Corneal CrosslinkingCorneal Collagen Crosslinking with Riboflavin (CxL) for keratoconus, ectasia, or unstable RK.

Keratoconus and ectasia create an irregular cornea that can be treated with Intacs inserts and/or CxL.

UVA light is applied in precise amounts using a specialized goggle with LED lights.

The theory behind CxL treatment is that the fibrils of the keratoconus cornea lose their ability to link to each other.

CxL treatment causes more cross-linking of the fibrils, making the cornea stronger.

A developing keratoconus and ectasia treatment is Corneal Collagen Crosslinking with Riboflavin (CxL), that has been proven outside of the US to strengthen a weakened corneal structure. CxL is currently in US Food and Drug Administration (FDA) clinical trials. For more information, visit CxL Clinical Trial. This method works by increasing collagen crosslinking, which are the natural "anchors" within the cornea. These anchors are responsible for preventing the cornea from bulging out and becoming steep and irregular, consequence of advanced keratoconus.

The image shows a map of an eye with keratoconus. The offcenter red and yellow area shows the forward bulging due to keratoconus.

Keratoconus is a disease of the cornea that makes the cornea become weak and may gradually bulge outward. Most often, this bulging is in the lower half of the cornea and first presents as astigmatism, however not all astigmatism is due to keratoconus. In mild or early stages of keratoconus (forme fruste keratoconus), eyeglasses may correct the astigmatic vision.

The 30-minute corneal crosslinking treatment is performed in the doctor's office. During the treatment, custom-made riboflavin eye drops are applied to the cornea, which is then Intacs are tiny plastic rings activated by ultraviolet light. This amazingly simple surgically added to the cornea. process has been shown in laboratory and clinical studies to increase the amount of collagen cross-linking in the cornea and strengthen the cornea. In published European studies, such treatments were proven safe and effective in patients. The abnormal curvature of the cornea due to keratoconus changes the corneas refractive error producing moderate to severe blurriness of vision. As keratoconus advances, rigid gaspermeable (RGP) contact lenses maybe the only non-surgical way to achieve clear vision. If keratoconus continues to advance, scarring of the central cornea may occur. Approximately half of keratoconus patients have no negative lifestyle effects beyond corrective lenses. The cornea stabilizes after a few years without ever causing severe vision problems. For others, the only resolution to keratoconus has been PKP, with a long healing period and unpredictable refractive error. Even after corneal transplant PKP, keratoconus can reoccur in the new donor cornea. Fortunately, there are two new methods to treat keratoconus that are much less invasive than a corneal transplant. An established treatment for keratoconus is Intacs. Intacs are a medical device approved by the FDA for the correction of 1.00 to 3.00 diopters of myopia (nearsighted, shortsighted) and virtually no astigmatism. Intacs inserts are the only refractive surgery procedure that adds structural integrity to the cornea. This unique attribute made Intacs an ideal treatment for keratoconus. Intacs are clear small semicircular plastic rings of various thickness that are inserted within the cornea at its outer edges. Insertion of these rings flatten the central area of the cornea and

correct myopic refractive error. A major advantage of Intacs is that no tissue is removed and there is no ablation or incision across the visual axis. Intacs surgery is not truly reversible because of the incision, but the Intacs can be completely removed or exchanged for a different size. Intacs inserts cannot be felt by the patient and are no more visible than a contact lens. After insertion and healing, Intacs require no maintenance. The placement of Intacs inserts remodels and reinforces the cornea, eliminating some or all of the irregularities caused by keratoconus. Follow-up visits will be required to monitor the healing process and to evaluate the visual benefits of the procedure. Even after a successful Intacs procedure for keratoconus, glasses or contacts may be required, however Intacs have been shown to improve vision and reduce or stop the progression of keratoconus, thereby saving the patient from needing PKP. Intacs have been approved for the treatment of keratoconus by the FDA under a Humanitarian Device Exemption (HDE) Humanitarian Use Devices (HUDs) are medical devices specially designated by the FDA for use in the treatment of fewer than 4000 patients per year with rare medical conditions. Corneal crosslinking treatments can be combined with Intacs to flatten the keratoconus cone even more than with Intacs alone. In these cases, corneal crosslinking treatments stabilize keratoconus from getting worse as well as help the Intacs reverse the keratoconus steepening that had already occurred. If you are ready to choose a doctor to be evaluated for conventional or custom wavefront Lasik, All-Laser Lasik, PRK, LASEK, Epi-Lasik, NearVision CK, RLE, or any refractive surgery procedure, we highly recommend you consider a doctor who has been evaluated and certified by the USAEyes nonprofit organization. Locate a USAEyes Evaluated & Certified Lasik Laser Eye Surgery Doctor. If this article did not fully answer your questions, use our free Ask Lasik Expert patient forum.

