Fuchs Endothelial Dystrophy

Excerpt

Fuchs endothelial dystrophy (FED) is a bilateral, slowly progressive, and often asymmetric corneal disease characterized by endothelial cell deterioration and the development of guttata—excrescences of the Descemet membrane. The disease advances gradually, leading to significant endothelial cell loss, impaired corneal deturgescence, and bilateral corneal edema affecting the stroma or epithelium. These changes result in ocular pain, glare, halos, and decreased visual acuity.

FED is the most common corneal dystrophy affecting the endothelium and the most frequent indication for keratoplasty worldwide. A key distinction between cornea guttata and FED is that the latter presents with corneal edema. Notably, a rare nonguttate form of FED exists, in which endothelial cell degeneration causes corneal edema without excrescences of the Descemet membrane. Since nonguttate FED is rarely reported in the literature, most discussions focus on its guttate form.

FED was first described in 1910 when Viennese ophthalmologist Ernst Fuchs reported 13 older adults with bilateral central clouding. Kraupa later detailed the continuum of corneal changes in FED, and Vogt introduced the term “guttata” (gutta is Latin for "droplet") in 1921. Subsequent research has expanded the understanding of guttata and its association with FED, although the precise mechanisms and progression of the disease remain under investigation. Advances in management over the past 2 decades have significantly improved the quality of life for individuals with FED.

FED is a progressive corneal disease characterized by endothelial cell dysfunction and loss, resulting in corneal edema, visual impairment, and, in severe cases, painful bullous keratopathy. This ocular disorder is a common indication for corneal transplantation, particularly in older adults, and occurs more frequently in women.

FED primarily affects the posterior cornea, where endothelial cells maintain corneal clarity by actively pumping excess fluid out of the stroma. Fluid accumulates as these cells deteriorate, leading to progressive visual decline, glare, and increased light sensitivity. The disease advances through distinct stages, beginning with asymptomatic guttata, followed by increasing corneal thickness due to endothelial decompensation, and ultimately progressing to bullous keratopathy, which significantly impairs vision and causes discomfort.

First described by Ernst Fuchs in 1910, FED was once considered rare. However, epidemiological studies now estimate that 4% to 5% of adults older than 40 may have some form of the disease, with women affected nearly 3 times more often than men. Advances in genetics, imaging, and surgical techniques have greatly improved the understanding and management of FED.

FED typically manifests in the 5th to 6th decade of life, though early-onset variants occur, particularly in individuals with COL8A2 gene mutations. A strong genetic component is evident, as nearly 40% of patients report a family history of the condition. The pathophysiology of FED involves endothelial cell loss, oxidative stress, and genetic susceptibility. Since the corneal endothelium is a nonregenerative monolayer, any damage or cell loss results in permanent dysfunction.

In FED, endothelial cells undergo apoptosis and lose their pump function, leading to excessive hydration of the corneal stroma and epithelium. The earliest sign is the formation of guttata—focal outgrowths of the Descemet membrane that appear as dark spots under specular microscopy. As the disease advances, stromal edema develops due to impaired fluid regulation, resulting in increased corneal thickness and blurred vision. In severe cases, epithelial bullae can rupture, causing pain and further visual deterioration. Corneal pachymetry often reveals significant thickening beyond 640 μm, reflecting endothelial dysfunction.

Genetic susceptibility plays a major role in FED, particularly TCF4 gene trinucleotide repeat expansions, which are identified in nearly 70% of individuals with late-onset disease, making it a strong genetic marker. Other mutations, including ZEB1 and COL8A2, have been implicated in early-onset cases. Beyond genetics, oxidative stress contributes to disease progression, as FED endothelial cells demonstrate increased susceptibility to reactive oxygen species (ROS), leading to mitochondrial dysfunction and accelerated cell death. Environmental factors such as chronic UV exposure and smoking have been associated with worsening endothelial degeneration. Additionally, hormonal influences may contribute to the higher prevalence in women, with estrogen deficiency proposed as a potential risk factor.

FED progresses slowly over decades, with clinical manifestations varying by disease stage. Early-stage FED is often asymptomatic and detected only through slit-lamp examination, which reveals corneal guttata. As the disease advances, morning blurry vision becomes a hallmark symptom due to worsening corneal edema, which is exacerbated upon waking by reduced evaporation during sleep. Patients also report glare, halos, and difficulty with contrast sensitivity, particularly under low-light conditions.

In moderate-stage disease, corneal thickening and endothelial dysfunction lead to persistent visual impairment throughout the day. Advanced-stage FED is marked by worsening stromal edema and the formation of painful epithelial bullae (bullous keratopathy), which can rupture and cause significant discomfort. If left untreated, chronic corneal decompensation results in irreversible fibrosis and scarring.

Diagnosis relies on clinical examination, imaging, and endothelial function assessment. Slit-lamp biomicroscopy reveals characteristic guttata in the central cornea, which initially appear as discrete excrescences and later coalesce into a more widespread "beaten metal" appearance.

Specular microscopy is essential for confirming the diagnosis by assessing endothelial cell density (ECD), morphology, and pleomorphism. Normal ECD ranges from 2,500 to 3,000 cells/mm², but this value progressively declines in FED, with fewer than 1,000 cells/mm² indicating moderate disease and fewer than 500 cells/mm² suggesting severe endothelial failure. Pachymetry and anterior segment optical coherence tomography (AS-OCT) quantify corneal thickness and edema, aiding in disease staging. Fluorescein staining highlights areas of epithelial compromise in cases of bullous keratopathy.

Treatment strategies depend on disease severity. In early-stage FED, medical management focuses on reducing corneal edema and improving visual quality. Hypertonic saline (5%) drops temporarily draw excess fluid from the cornea, providing symptomatic relief. Lubricating eye drops help maintain corneal hydration and prevent epithelial breakdown. Scleral contact lenses can improve vision in moderate cases by creating a smooth optical surface over the irregular cornea. However, these interventions do not halt disease progression, and worsening symptoms may necessitate surgical intervention.

Descemet membrane endothelial keratoplasty (DMEK) is the preferred surgical approach for significant corneal edema and visual impairment. DMEK involves the selective transplantation of a donor endothelial layer with the Descemet membrane, offering better visual outcomes, faster recovery, and lower rejection rates than older techniques. Descemet stripping endothelial keratoplasty (DSEK), a similar but slightly thicker graft technique, serves as an alternative for patients with complex ocular histories, such as prior glaucoma surgeries. Penetrating keratoplasty (PKP) is reserved for severe cases with corneal scarring or multiple graft failures. Postoperative care includes long-term topical steroids to prevent rejection, intraocular pressure (IOP) monitoring, and routine endothelial cell assessments.

Research into nontransplant alternatives for FED is ongoing, with several promising therapies emerging. ρ-Kinase (ROCK) inhibitors, such as netarsudil and ripasudil, have shown potential in enhancing endothelial cell survival and function, possibly delaying the need for keratoplasty. Cell-based therapies, such as cultured endothelial cell injections, are being investigated as a minimally invasive regenerative approach. Additionally, gene therapy targeting oxidative stress pathways is under development to protect and prolong endothelial cell function.

FED is a progressive, multifactorial disease that leads to corneal edema, visual impairment, and significant morbidity in advanced stages. While medical management provides temporary relief, keratoplasty remains the gold standard for restoring vision in severe cases. Emerging therapies, including pharmacological interventions and regenerative techniques, offer hope for treating endothelial dysfunction without corneal transplantation. Early diagnosis and timely intervention are crucial for preserving vision and improving quality of life for patients with FED.