Given the endothelium’s vital role in maintaining corneal function, any effort made in pursuit of preserving it is time well spent. Fuchs’ endothelial corneal dystrophy (FECD), the most prevalent of such dystrophies, commonly results in vision loss. Its prevalence can be quite high in certain populations; for instance, in an Icelandic cohort, 9.2% of those over 55 were affected. Additionally, it affects more women than men, and has been recognized as autosomal dominant in some familial cases. Recently, a review done by Zhang and Patel at the New Zealand National Eye Centre at the University of Auckland illustrates how using in vivo confocal microscopy (IVCM) has allowed studies to scrutinize the cornea with a precision that was previously unavailable, gaining a greater understanding of the changes that occur in FECD. Their observations, summarized below, provide a springboard from which to consider implications for clinical management.

Study in the Spotlight Zhang J, Patel DV. The pathophysiology of Fuchs’ endothelial dystrophy ─ A review of molecular and cellular insights. Experimental Eye Research. 2015;130:97-105.

Endothelium. When imaged by IVCM, the endothelium in FECD may resemble the surface of a strawberry, the study authors write, with hyporeflective round areas separated by hyper-reflective regions. The cells appear stressed and show markers of apoptosis. They transition into an epithelial or fibroblastic phenotype, and form a self-defense mechanism. Yet, the endothelium maintains the cornea’s barrier function until late stage FECD—the endothelial cells continue to migrate to, and populate, the stromal surface. Additionally, the endothelial pump rate shows no signs of change in early stages of FECD, and in fact may increase. However, as the disease progresses to late stage FECD, the pump rate follows a steady decline, resulting in fluid build-up and subsequent stromal edema.

A Pharmacological Approach to FECD Treatment? While endothelial graft surgery remains the best option for patients with Fuchs’ endothelial corneal dystrophy (FECD), researchers continue to hunt for alternative treatments. Recently, investigators from Japan have discovered a possible medical treatment option in the form of Rho-associated kinase (ROCK) inhibitor eye drops.1 Previous research showed that a ROCK inhibitor, Y-27632, promoted the healing of the corneal endothelium in vivo, and they sought to test its efficacy as a FECD treatment.2 Their latest report highlights a case of FECD successfully treated by ROCK inhibitor eye drops subsequent to transcorneal freezing.1 A 52-year-old Japanese man diagnosed with late-onset FECD underwent transcorneal freezing, after which 50mL of 10mM ROCK inhibitor was applied as eye drops 6 times daily for 7 days.1 Two weeks after the treatment, the patient’s cornea recovered complete clarity, and vision improved to 20/20—and increased to 20/16 six months post-treatment.1 Researchers note that although FECD is a progressive disease, this patient’s corneal clarity and good vision have been maintained up to the most recent observation 24 months after treatment.1 During post-treatment observation, investigators used contact specular microscopy and revealed relatively small endothelial cells, present at high cell density, in the central cornea where endothelial cells had been removed by the transcorneal freezing procedure.1 Although the investigators are optimistic about their findings, they know more work needs to be done. Studies have shown that the corneal endothelium in the Japanese population has a higher cell density than the American population, bringing into question whether or not the ROCK inhibitor would have the same effect on different patient populations.3 The case report authors also admit it’s possible the results were due to the denudation of the pathologic endothelial cells, not the ROCK inhibitor.1 But plans are in the works for a larger, more conclusive study to get to the bottom of this success story. And researchers are hopeful that, as evidence builds, your patients may ultimately benefit from a new treatment method. “We believe that our new findings will contribute to the opening up of a new approach to the treatment of corneal endothelial dysfunction,” they conclude.1 1. Koizumi, N, Okumura, N, Ueno M, et al. Rho-associated kinase inhibitor eye drop treatment as a possible medical treatment for Fuchs corneal dystrophy. Cornea. 2013; 32(8): 1167-1170. 2. Okumura N, Ueno M, Koizumi N, et al. Enhancement on primate corneal endothelial cell survival in vitro by a ROCK inhibitor. Invest Ophthalmol Vis Sci. 2009;50:3680–3687. 3. Matsuda M, Yee RW, Edelhauser HF. Comparison of the corneal endothelium in an American and a Japanese population. Arch Ophthalmol. 1985 Jan;103(1):68-70.

