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Ophthalmology / Cornea & anterior segment

Fuchs’ Endothelial Dystrophy

Timothy Chou, MD · Henry D. Perry, MD · Renée Solomon, MD · Eric D. Donnenfeld, MD
Article

Timothy Chou, MD · Henry D. Perry, MD · Renée Solomon, MD · Eric D. Donnenfeld, MD

Introduction

Fuchs’ endothelial dystrophy is a common bilateral hereditary posterior corneal dystrophy marked by progressive endothelial degeneration (Slide 1). Cornea guttata is a hallmark of Fuchs’ endothelial dystrophy, and almost one-third of patients develop corneal edema.1 Right and left eyes may be affected asymmetrically.2 Symptoms are often worse in the morning, because corneal edema increases overnight due to decreased evaporation of surface moisture and increased tear osmolarity.3 Conversely, as corneal edema decreases from evaporation, symptoms improve in the late afternoon. Post-menopausal women are affected from 2.5 to 4 times more frequently than men and with greater severity.1,3-5 Symptomatic patients are often older than 50 years of age, with 10% of patients approximately 60 years old, and 25% of patients between the ages of 80 and 85 (Slide 2). However, Fuchs’ dystrophy can also affect adolescents.6 Patients with Fuchs’ dystrophy have a higher incidence of cardiovascular disease (44%) compared to controls (11%).7 Rarely, Fuchs’ and keratoconus may occur concomitantly.8,9 A report of one patient with both bilateral Fuchs’ dystrophy and bilateral keratoconus may suggest a genetic correlation between the two conditions.8 Pitts and Jay10 found a higher incidence of narrow-angle glaucoma and short axial length (axial hypermetropia) in patients with Fuchs’ dystrophy and corneal edema.




Pathology

Abnormalities in the posterior cornea are present early in life, before age 20.11 Endothelial polymegathism and polymorphism are early indications of abnormalities in the posterior cornea. Endothelial cells become larger, less hexagonal, and flatter than normal, and cell counts decrease. Descemet’s membrane may become two or three times thicker than usual in longstanding Fuchs’ dystrophy, due to thickening of the posterior banded layer (Slide 3).2 Endothelial cells lay down excessive amounts of basement membrane material of abnormal composition in the form of a collagenous layer, which consists of bundles and sheets of widely spaced 110-nm banded collagen and multiple laminations of basement membrane material over Descemet’s membrane.12,13 Extreme amounts of this material create guttae drop-like, nodular excrescences from Descemet’s membrane, projecting into the anterior chamber (Slide 4).12 [The term gutta, coined by Vogt, was taken from the Latin word for “droplet.” Guttae is the plural form, and guttata is the the adjective form. Guttata is properly used to describe the cornea, as in cornea guttata.]3 Guttae may be prominent or buried, and discrete or confluent. Endothelial cells are sparse over the guttae, and pigment granules frequently accumulate intracellularly.3 On specular microscopy, dark areas devoid of cells are present. In some patients with “non-guttate Fuchs’ dystrophy,” multilayered Descemet’s thickening occurs with few excrescences. Whether these represent a variant of Fuchs’ dystrophy or an as yet undetermined form of endothelial degeneration is unclear.14



Areas of Descemet’s thickening and excrescences, along with endothelial attenuation, correspond to increased corneal edema.

Slide 5
15 Corneal edema results from increased endothelial permeability as well as failure of the endothelial pump, sodium-potassium adenosine triphosphatase. Endothelial Na/K ATPase is significantly decreased in the presence of cornea guttata, and decreases drastically during progression to end-stage disease.16-18 Excessive endothelial apoptosis is an important mechanism involved in this endothelial disease.19, 20 With stromal edema, the corneal lamellae become separated by fluid (Slide 3).3 Epithelial edema eventually occurs as the edema worsens and is a relatively late sign. As originally noted by Fuchs, subepithelial fibrocellular tissue may form after chronic, long-term epithelial edema with bullae.21 Stromal keratocytes migrate to lay down this subepithelial matrix.3 Endothelial cells rarely exhibit an epithelium-like appearance, which is a finding more characteristic of posterior polymorphous dystrophy (Slide 5).


