Do All Corneal Transplants Increase Glaucoma Risk?

Download PDF

Cornea surgeons currently have multiple transplant options. But one complication remains for all of the options: potential risk for glaucoma. It’s critical that ophthal­mologists understand the relative risks of glaucoma for full thickness versus partial thickness procedures as more and more corneal transplants are being performed, with partial thickness dominating full thickness nearly two to one.¹

Glaucoma risk depends on several factors besides transplant type, including patient history, indication for trans-plant, and postsurgical management. Ophthalmologists can reduce risk by vigilantly monitoring for elevated IOP after surgery and making optimal intra-and postoperative choices; the trick is being aware of what elevates glaucoma risk.

What Is Glaucoma, Anyway?

Lucy Q. Shen, MD, at Massachusetts Eye and Ear (MEE), Harvard Medical School in Boston, said that assessment of risk depends on how you define glaucoma. “In the glaucoma world, glau­coma is a disease of the optic nerve; IOP is only a risk factor. In cornea research, cases are often counted based on postoperative eye pressure and the need to use medical therapy.” That can lead to inconsistency regarding risk assessment, she said. “The literature is quite inconsistent on the incidence of glaucoma because it depends on which definition you use.”

Regardless of definition, corneal transplants can lead to glaucoma by in­ducing elevated IOP² (which, ironically, can also cause the graft to fail). Steven J. Gedde, MD, at Bascom Palmer Eye Institute at the University of Miami, said, “Controlling IOP prevents damage to the optic nerve and also reduces the risk of the corneal transplant failing.”

POST-OP. Patient with Fuchs dystrophy who had a trabeculectomy (1A) five months before PK (1B). With a contact lens, he has 20/40 vision.

Risk, by the Numbers

Dr. Shen and her colleagues at MEE conducted a retrospective cohort study of all consecutive corneal transplant surgeries performed at their institu­tion from April 2016 to December 2019.³ Using a definition of glaucoma that included IOP, medication usage, glaucoma surgery, and changes to the optic nerve on an exam, they found that within the first postoperative year, patients without preoperative glaucoma developed glaucoma at a rate of:

• Descemet membrane endothelial keratoplasty (DMEK): 18.8%
• Descemet stripping endothelial keratoplasty (DSEK): 35.3%
• Penetrating keratoplasty (PK): 46%

Approximately two years post-op, give or take five months, these same patients had developed glaucoma at a rate of:

• DMEK: 20.3%
• DSEK: 41.2%
• PK: 46%

Dr. Shen cautions against taking those numbers at face value, however: “Patient selection may partly explain the higher risk for glaucoma in patients receiving DSEK and PK. Many of these patients already had several risk factors for glaucoma preoperatively, such as more peripheral anterior synechia, causing secondary angle closure. Hence, the glaucoma incidence we described is probably explained by a combination of preoperative risk factors and the type of corneal surgery.”

Inconsistency in the literature. Stud­ies on posttransplant glaucoma show wildly varying numbers regarding risk. Some mechanisms of pressure elevation occur right after surgery, while some develop later, so it depends on when a study was done relative to surgery, said Dr. Gedde.

Dr. Shen points to the different defi­nitions of glaucoma used by different study authors and the fact that some eyes are inherently at greater risk: “Some of our DSEK patients are having their second, third, or fourth partial thickness transplants,” she said.

Other risk factors. Some patients are inherently more at risk for glaucoma than others, a factor not necessarily reflected in the numbers, said Dr. Gedde. “The most notable risk factor for posttransplant progression of glau­coma is preexisting glaucoma. Also, there’s an association between glauco­ma risk and the underlying indication for corneal transplant. Patients with Fuchs dystrophy and keratoconus are lower risk than those who have aphakic bullous keratopathy, trauma, or herpetic disease,” he said.

Corticosteroids

Ophthalmologists use topical steroids to prevent graft rejection, but the medication can cause elevated IOP and increase the risk of glaucoma and cat­aract formation. Francis Price Jr., MD, at Price Vision Group, Indianapolis, a pioneer in endothelial keratoplasty in the United States, and Marianne Price, PhD, at the Cornea Research Foun­dation of America, sought a way to prevent graft rejection without glauco­ma side effects.

