John Berdahl, MD

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	By John Berdahl, MD, and George O. Waring IV, MD; 

	As surgeons who have been involved with collagen corneal crosslinking (CXL) research over the past decade, we were enthusiastic about the approval in 2016 of the first crosslinking system available in the United States (KXL with Photrexa Viscous and Photrexa riboflavin ophthalmic solutions, Avedro).

	CXL provides an opportunity to stop the progressive corneal steepening that can lead to loss of best-corrected visual acuity (BCVA), scarring, contact lens intolerance, and corneal transplant.

 The incidence of keratoconus, as reported in peer-reviewed literature, is about 1 in 2,000.

	With the advent of advanced technology that enables detection of anterior/posterior corneal irregularity-including corneal tomography-clinicians now have the tools to detect keratoconus earlier and with greater sensitivity. Findings from international studies applying this technology suggest the incidence of keratoconus may be greater than previously reported.

	Now that there is an effective treatment that may help stop the disease from progressing, it is much more critical to diagnose these patients before visual function is lost. There are inherent challenges in doing so, as patients in the early stages of keratoconus may be comfortably fit in contact lenses or glasses, and may not present with overt slit lamp findings.

	It is incumbent to make sure partners in primary-care optometry are educated about the availability of CXL and the responsibility to refer patients with progressive keratoconus for treatment while they still have the best chance of preserving their vision.

	Insurance coverage for CXL is increasingly available. There are patient-assistance programs available to ensure access by providing the photoenhancing riboflavin solutions (Photrexa Viscous or Photrexa) at no charge to low-income uninsured patients and to minimize out-of-pocket expenses for the riboflavin solutions in cases of insurance denials. Coding, reimbursement, and co-management protocols are all still evolving.

	For ophthalmologists who already have a strong optometric network, it is easy to inform these existing partners when first performing CXL (or any other new procedure).

	In reaching out to potential new partners, it is essential to communicate effective screening criteria, the range of patients that CXL may be able to help, the results obtained in clinical trials, and expectations for follow-up care.

	CXL also represents an opportunity for ophthalmologists to differentiate their practices and expand their optometric networks. Unlike laser vision correction, where optometrists may have some ambivalence about referring contact lens or spectacle patients for surgery, CXL is filling an unmet need for keratoconus patients that the optometric community has been highly engaged in and enthusiastic about its development. This is important, because-also unlike LASIK-patients are not going to “self-refer” for keratoconus evaluations unless they already have advanced disease or a well-known family history.

	There are still relatively few providers of CXL to meet the needs of patients spread across the country. In rural areas, it is not uncommon for patients to have to travel 4 to 6 hours for a CXL procedure. Developing relationships with potential optometric partners across a wider geographic range for this procedure makes sense and can expand to other referrals in the future.

	Given that the diagnosis of keratoconus is primarily a topographic one, it would be ideal for primary eye-care providers (ECPs) to perform high-quality, Placido disc-based topography or corneal tomography on every patient. These diagnostic tools are increasingly being adopted by optometrists, but the reality is many practices do not have the patient volume to support the purchase of advanced imaging devices.

	For that reason, we have encouraged primary ECPs in our network to refer any young patient who is not correctible to high-quality, 20/20 or better vision for a keratoconus evaluation if there is no other explanation for decreased BCVA.

	Any history of eye rubbing or other risk factors (e.g., atopy or a family history of keratoconus) should heighten suspicion. Referring physicians should know that, for best results, contact lens wearers should be out of soft contact lenses for 1 to 2 weeks and out of rigid lenses for 3 to 4 weeks for every decade of wear prior to CXL evaluation.

	Keratoconus is known to be progressive-particularly in the teens and 20s-and clinicians want to diagnose early to minimize any changes in the cornea that could result in loss of visual acuity.

	Standards and expectations for keratoconus treatment in patients in their 40s and beyond are still developing.

	We encourage referrals of these individuals for evaluation if there has been any progression in the previous 5 years. While progression generally slows or stops in older patients as they become naturally crosslinked, it is a misconception that the disease stops progressing by age 40 in all cases. We have successfully treated patients as old as 65 years.

	There will continue to be cases where patients have progressed to the point that CXL cannot be performed. These patients will still need to be managed with specialty contact lenses or penetrating keratoplasty. In the future, we hope to have far fewer patients reach this stage through earlier diagnosis and appropriate treatment.

	Post-CXL, the number of visits and type of follow-up care is similar to PRK, so we have found that optometrists who are comfortable and knowledgeable in following PRK patients are well-qualified to follow CXL patients.

	Most patients appreciate the opportunity to have appointments closer to home, but it is important to inform patients they have a choice on where they do their follow-up and explain all the costs of that follow-up.

	Many cornea specialists will send patients back to their primary ECP before or just following the 1-month visit, after ensuring that the cornea has stabilized and re-epithelialized. We provide optometric partners with written guidelines detailing postoperative medications, the time course of recovery, and expected outcomes

	Getting the patient into a well-fitting rigid, hybrid, or scleral contact lens after re-epithelialization is critical in visual rehabilitation, so the optometrist’s contact lens-fitting skills become an important part of providing optimal patient care.

