Myopia is the most common refractive defect of the eye, affecting substantial proportions of adult populations; in one UK study, it was found to affect 49% of adults.

 The exponential increase in the prevalence of the condition is sparking increased interest in the geometric properties of the conjunctival-scleral tissue.

Generally referred to as short sightedness, myopia is an ametropia characterised by an eye that is too long for its optical system (cornea and lens). In recent years, there has been growing concern about the sharp rise in the prevalence of myopia in the juvenile population, and this has increased the need for research and development of new techniques to control axial elongation of the eye.

Myopia progression can be slowed with multifocal and orthokeratology lenses

 and post-mortem studies in humans have shown that the sclera is more extensible in high myopes than emmetropes, and that weakening of the scleral structure is related to the elongation of the eye, 

 examination of the geometric properties of the anterior sclera in eyes with different levels of myopia may improve our understanding of the variations in the anterior eye properties associated with increased ocular length.

The risk of suffering from diseases such as glaucoma or maculopathies increases very significantly as myopia increases. Therefore, it is important to understand the weakening procedure that takes place in the sclera, leading to progressive eye elongation, and to see whether this process also generates changes in the anterior portion of the structure (covered by the conjunctiva), which can be measured clinically. In this way, geometric factors at the level of the sclera might predict which cases are more susceptible to scleral changes.

OCULUS joins International Myopia Institute in mission to raise myopia awareness

Considering the existing technology for the clinical evaluation of the corneo-scleral geometry,

 as well as the comparison and validation of the main technologies applied in the clinic,

 Fourier domain profilometry (Eye Surface Profiler [ESP], Eaglet-Eye) stands out as being a reasonable way of studying the relationship between myopia and corneo-scleral geometry. Measurement with this device is minimally invasive and quickly captures all the data necessary to characterise such geometry with high levels of precision.

We recently conducted a prospective study to analyse the relationship between corneo-scleral geometry, measured with this type of technology, and the axial length of the eye, defining the differential aspects existing in myopic eyes and developing prediction models of the axial length of the eye based on clinical data.

In total, 64 eyes of 32 healthy participants (mean age 33 years) were evaluated in the Optometry Clinic of the University of Alicante, Spain, including complete analysis of the anterior segment, analysis of visual function and evaluation of the corneo-scleral topographic profile with the ESP system. The study methods adhered to the tenets of the Declaration of Helsinki and were approved by the ethics committee of the University of Alicante (Exp UA-2019-08-28).

A statistically significant and moderate-to-strong negative association was found between the axial length and the difference between temporal and nasal sagittal heights for different chord lengths (from 

 < 0.001 for 15-mm chord length). This suggests that nasotemporal sagittal height asymmetry has potential as a biomarker of myopic changes.

It is possible that the decrease in nasotemporal sagittal height asymmetry in myopic eyes is due to different insertion of the medial rectus muscle and the lateral rectus muscle

 combined with the noticeably lower rigidity of the sclera in such eyes.

 Specifically, there is a rearward displacement of the insertion site of the medial and lateral rectus muscles in myopic eyes,

 with rotation of the eyeball around the same nasal and anterior point to its geometric centre regardless of the axial length of the eye.

Exploring possibilities of myopia prevention and control in the US

A multiple linear regression analysis showed that the axial length could be predicted with acceptable levels of precision by means of a linear equation relating refractive, corneal and corneo-scleral variables, although the variables involved for the prediction seem to differ in right and left eyes. Specifically, the following linear equations for predicting the axial length (AL) were obtained:

< 0.001, adjusted R2: 0.843): AL=15.62-0.27 ×SE+0.99 ×CD+2.77 ×HOA RMS-1.77 ×MinSH14; and

< 0.001, adjusted R2: 0.730): AL=37.20-0.40 ×SE-0.33 ×Km+0.086 ×CD-3.96 ×HOA RMS

where SE is spherical equivalent; CD, corneal diameter; HOA RMS, high order aberration root mean square; MinSH14, minimum sagittal height for a chord length of 14 mm; and Km, mean keratometry.

SMILE procedure offers low enhancement rate after nomogram adjustment

The slight difference between the linear models used to predict axial length from the anterior segment parameters for the right and left eyes may be related to differences in the ocular globe between eyes: the asymmetry of the axial length between them has been shown to increase with increasing axial length.

