Evaluation and Management of Fuchs Dystrophy

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Fuchs dystrophy is a slow, progres­sive degeneration of the corneal endothelium, leading to stromal edema. The edema can cause symptoms such as blurry vision, eye pain, and light sensitivity. Signs and symptoms can begin to appear in the fourth decade of life, although the typical onset is between the fifth and seventh decades. In developed nations, Fuchs dystrophy is one of the most common indications for corneal transplantation.¹

Genetics

Fuchs dystrophy is inherited in an autosomal dominant pattern, with a strong predilection for women (3:1 ratio); evi­dence also suggests a higher prevalence in white populations. The disorder’s genetic basis and pathophysiology are multifactorial, with recent studies illu­minating various contributing genes.

One of these genes, COL8A2, is re­sponsible for the α2 subtype of collagen VIIIA, and a point mutation in this gene is responsible for altering a key com­ponent of Descemet membrane in the early-onset subtype of Fuchs.^1,2 The SLC4A11 gene, associated with a late-onset Fuchs subtype, encodes for the densely populated endothelial mem­brane borate pump (transportation of water and ammonia), responsible for maintaining deturgescence. The TCF4 gene encodes for the E2-2 protein, which belongs to a family of transcription factors responsible for cell growth and differentiation. Other associated genes include ZEB1, AGBL1, KANK4, LAMC1, ATP1B1, LOXHD1, and DMPK.^1,2

SLIT-LAMP PHOTOS. Eyes with Fuchs demonstrating (1A) cornea guttae highlighted with retroillumination and (1B) severe central bullous keratopathy (microcystic edema and bullae) and stromal fibrosis.

Diagnosis

The diagnosis of Fuchs is made primarily based on a comprehen­sive exam, as there is no definitive diagnostic test. A careful slit-lamp exam, including retroillumination, can identify central guttae (excrescences in Descemet membrane; Fig. 1A). The guttae may spread peripherally and may coalesce, forming a beaten metal appearance. Edema may appear as a fine gray haze (best seen with sclerotic scatter), and it may progress to fine ver­tical wrinkles (striae), overt Descemet folds, and microcystic epithelial edema and bullae (Fig. 1B). A pachymeter may be useful in identifying corneal edema, particularly if baseline pachymetry is available for the patient. Specular mi­croscopy can also be used to determine the number and quality of endothelial cells (Fig. 2).

Staging. Endothelial degeneration progresses slowly over the course of 10 to 30 years and can be clinically catego­rized by three stages of symptoms and signs.

• The initial stage is characterized by the presence of central guttae. Often asymptomatic at this stage, guttae can lead to symptomatic glare from higher-order aberrations and backscatter.
• The second stage is marked by the accumulation of fluid in the stroma and epithelium, producing blurry vision, halos around lights, and eye pain. Symptoms may be worse in the morning as a result of decreased evaporation of corneal fluid when the eyes are closed during sleep.
• The final stage is marked by loss in visual acuity (VA) and is remarkable for the development of avascular subepithelial fibrous scarring between the epithelium and Bowman membrane (best viewed with tangential illumi­nation), peripheral superficial corneal neovascularization, and a reduction in edema.

Treatment

Medical therapy. In the early course of the disease, medical management aims to remove excess fluid from the cornea by using topical hypertonic saline ointment/solutions (e.g., 5% sodium chloride), dehydrating the cornea with a blow dryer in the morning or throughout the day (at low heat and kept at an arm’s distance to avoid burning/damage), and reducing intraocular pressure. Bandage contact lenses may decrease symptoms from painful bullae or prevent recurrent erosions.

Keratoplasty. Surgery (see table below) is indicated when symptoms warrant intervention, often when there is a decrease in VA or discomfort from epithelial edema or erosions.

PK vs EK. Historically, penetrating keratoplasty (PK, full-thickness ker­atoplasty) was a common treatment. PK is now reserved for corneas with combined pathologies such as Fuchs in the setting of symptomatic anterior corneal scarring, stromal dystrophy, or keratoconus.

The currently preferred approach for symptomatic Fuchs is partial-thickness endothelial keratoplasty (EK), which selectively replaces the dysfunctional corneal endothelium. These procedures include Descemet stripping automat­ed endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK; Fig. 3).

