Corneal Collagen Cross- Linking with Riboflavin and UV light in Keratoconus and related corneal ectasia

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1 Corneal Collagen Cross- Linking with Riboflavin and UV light in Keratoconus and related corneal ectasia Ectasia Corneal ectasia is a condition where the shape of the cornea becomes unusually steep and irregular. This is most commonly seen in keratoconus, but may also occur after laser refractive surgery (LASIK), when the cornea has been thinned to an extent where it is structurally unstable. Corneal Cross- Linking Corneal collagen cross- linking with riboflavin is a treatment that increases the stiffness and rigidity of the cornea and stabilizes ectasia. Anecdotally; patients who previously had progressive ectasia have now been treated and followed for up to five years without evidence of any further change in their condition. At present it is not known whether the stabilizing effect of cross- linking is permanent, but the treatment could potentially be repeated if it was necessary. The procedure has good 5 year safety data behind it. However there are only 2 randomized controlled trials at the time of writing providing good evidence of efficacy for up to two years after a single cross- linking treatment How does cross- linking work? The bulk of the cornea is made from collagen fibres which are arranged in criss- crossing bundles. The strength and rigidity of the cornea is partly determined by how strongly the fibres are linked together. Over the course of a lifetime one's cornea becomes progressively stiffer due to natural cross- linking between the fibres. Riboflavin (vitamin B2) is a naturally occurring compound which strongly absorbs UV light. By applying riboflavin to the cornea at the same time as exposing it to a UV light source, the riboflavin not only enhances the cross- linking effect of the UV light, but also absorbs the light to an extent that the inner layers of the cornea and intra- ocular structures are protected from the potentially damaging effects of the light rays. Benefits of cross- linking

2 Cross- linking seems effective in stabilizing progressive ectasia. There is also much weaker evidence to suggest that at least in some patients the treatment gives an additional small measure of benefit in reduction of corneal steepness and irregularity. This in turn means some reduction in the myopia and astigmatism associated with the ectasia. In the past it was always considered that excimer laser correction of myopia or astigmatism was not possible when ectasia was present, since by removing corneal tissue with the laser the cornea would become even less stable and the ectasia would be made worse. However there are anecdotal reports that suggest that once the corneal condition is stabilized by cross- linking it may be possible to perform limited amounts of laser ablation whilst still maintaining structural stability of the cornea. Such treatment would usually be aimed at restoring a more spherical shape to the cornea (custom ablation). Any remaining optical defect could then potentially be corrected by spectacles, or alternatively with soft contact lenses, or by phakic intra- ocular lens implants. Such laser refractive surgery remains experimental until higher quality evidence becomes available in the published peer reviewed world literature. Risks of cross- linking UV light is known to be damaging to cells, and the treatment causes the stromal cells (keratocytes) in the outer layers of the treated parts of the cornea to die. However, these cells are replaced by new keratocytes which migrate from untreated parts of the cornea into the central area over a period of some months after the treatment. In theory the UV light could be damaging to the inner endothelial cell layer of the cornea, and this is why the corneal thickness needs to be at least 350 microns if a standard cross- linking treatment is to be undertaken. In clinical studies carried out so far, no evidence of damage to the endothelial cell layer has been documented. Although UV is potentially damaging to the lens and retina, it is believed that the riboflavin blocks the UV transmission to an extent that no measurable damage will occur. At present the long term effects of the treatment are unknown. How is cross- linking treatment given? The cross- linking treatment is carried out with topical anaesthesia (eye drops). The surface epithelial cell layer is removed from the central part of the cornea, and the riboflavin drops applied. Once the riboflavin has penetrated well into the eye, the UV light is focused onto the central area of the cornea for 30 minutes. Finally a bandage soft contact lens is applied. The contact lens is worn for three or four days until the surface epithelial cell layer has re- grown. During the first few days the eye will be sore and watery. Sometimes there is slight haziness under the epithelial layer for the first few months after treatment, but the vision stabilizes within a month or so of the treatment. Causes and types of optical defect Optical defects of the eye are mainly caused by abnormalities in the cornea, the lens, or in the overall length of the eyeball.

3 When the cornea is not spherical in shape there will typically be an astigmatic optical defect in the eye. Most astigmatism is regular and symmetrical, and this type of astigmatism can be corrected by spectacles, toric or rigid contact lenses, or conventional astigmatic laser surgery. However, sometimes corneal astigmatism is irregular and asymmetrical, and this type of optical defect cannot be corrected with spectacles. Irregular astigmatism is typically seen in the condition of keratoconus, and other types of corneal ectasia. Correction of irregular astigmatism Because irregular astigmatism is almost always due to abnormalities in the shape of the corneal surface, it can usually be corrected by fitting rigid gas- permeable contact lenses. These work by masking the corneal irregularity behind the smooth surface of the contact lens. Alternatively these corneal irregularities can now be permanently corrected by custom topography- guided excimer laser treatment. Accurate measurement of corneal surface irregularities can be made with a corneal topography device, and this information can be used to program an excimer laser to re- profile the cornea. Postoperative Care The operation usually takes place on a Thursday afternoon. The day after the procedure Dr McAlister s staff will telephone you to check how you are going. You will then be required to attend a post operative check up on Day 4 (Monday). The day 4 appointment will take a few minutes for Dr to check your eye/s and remove the bandage contact lens. The exact time of this appointment will be advised closer to the date. Further appointments to check your progress are required at 6 weeks, 6 months, and 12 months these appointments are made following each visit at Dr McAlister s instruction. Following the procedure day the patient will require approximately 2 weeks off from work and/or study. Occasionally some patients can require longer others are able to return to their usual activities sooner. It is important for annual review thereafter for up to 5 years as although continued progression after cross linking is rare it can happen and continued contact lens wear can mask the progression of the disease if not specifically checked for. Equally it is important to bring with you but not insert contact lens at each follow up appointment. You will be tested with the contact lens and then your vision checked again with the contact lens in.

