It’s not your father’s cornea care

Progress in understanding dry eye disease and keratoplasty is expanding treatment regimens.

By Michelle K. Rhee, MD

Medically speaking, the damaged cornea is attracting lots of important attention.

In keratoplasty, clinician researchers have made major advancements, shifting from a largely one-size-fits-all approach of penetrating keratoplasty (PK) to a customized, selective lamellar keratoplasty (endothelial keratoplasty [EK] or deep anterior lamellar keratoplasty), which targets the area of pathology.

And with concern to dry eye disease, which will become only more prevalent as Americans age, five million Americans have moderate to severe DED.¹ DED management plays an important role in achieving the best surgical results in the LASIK/PRK (photorefractive keratectomy) and refractive cataract patients (which, in 2016, includes every cataract patient).

A refined approach toward keratoplasty

Prior to 2004, data from the Eye Bank Association of America (EBAA) showed that over 95% of corneal grafts were used for penetrating keratoplasty. In 2014, Descemet’s stripping endothelial keratoplasty (DSEK) was the most commonly performed keratoplasty performed in the United States, and the number of Descemet’s membrane endothelial keratoplasty (DMEK) was steadily increasing.²

The advantages of lamellar keratoplasty include greater preservation of globe strength, quicker visual rehabilitation (three to six months compared to six to 12 months with PK) and less:

• Intra-operative risk of expulsive hemorrhage

• Postoperative astigmatism

• Risk of rejection

• Ocular surface disease.

This translates to fewer suture removal visits and emergency visits for suture-related infection. Despite its significant learning curve and complex donor graft preparation, lamellar surgery has succeeded due to improved instrumentation and graft preparation at eye banks (precut tissue, prestripped tissue).

The most common indications for keratoplasty are pseudophakic bullous keratopathy, Fuchs’ endothelial dystrophy, keratoconus and failed graft. Also, we are seeing a change in the distribution of these diagnoses among the various keratoplasty techniques. For instance, if indicated, keratoconus patients can be spared exposure to endothelial graft rejection by undergoing a deep anterior lamellar keratoplasty (DALK), in which only the anterior diseased portion of the cornea is transplanted. Previously, PK was the procedure of choice due to the interface haze that resulted in earlier anterior lamellar techniques.

Focus on EK

Gerrit Melles, MD, PhD, Mark Terry, MD, Francis Price, MD, and Mark Gorovoy, MD, each helped put endothelial keratoplasty-related surgeries on the ophthalmic surgical map by modifying the techniques involved.

Recently, Michael Straiko, MD, developed a modified Jones tube (in contrast to a plastic IOL cartridge) for use in DMEK tissue insertion. This EK procedure involves the transplantation of only posterior stroma, Descemet’s membrane, endothelial cells (DSEK) or Descemet’s membrane and endothelial cells (DMEK). The host’s Descemet’s membrane is stripped and removed from the eye, and the donor endothelial cells are transplanted through a small wound, approximately 5 mm or less in size. The donor graft is then apposed to the host stroma with the use of an air bubble. Postoperatively, dislocation of the graft can occur and require rebubbling.³

Eye-bank techs advance use of DSEK, DMEK

Eye-bank technicians have been trained to perform DMEK and its challenging first step outside of the OR. Precutting/prestripping the donor corneal tissue at the eye bank has helped to make DSEK and DMEK more predictable. The reason: Eye banks offer a controlled environment. If the tissue is not successfully prepared, surgery will not have to be rescheduled, because surgeons and patients know donor tissue will be ready to go.

Graft insertion techniques and transport ideas continue to develop as research progresses regarding which donors are most suitable for DMEK. Research shows that donor diabetes is associated with unsuccessful DMEK donor tissue preparation.⁴ Since diabetes is so prevalent and donor tissue is not limitless, our eye bank currently does not use donors with diabetes for DMEK preparation to reduce wastage.

Also, surgeons and eye banks, through their increased collaboration, have found higher rates of fungal infection in EK patients versus PK. Anthony Aldave, MD, and Elmer Tu, MD, led the study on fungal infection in EK patients, and an EBAA subcommittee formed to investigate this observation. Through their report of the EBAA Medical Advisory Board Subcommittee on fungal infection following keratoplasty, they found that donor rim cultures are not done routinely. Although less than 1% of them are positive, 17% of recipients of corneas from donors with positive rim fungal cultures develop an infection, typically endophthalmitis, associated with Candida species.⁵ Therefore, surgeons are encouraged to have high levels of suspicion for fungal infection when seeing postoperative EK patients.

