Advancements in Cell Regeneration Not Yet as Reliable as DMEK in Fuchs’ dystrophy

 By Francis W. Price, Jr., MD & Matthew T. Feng, MD

We are always looking for better ways to correct the visual difficulties of patients with Fuchs’ dystrophy.  In fact, that is why we helped pioneer the evolution of corneal transplants from full thickness grafts (penetrating keratoplasty) to PLK/DLEK to DSEK to DMEK.  Interest is building now to eliminate the transplant altogether and allow a person’s own endothelial cells to regenerate in a procedure called Descemet’s Stripping without Endothelial Replacement.
The corneal endothelium is a single layer of cells that lines the back surface of the cornea. These cells pump water out of the cornea to keep it crystal clear. In Fuchs’ dystrophy these cells become unhealthy and die off, starting in the center and moving toward the periphery over time.  This allows fluid to build up in the cornea causing swelling and hazy vision. Eventually blisters can develop; this can be painful and cause light sensitivity.

The corneal endothelial cells are attached to a thin membrane called Descemet’s membrane. In Fuchs’ dystrophy, abnormal deposits called “guttae” accumulate on Descemet’s membrane.  These guttae are like water drops on a windshield (guttae mean raindrops in Latin).  They distort the light coming into the cornea and also cause glare and halos and must be removed to improve vision.

DMEK is a tried and true treatment for Fuchs’ dystrophy in which we remove the central corneal endothelium and Descemet’s membrane and implant healthy donor tissue, which has normal endothelial cells and a clear Descemet’s membrane without guttae.  It provides rapid and reliable visual recovery within 2 days to one month after surgery with minimal risk of immunologic graft rejection (<1% with appropriate use of eye drops).[reference] With DMEK, the risk of developing glaucoma is reduced because of the improved corticosteroid eye drop dosing regimens we have developed, and long term graft survival is excellent.
In contrast, we and others have tried Descemet’s Stripping without Endothelial Replacement (stripping alone) which is performed in the same manner as with DMEK, except a smaller area of the central area of Descemet’s Membrane is removed and no donor endothelium is transplanted.  We then waited to see if the surrounding endothelial cells would regenerate.  There are two benefits of stripping alone that excited us. First, there would be no risk of immunologic graft rejection (0% rejection rate) since we are not using a donor cornea so there is no immune response to foreign tissue. Second, the need to use long term topical corticosteroids  to prevent graft rejection would be eliminated thereby reducing the side effect of intraocular pressure elevation that approximately one third of users experience.
Unfortunately, we found that the results of stripping alone were unpredictable.^1-3
In our analysis, we removed a 6-mm diameter area of the diseased Descemet’s membrane but we found that recovery was incomplete—the endothelial cells never fully filled in the area of cells that we removed, even after waiting for months.
Some surgeons have tried removing smaller areas of Descemet’s membrane (4-mm diameter area) and have had a higher rate of clearing.  Despite these successes we still do not recommend Stripping alone for Fuchs’ dystrophy for two primary reasons: we don’t believe that clearing only a 4-mm diameter is sufficient at giving patients the best possible vision, and there is still the potential for prolonged corneal swelling that may last for months.
Are patients getting the best possible vision with stripping alone? We have been told that patients are happy with the vision they get using a 4-mm area of treatment. But we wonder if they just notice some visual improvement with the central guttae removed without realizing how much better it could be if a wider area was treated. We know from laser refractive surgery (LASIK or PRK) that a small treatment zone causes patients to have significant glare and halos at night.  We also know that the intraocular lenses used in cataract surgery do not perform well when the clear optical zone is only a 4-mm diameter. Typically, clear zones of 6-mm diameter or more are needed to avoid glare and halos.
The question is not whether we can do Stripping alone, but whether we should do it.  Many of our Fuchs’ dystrophy patients tell us they only need one eye treated because their other eye is doing fine.  But after DMEK, they realize the “good” eye was not as good as they thought, and then they want to have the second treated as soon as possible to eliminate glare and haze.  Similarly, in the winter time when it snows, you can drive your car after just clearing a small area of the windshield, but obviously it is much better to clear a larger area to view the periphery.

For most patients, just removing 4-mm diameter of Descemet’s membrane will leave behind a lot of guttae in the surrounding areas of the cornea, and they would have better night vision with a larger area of removal. By way of comparison, we typically remove an 8-mm diameter when performing DSEK or DMEK.
The second concern is slow healing.  Often with stripping alone it takes two or more months for the cornea to clear.  In some cases it takes over 6 months.  There is evidence that when the cornea is continuously edematous (swollen) from non-functioning endothelium for 6 months or longer, permanent changes occur, so that when the edema does resolve, the vision does not return to a level as good as it would have if the cornea had cleared faster. Two centers found that if they waited over 6 months to replace a failed transplant, the visual results were disappointing.^4,5  In contrast, we find that when we replace a failed transplant promptly, the visual results are excellent.⁶  The longer a cornea remains edematous, the more likely it is that vision will permanently deteriorate.
In summary, we look forward to performing cell regeneration type surgeries on a routine basis once we can be assured that the cornea will reliably clear within a month or sooner after removing a 6-mm or larger diameter of the central Descemet’s membrane.  Remember, a 6-mm diameter clear zone is over twice as large as a 4-mm diameter zone. A larger clear zone can be particularly important for younger patients who have larger pupils. Patients who have already had stripping alone and are dissatisfied with their vision or speed of recovery often remain candidates for DMEK and may benefit from evaluation sooner rather than later.    
Looking ahead, cell culture techniques are improving, and someday we may be able to harvest your blood cells and reprogram them to become corneal endothelial cells.  But until we can either do that or use medications to get your peripheral corneal endothelial cells to reliably heal the central cornea in less than a month, we will continue to recommend DMEK.  Use of eye drops known as ROCK inhibitors may potentially help with regeneration of endothelial cells, not only with stripping alone, but also with corneal transplants.
Use of eye drops known as ROCK inhibitors may potentially help with regeneration of endothelial cells, not only with stripping alone, but also with corneal transplants.⁷
We certainly live in an exciting time with new developments occurring continually around the world. So stay tuned!

References:

1. Bleyen et al. Spontaneous corneal clearing after Descemet’s stripping. Ophthalmology 2013l120:215.
2. Arbelaez et al. Long-term follow-up and complications of stripping descemet membrane without placement of graft in eyes with Fuchs endothelial dystrophy. Cornea 2014 33:1295-1299 (our study)
3. Koenig SB. Planned Descemetorhexis Without Endothelial Keratoplasty in Eyes With Fuchs Corneal Endothelial Dystrophy. Cornea 2015;34:1149-51.
4. Baydoun et al. Repeat Descemet membrane endothelial keratoplasty after complicated primary Descemet membrane endothelial keratoplasty. Ophthalmology 2015; 122:8-16.
5. Cirkovic et al. Clinical and ultrastructural characteristics of graft failure in DMEK: 1-year results after repeat DMEK. Cornea 2015; 34:11-7
6. Price et al. Repeat Descemet Membrane Endothelial Keratoplasty: Secondary Grafts with Early Intervention Are Comparable with Fellow-Eye Primary Grafts. Ophthalmology 2015;122:1639-44.
7. Moloney et al. Descemetorhexis Without Grafting for Fuchs Endothelial Dystrophy-Supplementation With Topical Ripasudil. Cornea 2017;36:642-648.