Keratoconus - Frequently asked Questions: Cross-linking

Corneal Collagen Crosslinking (CXL) FAQs Produced Exclusively for KC Global

What is cross-linking? Cross-linking is a medical procedure that combines the use of ultra-violet light and riboflavin eye drops.

What is the purpose of cross-linking? The last two of years has seen a marked increase in the prominence of corneal collagen crosslinking as a treatment strategy for progressive Keratoconus. This interest has arisen from a body of evidence documenting the biomechanical and cellular changes induced by crosslinking. The findings of this research provide a rationale for its use in Keratoconus to retard the progression of this common disease. A rapidly growing number of clinical reports suggest a consistent stabilizing effect of cross-linking along with a variable improvement in corneal shape and visual function in some patients. As a first-line treatment the greatest aim of crosslinking is to reduce and stop Keratoconus in the early phase of the condition, and to treat the progressive vision loss that occurs which can lead to corneal transplantation.

How does cross-linking work? Riboflavin (vitamin B2) is dripped onto the cornea and then exposed to ultra violet light. The light causes the riboflavin to fluoresce, which leads to the formation of bonds between collagen molecules or simply stated, collagen cross-linking.

How effective is crosslinking? In 2008, Raiskup-Wolf et al. described what remains the largest published series comprising 241 eyes followed in Dresden for up to 6 years after crosslinking. This uncontrolled, retrospective study confirmed earlier findings with statistically significant improvements in astigmatism, best-corrected visual acuity (BCVA) and maximum simulated keratometry values (Kmax) at 12 months. Flattening was observed in 54% of eyes with a mean change in Kmax of -1.91 D (P 0.01). The effects of cross-linking were maintained over the duration of follow up with progression of the disease documented in only two patients (which responded to re-treatment). Subsequent published reports from several other centers have described similar results.

What is the safety profile regarding the use of ultra-violet light and of riboflavin in the eye? The ultraviolet light exposure during a crosslinking procedure is comparable to, or even less than, the exposure of the eye to the ultraviolet light in skylight for a full day outdoors in summer. The riboflavin drops are simply vitamin B2, commonly used in foods such as your breakfast

cereal.

How long ago was the first one done? The first human eyes were treated in 1998.

How safe is it in treating Keratoconus ? Very. There are no cuts in the body of the cornea. It is much safer than a corneal graft which has been very successful in the past, and even than a gas permeable contact lens, and also there is no chance of rejection (some grafts tend to last around 10 -15 years). The transplant carries risks such as infection, rejection, cataracts, glaucoma and astigmatism. At 15 years, there is no difference in the survival rate between penetrating corneal transplants performed for Keratoconus and those performed for all other indications. Young Keratoconus patients are likely to need one or more repeated grafts during their lifetime. Crosslinking avoids the removal of any corneal structural tissue (only the surface epithelial cells are removed and these grow back mostly within 2 days).

Who is suitable and who is not? With todays improved technology, the vast majority of people suffering from Keratoconus and other corneal ectasia may safely undergo cross-linking. However, there are exclusion criteria, so consult your ophthalmologist to determine if you are a candidate.

Are there any age limits? Not usually but consult your ophthalmologist.

How is cross-linking performed? Anesthetic eye drops are applied and the surface cells of the cornea (the epithelium) are gently removed so the riboflavin eye drops can penetrate into the cornea. The riboflavin eye drops are applied and allowed to soak into the cornea. The cornea is then irradiated with ultra-violet light. The amount of time the riboflavin soaks into the eye and the amount of time the cornea is irradiated with ultra-violet light vary significantly depending on the ultra violet light source used by the ophthalmologist. Advances in ultra violet light sources have reduced total procedure time from one-hour to as little as 12 minutes. At the completion of the procedure, a bandage contact lens is inserted and the eye is patched overnight.

Are there newer riboflavin formulations that do not require the epithelium to be removed? Studies are ongoing with riboflavin formulations that may allow the epithelium to remain

intact during cross-linking. Check with your ophthalmologist regarding this option. What are the possible complications and side effects of cross-linking? Often transient and treatable and a part of the healing process: Pain in the first 1-2 days, sensitivity to light for several days, haze within the cornea that may cause blurring for up to a few weeks. There are other, less common, possible complications and side effects that your ophthalmologist can discuss with you. Can cross-linking be combined with other treatments? Cross-linking can be combined with Corneal Rings, Phakic Lens Implants, Refractive Lens Exchange, ARK, PRK and LASEK. Can cross-linking be redone if needed? Yes, but during the past 13 years a one-time treatment has been shown generally to be enough to treat progression.

