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Key words

keratoconus, ectasia, riboflavin, cross-linking

Introduction

Cornea collagen cross-linking has emerged as a highly successful treatment for keratoconus and post-refractive surgery kerectasia [1-10]. The use of topical concentrated riboflavin solution, along with a calibrated ultraviolet light source has been shown to successfully cross-link and stiffen the cornea collagen stroma and arrest and in most cases, reduce the effect of corneal steepening in several degenerative cornea conditions including keratoconus and post-refractive surgery ectasia [2,3].

Cornea cross-linking with the Avedro commercial UV light source and concentrated topical riboflavin solution produced in a standard dose is widely accepted and was FDA approved in 2016 as a treatment for keratoconus and post-refractive surgery ectasia [3]. The high financial treatment cost, along with the high cost of the Avedro machine, has limited ophthalmologist’s and patient’s access to this new effective treatment modality [10].

We report three cases at three separate institutions where patients, either on their own or under the suggestion of their ophthalmologist ingested high doses of dietary riboflavin and were exposed to 15 minutes per day of direct sunlight and noted within 6 months to experience a significant amount of cornea flattening by both topographical and keratometric measurements. No adverse effects were observed or reported in patients taking up to 1500 milligrams of dietary riboflavin per day and spending 15 minutes daily outdoors without sunglasses.

Case 1

In February of 2012, patient #1, a 63-year-old Caucasian woman, was seen at Evergreen Eye Center in Federal Way, Washington for blurred vision after undergoing successful cataract surgery with a premium IOL. Prior treatment with LASIK surgery in both eyes for myopia was reported pre-operatively. Residual astigmatism in both eyes following her premium IOL surgery reduced uncorrected vision to less than 20/40 in each eye at her three months follow up exam. After informed consent, the patient underwent additional successful keratorefractive “touch-up” surgery (LASEK) six months following her cataract operations and visual acuity improved to 20/25 uncorrected in both eyes. Twelve months later she was noted to have signs of cornea ectasia on topography in both eyes, including with the rule astigmatism and a characteristic early “lobster claw” appearance with best corrected acuity decreasing to 20/40 OD and 20/30 OS.

The patient was offered commercial Avedro cornea cross-linking since Evergreen Eye Center was an early investigational site for the Avedro FDA study. When told of the cost, the patient became emotional and remarked that she was on a fixed income and could not afford the treatment. She asked her surgeon if there was anything else available that was cheaper and less painful. The surgeon (JJ) advised her that no alternative surgery or therapy (other than corneal ring segments, rigid contact lenses or spectacles) was available but that she “might try taking dietary supplement riboflavin capsules and walking outside in the sunlight for 15 minutes each day without sunglasses for six months.” The dose recommended by her surgeon was the highest dose he had noted in over the counter (OTC) riboflavin containing multivitamins of 50 mg per day.

The patient returned six months later noting that her vision had greatly improved, and she was noted to have 20/25 best corrected visual acuity with keratometric and topographical flattening of 1.5 diopters on topography. When questioned about her treatment the patient remarked that she had followed her EyeMD’s suggestion of taking dietary riboflavin but stated that she felt “if 50 mg was good, I thought 500 mg would be better.” She continued to follow up for 48 months maintaining excellent vision with no progression or worsening of her post-refractive surgery cornea ectasia.

Case 2

Because of the initial positive results of this first patient, several additional post-refractive and keratoconus patients were treated at Evergreen Eye Center, Federal Way, Washington and most recently at University of Missouri Department of Ophthalmology, Columbia, Missouri as part of an IRB and FDA approved investigation.

After informed consent and in compliance with the patient rights found in the Declaration of Helsinki, 11 additional patients have been enrolled in a prospective randomized, controlled study at the Department of Ophthalmology, University of Missouri – Columbia School of Medicine, taking 100 mg or 400 mg dietary riboflavin and walking briskly outdoors facing the sun without sunglasses for 15 minutes daily.

Patient #2, a 57-year-old Caucasian male with a 25-year history of moderate and progressive keratoconus treated initially with rigid contact lenses and with glasses was enrolled in the protocol in February 2017 and was randomized to 400 mg dietary riboflavin per day and 15 minutes of walking outdoors each day for 6 months without sunglasses.

At his initial presentation before treatment, his best spectacle corrected visual acuity measured 20/30 OD (-3.50 + 2.00 × 102 deg) and 20/25 OS (-3.75 + 3.25 × 95 deg).

