January 2019


Crosslinking playbook
Important considerations prior to crosslinking

by Ellen Stodola EyeWorld Senior Staff Writer/Digital Editor

A difference map showing improvement after crosslinking in a patient in their mid 50s (a little older than the typical crosslinking patient)
Source: J. Bradley Randleman, MD

Surgeons discuss preop factors

There are a number of preoperative considerations a surgeon may need to weigh when choosing crosslinking. These include evaluating the findings and different diagnostics as well as considering patient age, thickness of the cornea, and more. J. Bradley Randleman, MD, professor of ophthalmology, director of cornea, external disease, and refractive surgery, and medical director, USC Roski Eye Institute Beverly Hills, and Rajesh Rajpal, MD, chief medical officer, Avedro, Waltham, Massachusetts, and founder, See Clearly Vision Group, McLean, Virginia, discussed some of these considerations and important patient factors that go into the decision of when to perform crosslinking.

Recommending crosslinking

Dr. Randleman thinks that subjective findings are just as important as objective criteria in determining progression.
Worsening vision with current correction and inability to achieve reasonable correction with the current strategy (i.e., a patient who has been wearing glasses is no longer able to use them, the current contact lens prescription no longer works well, or best corrected night vision is worsening significantly) indicate keratoconus progression, assuming there are no other issues, he said.
Dr. Randleman noted that it may be too late to crosslink when the cornea “becomes severely thinned or scarred, or the cornea is too steep (usually above 70 D).” There is little benefit in crosslinking in these instances, he said.
On exam, Dr. Randleman documents the patient’s symptoms, the method of current correction, and how long the patient has kept the same/similar visual correction. Eye rubbing history is also important, and he asks how the patient rubs his or her eyes. “I often demonstrate the technique of eye rubbing using the knuckle (not in my eye) and see if that resonates with the patient or the family,” he said. “One may also see patients using the heel of their hand to vigorously rub.”
Dr. Randleman said he also wants to see the anterior curvature, regional corneal thickness, and epithelial thickness as determined by OCT. He uses topography and regional corneal thickness, either through Scheimpflug tomography or OCT. “I also always check for scissoring in retinoscopy for mild/borderline cases,” he said. “I have found this test to be as sensitive for early disease as topography.”
Crosslinking is indicated for patients with progressive keratoconus and those with corneal ectasia following refractive surgery, Dr. Rajpal said. “There are many findings that can suggest progression of keratoconus, therefore, we try to look at the patient as a whole rather than use a single indicator of progression,” he said. “Changes that we document include increasing keratometry, decreasing pachymetry, changes in visual quality, and/or increasing refraction (sphere/cylinder).”
Dr. Rajpal noted that there are different findings that may indicate the need for further work up, such as increasing astigmatism or change in astigmatic axis, anisometropia, scissoring reflex on retinoscopy, or unexplained loss of BCVA. “We remind optometrists and general ophthalmologists in our area to be aware of the early warning signs of keratoconus and to send these patients in for baseline topographic evaluation,” Dr. Rajpal said.
Crosslinking is intended to slow or stop the progression of keratoconus, he said, so early diagnosis is important as is treating patients as soon as it’s indicated. “Progression can lead to loss of BCVA or decreased contact lens tolerance that is not always reversible, and ideally, we want to catch these patients before vision is lost,” Dr. Rajpal said.

When crosslinking is not recommended

Generally, Dr. Rajpal said he does not perform crosslinking in a patient scheduled to undergo either a penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty (DALK) because in both cases, the majority of the central corneal stroma will be removed where the crosslinks would be formed. “Recurrent keratoconus after a graft may be seen in the peripheral host cornea, however, reintroduction of mechanical stresses (such as vigorous eye rubbing) may also be implicated,” he said. “The impact of crosslinking to the peripheral host cornea prior to a graft is an interesting area for clinical study.”
Dr. Randleman said that he would not recommend crosslinking prior to doing a planned DALK in a patient with advanced keratoconus. “Crosslinking has the most impact on the central cornea, so crosslinking will have little benefit prior to a planned DALK,” he said. “Some surgeons avoid crosslinking cases where they strongly anticipate performing DALK as crosslinking has been reported to make obtaining a bubble more difficult.”

