In concept, corneal crosslinking (CXL) is simple. You saturate the corneal stroma with riboflavin (vitamin B2), irradiate the cornea with ultraviolet (UV)-A light, a photochemical reaction occurs, covalently binding the molecules of the cornea together (mostly collagen fibrils) – and just 30 minutes of illumination in the operating room (OR) later, presto… the cornea is strengthened. Just the ticket for treating corneal ectasias like keratoconus and ectasia after laser-assisted in situ keratomileusis (LASIK). It is such a successful technique that it has halved the numbers of corneal transplants performed in Europe in the decade since its introduction.1 As the technique was developed in Dresden and Zurich, it might be time to say “Wunderbar”, right?
If it sterilizes, why bother with the OR?
A lot of work has been put into making CXL a faster and more effective treatment for corneal ectasias and expanding its indications, but let’s park all of that there for the moment. CXL is a treatment that is performed in an OR, under a medical-grade (with an associated medical-grade cost) UV illumination lamp. If you’re following the long-standing standard of care, the Dresden Protocol2, the time it takes to debride the corneal epithelium (to expose the stroma to the riboflavin that you apply next), then add anything between 10 and 30 minutes of riboflavin instillation, plus 30 minutes of UV illumination, this can quite quickly add up to a lot of OR time. And even accelerated protocols easily take 30 minutes in total – the time needed to perform two cataract surgeries.
But it is a sterile environment, and the epithelial cell scraping makes this a de facto surgical procedure. But ORs are costly, and they mostly all exist in developed infrastructure. If a patient in a remote part of a developing country has an ectasia, then the odds are against receiving CXL. But does CXL really need an OR?
Our friend, ROS
When the body’s immune system fights infection, one of the ways it attacks pathogens is by phagocytes producing reactive oxygen species (ROS) adjacent to the pathogen. The ROS damages the invader species’ cell membranes and nucleic acids, killing them. Crosslinking with riboflavin and UV light also generates ROS. And those ROS leave the corneal sterile by the end of the process.3 At this point, it’s worth bearing in mind that the CXL photochemical reaction is limited to the corneal stroma – all the epithelial cells above it are scraped away. The fact that the stroma is saturated with UV light-absorbing riboflavin means that the endothelial cells – just a few layers below – are shielded from UV irradiation. It’s a simple, yet highly targeted intervention, and it means if any cells are killed during the process, it’s those of pathogens, not your patients’ corneas. So, if CXL renders a cornea sterile, it begs two questions: Why do you need a sterile OR to perform it, and why can’t this be used to treat corneal infections?
Ubiquity beats infection
In response to the second question, CXL has been used to treat infectious keratitis for over a decade. The first clinical case series was performed in Zurich and published in 2008, and when CXL is used for this purpose, it’s called PACK-CXL (photoactivated chromophore for keratitis-corneal crosslinking). But again, PACK-CXL is normally performed in a sterile OR, which in some respects is counter-intuitive. You’re bringing an infection into a sterile room, and sterilizing it in there with PACK-CXL. And this is a room that needs to be sterilized again before it can be used once more . . .
So, irrespective of whether CXL is performed to treat ectasia or infectious keratitis, in principle at least, it doesn’t seem like you need to perform it in an OR. Why not perform it at the slit lamp? Pretty much every ophthalmologist has one, and they’re near ubiquitous wherever eye care is given (be it developing or developed countries). Just add a UV light source and you’re good to go, right?
Dancing past the stumbling blocks
Before this could be viewed as a sensible approach, two issues, one practical, and one theoretical, must be settled. First, patients might feel comfortable resting their chin on a slit lamp for 10 or 15 minutes, but they aren’t going to feel that way after 30 minutes – the time taken to perform the Dresden protocol CXL. Second, you need to saturate the stroma with riboflavin. If you’re then going to have the patient sit up and be cross-linked, the question is, does gravity have an effect on the riboflavin present in the cornea?
The second issue has a clear answer: there is no issue. There’s no significant settling or shift in riboflavin in the stroma even after one hour of sitting upright after saturation.4 Addressing the first issue sees us return to the first sentence of the second paragraph of this article: “A lot of work has been put into making CXL a faster and more effective treatment”.
