Gerd U. Auffarth, MD, PhD, FEBO

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Over 115 years ago, in 1905, Eudard Zirm successfully performed the first corneal transplantation.

 Penetrating keratoplasties remained the gold standard for the treatment of a variety of corneal conditions for much of the 20th century.

More recently, in 1998, Melles and colleagues successfully attached a posterior lamellar graft consisting of stroma, Descemet membrane and endothelium to the posterior surface of the cornea, which initiated a new era in the treatment of corneal diseases primarily affecting the endothelium.

 In 2006, Melles and associates first described the selective transplantation of the endothelium and Descemet membrane (EDM).

Descemet membrane endothelial keratoplasty (DMEK) involves the surgical removal of the diseased endothelial layer as well as the diseased Descemet’s membrane from the posterior corneal stroma.

 In comparison with traditional full-thickness or penetrating keratoplasty, DMEK allows the patient faster visual recovery, better refractive outcome and superior tectonic integrity.

Cataract surgeons on operating theatre waste: Less is often more

At present, endothelial keratoplasties such as DMEK are the gold standard in endothelial dysfunction,

 including Fuchs’ endothelial dystrophy,

 graft failure after penetrating or endothelial keratoplasty,

 and endothelial decompensation due to congenital glaucoma.

 Known complications such as primary or secondary graft failure, immunological graft rejection and interface keratitis remain a challenge and can have a negative impact on the success of the procedure.

Nowadays, donor tissue preparation and insertion into the anterior chamber is routine. However, rupture of the EDM during preparation can lead to graft loss, which can delay surgical intervention and disrupt organisational processes in a clinic.

 Furthermore, prolonged or careless manipulation of the EDM in the anterior chamber can lead to significant endothelial loss with potential primary or (early) secondary graft failure.

According to a report published by the German Keratopathy Registry, the majority of keratoplasties performed these days are posterior lamellar keratoplasties; only 30% remain penetrating keratoplasties.

 Additionally, because human donor corneas are in constant short supply,

 there is a need for alternative, universally available treatment options.

In 2018, Kinoshita and associates proposed the injection of cultured human corneal endothelial cells supplemented with a rho-associated protein kinase inhibitor into the anterior chamber to increase corneal endothelial cell density.

 A 5-year follow up published in 2020 by Numa and colleagues confirmed the safety and efficacy of this approach, however, it was tested only in a very small number of patients and further long-term data do not yet exist.

Let’s throw everything away…except the patient and the surgeon

Another recently introduced technique with no need for donor corneal tissue is Descemet membrane stripping only (DSO) with or without the topical treatment of rho kinase inhibitors. DSO involves removing a small area of central endothelium that has become dysfunctional, without performing an endothelial keratoplasty.

This method has proven successful in a small number of patients with Fuchs endothelial dystrophy but its long-term efficacy has yet to be evaluated.

 A very limited number of patients are eligible for this method because of the need for healthy peripheral endothelial cells as well as central corneal guttae.

A novel approach involves the implantation of an artificial endothelial layer to the posterior aspect of the cornea.

The EndoArt (EyeYon Medical) is a flexible, hydrophilic acrylic, dome-shaped permanent implant, 6 mm in diameter and 50 µm thick, specifically designed to replace the diseased corneal Descemet-endothelium layer (Figure 1). Implanting the lamella on the posterior surface of the cornea replaces the diseased endothelium and impedes the transfer of fluids into the central stroma. By covering around 40% of the back corneal surface, blocking the influx of fluids as well as epithelial evaporation leads to a reduction in corneal oedema to restore corneal homeostasis.

This artificial endothelial layer—which has been awarded a breakthrough therapy designation by the United States Food and Drug Administration (FDA), China’s Innovative Device Status and CE certification—could provide a paradigm shift in the treatment of patients with endothelial failure while eliminating the need for human donor tissues.

