TAKE HOME:

High-volume experience demonstrates the safety and efficacy of presbyopia correction using a small-aperture corneal inlay (Kamra, AcuFocus) placed at the time of LASIK or in eyes for postLASIK.

By Cheryl Guttman Krader; Reviewed by Minoru Tomita, MD, PhD

Tokyo—Simultaneous LASIK and implantation of a small-aperture corneal inlay (Kamra, AcuFocus) is a safe and effective method for treating ametropic presbyopes.

Minoru Tomita, MD, PhD, presented the outcomes from a series of 3,015 eyes that underwent the combined procedure between August 2009 and August 2012 at Shinagawa LASIK Center, Tokyo. In addition, he noted excellent results from a group of 3,782 postLASIK eyes with the small-aperture corneal inlay implanted in the nondominant eye to correct presbyopia. The latter operations were performed between November 2010 and August 2012.

The small-aperture corneal inlay is commercially available in Japan. The device is investigational in the United States; the manufacturer submitted its premarket approval for FDA approval in March 2013.

“This small-aperture corneal inlay increases depth of field so that patients can achieve improved near and intermediate vision with minimal effect on distance vision and has been reported to be a safe and effective treatment in emmetropic presbyopes,” said Dr. Tomita, executive medical director of Shinagawa LASIK Center. “The patients who come to our center are ametropes interested in LASIK, and this inlay offers an opportunity to treat presbyopia at the same time.

Preop evaluation, expectation

“Simultaneous LASIK and implantation of this intracorneal inlay is very easy for the refractive surgeon to perform and it has resulted in high patient satisfaction,” Dr. Tomita added. “However, careful preoperative evaluation is important to ensure patients are good candidates and that they have realistic expectations for their postoperative outcomes.”

Patients are eligible for the combined procedure if they are appropriate candidates for LASIK, 45 to 65 years of age, and have SE between –9 and + 3 D with <3 D cylinder in the inlay eye. Other inclusion criteria require a corneal thickness >470 μm, an estimated residual bed thickness >280 μm, keratometry between 39 and 47 D, regular topography, and endothelial cell density >2,000 cells/mm².

How it’s done

The procedure involves creation of a 200-μm flap with a femtosecond laser (Femto LDV Z6, Ziemer; iFS, Abbott Medical Optics) in the inlay eye, which is treated for a target refraction of -0.75 D using one of two excimer laser systems (Wavelight Allegretto, Alcon Laboratories; Amaris, Schwind). The dominant eye is treated with a target postoperative refraction of plano after creation of a 100-μm flap.

The 3,015 patients who underwent the combined procedure had a mean age of almost 52 years and mean SE of –2.84 D; 75% of patients were myopic. Mean uncorrected distance visual acuity (UDVA) improved from 20/125 preoperatively to 20/20 at 1 year (n = 1757) when 74% of patients achieved 20/20 or better UDVA in their inlay eye and 82% were 20/25 or better.

Mean uncorrected near visual acuity (UNVA) improved from J6 to J2 at 1 year when 77% of patients achieved J2 or better in the inlay eye and 56% could read J1. Results of a survey administered at 1 year showed 93% of patients were satisfied with their vision without reading glass, 7% of patients indicated they sometimes needed reading glasses, and only 3% said they needed reading glasses often.

PostLASIK inlay placement

Dr. Tomita’s method for inlay placement in the postLASIK eye involves use of a femtosecond laser to create a corneal pocket below the level of the LASIK flap. Pocket creation is performed with optical coherence tomography (OCT) guidance with the new Femto LDV Z6. Some patients may also need to undergo simultaneously a minor enhancement procedure with lifting of the prior LASIK flap in order to achieve a plano refraction.

The same inclusion criteria are used to determine eligibility for postLASIK inlay placement as for the simultaneous surgery except that patients must also have corrected distance visual acuity (CDVA) better than 20/25 in both eyes, UNVA worse than J3 in the implanted eye, and be at least 1 month postLASIK with a corneal thickness of at least 450 μm.

The patients included in the postLASIK inlay placement series had undergone primary LASIK for a mean attempted correction of –3.37 D and with an average flap thickness of about 100 μm. At the time of the inlay procedure, they had a mean age of about 53 years and mean SE was close to plano (–0.12 D), but ranged from –2.38 to +2.38. Mean CDVA was 20/12.5 and mean corrected near visual acuity was J1.