His topography on Pentacam (Figure 1) showed cornea steepening with Kmax of 58.1 diopters at 118 degrees OD and 58.8 diopters at 67 degrees OS. Central keratometry measurements were 43.6 D × 43.2 D at 118 degrees OD and 45.7 D × 44.4 D at 72 degrees OS. Central cornea thickness measured 0.535 mm OD and 0.534 mm OS.

At his six months follow up visit best spectacle corrected visual acuity measured 20/20 OD and 20/15 OS. (Kmax on Pentacam measured 52.2 diopters OD and central keratometry measured 43.2 D × 43.7 D at 158 degrees OD and Kmax on Pentacam (Figure 1) measured 56.2 diopters OS and central keratometry readings of 44.0 × 45.50 at 60 degrees OS. A closer look showed a reduction in posterior float and improved centration of the patient’s cone (Figure 2).

The patient, who is an avid outdoorsman and hunter noted elimination of “a tear drop distortion” that had been “present for years” and “a huge improvement” in his ability to hit targets 30 to 100 meters away with a bow and arrow or rifle shot.

Case 3

A 35-year-old clinical dietician with a history of progressive keratoconus reported to her cornea specialist at the Department of Ophthalmology University of Tennessee – Memphis, that she had taken “mega-doses” of riboflavin after reading about its high tolerability and low risk of side effects. When seen by her cornea specialist, (A.S.), the patient was found to have 2.17 diopters OD and 1.33 diopters OS of cornea flattening on topography compared to her pre-treatment K average findings (Table 1).

Table 1: Cornea flattening on topography compared to pre-treatment K average findings.

Date	OD	OS
9/20/2016	47.99 × 38.83	51.79 × 36.39
3/21/2017	49.34 × 41.85	52.97 × 38.72
9/30/2017	49.00 × 37.85	50.84 × 38.09
Kavg 45.60 - 43.43 = 2.17D flattening; Kavg 45.84 - 44.47 = 1.33D flattening

Discussion

In 2016, we submitted Institutional Review Board (IRB) application for a high dose dietary riboflavin and direct sunlight exposure study in treatment of keratoconus and post-refractive surgery cornea ectasia, which was approved for patient enrollment in 2016 and has recruited 11 patients to date with a minimum of 6 months follow up at University of Missouri Department of Ophthalmology. Prior to initiating our IRB and FDA approved and NIH registered study, several patients with keratoconus, post radial keratotomy and post LASIK ectasia were treated at Evergreen Eye Center with a minimum of 24 months follow up with our initial patient now at 60 months follow up.

All patients have shown cornea stabilization with flattening averaging 1.2 Diopters and ranging from zero to 2.5 Diopters.

One interesting 32-year-old patient with progressive keratoconus enrolled in the Missouri group served as an unintentional control. He did not show any worsening nor any improvement in topography or Kmax measurements after six months of treatment. In questioning the patient further on his compliance, he affirmed that he had followed the IRB and FDA protocol faithfully but that he wore his rigid gas permeable contact lenses whenever he was outdoors in the sunlight, likely minimizing the UV effect of direct sunlight.

Conclusion

We believe that high-dose dietary riboflavin and direct sunlight UV exposure may provide a safe and inexpensive – yet slower - alternative and adjunctive treatment to standard commercially available cornea cross-linking. Further studies will determine the optimum dose of dietary riboflavin and natural sunlight UV exposure for comparable results with commercial cross-linking and whether high-dose dietary riboflavin and natural sunlight UV therapy has a place in the initial or adjunctive treatment of keratoconus and post-refractive kerectasia. Further studies measuring tissue concentration of dietary riboflavin taken prior to penetrating keratoplasty along with animal studies could help to determine if sufficient dietary riboflavin accumulates in cornea tissue and if direct sunlight UV effects are sufficient and comparable to commercially available cornea cross-linking therapy [8,10-12].

At the recent 2017 International CXL Experts Meeting in Zurich, Switzerland, Professor Theo Seiler recalled the use of dietary riboflavin in Swiss Air Force pilots who were diagnosed with early keratoconus several decades ago, which reportedly maintained cornea shape to allow those pilots to continue flying (personal communication).

With the proven safety of long-term high-dose dietary riboflavin in treating pediatric patients with migraine [13], along with the known incidence of regression in young keratoconus patients when examined several years following commercial cross-linking therapy, there may be a place for preventing regression of keratoconus in this age group of patients, along with pregnant women who may be at higher risk for complications when treated with commercial cross-linking compared with the alternative treatment using high-dose dietary riboflavin and direct sunlight exposure [14].

References

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