Investigators analyse factors associated with patient satisfaction after refractive surgery

The Department of Ophthalmology of the University Eye Clinic in Heidelberg, Germany, was one of the first centres to implant this innovative device, with patients having completed 2 years’ follow-up. The initial long-term evaluations are promising and demonstrate good safety and efficacy results. Currently, the implant is undergoing a first-in-human, multicentre trial across Europe and Asia.

A 9-mm ring marks the central corneal surface to outline the peripheral extent of the Descemet membrane excision. With two paracentesis incisions at the 10 o’clock and 2 o’clock positions, the implant is folded into the cartridge of an IOL-injector and injected through a 2.2-mm clear cornea incision into the anterior chamber of the eye. The lamella then unfolds itself and is manually positioned onto the posterior corneal surface using an air bubble technique, similar to a DMEK procedure.

Combined MIGS and cataract surgery option offers positive results

Unlike a human donor lamella, the implant can actually be touched and moved by the surgeon, using a cannula, without compromising its function. The experienced corneal surgeon who is already familiar with the DMEK procedure should be able to place the implant without the need for extra training. Cataract surgeons may require a few extra training sessions.

Figure 2: Slit-lamp pictures and OCT images before (A+C) and 12 weeks after implantation (B+D). Significant corneal oedema is shown in A and quantified via OCT in C. Marked resolution of corneal oedema 12 weeks after implantation is shown in B. Significant reduction in corneal thickness is measured by means of OCT in D. The white arrows show the outlines of the implant on the posterior surface of the cornea in B and D. 

A 79-year-old man presented to our clinic after complicated cataract surgery at a private practice. DMEK was not a treatment option because of his wide and non-light reactive pupil and anterior synechiae. The patient was complaining of decreased vision.

On examination, the patient showed significant corneal oedema with corneal bullae and reminiscent lens material in the anterior chamber of the left eye. The patient perceived finger count with the left eye. An epiretinal gliosis was present on both eyes and the patient had received cryotherapy on the left eye due to a retinal tear 10 years earlier.

Figure 2 shows the diseased cornea before and after implantation. After 12 weeks, the cornea was clear with only a slight residual peripheral oedema (Figure 2 B+D). Corneal thickness was stable at 635 µm and visual acuity increased to 20/200 Snellen (Figure 2 D).

Retinal optical coherence tomography imaging revealed a pre-existing macular oedema, which is currently the limiting factor for visual improvement. The patient is being treated with parabulbar injections of steroids and further visual improvement is expected.

In conclusion, this technique shows that an artificial endothelial layer is feasible for treatment of patients with endothelial dysfunction. This shows promise for overcoming the worldwide shortage of donor endothelial tissue. Furthermore, in cases where endothelial keratoplasty may not be possible, this may be a readily available treatment option.

Victor A. Augustin, MD, Maximilian K. Köppe, MD, and Gerd U. Auffarth, MD, FEBO

The authors are based at the David J. Apple International Laboratory for Ocular Pathology and International Vision Correction Research Centre (IVCRC), Department of Ophthalmology, University of Heidelberg, Germany. Drs Augustin and Köppe declare no conflicts of interest. Prof. Auffarth reports grants, personal fees, non-financial support and consulting fees from Johnson & Johnson and Alcon; grants, personal fees and non-financial support from Carl Zeiss Meditec, Hoya, Kowa, Oculentis/Teleon, Rayner, Santen, Sifi and Ursapharm; grants and personal fees from Biotech, Oculus and EyeYon; and grants from Acufocus, Anew, Contamac, Glaukos, Physiol and Rheacell, outside the submitted work.