Data from follow-up to 6 months was available for 1,938 patients. Mean UDVA changed from 20/16 preoperatively to 20/20 with 80% of patients achieving 20/20 or better in the inlay eye and 86% being 20/25 or better. Mean UNVA improved from J6 to J2, with two-thirds of patients achieving J2 or better in the inlay eye and 80% being J3 or better.

As in the simultaneous LASIK-inlay group, 93% of patients were satisfied with their vision without reading glasses and the rest were equally divided between needing reading glasses sometimes and often.

Minoru Tomita, MD, PhD

E: tomita@shingawa-lasik.com

Dr. Tomita is a consultant to AcuFocus and Ziemer. This article is adapted from Dr. Tomita’s presentation during Refractive Surgery 2012 at the annual meeting of the American Academy of Ophthalmology.

Take-home

Amniotic membrane technology may be a welcome addition to the DSAEK technique armamentarium, especially for the majority of cases that already have epithelial edema, haze, and scarring.

By Michael P. Ehrenhaus, MD, and Sebastian Guzman, MD; Special to Ophthalmology Times

Descemet’s stripping automated endothelial keratoplasty (DSAEK) is an excellent choice for many patients—whether they have moderate to advanced Fuchs’ dystrophy alone, are in a post-surgical status from weeks to years later, or have endothelial dysfunction from other contributing factors.

DSAEK is often done with the epithelium intact to help with both the surgical view and with patient discomfort. However, as most of us have experienced, many of these cases are done through a loose and often hazy epithelial sheet, either due to long-standing edema, chronic micro or macrobullae or even a coincident basement membrane dystrophy. This may actually end up causing more discomfort though due to increased surgical time as well as possible poorer surgical outcomes.

In addition, an intact epithelial surface may be an important layer that helps with the implanted corneal endothelial discs adhesion. Think of the cornea as a book lying on the ocean, with intact front and back book-covers. The back cover pumps work to keep the books pages clear by pumping out the fluid that is slowly seeping in, while the front cover protects the pages from the elements. In theory, if the front cover is missing, the pump forces have a decreased counter-balancing layer that helps with the back covers pump function to improve the clarity and relative dehydration of the stroma.

However, in cases where the epithelium is cloudy, loose, edematous or scarred, by removing the epithelium your surgical view is dramatically improved. Difficult cases now become more “routine” because you can now better appreciate the anatomy that you need to work with.

The problem with epithelial removal has been greater post-operative discomfort causing patients to squeeze their eyes more often and more forcefully which we know is a contributing factor to endothelial disc dislocation off of the posterior stroma. Additionally, the proposed decreased counter-balancing force utilized by the endothelial pump layer is missing, which is needed in theory to improve the pump gradient and help with adherence, may lead to dislocations as well.

By utilizing the well-known properties associated with preserved amniotic tissue and epithelial healing, as well as covering the corneal epithelial defect with a bandage contact lens, the surface counter-balancing layer can be re-established, the patient’s discomfort can be minimized, and the epithelium can more rapidly heal, allowing for both improved surgical outcomes as well as improved postoperative visual acuities.

To prove this ourselves, we perfomed DSAEK surgery on a more routine post-phaco bullous keratopathy as well as a more complex failed prior DSAEK case that also had other prior complicating surgical history with resultant irido-corneal adhesions. Both cases had increased epithelial clouding and looseness. During the surgery, the epithelium was removed to drastically improve the surgical view which allowed for a complete Descemet’s layer removal, appropriate synechiolysis, and enhanced viewing of the endothelial disc insertion and centration.

At the end of the cases, we placed an AmbioDisk with an Acuvue2 soft contact lens onto the surface of the cornea. The Amniotic disc in these cases was created by using an 8-mm trephine to cut an Ambiodry2 graft. The amniotic disc was placed to the surface of the cornea, covering the epithelial defect and antiotic drops and BSS drops were placed to hydrate it slightly. The contact lens was soaked in topical antiotic drops and then placed to the surface of the eye as well prior to placement of a patch and shield.

Postoperatively, the patients stated that their eyes were comfortable both immediately after surgery as well as during the visits the following day and thereafter. During the first week, the AmbioDisk and contact lens remained intact and well centered. Visual acuity was only slightly decreased initially due to the epithelial defect, the thin, slightly opaque amniotic tissue layer and the bandage contact lens, but the donor tissues were attached 100%, centered and already thinning nicely. When the lens and tissue were removed at 1 week, the epithelium had healed completely and the visions were dramatically improved from both pre-operative baseline and on postoperative day 1.

