Refer this article as: Bourges, J., Progress made in corneal treatment over the first 10 years of the 21st century, Points de Vue, International Review of Ophthalmic Optics, N64, Spring 2011
Progress made in corneal treatment over the first 10 years of the 21st century
It is almost as if they have always existed. And yet although some aspects of ophthalmological progress only entered our clinical corneal practices after the year 2000 they have now become an essential part of our work. From a medical point of view topical cyclosporin and antiangiogenics can be mentioned, whilst in surgery femtosecond laser cutting and predescemetic or endothelial lamellar keratoplasty techniques are the most popular. Cross-linking may also be mentioned along with intra-corneal rings and high precision corneal imaging. The first ten years of the 21st century are thus coming to an end with corneal ophthalmological progress proving to us that our speciality is still exciting and stimulating and is being ceaselessly renewed.
A few steps forward with treatment of the cornea were made during the last century, including the transplantation of limbic stem cells or the transplantation of amniotic membrane. Clearly it would be too ambitious to seek to mention here all the progress made in the field of medical or surgical corneal treatment that was discovered at the dawn of the 21st century. However, although we would like to believe that some of these practices have always existed, some only became part of the corneal treatment we use in ophthalmology after the year 2000 but have already become an essential part of our work. Mention may be made of topical cyclosporin A and anti-angiogenics, femtosecond laser cutting, predescemetic or endothelial lamellar keratoplasty techniques, cross-linking, the insertion of intra-corneal rings and the use of data obtained from high precision corneal imaging.
Your "point of view"
When our colleagues are asked the following question, "In your opinion what is the most remarkable progress (medical, surgical, technical, treatment, etc.) made in the field of corneas between the year 2000 and the present date?", practitioners in our country, whether corneal specialists or not, reply in their vast majority, femtosecond laser cutting (45%, table 1). New lamellar transplant techniques come second (29%) ahead of new screening techniques and keratoconus treatments. Actually it is these new transplant techniques that have most affected university-hospital practitioners in France, whilst femtosecond cutting, which is mainly important to refractive surgery, is, quite logically, most often mentioned by ophthalmologists in private practice.
Medical progress in corneal pathology
Although it would not appear to have particularly marked our colleagues, progress made at the start of this 21st century in medical ophthalmology and corneal imaging enables us to treat our patients better now, compared to last century. Cyclosporin A (CsA) drops, antiangiogenics applied to the cornea or high-precision corneal imaging are all good illustrations.
Cyclosporin A drops
CsA, discovered in 1969, is extracted from a fungus. It has no cytotoxic action but prevents, reversibly, the activation and proliferation of T helpers lymphocytes . Its lipophile properties lead to low ocular bioavailability when systemically administered. It fixes on lipoproteins and its action is expressed as from 50 to 300 ng/g of tissue, which is close to its toxic dose in blood (around 300 ng/ml). Now, the number of ocular pathologies involving harmful action by lymphocytes T sometimes justifies the used of CsA in our patients. Because of this fact, in ophthalmological research, its galenic form as drops has been tested since 1986 in order to obtain therapeutic ocular doses with negligible systemic passage . The first experimental protocols on Thygeson's keratitis or severe vernal keratoconjunctivitis using CsA drops date back to the 1990s [3, 4, 5]. It has only been since the year 2000 that this treatment has been used in clinical practice, since its usefulness has been observed in certain forms of dry inflammatory syndrome, ocular rosacea, Mooren's ulcer, Theodore's superior limbic keratoconjunctivitis and in the prevention of alloimmune rejection of a corneal transplant.
These have revolutionised ophthalmological practice in the field of medical retina treatment. On the other hand they are used to a much lesser extent in general corneal practice. Yet the work done by Mr Berlin and then by C. Cursiefen and R. Dana has shown the importance of blood and lymphatic corneolimbic vascularisation in the physiopathology of corneal transplant rejection. Thus, anti-VEGF (antibodies and VEGF-trap) and now anti-insulin receptor substrates (anti-IRS1), in phase III studying Germany, are being used in the prevention of transplant rejection. Similarly, these treatments offer new and interesting therapeutic solutions for glaucoma surgery with a risk of external failure or neovascular glaucomas, for which previous antalgic treatment was subject to highly inconsistent efficacy.
High precision corneal imaging
One should not forget, in terms of progress made at the start of this century, the immense progress made in medical corneal imaging. We are now able to detail the cornea, lamellar or transfixing grafts and the anterior chamber using high resolution OCT of the anterior segment , in vivo confocal microscopy and UBM, not forgetting the new elevation topography techniques. The latter now enable us to evaluate the aberrometric profile of a cornea and use efficient diagnosis-assistance software for improved identification of pathological corneas, specifically frustrated keratoconus.
Surgical progress in corneal pathology
This is the most remarkable and the most popular according to our survey (table 1). The start of this century saw the arrival of the femtosecond laser surgery tool for corneal cutting whilst lamellar corneal surgery, which had previously been relatively unknown, difficult to perform and with only mediocre visual results, truly exploded with the development of new dissection techniques. It is also now possible to offer new therapeutic solutions to those of our patients suffering from keratoconus such as cross‐linking (CXL) or the implanting of intracorneal segments .