	By establishing a system for continuity of care that takes advantage of the skills and expertise of both ophthalmologists and optometrists, CXL can be made more accessible and convenient for patients. CXL provides an opportunity for ophthalmologists not only to perform more procedures, but also to build or strengthen optometric networks.

	1.         Hersh PS, Stulting RD, Muller D, et al; U.S. Crosslinking Study Group. United States multicenter clinical trial of corneal collagen crosslinking for keratoconus treatment. Ophthalmology 2017 [Epub ahead of print].

	2.         National Eye Institute (NEI). Facts about The Cornea and Corneal Disease. http://www.nei.nih.gov/health/cornealdisease/#12

	3.         Godefrooij DA, de Wit GA, Uiterwaal CS, et al. Age-specific incidence and prevalence of keratoconus: A nationwide registration study. Am J Ophthalmol 2017;175:169-72.

	Dr. Berdahl is associate professor of ophthalmology at the University of South Dakota and in practice at Vance Thompson Vision in Sioux Falls, SD. He also serves as medical director of the South Dakota Lions Eye Bank and is a member of the Avedro Medical Advisory Board.

	Dr. Waring is assistant professor of ophthalmology at the Medical University of South Carolina (MUSC), director of refractive surgery at MUSC’s Storm Eye Institute, and medical director of MUSC’s Magill Vision Center. He is a member of the Avedro Medical Advisory Board.

Articles

Crosslinking meets the previously unmet needs of progressive keratoconus patients and provides an opportunity to increase engagement with optometrists, explain John Berdahl, MD, and George O. Waring IV, MD.

CXL demands continuity of care

Dr. BerdahlMicroinvasive glaucoma surgery (MIGS) has revolutionized the treatment of glaucoma. With compliance concerns regarding topical medications, the benefits of MIGS may even outweigh those of medical therapies in patients with pressures adequately controlled on medications.



	Several companies are currently striving to add more tools to the MIGS armamentarium (including Glaukos with the iStent Trabecular Micro-Bypass device).

	Past focus for stents has been in the trabecular meshwork. However, companies are currently developing suprachoroidal devices, which are in various stages of FDA review. These include the iStent SUPRA (Glaukos), the CyPass Micro-Stent (Alcon Laboratories), and the Solx Gold Shunt (Solx). These additions will provide more surgical options and allow surgeons to individualize treatments to patients more effectively.

	The eye has two outflow pathways: the trabecular outflow and the uveoscleral outflow pathway. The trabecular outflow pathway is more pressure dependent and is where 75% of the aqueous humor outflow occurs,

 making this area a logical place to insert a stent to restore natural physiologic aqueous outflow.

The episcleral venous pressure present is in the range of 6 to 12 mm Hg, and while distal outflow resistance adds a few mm Hg to the IOP,

 trabecular bypass stents are still capable of producing effective IOP lowering. The essential benefit of the episcleral venous pressure is that it virtually ensures no hypotony will occur.

	The iStent has a strong safety and efficacy profile, as proven in the pivotal FDA trial.

 Results have only improved with time as surgeons continually become more experienced with the procedure.

Courtesy of GlaukosIn a recently published study,

 a single stent in combination with cataract surgery resulted in a post-treatment mean IOP of 14.9 mm Hg ± 2.3 mm Hg at 3 years, a 36% reduction in IOP from medicated baseline and an 86% reduction in the mean number of medications. This was accomplished with no cases of hypotony, IOP spikes, or hyphema within 1 month. Similar studies have shown corroborating results.

	Further studies demonstrate the efficacy of multiple stents in reducing IOP and medications, illustrating the possibility of titrating treatment with the stent.

	Optimizing patient benefit-to-risk is the cornerstone of every glaucoma clinician’s management of glaucoma disease and iStent has arguably demonstrated the highest benefit-to-risk profile of any MIGS device to date.

	Suprachoroidal devices bypass the episcleral venous pressure system and shunt fluid directly into the suprachoroidal space to be reabsorbed into the body. The intrinsic pressure differential between the anterior chamber and the suprachoroidal space may aid in transferring aqueous from the anterior chamber.

 However, without the episcleral venous pressure back-stop there may be a greater risk of hypotony. A 2-year study of the CyPass demonstrated hypotony prior to 1 month in 15.4% of patients and hypotony after 1 month in 1.9% of patients.

 With suprachoroidal stents there is also potential for corneal edema

	Published clinical evidence on suprachoroidal shunts has at best shown comparable efficacy to a single trabecular bypass stent. Initial data for a CyPass inserted at the time of cataract surgery in patients with an IOP of > 21 mm Hg show a reduction from a baseline mean IOP of 25.5 mm Hg to a mean of 15.8 mm Hg at 24 months which is meaningful

 and it is possible that safety and efficacy rates will improve over time as surgeons gain experience but further long-term study will be needed.