These models should be considered as a preliminary approach that provides information on the potential value of the geometry of the anterior sclera for the prediction of axial length. Future studies should validate and refine these models in large samples including subjects with different ethnicities.

Multifocal lenses for presbyopia in eyes with previous corneal surgery

The analysis of the relationship between the corneo-scleral geometry measured with Fourier domain profilometry and the axial length of the eye has shown that nasotemporal sagittal height asymmetry may be a good biomarker of myopic changes. More studies are needed to clarify this issue as well as determine how these corneo-scleral parameters change during myopia progression.

Laurent Bataille, PhD, Ainhoa Molina-Martín, PhD, and David P. Piñero, PhD

Dr Bataille and Dr Molina-Martín are post-doctoral researchers from the Group of Optics and Visual Perception of the Department of Optics, Pharmacology and Anatomy, University of Alicante, Spain. Dr David Piñero is a senior researcher and lecturer from the same group and is responsible for the advanced optometry unit of the Department of Ophthalmology of Vithas Medimar International Hospital, Alicante, Spain. The authors have no proprietary or commercial interest in the medical devices that are mentioned in this manuscript.

1. Pan C-W, Ramamurthy D, Saw S-M. Worldwide prevalence and risk factors for myopia: Prevalence and risk factors for myopia. 

2. McBrien NA, Jobling AI, Gentle A. Biomechanics of the sclera in myopia: extracellular and cellular factors. 

3. Backhouse S, Gentle A. Scleral remodelling in myopia and its manipulation: a review of recent advances in scleral strengthening and myopia control. 

4. Vurgese S, Panda-Jonas S, Jonas JB. Scleral thickness in human eyes. PLoS One 2012;7:e29692.

Characterization of the geometric properties of the sclero-conjunctival structure: a review.

6.Bataille L, Molina-Martin A, Piñero DP. C

omparative analysis of two clinical diagnostic methods of the corneoscleral geometry.

. 22 Mar 2021. DOI:10.1097/ICL.0000000000000785.

Bataille L, Molina-Martin A, Piñero DP. Intrasession repeatability of corneal, limbal and scleral measurements obtained with a Fourier transform profilometer.

 23 Nov 2020. DOI: 10.1016/j.clae.2020.11.002.

8.Bataille L, Molina-Martín A, Piñero DP. 

Relationship between axial length and corneo-scleral topography: a preliminary study.

9.Haładaj R. Normal anatomy and anomalies of the rectus extraocular muscles in human: A review of the recent data and findings. 

10. McBrien NA, Gentle A. Role of the sclera in the development and pathological complications of myopia. 

11. McMonnies CW. An examination of the relation between intraocular pressure, fundal stretching and myopic pathology: The relation between IOP, fundal stretching and myopic pathology. 

12.El-Fayoumi D, Bahgat N, Khafagy M, et al. Horizontal extraocular muscle insertion site in relation to axial length using swept-source anterior segment OCT. 

13. Clark RA, Demer JL. The effect of axial length on extraocular muscle leverage. 

14. Rajan MS, Bunce C, Tuft S. Interocular axial length difference and age-related 

Articles

A recent prospective study analysed the relationship between corneo-scleral geometry and the axial length of the eye to develop preliminary prediction models of the axial length of the eye based on clinical data.

The relationship between myopia and conjunctival-scleral geometry

 of cataract surgeons and nurses found that most are concerned about operating theatre waste and believe that having more re-usable products in the operating theatre is a step in the right direction. The survey was developed by the Ophthalmic Instrument Cleaning and Sterilization Task Force, which has representatives from the American Society of Cataract and Refractive Surgery, the American Academy of Ophthalmology (AAO), the Outpatient Ophthalmic Surgery Society and the Canadian Ophthalmological Society. The survey was disseminated to the members of all four societies.

Some impetus for the survey came from two published studies from the Aravind Hospital System in India. The first report in 2017

 found that their carbon footprint for phacoemulsification was one-twentieth of that in the United Kingdom and the United States, largely because they re-use as many surgical supplies and drugs as possible. A second study in 2019

 found that despite such widespread re-use, the rate of endophthalmitis in the Aravind system was 0.01% – lower than that in the United States, with the AAO IRIS registry rate of 0.04%.

