The Modified Epi-Off Protocol
How to avoid the complications of epithelium-off cross-linking
Neel Desai | | Longer Read
I see many keratoconus cases in my referral-based practice here in Tampa, Florida – but, locally, the lion’s share of this condition is found within the practices of primary care ophthalmologists and optometrists. We’ve made significant efforts to educate these colleagues with regard to keratoconus identification; the diagnostic criteria we recommend to them include rapidly shifting refractions that are not refractable to 20/20, better vision with hard rather than soft contacts, atopic keratitis or keratoconjunctivitis, allergies, and eye-rubbing habits. Our broad aim is to help primary care physicians screen their patients and identify keratoconus as early as possible. And it’s working – we see far more cases today than a few years ago. In fact, I’d say we get about 25 to 50 newly-diagnosed keratoconus patients in any given month.
But once we have identified keratoconus, how should we manage it? The epithelium-on (“epi-on”) method is used in Europe but is not yet approved in the US market; here, therefore, the standard approach remains “epi-off” cross-linking. The epi-off technique has been approved by the FDA on the basis of efficacy data showing good riboflavin penetration into both anterior and posterior stroma. Unfortunately, this method has some attendant issues that we must manage carefully.
Put off by epi-off?
Briefly, the epi-off technique comprises creation of a limbus-to-limbus epithelial defect followed by 30 minutes of UV irradiation. Inevitably – since there’s no standardized protocol for masking the corneal limbus from the UV light – the limbal stem cells are also UV-irradiated throughout this time. Furthermore, given that the protocol involves thirty minutes of induction with riboflavin followed by thirty minutes of UV light, the eye is exposed to air – without blinking – for a total of an hour or more. Thus, the epi-off procedure increases the risk of ocular surface inflammation, particularly in predisposed patients; we can provide a contact lens for wound coverage and comfort, but some patients unavoidably will develop side-effects. Risk amelioration strategies include treatment of the post-operative ocular surface with prophylactic steroid – but this can interfere with post-operative re-epithelialization. In this way, the net effect of the epi-off cross-linking approach is to set up some patients for chronic non-healing epithelial defects, infectious keratitis, scarring and potential long-term visual decline.
Put on Prokera
Therefore, while epi-off is generally very safe and beneficial, my view is that it is associated with risk factors that we should modulate if we can. Consequently, I have modified the way I perform cross-linking for keratoconus as follows:
- during the cross-linking step, I mask the corneal limbus with a custom-cut, doughnut-shaped sponge that blocks UV light, thereby protecting limbal stem cells while still allowing riboflavin to cross the cornea and penetrate the stroma;
- after surgery, I monitor limbal stem cell progression and re-epithelialization:
- if there is no progress at 24 hours, I apply a Prokera immediately
- if progress is normal at 24 hours, I continue to monitor them, and apply a Prokera if re-epithelialization is not complete by 3-5 days.
About 10-15 percent of my patients end up getting a Prokera with this protocol.
For me, Prokera is more than just an amniotic membrane – the cryopreservation-based manufacturing process preserves bioactive molecules, notably high molecular weight compreses (HCHA) and PTX3 (Pentraxin 3), such that these are delivered to the ocular surface along with Prokera. These molecules have potent anti-inflammatory and pro-healing properties; for example, they are known to stimulate limbal stem cell expansion and nerve regeneration. In consequence, they promote tissue repair, prevent scarring and corneal haze, reduce the activation of inflammatory cells, assist in the management of post-surgical conditions (such as neurotrophic cornea or neurotrophic ulcer), increase goblet cell density and relieve dry eye symptoms. In other words, Prokera is a delivery device for bioactive molecules that mitigate the side-effects of the standard epi-off collagen cross-linking protocol, offering broad benefit to the post-surgical ocular surface. No longer must we depend on steroid-mediated reduction of inflammation at the cost of inhibited re-epithelialization. Furthermore, the well-preserved cellular architecture of Prokera allows it to act as an antibiotic depot – it takes up antibiotic and releases it in a sustained manner, thereby preventing post-surgical infection. Importantly, antibiotic release from Prokera avoids the peaks and troughs typical of standard administration methods, such that high antibiotic levels are maintained on the ocular surface. This pharmacokinetic pattern is expected to be more effective than that achieved by intermittent administration.
Onward and upward
In summary, Prokera enables us to avoid many of the complications associated with delivery of vision-saving epi-off therapy. It promotes healing, prevents scarring, inhibits inflammation, improves goblet cell numbers and stimulates corneal nerve regeneration; furthermore, it may enhance antibiotic efficacy via sustained release drug delivery. For us, this is a win-win outcome – we can continue using the approved epi-off therapy to save vision, and at the same time avoid much of the associated risk of scarring, infection and delayed healing. Specifically, our rates of any delayed healing and corneal infections have gone down to zero, and we’re getting less scarring and haze. At the same time, our patients are healing more quickly, and require less chair time and fewer follow-ups. Everybody’s happy!
More awareness, more diagnosis
Desai has done a lot to raise awareness of keratoconus in Tampa, Florida – but what about the rest of the US? Is it fair to say that too many patients are being diagnosed too late?
Our community is probably unique in the US in terms of the effort we have made to provide keratoconus education to local optometrists, ophthalmologists, primary care physicians and pediatricians. We really encourage them to screen for keratoconus signs and symptoms in younger people – we want to catch patients as teenagers if we can – and I think we’ve had a significant impact. But our situation is not representative of the US at all – it’s actually rather atypical. To make changes at a national level will require far more publicity and media attention, which seems to be the most effective way to encourage doctors to look for keratoconus cases and refer them to specialists. Even that wouldn’t entirely resolve the case-finding problem – mainly because current keratoconus diagnostics leave much to be desired. In particular, early keratoconus remains a judgement call: is it frank keratoconus, is it just forme fruste keratoconus, or are there co-morbidities that confound the diagnosis? And deciding whether or not it is progressive keratoconus that requires cross-linking represents yet another judgement call.
Genetic testing for keratoconus is interesting, and might bring more rigor to keratoconus diagnostics, but I think its utility will be relatively limited. Remember, we even have trouble identifying those patients with sufficient risk factors to merit an eye exam, and still more trouble getting them to take an eye exam. It would require even more effort to implement an effective genetic screening program, and I certainly can’t see us getting to the point where everyone is genetically screened for keratoconus at birth. Far better, I believe, to apply our resources to the education of our primary care colleagues with regard to the diagnostic signs and referral criteria for keratoconus.