Genetics

Fuchs’ dystrophy is variably autosomal dominant, with high but incomplete penetrance and variable expressivity.6,12 Researchers have postulated that the condition may be multifactorial, possibly with genetic heterogeneity, or influenced by as-yet-unknown environmental factors.3,22 In addition to being more prevalent in women, Fuchs’ dystrophy is encountered more commonly in western countries (the diagnosis accounting for 10% to 29% of corneal transplants3,23,24,25) but is more rare in the Middle East and seldom seen in Japan.3 The diagnosis accounted for 4.5% of corneal grafts at the National Taiwan University Hospital between 1987 and 1999.26 Missense mutations in the COL6A2 gene of chromosome 1p34.3-p32 occur in patients with Fuchs’ endothelial corneal dystrophy and patients with posterior polymorphous dystrophy.27 Chromosome 1 is also affected in early-onset Fuchs’ dystrophy.28 Evidence exists that mitochondrial defects might play a causative role.29,30 Cytochrome oxidase (a mitochondrial enzyme) is reduced, suggesting reduced metabolic activity and/or decreased mitochondria.31 Other research has demonstrated the presence of beta ig-h3 in the subepithelial matrix and posterior collagenous layer, suggesting a possible epithelial connection.32 One case report describes a patient with Fuchs’ dystrophy who had viral inclusions within endothelial cells. The investigators postulate that the pathogenesis of Fuchs’ dystrophy may be related to endothelial damage from a variety of causes, including viral infection.33

Diagnosis

Corneal guttae most commonly result as a normal age change in the corneal periphery and are referred to as Hassall-Henle bodies. By contrast, guttae in Fuchs’ dystrophy,

Slide 6
which are located most densely in the central cornea, often appear around age 30.3 The irregular posterior corneal surface appears as a dewdrop pattern by slit lamp retroillumination. Individual guttae, as well as endothelial cell layer changes, may also be distinctly seen with specular reflection technique.34 In milder cases, guttae may be shallow and the endothelial surface may have an orange-peel-like texture. The disease may progress slowly in different stages, over 20 or more years (Slide 2). 3,35 In stage 1, where patients are initially asymptomatic and vision is unaffected, guttae appear in the central cornea. Gradually, guttae increase and progress peripherally. As the condition progresses, the guttae become more confluent and plaque-like, and Descemet’s membrane thickens. The endothelium may take on a beaten metal appearance. Often, a fine pigment deposition occurs due to phagocytosis of melanin by endothelial cells and Descemet’s folds. In addition, corneal nerves may be thickened. With progressive endothelial dysfunction and cell loss, the cornea begins to swell with edema (Slide 6). Stage 2 has both guttae and stromal edema, beginning around age 60, progressing to include epithelial edema over 10 to 20 years. Bullae may rupture causing pain and predisposing patients to infection, as well as vascularization. In stage 3, avascular subepithelial fibrosis/connective tissue and a fibrovascular pannus develop. These findings represent late development. At the end stage, there is stromal scarring and vascularization.

In cornea guttata, guttae occur centrally but do not affect vision nor progress in severity.36 Clinical difference between cornea guttata and Fuchs’ dystrophy is ascertained over time.37 If the cornea guttata worsens, it might be reasonable to refer to this condition as Fuchs’ endothelial dystrophy. From a practical standpoint, numerous or confluent central guttae may be assumed to represent Fuchs’ endothelial dystrophy. When with these endothelial changes corneal edema and decompensation occur, the condition may be called Fuchs’ corneal dystrophy, equivalent to the more classical combined dystrophy of Fuchs. A patient younger than 45 years old with cornea guttata and low endothelial cell counts may potentially be considered to have Fuchs’ dystrophy, especially if a positive family history exists.

Management

When only a few guttae are present, patients are considered asymptomatic and no treatment is necessary. However, as the cornea guttata worsens, the cornea may thicken. Serial pachymetries and cell counts help monitor progression. When corneas are more than 650 microns thick, a greater than 85% probability exists of epithelial edema.38 When endothelial cell counts fall to 400 to 700 cells per mm2, patients may also begin to develop epithelial edema.39 In patients with confluent or nearly confluent guttae, corneal thickness is significantly increased.40 For focal microcystic edema and morning visual blurring, hypertonic saline may be used. Blowing a hair dryer into the eyes has been a traditional home remedy. Keeping IOP low to normal can also help to decrease edema. Bullous edema is often associated with a decrease in visual acuity. Bullae may break, causing severe pain, and predisposing the patient to infection. Patching, bandage contact lenses, lubricant, and antibiotic drops may be used for short-term treatment of ruptured bullae. The presence of bullae usually implies the need for keratoplasty. In eyes with limited visual potential or patients who are otherwise poor candidates for keratoplasty, a conjunctival flap may be preferred.