1. Zirm EK. Eine erfolgreiche totale Keratoplastik (A successful total keratoplasty).

2. Melles GR, Eggink FA, Lander F, et al. A surgical technique for posterior lamellar keratoplasty. 

3. Melles GR, Ong TS, Ververs B, et al. Descemet membrane endothelial keratoplasty (DMEK). 

4. Kruse FE, Schrehardt US, Tourtas T. Optimizing outcomes with Descemet’s membrane endothelial keratoplasty. 

5. Dapena I, Ham L, Melles GR. Endothelial keratoplasty: DSEK/DSAEK or DMEK—the thinner the better? 

6. Melles GR, Ong TS, Ververs B, et al. Preliminary clinical results of Descemet membrane endothelial keratoplasty. 

7. Price MO, Price FW, Jr. Endothelial keratoplasty – a review. 

8. Seitz B, Daas L, Flockerzi E, et al. “Descemet membrane endothelial keratoplasty” DMEK – Spender und Empfänger Schritt für Schritt. 

9. Anshu A, Price MO, Tan DT, et al. Endothelial keratoplasty: a revolution in evolution. 

10. Asi F, Milioti G, Seitz B. Descemet membrane endothelial keratoplasty for corneal decompensation caused by herpes simplex virus endotheliitis. 

11. Hos D, Matthaei M, Bock F, et al. Immune reactions after modern lamellar (DALK, DSAEK, DMEK) versus conventional penetrating corneal transplantation. 

12. Birbal RS, Baydoun L, Ham L, et al. Effect of surgical indication and preoperative lens status on Descemet membrane endothelial keratoplasty outcomes. 

13. Flockerzi E, Maier P, Böhringer D, et al. Trends in corneal transplantation from 2001 to 2016 in Germany: A report of the DOG-section cornea and its keratoplasty registry.

14. Kinoshita S, Koizumi N, Ueno M, et al. Injection of cultured cells with a ROCK inhibitor for bullous keratopathy. 

15. Numa K, Imai K, Ueno M, et al. Five-year follow-up of first 11 patients undergoing injection of cultured corneal endothelial cells for corneal endothelial failure. 

16. Moloney G, Garcerant Congote D, Hirnschall N, et al. Descemet stripping only supplemented with topical ripasudil for Fuchs endothelial dystrophy 12-month outcomes of the Sydney Eye Hospital Study. 

Articles

Newly developed acrylic implant provides option for patients with endothelial dysfunction.

Artificial DMEK could help tackle endothelial donor tissue shortage 

When paired with multifocal extended depth-of-field technology, the new, small aperture ocular IOL, IC-8, delivers excellent extended depth of focus at near, far and intermediate ranges whilst reducing halo and glare.

A new small-aperture ocular IOL, IC-8 (Acufocus), which is CE Marked and currently under investigation by the United States Food and Drug Administration (FDA) employs the pinhole camera effect to correct presbyopia. By flattening the defocus curve on both the myopic and hyperopic sides, the IOL essentially creates a small amount of myopia, thereby extending the patient’s depth of focus and eliminating visual effects from corneal astigmatism or other irregularities.

This high-technology, one-piece hydrophobic acrylic ocular implant comprises an embedded opaque annular mask with a central aperture. Aligned light rays converge through the 1.36-mm central aperture, while peripheral defocused and, often, aberrated rays are blocked from disrupting the image.

As a result, patients experience a continuous range of vison from near to far, including the increasingly important intermediate range. At 1.5- to 7-feet away, the intermediate range represents a critical zone of activity for most people. It is where we eat most of our meals, do our desk work and watch the majority of our large-screen media. It is where many people earn their livings, including refractive surgeons.

Originally intended to be paired with a monofocal IOL, it has been found that, when paired with a multifocal IOL, the IC-8 is better than previous alternatives at enhancing visual acuity at intermediate distances, and so has the potential to benefit this underserved cohort. Likewise, patients who have had previous refractive procedures are becoming more common.

As they proliferate, so does our necessity for techniques and technologies tailored to support their special needs. The IC-8 has shown good outcomes in these ‘veteran’ surgical patients.