Less inflammatory. In 2011, the Prices searched their database for epi­sodes of graft rejection and found that two years after surgery, DMEK had an extremely low rate of rejection episodes compared with DSEK and PK even though the same steroid dosage was used for all three.

That led the Prices to a surprising insight: “We gave everyone the same dosing level because everybody thought that with a full thickness transplant, the part of the cornea that led to rejection was the endothelial layer. But when we saw our data, we could see that it was probably more based on the cells that were being transplanted—not just the endothelium but stroma cells too,” said Dr. Francis Price.

Reduced corticosteroids. That made them wonder if they could safely de­crease the dose of steroids with DMEK. In 2014 and 2015, they conducted pro­spective randomized trials comparing a weaker steroid and a potent steroid, after DMEK. They found the weaker steroid was as effective a year out and significantly less likely to cause IOP elevation.^4,5

Were steroids even necessary with DMEK? In 2016 the Prices published a prospective study wherein one year after DMEK patients were given the option to either stop topical steroids or stay on a low once-a-day dose.⁶ “Over the next year, no one on the low dose got a rejection episode, versus 6% of the people who went off. Of the rejection episodes, 70% were asymptomatic, and we reversed the rejection episodes in all but one case. That gave us an idea of what happens if you stop steroids a year out.” Previous randomized studies showed a higher incidence of rejections when topical steroids were stopped after PK.^7,8

A nonsteroid option. One alternative that can minimize the frequency of steroid administration is use of T-cell inhibitors, including topical cyclospo­rine 0.5%-2% and tacrolimus. “These immunosuppressants do not cause pressure elevation and can be used adjunctively in the setting of corneal transplantation,” said Dr. Gedde. How­ever, the Prices did a prospective study with commercially available cyclospo­rine 0.05% dosed four times daily and found that it did not prevent rejection episodes after PK.⁹

Management

Ophthalmologists may be able to reduce the risk of glaucoma through choice of surgery; intraoperative techniques; vigilant monitoring and aggressive management of IOP; and communication with other specialists. Nevertheless, patients should be well advised in advance of surgery that they may develop glaucoma.

Selecting a surgery. When possible, choose a thinner transplant, said Dr. Francis Price. “We always do DMEK if we can; if not, DSEK. If we must, we’ll do PK, or DALK [deep anterior lamellar keratoplasty] for keratoconus or anterior stromal scars.”

During surgery. DMEK and DSEK use an air bubble to hold the cornea in place during surgery, which can cause pupillary block glaucoma. To help prevent that, Dr. Francis Price performs an iridectomy in the lower part of the iris, “usually down at six o’clock.” After surgery, he has patients lie down in the postop area for half an hour and checks them in the clinic for too much pressure or air in the eye.

Diagnosis. Glaucoma can be difficult to diagnose in this population. Checking IOP, imaging the nerve fiber layer, or doing visual field tests require a clear cornea, but “the cornea is hazy in many transplant patients, both pre-and some-times postoperatively,” said Dr. Shen, “so we don’t have a clear window.”

Dr. Gedde uses larger stimuli during visual testing to address some of these problems. He also cites other problems with measuring IOP in this popu­lation—thickness or scarring of the cornea, irregularity on the eye surface, and higher degrees of astigmatism.

Monitoring. The same difficulties with diagnosis apply to monitoring, but early detection and intervention are crucial to preventing damage to the optic nerve.¹⁰ The cornea specialist who does the surgery usually manages the patient postoperatively, but Dr. Shen and Dr. Gedde recommend collab­oration with a glaucoma specialist if problems arise, such as IOP spikes of 30 mm Hg or more or when a patient becomes less responsive to IOP-lower­ing medical therapy. Dr. Francis Price and his team do their own glaucoma treatments and surgery.

Treatment. Treatment for glaucoma consists entirely of lowering IOP.

Medical therapy. The Prices’ 2014 and 2015 studies show that lower-dose steroids, taken sparingly, are less likely to raise IOP and may reduce glaucoma risk. Dr. Francis Price cautions that the preservatives in drops can cause ocular surface toxicity.