Penetrating keratoplasty is the mainstay of treatment and may be successful in 89% of patients.41 The Price Vision Group reported success rates of 97% after 5 years and 90% after 10 years.25 Fuchs’ dystrophy may sometimes occur within the graft over time, presumably representing unrecognized Fuchs’ in the donor, because regeneration of the host endothelial layer within the graft tissue is not considered likely to occur.3,42-44 Borderie and colleagues45 screened donor corneas for guttae, using light and transmission electron microscopy. Low-density guttae were found in one-in-four donor corneas. Furthermore, the presence of grouped guttae in the donor cornea was associated with decreased graft survival and a greater likelihood to develop postoperative stage 3 corneal guttata. This suggests that the development of clinical Fuchs’ dystrophy within a graft may be related to donor rather than recipient status.

Progression toward visually significant cataracts is frequent after keratoplasty for Fuchs’ dystrophy, occurring in 44% of patients after 5 years, including 75% of grafted patients age 60 and older.46 This, and the purported association with shallow chambers and narrow angle glaucoma, has caused surgeons to recommend routine removal of the crystalline lens in the course of keratoplasty.10 Triple procedures are comparable to non-simultaneous procedures in success of graft (96% vs 91%) and visual outcome (65% vs 66% of patients had 20/40 or better best-corrected visual acuity, in a study by Pineros and colleagues47). Nevertheless, it seems wise to consider whether to combine cataract surgery with keratoplasty on a case-by-case basis.48

Posterior keratoplasty is an alternative surgical approach that appears to be well suited for endothelial dystrophies. Melles and colleagues,49-51 from The Netherlands Institute for Innovative Ocular Surgery in Rotterdam, developed the technique of posterior lamellar keratoplasty (PLK). A sclerocorneal pocket incision is first created. A posterior lamellar disc is then excised and replaced with a donor posterior disc, without suture fixation. Terry and Ousley52-54, have reported extensively on their experience with deep lamellar endothelial keratoplasty (DLEK), which is similar to PLK. They reviewed the results of DLEK for 30 patients with Fuchs’ endothelial dystrophy. The average of the best-uncorrected visual acuity was 20/162 before transplant surgery and was 20/63 at 3 months and 20/48 at 2 years, postoperatively. Endothelial cell counts averaged 2151657 mm2 at 2 years, postoperatively. The rapid postoperative visual rehabilitation was emphasized. Corneal curvature is also better retained, so that IOL calculations can be more accurate. One drawback to this technique is that manual deep lamellar dissection of the cornea can be technically challenging. Azar and colleagues55,56 have described their approach, utilizing a microkeratome to create a hinged anterior stromal flap in the host cornea. The microkeratome is also used to make the initial lamellar dissection in the donor cornea, in conjunction with an artificial anterior chamber. The advantage is that the flap can be lifted later for purposes such as suture removal, and to perform excimer laser ablation for refractive error. The femtosecond laser is being evaluated for the same purposes as the microkeratome.57 Another line of investigation has involved transplanting Descemet’s membrane and, with it, a fresh supply of endothelial cells.58 Further research and studies are necessary to determine whether these approaches may prove to be comparable or superior to traditional penetrating keratoplasty.59

Cataract surgery is a common factor that may cause a cornea with Fuchs’ dystrophy to decompensate. In a recent study, Seitzman, Gottsch, and Stark suggest that cataract surgery may be attempted, and can be highly successful, even with corneal pachymetry increased above 640 microns.60 Closed loop anterior chamber IOLs should be avoided in patients with Fuchs’ dystrophy because of frequency of corneal decompensation.61 In the absence of adequate capsular support, strong consideration should be given to a sulcus or suture-fixated IOL. Patients with subepithelial scarring should not be treated with phototherapeutic keratectomy, as this may lead to further scarring and decreased visual acuity.62 Caution should also be observed when contemplating LASIK or argon laser iridotomy, as generalized corneal decompensation has occurred after these procedures in patients with Fuchs’ dystrophy.63-65

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