Can I wear soft contact lenses after cross-linking? One of the goals of cross-linking is to make the cornea more regular, allowing for soft contact lenses to replace the need for rigid gas permeable lenses. Rigid gas permeable lenses are good for vision in Keratoconus, but without warning can cause central scarring and/or can aggravate the condition. Your ophthalmologist will tell you if soft contact lenses are possible after cross-linking and how soon after treatment you may begin wearing them.

Are there any limitations or restrictions as to what I can do after cross-linking? The blurring mentioned earlier may affect some people, especially in the first few days, and could limit work and driving during that time. However, consult your ophthalmologist. Can anyone tell by my appearance that I have had cross-linking? No. There is no change in the appearance of your eyes following cross-linking.

How many people have undergone a cross-linking procedure? Tens-of-thousands of people have had their corneas cross-linked during the past 13 years. Due to the universal acceptance of the benefits of cross-linking among ophthalmologists, and recent advances in technology, the annual number of cross-linking procedures is expected to increase substantially.

Is cross-linking approved for general use in treating keratoconus? Cross-linking was fully approved for use in the EU in January 2007 and almost all other

countries have now approved its general use to treat Keratoconus. Cross-linking began FDA clinical trials in the United States in 2008 and at least one company has completed those trials and is expected to submit its results during 2011.

Can both eyes be cross-linked at the same time? Technically yes, but the short term blurring due to the current procedure makes this impractical. Will other eye treatments be a problem to perform after cross-linking? No. It has no effect on any future surgery as far has been determined until now. What other eye conditions can be treated with cross-linking? Although most research to date has related to the treatment of Keratoconus, a role for CXL has also been suggested for other forms of corneal ectasia and a number of unrelated corneal conditions (Table 1). Although cross-linking has been used in all these circumstances, other than for progressive Keratoconus, there is currently little published evidence to support these applications.Table 1. Potential applications of corneal collagen crosslinking

The Indications Include: Keratoconus Pellucid marginal degeneration Iatrogenic keratectasia(post laser in situ keratomileusis)

Prevention of keratectasia(prior to refractive surgery)

Bullous keratopathy Microbial keratitis Corneal (stromal) ulceration Donor tissue modification prior to keratoplasty As an adjunct to orthokeratology

What companies offer ultra violet light sources and what are their differences? See Table 2.(click to enlarge) Table 2. Ultra Violet Light Sources by Company

Has it become a common treatment? Yes, hugely and rapidly in various locations all over the world. Corneal collagen crosslinking has so many potential uses and so few side effects and complications that it is being taken up at a very rapid rate by doctors. If it fulfills its promise of saving many patients from corneal transplants then it will be a very great advance.

Complied for KC Global with thanks to Mellisa.

Dr. David Jory MBBS FRCOphth Consultant Ophthalmologist Keratoconus Clinic ASC, Unit 6, The Technology Park

Farhad Hafezi MD PhD Professor and Chair of Ophthalmology Department of Clinical Neurosciences University Hospitals of Geneva

Colindeep Lane London NW9 6BX Tel: +44 (0)207 099 0970 Fax: +44 (0)207 580 9020 Web: www.davidjory.co.uk E-mail: dwj@davidjory.co.uk

Rue Alcide-Jentzer 22 CH-1211 Geneva 14 Switzerland Tel: +41 / 22 - 382 83 62 (Medical secretariat) Tel: +41 / 22 - 382 83 60 (Admin secretariat) Fax: +41 / 22 - 382 84 33 E-mail: farhad.hafezi@hcuge.ch

Last review made on the 23rd of May 2011 for this first ever published FAQs on corneal collagen cross-linking, originally produced by Dr David Jory on the 31st of July 2007 and updated by Dr Farhad Hafezi on the 23rd of January 2009.

[1] Grant R Snibson FRANZCO; Collagen cross-linking: a new treatment paradigm in corneal disease a review; Clinical and Experimental Ophthalmology 2010; 38: 141153 doi: 10.1111/j.1442-9071.2010.02228.x [1] Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008; 34: 796801. [1] Optical Radiation Safety of the Avedro KXL System and Accelerated Cross-Linking Procedure; DAVID H. SLINEY, Ph.D.

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