Combined MIGS and cataract surgery option offers positive results

“The results suggested that much of our surgical waste due to single use of everything is excessive and of unproven benefit for preventing endophthalmitis,” said Dr David F. Chang, clinical professor of ophthalmology, University of California, San Francisco, US. Dr Chang co-authored the survey report with Dr Cassandra Thiel, assistant professor, New York University School of Medicine, US.

The respondents felt that the major factors accounting for operating theatre waste were wasteful packaging of single-use items (71%), hospital/regulatory policies (74% and 82%, respectively) that limit surgeon discretion in re-using supplies, manufacturer mandates in instructions for use (IFU) for single-use products to limit liability (70%) and manufacturers driving the market towards more profitable single-use products (77%). Surgeon or patient preference for single-use products was felt to be a driver by only 26% and 7%, respectively.

Support of re-use of devices and supplies

The surgeons strongly/somewhat agreed that manufacturers of devices and supplies should use recycled content in packaging of medical supplies (90%) and that they should consider the environmental/carbon footprint in product design (92%). “However,” Dr Chang said, “the real impact would be to offer more re-usable instruments and supplies as options (94%) and allow surgeons greater discretion within their IFUs for re-using supplies (93%).”

Other areas with which surgeons strongly/somewhat agreed were more surgical discretion in the re-use of supplies by regulatory bodies (95%) and advocacy by medical societies to reduce the carbon footprint in operating theatres (87%).

Regarding the use of topical pharmaceuticals and intra-ocular pharmaceuticals, 98% and 95%, respectively, would consider using them in multiple patients; there was also strong agreement for re-using compounded pharmaceuticals (86%). Most surgeons are or would consider sending pharmaceuticals home with patients from the operating theatre (93%).

Investigators analyse factors associated with patient satisfaction after refractive surgery

Surgeons were very willing to re-use phaco tips (92%), phaco tubing and irrigation bottles (77%), cystotomes (72%), single-use cannulas and metal blades (74%), iris retractors (72%) and the unused halves of sutures (59%). During cataract surgeries, 91% are or would consider using short-cycle sterilisation and 56% would consider simultaneous sequential bilateral cataract surgery, although 34% would not be willing to do so.

Among other conservation proposals, eliminating the full-body drape was supported by 95%, not having the patient wear a hospital gown was supported by 90% and operating theatre staff using the same surgical mask all day was supported by 95%. Two-thirds of respondents were open to not changing surgical gowns between every case, but 77% would not be willing to re-use surgical gloves. Endophthalmitis (48%) and toxic anterior segment syndrome (43%) risks and malpractice liability (51%) were factors that decreased willingness to use supplies and medications on multiple patients.

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

Factors potentially driving single-use instruments included reduced staff processing requirements (45%) and improved operating theatre efficiency (37%). “However, the main factors driving manufacturers to promote single-use instruments were felt to be increasing profit (62%), reducing liability (66%) and an easier regulatory approval pathway (65%),” Dr Chang said.

According to Dr Chang, the findings showed that more than 90% of surgeons are concerned about global warming; excessive operating theatre refuse; the need for more re-usable and multi-use options; strong preference for re-usable over disposable instruments; discretion from regulatory agents and manufacturers in re-using materials; and greater manufacturer consideration of carbon footprint.

This article is adapted from Dr Chang’s presentation at the American Academy of Ophthalmology’s 2020 virtual annual meeting. He has no financial interest in this subject matter.

1. Chang DF, Thiel CL. Ophthalmic instrument cleaning and sterilization task force. Survey of cataract surgeons’ and nurses’ attitudes toward operating room waste.J Cataract Refract Surg. 2020;46:933-940.

2. Thiel CL, Schehlein E, Ravilla T, et al. Cataract surgery and environmental sustainability: waste and lifecycle assessment of phacoemulsification at a private healthcare facility. J Cataract Refract Surg. 2017;43:1391-1398.

3. Haripriya A, Chang DF, Ravindran R. Endophthalmitis reduction with intracameral moxifloxacin in eyes with and without surgical complications: results from 2 million consecutive cataract surgeries. J Cataract Refract Surg. 2019;45:1226-1233.