Descemet’s membrane (DM). Studies suggest a thickening of the DM in FECD, initially in the central cornea and extending to the peripheral cornea as the disease progresses. Endothelial secretion of modified collagen and other extracellular matrix proteins leads to formation of guttae in DM. Compromised endothelial water pump function causes corneal edema, leading to thickening of Descemet’s layer. The study also suggests that while the pathological endothelium affects the DM and stroma, the DM and stroma still support endothelial growth.

Stroma. Because the majority of IVCM studies have involved patients with late stage FECD, the study authors postulate the stromal changes of FECD likely occur secondary to corneal edema. The signs of this edema include keratocyte hyper-reflectivity, dark, small paranuclear intracellular vacuoles (10µm to 20µmm), and large extracellular lacunae (40µm to 100ųm) between keratocytes. IVCM studies have revealed some surprising insights into the disease progression when it comes to posterior and anterior keratocyte density. IVCM and histological studies have shown significantly lower anterior keratocyte density in late stage FECD, but no significant difference in posterior stromal keratocyte density. However, examining cases of mild FECD with IVCM revealed significantly higher posterior keratocyte density compared to controls, and no difference in anterior keratocyte density. Stromal nerve changes, such as the appearance of tortuous nerves, may also appear.

Corneal sub-basal nerve plexus. By observing mild cases of FECD with IVCM, researchers have found that mild cases have significantly lower sub-basal nerve density compared to healthy controls, while late stage FECD may be completely lacking in sub-basal nerves.

Epithelium. Epithelial changes appear clinically and on IVCM in late FECD. Bullae manifest as dark circles with three distinct patterns. IVCM also reveals that sub-epithelial hyper-reflectivity, representing scarring, is common. Observers have noted map-dot fingerprint dystrophy-like epithelial changes in patients with chronic corneal edema. According to research, molecular changes in FECD epithelium include: the presences of apoptosis, oxidative damage, abnormal extracellular matrix material expression and scarring at or below the epithelial basement membrane, and altered water pump expression despite normal aquaporin expression.

Clinical Implications
“In Fuchs’ dystrophy, the problem occurs when patients get swelling of the cornea,” says Theodore Perl, MD, medical director at Corneal Associates of New Jersey in Fairfield, NJ, and medical director of the Keratoconus Center of New Jersey. “The endothelium is letting fluid into the cornea, and it’s swelling, and it’s causing blurred vision.”

The good news is that today’s endothelial transplant procedures are highly effective and offer significant advantages over a full-thickness penetrating keratoplasty. “We have miraculous treatments that weren’t available 10 years ago,” Dr. Perl says. “Now we do only a partial transplant where all we replace is the diseased endothelial cells with a little bit of Descemet’s membrane and/or a little bit of posterior stroma.” The advantages to this new approach include: quicker healing, no induced astigmatism, no risk of a wound rupture that may occur following a full-blown corneal transplant, low incidence of rejection and, in the absence of sutures, no suture infections.

It’s important therefore for optometrists to be ready to refer patients for surgery in a timely manner. “If you allow corneal edema to persist to the chronic stage where they start getting swelling of the surface, meaning microcystic edema or bullous keratopathy, then you can get secondary changes to the anterior part of the cornea, and basically you get scarring,” Dr. Perl says. The problem, he says, is that although the transplant eliminates the Fuchs’-affected tissue and the edema, “the patient can’t see very well because there’s still scar tissue on the surface.”

Clinical vigilance for the characteristic signs of advancing FECD is essential in order to refer for an endothelial transplant when this is indicated. “You’ve got to get these people to have surgery before they develop the changes that are described in this article: the microcystic edema, the bullae, those fingerprint lines, the secondary epithelial basement membrane dystrophy that you see, the granularity in the anterior stroma and Bowman’s membrane,” Dr. Perl says. “You don’t want to wait, because once they get scar tissue, they may require penetrating keratoplasty” to minimize or clear it.  

And that’s where this review comes into play for clinicians. While most histological studies focus primarily on late stage FECD, IVCM studies have been able to take a closer look at mild and moderate cases to better understand the pathophysiology of FECD. And the more you understand about the disease process, the better equipped you are to identify early signs and symptoms—and possibly offer an earlier diagnosis.  

While IVCM has already revealed so much about the FECD disease process, the study authors realize there is more work ahead. Focusing on early and mid-stage FECD with IVCM could provide new insights that could have a significant impact on early detection and diagnosis of Fuchs’ Endothelial Dystrophy.