4 Is the procedure painful? The procedure itself is painless. Usually 1 or 2 Panadeine Forte tablets are taken prior to the procedure to help you relax. The discomfort happens after the procedure, about half an hour after the last anaesthetic drop. A bandage contact lens is inserted to reduce the lids abrading the treated cornea which has had the skin layer removed to allow the penetration of the drops. Furthermore a single ampoule of the anesthetic drops which will also help reduce the discomfort overnight and please feel confident to use this. These are toxic when used excessively and no more than one will be dispensed after treatment. The first night is the most uncomfortable. After that the level of discomfort drops off dramatically. So by the time the skin of the eye has healed (usually on the Monday) the bandage contact lens can be removed with little further discomfort appreciated. How long will my vision remain Hazy? Everyone is different. One can expect the eyes to be very blurred for the first week after treatment and for things to improve greatly during the second week after treatment. Slower changes happen there after. The hazy vision is better tolerated and patients feel they get back to their preoperative level quicker if we; (1) Treat one eye at a time (2) The vision in the untreated eye is good (3) The treated eye is not dependent on contact lens wear to see well.

5 Glare, haziness, frosted vision and dry eye can all persist to a greater or lesser degree for 2-6 weeks. Occasionally from patients who need to wear a contact lens to see well in the treated eye. The eye is unable to tolerate a contact lens for at least 6 weeks. Changes in the corneal contour with treatment mean that some contact lenses become unstable after treatment. Corneal rigid gas permeable (RGP) lens wearers in particular may need to wait for at least 6 months to get a relatively stable fit whereas scleral and the more popular mini scleral rigid contact lenses can be reinserted from 6 weeks onwards. What can I expect from treatment? On average people can expect 1-2 Diopters flattening of the cornea, 1-2 Diopters reduction in the astigmatism and 1-2 lines improvement in best corrected vision. If you are on the verge of spectacle wear, contact lens wear or needing a corneal graft this may be enough to avoid the need to move to the next level of vision correction. If you need contact lenses to see well or have a high level of astigmatism this also means you are very unlikely to see well unaided after treatment. What about intracorneal ring segments? These are a valid treatment option. No one is sure of their exact place in the management of keratoconus. For high astigmatism and a much decentred cone they may be beneficial in reducing astigmatism and making the apex of the cone more central. They are however imprecise and many surgeons have concerns about the long term safety of placing a foreign body into an already weakened- diseased cornea. What have the trials shown? The Australian randomized controlled trial run out of Melbourne has provided some of the most accurate and reliable data on what to expect from this treatment in moderate progressive keratoconus. This has been repeated in American trials and there is also good evidence of large prospective case series from Germany, Italy and elsewhere which supports the benefits listed above for moderate progressive keratoconus. There is no evidence to support the benefits of cross linking in stable keratoconus, or either early or advanced keratoconus. Similarly the safety and efficacy of the treatment in thin corneas is only modest from publications of small case series to date. Only weak evidence exists for the benefits of cross linking in juveniles who have early onset more aggressive disease and a much higher lifetime risk of requiring a corneal graft. My own experience is that the risk of continued progression after corneal cross linking is 20% for juveniles rather than 5% as for adults with moderate progressive keratoconus. Other Common Q & A

6 Q. How long am I likely to need off work/study for recovery time? A. Following the procedure day the patient will require approximately 2 weeks off from work and/or study. Occasionally some patients can require longer others are able to return to their usual activities sooner. Q. How long until I can wear my contacts again? A. 6 weeks for mini sclerals but up to 6 months for corneal RGP lenses. For the latter an update is also much more likely. Q. How long after the procedure can I start driving? A. Legally driving limits require vision better than 6/12. For practical reasons this is usually 2 weeks after the procedure but may be sooner. Occasionally it is later. Therefore you should wait until you are confident in addition to the legal requirement. The procedure creates mistiness and glare to the vision which takes a variable time to settle. Q. How long after the procedure do I wait until getting new contacts or spectacles? A. Give it six months unless you are desperate to improve your functional vision or do not mind the associated cost for further spectacles much sooner than you would normally expect to do so. Q. How long after the procedure will I have to wait before swimming? A. Give this 2 weeks Q. How long after the procedure do I wait until I can play sport and weight lift? A. Immediately after surgery your cornea is stiffer. There is no bar to such sports but you will probably not be in the mood and shouldn t expect to play competitively for at least a week or two. Q. How long after the procedure will I have to wait before flying? A. There is no bar to flying at any time after corneal cross linking surgery. Do I still take my regular medication leading up to, and on the day of the procedure? A. Yes Q. Do I have to fast on the morning/day of the procedure? A. No, however try to have a light, early lunch prior to surgery. Panadeine Forte tablets given by Dr McAlister may cause slight nausea. Are there any useful websites to look at? Two useful and what appear to be patient orientated independent websites are;

7 Keratoconus Australia: Keratoconus Foundation