Younger patients

Patients younger than 18 have particularly aggressive keratoconus, Dr. Randleman said, and when they present with any signs, they are likely to progress quickly. The consideration would be timing of treatment, he said, especially since parents may be motivated to postpone treatment for months due to school. “I highly encourage pediatric patients to have treatment as soon as possible as progression typically occurs in this group even in 1–2 months,” he said. “That said, progression can occur at any age or stage of disease, so I follow all keratoconic patients closely until both the patient and I are convinced they are not progressing.”
Dr. Rajpal said that patients diagnosed at a younger age tend to show more rapid progression, however, progression can occur at any age. “A recent study evaluating patients over the age of 30 demonstrated that while most eyes showed little progression, up to 37% of subjects showed at least 1 D of progression in topographic parameters in at least one eye over the study period,” he said.1
Progression in younger patients is expected, he added, and they are followed at more frequent intervals. Crosslinking is recommended as soon as indicated. “In older patients, we are more critical in our assessment of progression, but we never assume that a patient is no longer at risk for progression, and we continue to pay close attention to symptoms, signs, and risk factors throughout the patient’s lifetime,” he said.

Keratoconus vs. post-LASIK ectasia

“When both entities are in the progressive phase, I do not differentiate between them,” Dr. Randleman said. “If postoperative ectasia has occurred many years prior with no new progression, I still discuss the potential for crosslinking but do not necessarily perform the treatment.”
Dr. Rajpal said that in both keratoconus and ectasia following refractive surgery, the treatment goal is to slow or stop progression. “On average, patients with keratoconus tend to show more flattening after crosslinking than patients with refractive surgery ectasia, however, crosslinking treatment has been demonstrated to be safe and effective in both groups,” he said. “In patients with ectasia following refractive surgery, the treatment protocol is the same as for those with keratoconus. The only difference is that in the ectasia cases, we take care during the epithelial removal step to avoid dislocation of the flap.”

Corneal thickness and CXL

Dr. Rajpal said that the FDA-approved protocol requires corneal thickness of 400 microns prior to initiation of the UV light. “This thickness is measured after the Photrexa Viscous formulation [Avedro] has been applied and riboflavin flare has been visualized in the anterior chamber,” he said. If the cornea is below this threshold, Photrexa is used to thicken the cornea to reach the minimum thickness. It is instilled at 5- to 10-second intervals until the corneal thickness increases to at least 400 microns. “We allow patients to close their eyes between Photrexa drops to facilitate this thickening,” he said.
Dr. Rajpal added that the theory behind contact lens assisted crosslinking is that either a UV blocking lens or a contact lens that has been saturated with riboflavin can act as a barrier and reduce the effective dose of UV reaching the stroma. “While it’s an interesting thought, it is not a controlled method of reducing total UV energy dose, and a reduced dose may impact treatment efficacy,” he said. “This has not been studied in randomized, sham controlled clinical trials.” The FDA-approved approach, in which the cornea is thickened to the desired minimum thickness of 400 microns using Photrexa, has been validated as a safe and effective way to treat these thinner corneas, he added.
Dr. Randleman said that 400 microns is not an arbitrary cut-off. “It was derived through extensive in vitro testing decades ago,” he said. “It is likely a bit conservative of a recommendation, but that adds a layer of safety to the procedure.”
Most corneas can be swollen to above 400 microns, he said, but crosslinking loses some efficacy if corneas are swollen too much at the time of treatment.
Adding a contact lens is not an approved technique in the U.S. but is likely a safe approach, Dr. Randleman added. “We are currently evaluating the potential impact of this in the laboratory, and the technique appears similar in crosslinking effect.”


1. Gokul A, et al. The natural history of corneal topographic progression of keratoconus after age 30 years in non-contact lens wearers. Br J Ophthalmol. 2017;101:839–844.

Editors’ note: Dr. Rajpal has financial interests with Avedro. Dr. Randleman has no financial interests related to his comments.

Contact information

: rrajpal@seeclearly.com
Randleman: randlema@usc.edu

Important considerations prior to crosslinking Important considerations prior to crosslinking
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