Cataract surgeons and nurses would support having re-usable equipment and supplies to reduce operating theatre waste and carbon footprint. 

Cataract surgeons on operating theatre waste: Less is often more

Treatment with voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) resulted in a short-term change in foveal morphology in one young visually impaired patient, according to Dr Friederike C. Kortuem of the Eye Clinic Tübingen, Eberhard Karls University of Tübingen in Baden-Württemberg, Germany. The patient was a 15-year-old girl whose visual impairment included nyctalopia and decreased visual acuity (VA) in early childhood.

Visual deterioration generally occurs early in Leber congenital amaurosis type 2 (LCA2) and early-onset severe retinal dystrophy (EOSRD), from as soon as birth to 5 years of age. Characteristically, rapid degeneration of the rods and cones; visual field reduction; sluggish or near-absent pupillary responses; photophobia; nystagmus; and nyctalopia can occur. By the fourth decade of life, patients are usually legally blind.

Future gene therapy for inherited retinal disease

Sub-retinal administration of voretigene neparvovec-rzyl in an adeno-associated viral vector was approved in the United States by the Food and Drug Administration in 2017, and in Germany in 2019, to treat retinal dystrophies caused by bi-allelic 

 is involved in the vitamin A restoration cycle in the eye.

 homozygous mutation. The VA in the right eye at examination was 20/63 and the anterior segment was unremarkable. The retinal examination in that eye showed central macular atrophy, narrowed vessels and diffuse peripheral atrophy. Dr Kortuem demonstrated the overall decreased retinal thickness in the right eye.

The clinical examinations included measurement of the best-corrected VA (BCVA), spectral-domain optical coherence tomography (OCT) and adaptive optics retinal imaging. At baseline, the patient was injected with the gene therapy vector, which was successfully positioned between the neural retina and the retinal pigment epithelium. She was evaluated at baseline and then at 2 and 5 weeks and 3 months following treatment.

At baseline, compared with healthy individuals of the same age, this patient’s retina was thinner. Dr Kortuem showed that the central fovea had alterations in its layers and the retinal structures were not well demarcated, in contrast to the parafoveal layer with a preserved outer retina and photoreceptors.

German investigators report eye development from lab-grown brain organoids

As soon as 2 weeks after treatment, the foveal layer started to change. The external limiting membrane was visualised in the fovea.

“The overall disrupted appearance improved,” Dr Kortuem commented. After 5 weeks, the layering of the central fovea further improved out to 3 months.

The adaptive optics images obtained at baseline showed a mosaic of disrupted photoreceptor cells that, according to Dr Kortuem, is characteristic of inherited retinal diseases. Following treatment, the superior nasal area appeared partly clear and the cones were identifiable.

Retinal gene therapy clinical trials are addressing disease at core

In the first 5 weeks following treatment, the initially patchy areas seemed to be decreasing over time. These morphological rescue parameters changed gradually and were correlated partly with the improvement in the foveal-mediated vision after the treatment.

Regarding the safety of the treatment, no signs of inflammation were observed. Cone functionality improved slightly and the patient reported “brighter” vision, which she also reported 5 weeks after surgery. At 3 months after surgery, the objective changes persisted.

The VA remained stable from baseline to week 5 and then improved by one line to 20/50. The contrast sensitivity also remained stable over time.

Chromatic pupil campimetry showed a dramatic increase in the central 10 degrees of the pupil from week 2 to week 5, and this improvement persisted to month 3. “Rapid changes in the photoreceptor morphology seen on OCT and adaptive optics imaging after successful gene therapy in patients with LCA and EORD can be quantifiable at the individual level,” Dr Kortuem concluded.

This article was adapted from Dr Kortuem’s presentation at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting. She has no financial interest in this subject matter.

Gene therapy has produced early and lasting improvements in retinal cell morphology and visual acuity in a patient with inherited retinal disease.

Leber congenital amaurosis: Gene therapy sparks foveal morphological changes

Findings of a retrospective, comparative cohort study demonstrate the benefits of integrating spectral-domain optical coherence tomography (SD-OCT) with ultra-widefield (UWF) imaging in a diabetic retinopathy (DR) telemedicine screening programme.