Surgeons are only now beginning to appreciate the additional benefits made possible by combining the small-aperture lens with IOLs that function on completely different optical principles. Experimentation is ongoing, and this novel strategy may ultimately lead us to maximise the full potential of the IOL, providing patients with truly satisfying customised outcomes.

LOW-ADD MIOLS 
	Low-add multifocal lenses (MIOLs) have been shown to improve intermediate visual acuity and offer surgeons the ability to further individualise patients’ visual outcomes, particularly when mixed with another refractive technology. Combining a multifocal lens with a different type of lens also can act to minimise glare and halo, an intrinsic characteristic of MIOL optics.

It is well known that most types of presbyopia-correcting IOLs-including multifocal refractive and diffractive, and even the newest trifocal technology-sacrifice distance vision to some extent in order to correct near vision and induce a variable amount of dysphotopsias.

 One study of the AcrySof ReSTOR +2.50 D IOL (Alcon) found it provided good intermediate and functional near vision for patients who did not want to accept the higher potential for visual disturbances associated with the +3.00 D version of the same IOL, but wanted more near vision than a monofocal IOL generally provides.

Another prospective comparative investigation evaluated bilateral cataract surgery using the +3.00 D AcrySof IOL or a +4.00 D power of the implant.

 The +3.00 D IOL provided superior uncorrected distance visual acuity, significantly better uncorrected intermediate visual acuity at 40, 50, 60 and 70 cm, and functional reading acuity at 38.9 cm. Eyes with the +3.00 D IOL had better intermediate vision than those with the +4.00 D model without compromising distance and near visual acuity.

MF EXTENDED DEPTH OF FOCUS
	The Lentis Mplus LS-313 MF20 (Teleon; available in Europe but not in the US) is a foldable, one-piece, aspherical multifocal posterior chamber IOL that extends a patient’s depth of focus. Its refractive rotationally asymmetric design helps minimise the loss of light to below approximately 7%, thereby improving contrast and retinal image quality.

An evaluation of the implant, with +2.00 D of near add compared with +3.00 D, found superior visual outcomes from far distance to a near of about 25 cm with the latter lens. The +2.00 D demonstrated excellent visual results from far distance to an intermediate distance of about 50 cm.

Unlike the aforementioned multifocal implants, the IC-8 IOL functions due to the pinhole effect: by reducing scattered light and permitting only parallel rays to reach the macula, depth of focus is extended and visual disturbances such as glare and halo are reduced. Small-aperture technology can even overcome problems with corneal asphericity and irregularities. Astigmatism up to 1.50 D can be corrected with the lens alone.

Typically, the IC-8 IOL is implanted in the non-dominant eye, with a monofocal lens in the contralateral eye. To enhance acuity, the small-aperture IOL can be paired with other technologies, such a multifocal, a low-add multifocal or even a trifocal lens. There are many combinations to consider, with the basic idea being that using different types of implants can enhance the sharpness of vision at near, intermediate and distance, and minimise the side effects of the competing technologies.


	The ongoing prospective, multicentre Mosiac study was undertaken to evaluate visual outcomes from the combination of the IC-8 IOL and the Lentis LS-313 MF-20.

 Our group presented 5-month follow-up data on 13 patients with bilateral implantation of the IC-8 IOL with the Lentis LS-313 MF-20 with +2.00 D of near add. We looked at parameters including:

Uncorrected and corrected (binocular) far, intermediate and near visual acuity;

Photic phenomena (halo and glare simulator).

Included were the 26 eyes of 13 patients with cataracts whose average age was 68.5±10.8 years. The targeted refraction for the IC-8 IOL eyes was –0.43±0.18 D with an achieved refraction of 0.42±0.41 D.

The achieved refraction was within ±0.50 D 62% of the time. The targeted refraction for the MF-20 eyes was –0.15±0.16 D and the achieved refraction was –0.33±0.42 D. The achieved refraction was within ±0.50 D 85% of the time.