Tab. 1: Survey undertaken in July 2010 amongst 96 ophthalmologists, corneal specialists (n=46) or not (n=50). The end level of participation was three quarters of all practitioners questioned. [We would like to offer our warmest thanks to all our colleagues whose answers are given here].
The femtosecond laser
Corneal cutting with a femtosecond laser (pulse duration =10‐15 seconds) is a technology used in clinical application for the first time in the 21st century, even though these lasers were developed before then for use in corneal research or for other applications [7, 8]. Indeed, since the very first prototype costing 14.3 million dollars, tested by T. Juhasz and his team in Michigan (USA), it is now possible, since 2001, to use this technology with a laser sold by Intralase ® (1997, table 2).
Tab. 2: Summary of the commercial history of femtosecond lasers.
The vast majority of surgeons using this technology now prefer to use it for all refractive surgical cutting because it offers greater safety and additional functionalities [9, 10]. Femtosecond cutting profiles in corneal grafts mean that the surface of the scar can be increased, compatibility between donor-receiver is improved and the ocular surface is improved too . These lasers have meant increased use and safety of the implanting of intracorneal rings, particularly in keratoconus, which have themselves also started to be used increasingly since the beginning of this century . Finally, there are still many more possible application developments for these lasers (see below).
Deep anterior lamellar and posterior endothelial surgery
Renewed current interest in the techniques of lamellar corneal grafts (KL) is linked mainly to the use of new grafting methods. Anterior KL has been used for 150 years but it suffered from low surgical reproducibility and mediocre visual results due to opacification of the residual corneal stroma. Deep anterior KL is now predescemetic with the performance of a perioperatory dissection ("Big Bubble" orderivative technique) and no longer preserves the posterior stroma of the receiver which was becoming opaque [12, 13, 14]. The endothelial KL practised today was described at the end of the 20th century by G. Melles  and then by M Terry  and was improved significantly during the early years of the 21st century (Figure 1). According to the surgeon, the pathological endothelium is now detached (stripping) or cut out and the graft is cut mechanically or by laser, allowing the corneal stroma to persist, or not, on the grafts. This has given rise to Anglo Saxon terminology that is sometimes somewhat complicated, as summarised in table 3. These procedures have the enormous advantage of being less invasive. They avoid rendering the cornea fragile and remove complications relating to sutures. They reduce recuperation time and increase medium term post-operative comfort without modifying the ocular surface or the astigmatism, at the price, of course, of possible specific complications such as secondary mobilisation of the graft, pupillary block or increased endothelial cell loss. .
Tab. 3: Summary glossary of corneal lamellar grafts.
Cross linking (CXL) and intra-stromal corneal ring segments
Reinforcement of the corneal biomechanical structure by bridge induction between the collagen fibrils (cross‐linking or CXL) was tested for the first time on a cornea by T. Seiler's team in 1998 . It was only after the year 2000 that CXL was used to treat patients suffering from keratoconus with the aim of stabilising their pathology and, possibly, avoid the need for a corneal graft . Alongside this, intra-stromal corneal ring segments (ICSR), which had already been used in a small amount of cases for refractive correction of myopia since 1988 , found a new application to regularise astigmatism of the keratoconus . Previously they had been difficult to implant in keratoconus corneas due to pachymetric risk and the mechanical limitations involved in implanting. Because of this, the risk of perforating was quite considerable for an unpredictable result. Now, with femtosecond stromal cutting and their extended range of profiles, they are more efficient, results are easier to predict and they are safer and well tolerated .
Applied corneal research over the first ten years of the 21st century
Although progress made in the field of the cornea over the first ten years of the 21st century has mainly affected us in terms of successful clinical applications, there are more applications about which little is yet known, which are still at the incubation stages but which are promising; some of these are already being used in experimental applications.
Fig. 1: Deep lamellar endothelial keratoplasty (KLE) examined by biomicroscope one month after surgery (A) where one can clearly see the edges of the endothelial graft (A, grey arrow heads) behind a lightened corneal stroma
and in front of a pseudoirien implant (A, white asterisk) in a patient operated for post-traumatic endothelial decompensation, cataract and aniridia. The graft, measuring around 120 μm, is perfectly attached to the posterior stroma from which the endothelio‐descemetic layer has been removed (B, arrows).
Experimental biocorneas, in their various development programmes (European, Canadian, Japanese, …) now enable us to graft corneal endothelia or to obtain reepithelialisation and nerve regeneration of artificial corneal matrices, which may be biodegradable [22, 23, 24, 25].
Although it is still too early to know what the future impact of the lasers currently being developed will be, the principle sought is to enable the most independent possible cutting of the transparency of the medium, then enabling cutting of the anterior lamella to be addressed on opaque corneas or scleral cutting in other surgeries, without injuring the environment. Acquisition systems that would enable us to know the "state of the cornea" in real time are also being studied in order to adjust fluence and shooting rate parameters in real time.
At the same time, high precision imaging continues to become increasingly detailed with multimodal non-linear imaging, for example . Finally, new healing products could perhaps help those of our patients whose ulcerated trophic corneas currently have very few efficient treatments available to them, in cases where amniotic membranes are not sufficient .
The first ten years of the 21st century are coming to a close and progress made in corneal ophthalmology is proving to us that our speciality is still exciting and stimulating and is being ceaselessly renewed.