	Like trabecular stents, implanting suprachoroidal shunts requires a good understanding of the anatomy. Surgeons should be deliberate about placing a shunt in such a highly vascularized space as it does present the possibility of serious intraoperative complications. Risks can include bleeding from the highly vascular iris and ciliary body and from the anterior ciliary arteries while unintended cyclodialysis clefts may result from implantation of suprachoroidal shunts.

	Other possible complications include peripheral anterior sequelae (PAS), small areas of scarring around the device, which could impair long-term efficacy. The creation of passageways in the suprachoroidal space could cause abrupt closures of the cleft, resulting in high-pressure spikes. The CyCLE trial showed PAS formation at 10%,

 while the COMPASS trial showed PAS formation reducing to 3.1% over a 2-year period.

	However, suprachoroidal shunts may be a valuable tool, especially as an adjunct to a trabecular outflow procedure in cases where disease progression required additional pressure lowering. I would like to see a diagnostic that could easily determine episcleral venous pressure.

	For low episcleral venous pressures, a trabecular meshwork stent would be more logical, while higher episcleral venous pressures might yield better results with suprachoroidal stents. Perhaps in the future that technology will be available.

	Our collective experience and the accumulation of data will determine the best use for suprachoroidal and trabecular stents. Exploiting both the conventional and uveoscleral pathways will enable enhanced treatment of patients with progressive glaucoma disease who require lower target pressures than can be obtained by trabecular bypass treatment alone.

	Dr. Berdahl is an ophthalmologist at Vance Thompson Vision, Sioux Falls, SD. He specializes in advanced corneal and glaucoma surgery.

	1. Grant WM. Further studies on facility of flow through the trabecular meshwork. AMA Arch Ophthalmol. 1958;60(4 Part 1):523-533.
	2. Rosenquist R, Epstein D, Melamed S, Johnson M, Grant WM. Outflow resistance of enucleated human eyes at two different perfusion pressures and different extents of trabeculotomy. Curr Eye Res. 1989;8:1233-1240.
	3. Samuelson TW, Katz LJ, Wells JM, Duh Y-J, Giamporcaro JE. Randomized evaluation of the trabecular micro-bypass stent with phacoemulsification in patients with glaucoma and cataract. Ophthalmology. 2011;118:459-467.
	4. Neuhann TH. Trabecular micro-bypass stent implantation during small-incision cataract surgery for open-angle glaucoma or ocular hypertension: Long-term results. J Cataract Refract Surg. 2015;41:2664-2671.
	5. Katz LJ, Erb C, Carceller Guillamet AC, Fea AM, Voskanyan L, Wells JM, Giamporcaro JE. Prospective, randomized study of one, two, or three trabecular bypass stents in open-angle glaucoma subjects on topical hypotensive medication. Clinical Ophthalmology. 2015;9:2313-2320.
	6. Donnenfeld ED, Solomon KD, Voskanyan L, Chang DF, et al. A prospective 3-year follow-up trial of implantation of two trabecular microbypass stents in open-angle glaucoma. Clinical Ophthalmology. 2015;9:2057-2065.
	7. Ahmed II, Katz LJ, Chang DF, Donnenfeld ED, Solomon KD, Voskanyan L, Samuelson TW. Prospective evaluation of microinvasive glaucoma surgery with trabecular microbypass stents and prostaglandin in open-angle glaucoma. J Cataract Refract Surg. 2014;40:1295-1300.
	8. Emi K, Pederson JE, Toris CB. Hydrostatic pressure of the suprachoroidal space. IOVS. 1989;30:233-238.
	9. Höh H, Grisanti S, Grisanti S, Rau M, Ianchulev S. Two-year clinical experience with the CyPass micro-stent: safety and surgical outcomes of a novel supraciliary micro-stent. Klin Monbl Augenheilkd, 2014. Vol. 231(4), pp. 377-81.
	10. Grisanti et al. [Supraciliary microstent for open-angle glaucoma: clinical results of a prospective multicenter study]. Ophthalmology. 2014;111:548-552.
	11. Brown R. Minimally invasive supraciliary microstent for IOP control in combined POAG-Cataract surgery: 2-year COMPASS RCT results. Presented at the ASCRS Symposium and Congress. May 7, 2016. New Orleans.
	12. García-Feijoo J, Rau M, Grisanti S, Grisanti S, Höh H, Erb C, Guguchkova P, Ahmed I, Grabner G, Reitsamer H, Shaarawy T, Ianchulev T. Supraciliary Micro-stent Implantation for Open-Angle Glaucoma Failing Topical Therapy: 1-Year Results of a Multicenter Study. Am J Ophthalmol. 2015;159:1075-1081 

Though much focus for stents has been in the trabecular meshwork, many companies are currently developing suprachorodial devices, which are in various stages of FDA review.

John Berdahl, MD

Articles

CXL demands continuity of care

Exploring risk, reward in trabecular bypass, suprachoroidal devices