Much effort has been made to make CXL a faster procedure, in particular, in reducing the time needed to treat corneal ectasias. The classic Dresden protocol might require 3 mW/cm2 UV illumination for 30 minutes, but simple photochemical reactions are governed by something called the Bunsen-Roscoe law of reciprocity, which boils down to this: If all reagents in the reaction are in excess, you can increase the speed of the reaction in direct proportion to the amount of extra irradiation you supply the reaction. That 30 minutes of 3 mW/cm2 UV-A exposure turns into 15 minutes of 6 mW/cm2, and 10 minutes of 9 mW/cm2, although it can be pushed too far.5 The efficacy of the crosslinking reaction starts to drop off with too much illumination. The reason? The classic corneal crosslinking reaction consumes oxygen.6 Oxygen has to diffuse into the stroma for the crosslinking reaction to occur, and that is the rate-limiting step in the treatment of ectasias. Nevertheless, we’re down to 10 minutes, and that’s not an unreasonable amount of time to have a patient sit at the slit lamp.
Two distinct beasts
What might surprise you is that this Bunsen-Roscoe limit doesn’t constrain PACK-CXL like it does CXL for ectasia. You treat for three minutes at 30 mW/cm2 and still get effective pathogen killing.7 This is particularly interesting in terms of PACK-CXL’s mechanism of action – perhaps there’s an anaerobic component involved – but it also means that you’re treating a patient in a very short period, well within the comfort zone of almost all adult patients you’ll see, and many older children, too. Whether the crosslinking has been for ectasia or infection, the immediate next step after illumination is complete (and the sterilizing effect is over) is to administer antibiotic prophylaxis. And the data is out there – in bacteria, it’s possible to accelerate the PACK-CXL photochemical reaction down to 150 seconds at 36 mW/cm2, and still maintain the same killing efficacy as the Dresden protocol’s 30 minutes at 3 mW/cm2 (overall fluence of 5.4 J/cm2).7 And there is room for further improvement, since in actual eyes, we know that even a fluence 15 J/cm2 illumination is still safe to use.8
PACKing some power to make a difference
Whereas slit lamp CXL for treating ectasia is a big deal, as eliminating the need for an OR eliminates the (pretty significant) cost of the OR, and the ability to bring CXL to treat ectasia to developing countries (where ORs are scarce and concentrated mostly in major cities) – it’s actually PACK-CXL at the slit lamp that looks like it will have the greatest global impact.
PACK-CXL is typically used as an adjunct to antimicrobial drugs. But a seminal paper by Jes Mortensen’s group in Sweden in 2012 really opened up the procedure’s possibilities. Mortensen was bold enough to ask his local ethics committee for approval of PACK-CXL as a primary procedure – no antimicrobials (even in follow-up). He had a case series of 16 eyes and 14 of them healed spontaneously after a single PACK-CXL procedure.9
Keep this in mind when you start to consider what a truly global burden infectious keratitis is. The World Health Organization (WHO) speaks of a ‘silent epidemic’, and this disease is one of the leading causes of visual impairment worldwide, especially in developing countries.10 Combine this with the phenomenon of antimicrobial resistance – the antibiotics and anti-fungal agents we have today are becoming less and less effective. New drugs aren’t coming through the pipeline; and we’re looking at a future where we just can’t treat certain infections if they’re resistant to the drug arsenal we have.11 This means that anything that can treat infection without requiring antibiotics is so incredibly important.
An irresistible broad-spectrum approach
I’m based in Switzerland: A beautiful country with a temperate climate. When a patient comes to the ELZA Institute for PACK-CXL, over 9 times out of 10, it’s bacterial in origin. But in developing countries, especially those with a humid climate, that’s not the case. Often, these patients have fungal, or worse, mixed (e.g. bacterial/fungal) infections. If you consider that infectious keratitis is something that can rapidly spread and needs urgent treatment, and that it’s difficult to tell which type of pathogen is present at the time of presentation, this means that making the wrong treatment decision here (in other words, prescribing an ineffective drug) wastes precious time. Whereas one might prescribe a broad-spectrum antibiotic until the cultures come back, PACK-CXL might be considered not a broad-spectrum antibiotic against bacteria, but a broad-spectrum antimicrobial therapy against bacteria and fungi. And the happy side-effects of PACK-CXL is that it will stiffen the cornea and at the same time increase its resistance to digestion by pathogens (and reduce the size of the eventual scar, too).
Effectively managing patients who never return
But perhaps the biggest advantage of PACK-CXL – and especially PACK-CXL at the slit lamp – is cost effectivity. In medicine, there are two main costs: costs relating to the doctor, and costs relating to the therapy. Most antibiotics are relatively inexpensive. By far, the biggest cost is the doctor. In many developing countries, doctors are simply too expensive to treat a case of infectious keratitis where they tell the patient, ‘come and see me three times next week’.12 Patients will not come back; they simply cannot afford to do so.