Compared with traditional PK, EK has the advantages of superior visual outcomes, faster recovery, fewer intra­operative and suture-related complica­tions, lower graft rejection and failure rates, and greater tectonic integrity. Re­viewing long-term outcomes in Fuchs eyes, Woo et al. found that PK had worse graft survival rates (73.5%) than DMEK (98.7%) or conventional DSAEK (96.2%).³ Addition­ally, PK had a higher graft rejection rate (14.1%) than DMEK (1.7%) or conven­tional DSAEK (5.0%).

DMEK. Series reported in the literature^4-6 show that DMEK provides an average best-corrected VA (BCVA) of 20/25 in 50% to 80% of Fuchs and pseu­dophakic bullous keratopathy cases at six months. DMEK achieves 20/20 or better in at least 40%, although Fuchs eyes tend to attain better results.

The DETECT trial showed that DMEK yields superior visual results compared with ultrathin DSAEK and has similar endothelial and complica­tion outcomes.⁷ Despite the superior clinical outcomes of DMEK (better BCVA, faster visual recovery, decreased rejection rates), DSAEK is still performed more commonly in the United States. This is because DMEK has a steeper learning curve and higher postopera­tive graft dehiscence rate.

Advanced DSAEK. Thinner DSAEK grafts in the ultrathin (50-100 μm) and, more recently, nanothin range (≤50 μm) have shown promising results that are close, if not comparable, to DMEK in terms of BCVA (53% achieving 20/20 at five years for ultrathin, and 57% achieving 20/20 at one year for nanothin in certain series).^8,9 Although DMEK still allows for quicker visual recovery than the new DSAEK approaches, ultrathin and nanothin DSAEK provide EK surgeons with a viable alternative that af­fords the same comfort and predictability as conventional DSAEK. Intraoperatively, the tissue behaves similarly in eyes with complex anterior segment anatomy as it does for routine Fuchs cases.

DWEK/DSO. Certain Fuchs patients may benefit from descemetorhexis without endothelial keratoplasty (DWEK), also known as Descemet stripping only (DSO). These are patients with symp­tomatic central guttae or edema and clear peripheral cornea with an endo­thelial cell count (ECC) of at least 1,000 cells/mm². In this technique, the central 4 mm of Descemet and endothelium is removed by means of descemetorhexis. Resolution of central corneal edema occurs through migration and regen­eration of peripheral endothelial cells after a mean of three months.

While reported clearance rates range from 63% to 100%, the use of ripasudil, a topical rho-associated protein kinase (ROCK) inhibitor, may improve endothelial proliferation and corneal clearance.¹⁰ DSO eliminates graft complica­tions, rejection, and the need for long-term postoperative corticosteroids.

However, because experience is limited with this procedure compared to the others, careful patient selection is important. DSO may be rescued with a DMEK surgery if the cornea fails to clear.

SPECULAR MICROSCOPY FINDINGS. (2A) Polymegethism and occasional guttae compared with (2B) severe polymegethism and significant guttae.

Other Procedures

For Fuchs patients with corneal edema and recurrent erosions who are not candidates for keratoplasty, anterior stromal micropuncture may be applied in focal areas of painful bullae. This technique can also be used after EK for residual bullae (i.e., in the areas of bare stroma if there is a mismatch between the descemetorhexis and the EK graft).

Another option for treating bullous keratopathy may be corneal cross-link­ing, which can improve symptoms, vision, and/or pachymetry in certain cases.¹¹ Although improvement can be seen in the first month, regression may occur over the ensuing months.

BEFORE AND AFTER. Anterior segment OCT of Fuchs eye (3A, top) before and (3A, bottom) one week after DMEK surgery. Note the cornea edema with visible folds, thickened Descemet, and guttae in the top image. The cornea is appreciably thinner in the bottom image; it is also impossible to detect the graft, as it is an anatomic replacement. (3B) Slit-lamp photograph one day after DMEK surgery with a 60% gas fill shows that the cornea has already thinned.