Laser therapy. Laser trabeculoplas­ty could be performed after PK, but “technically it may be difficult or im­possible if you can’t visualize the angle structures,” said Dr. Gedde. He suggests continuous wave or micropulse trans­scleral diode cyclophotocoagulation as treatment options.

Surgery. Surgery is recommended when other therapies aren’t adequate for IOP control. Dr. Gedde prefers traditional trabeculectomy with mito­mycin C when the conjunctiva is not scarred. With significant scarring, he implants a tube shunt and positions the tube as far away from the cornea as possible to avoid traumatizing the corneal endothelium.

Rather than tube shunts, Dr. Francis Price uses a Xen collagen tube. “It has a small lumen so there’s not too much drainage at the beginning, minimizing the risk of a shallow chamber or early postoperative hypotony. For eyes with scarred angles or conjunctiva, we use a micropulse transscleral laser. We are trying to find treatments that min­imize the loss of the blood aqueous barrier.”

Beyond IOP. Scientists are investi­gating neuroprotection, which involves treatments that prevent or delay glauco­matous damage independent of IOP. These treatments are not yet available, said Dr. Gedde.

Dr. Shen is examining the inflamma­tory responses of patients who received a Boston KPro artificial cornea.¹¹ She’s investigating whether the inflammatory pathway may be a potential target for treating transplant-induced glaucoma.

It Works Both Ways

Posttransplant treatments for glaucoma may cause a corneal graft to fail or even necessitate a new transplant. For this reason, Dr. Shen believes that glaucoma specialists and cornea specialists should collaborate, especially when a patient has multiple risk factors for glaucoma. “You go back and forth—either the patient gets another corneal transplant and the pressure goes up and they get more glaucoma, or we put in a tube shunt and the graft fails, and they get hazy cornea. Subspecialists need to consult with each other: Do I perform tube shunt surgery before you perform a corneal transplant, or after? What’s the best location for the tube? Ultimate­ly, we’re all trying to preserve vision for our patients, so we should work togeth­er to prolong the survival of the corneal transplant while keeping eye pressure under control.”

___________________________

1 2022 Eye Banking Statistical Report. https://restoresight.org/members/publications/statistical-report/.

2 Al-Mahmood AM et al. J Ophthalmol. 2012; 2012:1-9. Article ID 576394.

3 Saini C et al. Eye. 2023;37:2117-2125.

4 Price MO et al. Cornea. 2015;34(8):853-858.

5 Price MO et al. Cornea. 2014;33(9):880-886.

6 Price MO et al. Ophthalmology. 2016;123(6):1232-1236.

7 Shimazaki J et al. Ophthalmology. 2012;119(4):668-673.

8 Nguyen NX et al. Am J Ophthalmol. 2007;144(2):318-319.

9 Price MO et al. Ophthalmology. 2006;113:1785-1790.

10 Kornmann HL, Gedde SJ. Curr Opin Ophthal­mol. 2016;27(2):132-139.

11 Eleftherios IP et al. Curr Eye Res. 2019;44(6):599-606.

___________________________

Dr. Gedde is Executive Vice Chair, Vice Chair of Education, Director of Global Center for Oph­thalmic Education, and Professor of Ophthalmol­ogy, John G. Clarkson Chair in Ophthalmology at the Bascom Palmer Eye Institute, University of Miami. Relevant financial disclosures: None.

Dr. Price is Founder, Price Vision Group. Relevant financial disclosures: Aerie: S; Alcon: C; Carl Zeiss Meditec: C; EyePoint: C; Gebaur Medizintechnik: C; Kala: S; RxSight: PS; Staar: C; Strathspey Crown: PS.

Dr. Shen is Fellowship Director, Glaucoma Fellowship at MEE and Associate Professor of Ophthalmology at Harvard Medical School. Rele­vant financial disclosures: Mass General Brigham, a nonprofit health care organization that markets and distributes the Boston Keratoprosthesis: E.

For full disclosures and the disclosure key, see below.