Dr Aiello, a professor of ophthalmology at Harvard Medical School and director of the Beetham Eye Institute of Joslin Diabetes Center, Massachusetts, United States, presented study data from 422 eyes of 211 patients with diabetes who were consecutively imaged between 8 January and 16 March 2020, using the commercially available platform Monaco (Optos), which allows SD-OCT and UWF imaging in a single sitting. Participants were seen in a UWF image-based DR teleophthalmology programme at the Joslin Diabetes Center.

The results showed that the dual imaging substantially increased detection and reduced false positive assessments of diabetic macular oedema (DMO) and epiretinal membrane (ERM). “Given the reduced effort, compact footprint and reduced overall cost of integrated SD-OCT/UWF devices, their use in large DR screening programmes could substantially improve disease identification and reduce unnecessary referrals,” said Dr Aiello.

“However, it should be noted that this study only evaluated 422 eyes and all images were evaluated in a centralised reading centre using standardised protocols,” he said. “Thus, the applicability of the findings in other settings is unknown.”

Because US Food and Drug Administration (FDA) approval of normative OCT measurements for the Monaco instrument is pending, the OCT images were evaluated qualitatively using a standardised template. Each scan was evaluated for macular pathology, including looking at the foveal contour and looking for macular oedema, ERM, signs of macular degeneration and other macular diseases. The UWF graders were masked to the OCT images and OCT findings, and graders evaluating the SD-OCT images were masked to the UWF images.

The 211 patients included in the study had a mean age of 53.5 years. Based on UWF grading, DR was absent in 58% of eyes and 93% of eyes had no DMO. Eyes with DR spanned the spectrum of severity, but the distribution was weighted towards less severe disease, with most eyes having mild non-proliferative DR. Sixty eyes (14.2%) were graded as having referrable DR, which was defined as moderate non-proliferative DR or worse or any level of macular oedema.

With UWF imaging, less than 1% of eyes were ungradable for determining DR severity and less than 1% were ungradable for determining DMO presence. For both modalities, less than 1% were ungradable for overall macular pathology.

Macular pathology was identified by UWF in 8.1% of eyes and by OCT imaging in 13% of eyes. DMO was the most commonly identified pathology on UWF imaging (75%) but accounted for only 36% of macular disease identified by OCT. ERM accounted for 29% of macular pathology on UWF imaging but 52.7% of macular disease by OCT.

Comparisons between the UWF and SD-OCT gradings showed good agreement when the determination was that DMO was not present; when UWF imaging alone found that DMO was not present, SD-OCT found DMO in only 1.5% of those eyes. When the UWF image grading identified DMO present, however, the determination was not confirmed by SD-OCT in 75% of those cases.

“Overall, UWF image grading suggested that DMO was present in 4.7% of eyes, [whereas] grading by SD-OCT determined DMO was present in only 2.1% of the cohort,” Dr Aiello explained. “Thus, UWF alone had low sensitivity and low positive predictive value for DMO detection, but high specificity and high negative predictive value compared [with] SD-OCT.”

The results were similar in considering detection of clinically significant macular oedema (CSMO), although the sensitivity of UWF was even lower for this diagnosis. Approximately 27% of eyes with CSMO present on SD-OCT were identified by UWF imaging alone.

ERM was detected by UWF image grading in 2.4% of eyes and by SD-OCT in 6.8% of eyes. Only 3.4% of ERMs detected on SD-OCT images were identified on UWF imaging alone. When UWF imaging alone found that ERM was absent, SD-OCT found an ERM in 6.8% of eyes. When UWF grading showed that ERM was present, however, only 10% of those cases were confirmed by SD-OCT.

This article is based on a presentation made at the Association for Research in Vision and Ophthalmology’s 2021 virtual annual meeting. Dr Aiello is a consultant to Optos but is not paid for his services.

Integration of spectral domain optical coherence tomography with ultra-wide field imaging can increase accurate detection of diabetic macular oedema and epiretinal membrane.

Dual imaging in telemedicine screening improving macular pathology detection

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.

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.

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.

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.

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.

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. 

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

Artificial DMEK could help tackle endothelial donor tissue shortage 

Presbyopia is a natural consequence of ageing. It affects more than 1 billion individuals globally and approximately 123 million in the United States. Over the years, many surgical approaches to the correction of the condition have been attempted, but none has yet become widely adopted for patients without significant cataract.