We found that patients had excellent binocular visual acuity at far and intermediate distances, as well as functional vision at near. Furthermore, they had functional reading acuity at near and intermediate distances, and there was a comparatively low incidence of photic phenomena (see Figures 1 and 2). The combination of the small-aperture implant with a low-add multifocal lens like the Lentis LS-313 MF-20 is a good treatment option for patients who are motivated to achieve spectacle independence.

Multifocal lens designs can exhibit pronounced peaks and troughs, but the IC-8 IOL provides uninterrupted functional vision over 3.00 D of defocus.

 The small-aperture principle has the ability to produce a high-quality full range of vision without blurry zones, and it is more forgiving of refractive error misses or surprises.

The implant has been shown to provide good visual outcomes in post-LASIK and post-RK eyes

, making it an attractive option for patients who previously could not find an appropriate presbyopia-correcting IOL. Likewise, patients with corneal irregularities can benefit from the technology’s ability to reduce aberrations.

When paired with multifocal extended depth-of-focus (EDOF) technology, the IC-8 delivers excellent EDOF at near, far and intermediate ranges whilst reducing halo and glare. It can enhance the physician’s ability to customise successful visual outcomes for each patient, even for those who have undergone previous refractive surgeries. Based on the simple, proven and ancient understanding of the pinhole’s effect on light ray alignment, this IOL is a versatile tool to help cataract patients achieve their paramount postoperative visual goals.

1. Gundersen KG, Potvin R. Comparative visual performance with monofocal and multifocal intraocular lenses. Clin Ophthalmol. 2013;7:1979-1985.
	2. de Vries NE, Webers CA, MontÃ©s-MicÃ³ R, Ferrer-Blasco T, Nuijts RM. Visual outcomes after cataract surgery with implantation of a +3.00 D or +4.00 D aspheric diffractive multifocal intraocular lens: Comparative study. J Cataract Refract Surg. 2010;36(8):1316-1322.
	3. Linz K, Attia MS, Khoramnia R, et al. Clinical evaluation of reading performance using the Salzburg Reading Desk with a refractive rotational asymmetric multifocal intraocular lens. J Refract Surg. 2016;32(8):526-532.
	4. Venter JA, Pelouskova M, Bull CE, et al. Visual outcomes and patient satisfaction with a rotational asymmetric refractive intraocular lens for emmetropic presbyopia. J Cataract Refract Surg. 2015;41(3):585-593.
	5. Calvo-Sanz JA, SÃ¡nchez-Tena MA. Characterization of optical performance with defocusing curve: Analysis of two refractive intraocular lens models with high and medium addition. J Optom. 2018 Oct 31.
	6. https://www.healio.com/ophthalmology/cataract-surgery/news/online/%7B2809ee76-e466-43fe-b70b-dd94ff661925%7D/video-edof-iol-using-pinhole-effect-lessens-ocular-effects.
	7. Dick HB, Elling M, Schultz T. Binocular and monocular implantation of small-aperture intraocular lenses in cataract surgery. J Refract Surg. 2018;34(9):629-631.
	8. Dick HB. Small-aperture strategies for the correction of presbyopia. Curr Opin Ophthalmol. 2019;30(4):236-242.

GERD U. AUFFARTH, MD, FEBO
	E: auffarthg@aol.com
	Prof. Auffarth is chairman and medical director of the Department of Ophthalmology of the University Clinic of Heidelberg, Heidelberg, Germany, director of the David J. Apple, MD International Laboratory of Ocular Pathology, and director of the International Vision Correction Research Center in Heidelberg. He receives research grants and lecture fees from Alcon, Johnson and Johnson, Zeiss, Hoya, Oculentis, Rayner, Acufocus, KOWA and Biotech.

Author | Gerd U. Auffarth, MD, PhD, FEBO

Articles

Artificial DMEK could help tackle endothelial donor tissue shortage

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