If PACK-CXL – performed at the slit-lamp to bring the procedure to as many people as possible at the lowest-possible cost – can act as a one-shot treatment for a significant proportion of patients, then many of those who never return for follow-up are more likely to have had their infectious keratitis successfully treated. Multiply this by the number of people who aren’t visually impaired for the rest of their life, who can lead economically productive and more fulfilling lives, then the impact of PACK-CXL to help deal with this ‘silent epidemic’ can be quite profound.
The evidence base
PACK-CXL was evaluated in a phase III, interventional, prospective, multi-center, randomized controlled clinical trial, where patients received either antimicrobials (alone) or PACK-CXL (alone). If patients on the PACK-CXL arm worsened after a day, they received antimicrobials, and PACK-CXL was considered to be a treatment failure.
What have we seen so far? PACK-CXL is associated with smaller ulcer sizes, although the time to re-epithelialization was five days longer than in antibiotic-treated eyes. You might initially think, “Yeah, so it takes longer to heal”. But really, the message is “It heals without antibiotics – after a single treatment!” – in 85% of patients. In those patients that dropped out, keratitis was treated with the addition of topical antimicrobial treatment (Hafezi et al., in preparation).
Nobody is suggesting that PACK-CXL should be used alone in regular clinical practice just because it can (if effective antimicrobial agents are available). But in developed countries, PACK-CXL is attractive as it may reduce scar sizes, and work in antimicrobial drug-resistant infections.
In developing countries, PACK-CXL is attractive as it can be used where antibiotics are unavailable (especially in tertiary centers, where a slit lamp and a slit-lamp mountable crosslinking device are available), and it can give the doctor peace of mind, knowing that if a patient does not return for follow-up appointments, it’s more likely that the procedure has been effective.
The bottom line
So, by taking crosslinking portable and out of the OR and on to the slit lamp, you’re able to reduce costs for both you and your patients, and bring effective treatments for both ectasia and keratitis to a far greater population, democratizing CXL for patients, irrespective of whether they live in Berlin, Brunei, or Bulawayo.
1 Godefrooij DA, Gans R, Imhof SM, Wisse RP. Nationwide reduction in the number of corneal transplantations for keratoconus following the implementation of cross-linking. Acta ophthalmologica. 2016;94(7):675-678.
2 Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135(5):620-627.
3Randleman JB, Khandelwal SS, Hafezi F. Corneal Cross-Linking. Surv Ophthalmol. 2015;60(6)509-523.
4Salmon B, Richoz O, Tabibian D, Kling S, Wuarin R, Hafezi F. CXL at the Slit Lamp: No Clinically Relevant Changes in Corneal Riboflavin Distribution During Upright UV Irradiation. J Refract Surg. 2017;33(4):281.
5Hammer A, Richoz O, Mosquera S, Tabibian D, Hoogewoud F, Hafezi F. Corneal biomechanical properties at different corneal collagen cross- linking (CXL) Irradiances. Invest Ophthalmol Vis Sci. 2014;55(5):2881-2884.
6 Richoz O, Hammer A, Tabibian D, Gatzioufas Z, Hafezi F. The Biomechanical Effect of Corneal Collagen Cross-Linking (CXL) With Riboflavin and UV-A is Oxygen Dependent. Transl Vis Sci Technol. 2013;2(7):6.
7Richoz O, Kling S, Hoogewoud F, et al. Antibacterial Efficacy of Accelerated Photoactivated Chromophore for Keratitis-Corneal Collagen Cross-linking (PACK-CXL). J Refract Surg. 2014;30(12):850-854.
8 Seiler TG, Fischinger I, Koller T, Zapp D, Frueh BE, Seiler T. Customized Corneal Crosslinking: One Year Results. Am J Ophthalmol. 2016;166:14-21.
9Makdoumi K, Mortensen J, Sorkhabi O, Malmvall BE, Crafoord S. UVA-riboflavin photochemical therapy of bacterial keratitis: a pilot study. Graefes Arch Clin Exp Ophthalmol. 2012;250(1):95-102.
10 Whitcher JP, Srinivasan M. Corneal ulceration in the developing world –a silent epidemic. Br J Ophthalmol. 1997;81(8):622-623.
11 WHO. Antimicrobial resistance: global report on surveillance 2016. http://www.who.int/drugresistance/documents/surveillancereport/en/. Published 2016. Accessed November 7, 2016.12 Keay L, Edwards K, Brian G, Stapleton F. Surveillance of contact lens related microbial keratitis in Australia and New Zealand: multi-source case-capture and cost-effectiveness. Ophthalmic Epidemiol. 2007;14(6):343-350.