A review of available and emerging treatments for presbyopia was recently published.

 Finding the ultimate solution for this problem has long been the holy grail of ophthalmology because the demand—and the potential rewards—are great.

Companies have begun testing topical therapies for the temporary correction of presbyopia. Several of these drugs may be approved over the next 1 to 3 years, opening a new treatment avenue for patients who wish to be less dependent on reading glasses.

Most of the drops being evaluated aim to modulate the pupil for better near vision. There are likely to be significant differences among them in duration, tolerability and other factors.

There are various topical agents and clinical results available to date, discussed as follows.

Pilocarpine is a cholinergic muscarinic receptor agonist well established in managing pupillary miosis and is the most employed agent in emerging presbyopia therapeutics. What distinguishes the new presbyopia formulations from currently available generic pilocarpine is the lower concentration (in most cases, ≤ 1% vs up to 6% in generic pilocarpine) and that the investigational agents rely on sophisticated delivery vehicles that are better at modulating how much of the active ingredient reaches the ocular tissues. Several companies have pilocarpine-based drops in clinical trials:

Two Phase 3 clinical trials (Gemini I and II) with a total of 750 participants have been completed. No published studies are available, but public reports note that primary endpoints in both studies

 were met, with more patients in the treatment group vs the vehicle-controlled group gaining three or more lines of mesopic high contrast binocular distance-corrected near visual acuity (DCNVA) at 3 hours over 30 days of bilateral single-dose use.

Headache, conjunctival hyperaemia, blurred vision and eye pain were each reported by 3% or fewer of the patients treated with AGN-190584. A New Drug Application has been submitted to the US Food and Drug Administration (FDA) and approval is anticipated in late 2021.

 with 166 participants was completed in 2019, with reportedly good tolerability of the drop and statistically significant gains of three or more lines of DCNVA when dosed twice daily.

 There was no impact on distance or night vision. A Phase 3 study of 300 participants has recently begun.

This company has a novel microdose dispenser (Optejet) that sprays the drug at the eye. A Phase 3 trial in which 84 subjects’ DCNVA were tested 2 hours after treatment with 1% or 2% pilocarpine1 showed that a statistically significant proportion of patients treated had a three-line or more increase in DCNVA vs placebo in low light 2 hours after treatment.

Ocuphire Pharma is evaluating a kit that combines a moderate and long-acting evening dose of the non-selective a-1/a-2 adrenergic antagonist phentolamine 0.75% with a morning dose of pilocarpine 0.4%. Synergistically activating the iris sphincter muscle while inhibiting the iris dilator muscle allows for lower concentrations of the active ingredients and may reduce the likelihood of adverse reactions.

A Phase 2 study in 152 patients whose NVA was tested for up to 6 hours post-dose met its primary endpoint with statistical significance at 1 hour. More than half (61%) of patients treated with Nyxol plus low-dose pilocarpine gained 15 letters (three lines) in near VA.

Similar to pilocarpine, aceclidine is also a parasympathomimetic cholinergic muscarinic receptor agonist. A Phase 2 study of an aceclidine-based miotic treatment for presbyopia in 58 participants was completed by Presbyopia Therapies in 2018.

 At the time, the company reported that 47% of study eyes gained three or more lines of near vision and 92% gained at least two or more lines 1 hour after instillation, a statistically significant benefit over placebo.

Approximately half the eyes maintained a two-or-greater line improvement for up to 7 hours. Little information has been released about the drop since and no additional studies have been registered, although the company has reorganised and is moving forward under its new name, Lenz.

Fixed-combination carbachol/brimonidine tartrate

Brimochol is a fixed combination of carbachol and brimonidine invented by Dr Herbert Kaufman and now under development by Visus Therapeutics for the treatment of presbyopia. Carbachol has previously been shown to be a more potent cholinergic miotic than pilocarpine.

 Combining it with brimonidine, which prevents pupil dilation and may inhibit ciliary muscle contraction, achieves synergistic effects, and may reduce the severity of adverse effects.

 which may prevent the redness typically associated with miotics. Four peer-reviewed studies evaluating this combination have been published in the literature, though using different formulations than are currently being tested by the company.