A better understanding of DED

DED affects 5% to 30% of patients age 50 and over.¹ This multifactorial disease of the tears and ocular surface⁶ involves tear film hyperosmolarity, inflammation in the ocular surface, and dysfunction of one or more tear film components. This results in tear film instability, damage to the ocular surface, and possible discomfort and visual disturbance, which can have a significant impact on patient quality of vision and life. Patients can experience ocular surface damage even in the absence of symptoms. The Dry Eye Workshop II, the updated first cousin of the 2007 landmark DEWS report, is slated to come out in early 2017.

DED diagnostic toolbox expands

While we have a depth of knowledge regarding DED, it’s only been recently that office-based, objective diagnostic tools have been made available. These point-of-care tools include:

• Tear osmolarity (TearLab). Hyperosmolarity is a major component of DED. Tear osmolarity is elevated and unstable in DED patients. Normal tear osmolarity is between 280-295 mOsml/L, and an inter-eye difference of > 8 mOsms/L is abnormal. This is a familiar concept with glaucoma patients: Fluctuating and inter-eye IOP differences are suspicious.



Figure.
OCT image of donor cornea prepared for DMEK.

• Matrix metalloproteinase 9 (InflammaDry, RPS). MMP-9 is a cytokine produced by inflamed epithelial cells and elevated in DED tear film. It is a biomarker for early DED.

• Sjögren’s Syndrome (SS) (Sjö, Bausch + Lomb). This fingerstick test measures biomarkers in the blood that are associated with early-stage SS. The panel includes traditional biomarkers (SS-A, SS-B, ANA, RF) and three novel biomarkers (salivary protein [SP-1], carbonic anhydrase [CA6] and parotid secretory protein [PSP]). According to the company, it can identify some cases missed by traditional biomarkers alone and has a high sensitivity (89%) and specificity (78.2%) for SS.

Technicians can perform these tests simply, quickly and without inflicting pain. Results for tear osmolarity and MMP-9 take minutes; Sjö results require about one week.

In conjunction with clinical history and exam, these tests help to provide early diagnosis and monitor response to a targeted treatment. For instance, we can prescribe cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan) and follow its efficacy by checking tear osmolarity and MMP-9 levels throughout treatment. This provides an objective metric to chart, as well as a customized approach to the dry eye patient.

In addition, because these tests are physiologic markers, they can help corroborate patient symptoms and clinical exam signs. Some signs (tear breakup time, conjunctival and corneal staining and Schirmer testing) may not correlate with each other or patient symptoms.⁷

Our thoughts of DED now resemble our approach to glaucoma suspects; we do not wait for visual field defects to start topical antihypertensive agents. Similarly, we can treat our cornea patients before slit-lamp findings of punctate epithelial changes and vision loss.

DED treatment advances

LipiFlow (TearScience) and MiBoFlo ThermoFlo (Mibo Medical Group) offer targeted therapy for meibomian gland dysfunction/evaporative DED by using thermal pulsation and thermal massage, respectively. Both devices achieve the therapeutic heat level of at least 40°C.

Not since 2002 has a topical medication for DED been FDA approved (cyclosporine ophthalmic emulsion 0.05%). In the pipeline is lifitegrast ophthalmic solution 5.0% (Shire), an integrin antagonist that decreases T-cell-mediated inflammation associated with DED. It is currently an investigational product that shows promise.⁸

Integrative medicine is also addressing DED. In a soon-to-be-published study, Deepinder Dhaliwal MD, LAc, performed a randomized, sham-controlled study that showed an improvement in subjective symptoms of DED after receiving acupuncture treatment.

The future

The introduction of endothelial keratoplasty has initiated a research renaissance into the cornea and eye-banking world, with investigations into all facets of corneal transplantation from donor tissue storage media, tissue preparation, transport and insertion techniques. However, even with these advances, EK has not replaced PK, as it has its own indications such as full-thickness disease. Also, EK has additional challenges in patients with abnormal iris anatomy and glaucoma surgeries.

The future may also find us treating some keratoplasty candidates with Rho-associated kinase inhibitor eyedrops to stimulate corneal endothelial cell proliferation, resulting in the recovery of corneal clarity.⁹ OM

REFERENCES

About the Author
	Michelle K. Rhee, MD is an assistant professor of ophthalmology and co-director of refractive surgery at the Icahn School of Medicine in New York City. She is also the medical director of the Eye-Bank for Sight Restoration in New York City. Dr. Rhee can be reached at michelle.rhee@mssm.edu.