EK With Cataract Surgery

In Fuchs patients with a visually sig­nificant cataract, cataract surgery can be performed alone, at the same time as EK, or in a staged process based on which pathology (cornea or cataract) is more symptomatic or which order the ophthalmologist is most comfortable with. When the cataract appears to account for the visual decrease, cataract surgery may be considered earlier when there is more endothelial reserve. An ECC less than 1,000 cells/mm² or corneal thickness greater than 640 μm should raise concern about the possi­bility of corneal decompensation with intraocular surgery.¹²

Cataract technique and lenses. During cataract surgery in Fuchs, an effort should be made to replenish dispersive ophthalmic viscosurgical devices (OVDs) during nuclear disas­sembly to give continued protection to the endotheli­um. Femtosecond laser may decrease the phacoemulsi­fication energy needed and the subsequent endothelial damage.

Hydrophilic IOLs should be avoided, as they can develop hydroxyapatite deposition from the gas or air fill if an EK is needed in the future. Multifocal IOLs should also be avoided in Fuchs because of their dif­fractive optics and reduced image quality. In patients who are expected to undergo EK in the future, the surgeon may select the IOL power for postsurgical myopia to compensate for EK-induced hyperopia.

Combined surgery. For combined cataract surgery and EK, the surgeon should adjust the paracentesis sites for the EK (postoperatively, a superior paracentesis allows for selective gas removal, while an inferior paracentesis allows for aqueous removal). A smaller anterior capsulorrhexis (~4.5 mm) will minimize anterior displacement of the IOL during the anterior chamber shal­lowing and filling that occurs during EK. A cohesive OVD is utilized to ensure complete removal, and phacoemulsifi­cation can be performed above the iris plane to protect the posterior capsule without concern for the endothelium. IOL power selection should account for the expected hyperopic shift of approx­imately 0.50 to 0.75 D for DMEK and 1.00 to 1.25 D for DSAEK. Eyes with greater corneal edema (thicker central pachymetry) as well as flatter and more oblate posterior corneal surfaces may have greater-than-expected hyperopic shifts.

Surgical Treatments

Future Options

Kinoshita and colleagues have pub­lished results of a clinical trial using cultured human corneal endothelial cells (CECs) supplemented with a ROCK inhibitor in eyes with endothe­lial disease, including Fuchs.¹³ After mechanical removal of abnormal extracellular matrix on the Descemet membrane, the cultured CECs were injected into the anterior chamber, and the patients were positioned face down for three hours. Results were promis­ing, with an increase in CEC density, decrease in pachymetry, and clearing of the cornea by 24 weeks; at two years, corneal transparency was maintained, and no serious adverse events were noted.

Conclusion

Fuchs dystrophy is an endothelial degeneration that results in progressive stromal edema. Endothelial keratoplasty (DSAEK, DMEK) currently remains the preferred treatment for symptom­atic Fuchs; however, newer surgical techniques such as DSO may benefit specific patients. Future advances with cultured human CECs eventually may change the treatment paradigm.

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For more information, see “Genetic Disorders of the Cornea: Preventing Surgical Surprises.”

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1 Nanda GG, Alone DP. Mol Vis. 2019;25:295-310.

2 Sarnicola C et al. Eye Contact Lens 2019;45(1):1-10.

3 Woo JH et al. Am J Ophthalmol. 2019;207:288-303.

4 Trindade BLC, Eliazar GC. Clin Ophthalmol. 2019;13:1549-1557.

5 Guerra FP et al. Ophthalmology. 2011;118(12):2368-2373.

6 Rodriguez-Calvo-de-Mora M et al. Ophthalmol­ogy. 2015;122(3):464-470.

7 Chamberlain W et al. Ophthalmology. 2019;126(1):19-26.

8 Madi S et al. Cornea. 2019;38(9):1192-1197.

9 Kurji KH et al. Cornea. 2018;37(10):1226-1231.

10 Garcerant D et al. Curr Opin Ophthalmol. 2019;30(4):275-285.

11 Ucakhan OO, Saglik A. Case Rep Med. 2014;463905.

12 American Academy of Ophthalmology. Cataract/Anterior Segment Panel. Cataract in the Adult Eye Preferred Practice Pattern. aao.org/preferred-practice-pattern/cataract-in-adult-eye-ppp-2016.

13 Kinoshita S et al. N Engl J Med. 2018;378:995-1003.

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Mr. Im is a second-year medical student at East­ern Virginia Medical School (EVMS) in Norfolk, Va. Drs. Cheung and Yeu are cornea specialists at Virginia Eye Consultants/CVP in Norfolk and are on faculty at EVMS’ Department of Ophthalmol­ogy. Relevant financial disclosures: None.

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