 One of these demonstrated superiority of the fixed combination over the individual components,

 something that is essential for FDA approval of any fixed-combination drop.

Results of the most recent study, in 2019, showed a 12-hour duration of effect on near vision in 57 participants without any reported symptoms of headache or brow ache.

 A Phase 2 crossover study in 45 phakic and pseudophakic patients dosed once daily with one of two different Brimochol formulations or carbachol monotherapy has recently begun.

Unlike the other drops that act by modulating the pupil, Novartis is developing UNR844, a lipoic acid choline ester chloride that acts on disulphide bonds between crystalline lens proteins. The idea is that by hydrolysing the disulphide bonds, this drug would soften the lens and restore some accommodative ability.

Results of an early Phase 1/2 study found an improvement in DCNVA of 8.1 letters in the treated group vs 4.3 letters in the placebo group.

 A Phase 2 controlled trial evaluating safety and efficacy after 3 months of twice-daily dosing treatment in early presbyopes (aged 45–55) has also been completed, with a gain of 6.1 letters in the treatment group vs 4.5 letters in the placebo group.

In addition, 25% of the treatment group vs 16% of the placebo group achieved 75 or more letters in total. The most common adverse events reported were dysgeusia and headache, in 5% and 3% of treated participants, respectively. Thus far, study sponsors have reported only functional effects on vision from this lens-softening agent, rather than any lens outcomes such as change in accommodation.

Also, as trials are attempting to reverse presbyopic lens changes, it seems likely that such a drop would be used in younger individuals to prevent lenticular changes in the first place. This would increase the burden of proving that the lens is safe for long-term use. This is a fascinating therapeutic category, but I think ophthalmologists are going to want to see a great deal more data, including whether these drops work consistently across the entire lens.

As presbyopia-correcting drugs come to market, one of the most important factors for both physician and patient acceptance will be efficacy – how well the patient can read and use a computer. Everybody likes to see J1 clinical trial results, but most individuals do not actually need to be able to read J1. A drop that can provide J6 or better for 8–12 hours, to cover most of a person’s working hours, would be a big advancement for patients.

Although most of the pupil-modulating drops in development are being tested for use in both eyes, patients may experiment with using the drops monocularly and binocularly. The newer drops will likely have vehicles that are kinder to dry eyes or will make use of sustained delivery nanomicelle technology.

Some presbyopia-correcting drops may be available in preservative-free formulations, which will make them more comfortable for patients with pre-existing ocular surface disease. This was true for glaucoma patients who had been on 4% or 6% pilocarpine for years, which had a high concentration of the active ingredient and were preserved, but it may not be an issue with the much lower concentrations of pilocarpine that are being developed for presbyopia.

Although there are quite a few presbyopia-correcting drops in development, there will probably be room for all—or at least several—of them. It will be relatively easy for patients to try several types and for practitioners to customise drop choice to patients’ lifestyles and ocular needs.

Prof. McDonald is a clinical professor of ophthalmology at New York University in Manhattan, New York, US, and Tulane University in New Orleans, Louisiana, US. She is in private practice at OCLI Vision in Garden City, New York, Manhasset, New York, and Oceanside, New York. She is a consultant to Allergan, Visus Therapeutics and Ocuphire Pharma and she has stock ownership in Ocuphire Pharma.

1. McDonald MB, Mychajlyszyn A, Mychajlyszyn D, Klyce SD. Advances in corneal surgical and pharmacological approaches to the treatment of presbyopia. 

2. Allergan. A phase 3 efficacy study of AGN-190584 in participants with presbyopia. ClinicalTrials.gov. 28 February 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT03857542. Accessed 22 April 2021.

3. AbbVie. Allergan, an AbbVie company, announces positive phase 3 topline results for investigational AGN-190584 for the treatment of presbyopia. PR NewsWire. 28 October 2020. Available at: https://www.prnewswire.com/news-releases/allergan-an-abbvie-company-announces-positive-phase-3-topline-results-for-investigational-agn-190584-for-the-treatment-of-presbyopia-301161348.html. Accessed 22 April 2021.

For ophthalmologists, finding the ideal solution for presbyopia has long been the ‘holy grail’ of the field. 

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