell function, postoperative management, and patient adherence to care. When endothelial cells remain functional, DMEK and DSEK can sustain vision for more than a decade. Steroid tapering and regular monitoring for graft rejection are essential for long-term graft survival. However, late graft failure, occurring more than 10 years postoperatively, may necessitate repeat keratoplasty in some patients.

With early diagnosis, appropriate medical management, and timely surgical intervention, individuals with FED can maintain functional vision for decades. Advances in DMEK and DSEK have significantly improved prognosis, providing durable visual rehabilitation with low complication rates. Consistent follow-up and adherence to postoperative care remain critical for long-term success.[94]

Complications

FED can lead to complications such as corneal scarring and progressive vision loss. Without treatment, endothelial cell loss may result in corneal decompensation and the need for transplantation. However, while surgical interventions can restore vision, they also carry risks (see Image. Fuchs Endothelial Dystrophy Postsurgical Complications). Early recognition, interprofessional care, close follow-up, and patient education regarding these complications are essential for optimizing outcomes.[95]

Complications of untreated FED primarily stem from progressive endothelial cell loss, leading to corneal edema, vision impairment, and increased surgical risks. Loss of endothelial cells allows fluid to accumulate in the stroma, increasing corneal thickness and reducing transparency. In the early stages, transient morning blurring occurs due to overnight swelling, improving as the day progresses. As the disease advances, persistent vision haze, glare, and difficulty with night vision develop. Severe cases progress to bullous keratopathy, characterized by fluid-filled epithelial blisters that cause significant pain and discomfort.

Chronic endothelial failure results in permanent stromal scarring, leading to corneal opacification and progressive visual deterioration. Patients experience increasing corneal haze, loss of contrast sensitivity, and functional vision loss. In advanced cases, corneal transplantation with DMEK, DSEK, or PKP is the only effective treatment.

FED by itself also increases the risk of complications from intraocular surgery. Cataract surgery accelerates endothelial cell loss, worsening corneal edema and increasing the likelihood of postoperative decompensation, particularly when preoperative ECD is low. Proper assessment of corneal thickness and endothelial function is essential before cataract surgery in these patients.[96]

Surgical management of FED with DMEK, DSEK, or PKP carries risks that can impact long-term graft survival and visual outcomes. Graft dislocation, the most common complication of DMEK, occurs in 10% to 20% of cases due to incomplete attachment of the donor Descemet membrane. Patients may experience reduced vision postoperatively, with persistent corneal edema detected on slit-lamp and AS-OCT examination.[97] Management involves a rebubbling procedure with air or gas injection to reattach the graft, along with strict supine positioning to promote adherence.[98]

Graft rejection, occurring in 1% to 10% of cases, is more frequent in DSEK and PKP than in DMEK. Immune-mediated rejection of the donor endothelium presents with redness, photophobia, vision loss, and pain due to inflammation and corneal decompensation.[99] Treatment includes intensive application of topical corticosteroids such as prednisolone 1% administered hourly, with oral steroids reserved for severe cases. Close monitoring is essential to detect recurrent rejection episodes.

Steroid-induced glaucoma results from prolonged corticosteroid use after DMEK or DSEK, leading to trabecular meshwork dysfunction and elevated IOP. Patients with preexisting glaucoma or extended steroid use exceeding 6 months are at higher risk. Management includes regular IOP monitoring and the use of β-blockers, CAIs, or ROCK inhibitors while avoiding prostaglandin analogs that may exacerbate inflammation.

Primary graft failure, occurring in 3% to 5% of cases, is characterized by persistent corneal edema beyond 3 months postoperatively due to poor-quality donor tissue, surgical trauma, or preexisting endothelial dysfunction. When endothelial cells fail to function, repeat endothelial keratoplasty may be necessary.[100]

Infectious keratitis is more common in PKP than in DMEK or DSEK due to the presence of sutures, which create entry points for microbial infection. Long-term steroid use further increases susceptibility. Clinical signs include corneal infiltrates with ulceration, increased discharge, and pain. Management involves intensive topical antibiotic therapy, corneal cultures to guide treatment, and suture removal if they contribute to infection.[101]

Late graft failure, which can occur more than 5 to 10 years postoperatively, results from gradual endothelial cell loss leading to corneal decompensation. Chronic IOP elevation and repeated graft rejection episodes increase the risk. Regular endothelial cell counts and pachymetry measurements help monitor progression. Repeat endothelial keratoplasty may be considered for visual rehabilitation.[102]

Graft detachment rates after DSAEK range from 0.9% to 36.4%, while a large multicenter study reported a 36.4% detachment rate after DMEK.[103][104] Detachments are typically managed with an additional procedure to reattach the graft using air or sulfur hexafluoride. Marques et al demonstrated that patients who underwent DMEK had better-corrected distance visual acuity and a 60% lower rejection rate than those who received DSAEK, though DMEK required more rebubblings due to graft detachment.[105]

Individuals who undergo PKP face risks such as postoperative astigmatism and wound rupture. Given these potential complications, endothelial keratoplasty techniques are the standard of care for FED. Cataract progression is also a concern after keratoplasty.

Other potential perioperative complications of surgical treatments for FED include aqueous leakage and vitreoretinal injury, which require prompt evaluation and appropriate surgical intervention. Meanwhile, long-term sequelae necessitate ongoing management and rehabilitation. Lifelong immunosuppression may be required to prevent chronic graft rejection, often in the form of low-dose topical steroids. However, prolonged steroid use increases the risk of glaucoma and cataract formation, making regular monitoring essential.

Postoperative astigmatism or irregular corneal curvature can result in residual refractive error and visual distortion, sometimes requiring spectacle correction or scleral lenses. Additionally, some patients, particularly those who undergo DSEK, experience persistent glare and halos at night due to graft-host interface haze. Wavefront-guided corneal topography can help evaluate and address residual aberrations.[106]

Even in successfully transplanted corneas, ECD continues to decline over time. Long-term graft survival depends on strategies to preserve endothelial function and early intervention if signs of decompensation emerge.[107]

Effective preventive strategies can minimize complications associated with keratoplasty and improve long-term outcomes. Preoperative risk assessment involves using specular microscopy and pachymetry to evaluate endothelial reserve before cataract surgery. Careful IOP control is also essential to prevent secondary endothelial damage.[108]

Postoperative care optimization includes a strict steroid tapering protocol to balance the risk of rejection with the potential for steroid-induced IOP elevation. In DMEK, timely rebubbling is necessary to prevent prolonged corneal edema and ensure graft adherence.[109]

Long-term monitoring involves annual ECD assessments to detect late-stage graft dysfunction. Additionally, patient education on recognizing early signs of graft rejection using the RSVP mnemonic can facilitate prompt intervention.