We plan to do more cases this way and feel it will prove to be a welcome addition to the DSAEK technique armamentarium, especially for the majority of cases that already have epithelial edema, haze, and scarring. We look forward to enjoying the improved surgical view and improved outcomes, without the worry of possibly causing disc locations as a direct result of the epithelial removal.

Michael P. Ehrenhaus, MD, is director, New York Cornea Consultants, Bayside, NY. Readers may contact him via phone at 718/428-8400 or e-mail at corneaconsult@me.com. Dr. Ehrenhaus is a speaker/consultant for Allergan and Bausch + Lomb.

Sebastian Guzman, MD, is director, ophthalmology, Clinica Corominas, Santiago, Dominican Republic. Readers may contact Dr. Guzman via phone at 809/971-2020  or e-mail at sebastianguzman@hotmail.com. Dr Guzman has no financial interests.

References

1. Dua HS, Gomes JA, King AJ, Maharajan VS. The amniotic membrane in ophthalmology. Surv Ophthalmol. 2004;49:51-77.

2. Tseng SC, Espana EM, Kawakita T, Di Pascuale MA, Li W, He H, Liu TS, Cho TH, Gao YY, Yeh LK, Liu CY. How does amniotic membrane work? Ocul Surf. 2004;2:177-187.

Take-home

Algorithm-based software can help ophthalmologists choose the best keratoconus treatment option for their patients based on patients’ unique needs.

By Mazen M. Sinjab, MD, PhD, Special to Ophthalmology Times

Damascus, Syria—When treating ectatic corneal disorders, such as keratoconus, ophthalmologists have a plethora of management options from which to choose. However, choosing among these treatment modalities is not easy, because different patient parameters (i.e., age, gender, corneal astigmatism, and visual acuity) are often indicative of different treatment options.

To address this, I developed an algorithm-based software (Sinjab Data-Based Algorithm for Managing Keratoconus, or DamaSKo-Gram [the software name reflects the city where it was developed, Damascus, Syria]) that can help ophthalmologists decide the best management option for their patients based on patient data. In this article, two case studies demonstrate how this software functions and how it can help improve keratoconus management.

Case 1

A 42-year-old male patient was referred for keratoconus in his right eye. Upon presentation, he had a clear corneal surface and stable disease. Uncorrected distance visual acuity (UDVA) was counting fingers and best-corrected visual acuity (BCVA) was 0.7 D. He had a manifest refractive error of –3 D Sph/–4 D Cyl ´ 35 axis and a maximum K reading (Kmax) of 58 D. The thinnest location of his cornea was 459 mm and he had topographic astigmatism of 4 D, consistent with his refractive cylinder. To decide the best treatment option for this patient, I entered this information into the patient information window of the software.

With a simple click on the “management” button, the software analyzed the patient’s data and suggested four treatment options customized for this patient, listed in the order of most favorable to least favorable:

1. Advise using contact lenses and observe the case in close follow-ups every 3 months, or

2. Perform intracorneal ring (ICR) segment(s) implantation; observe the case in close follow-ups every 3 months, or

3. Perform topography-guided photorefractive keratectomy (TG-PRK) followed by same-session corneal crosslinking (CXL, either iso- or hypotonic), or

4. Advise using glasses and observe the case in close follow-ups every 3 months.

To help decide among these options, the software also provides a “discussion” that highlights the conditions under which one treatment option would be better than the other. For instance, in this case, the discussion suggested using contact lenses as the first option based on the patient’s tolerance due to the high refractive error and K readings. It also highlighted the fact that the patient’s parameters made him suitable for ICR implantation, CXL, and TG-PRK, with TG-PRK being preferable to CXL due to high astigmatism.

The discussion also warned that the patient’s high Kmax value increased the possibility of CXL failure. The last treatment option of using spectacles was suggested because of the good CDVA and CDVA-UDVA difference; however, it was discouraged due to high refractive error.

In this case, since the patient was intolerant to contact lenses, I chose the second recommendation and implanted two ICR segments (Keraring SI5, Mediphacos). Three months postoperatively, the patient’s UDVA was 0.7 D and CDVA was 1 D with –0.75 D Sph\–0.5 D Cyl ´ 43 axis. The patient was very satisfied with the results, even without glasses.

Case 2

A 25-year-old female presented with a diagnosis of keratoconus in her left eye. She had previously had penetrating keratoplasty (PKP) for the same condition, but in her right eye. When she presented, she had progressive disease in her left eye and had a clear corneal surface, with UDVA of counting finger and a CDVA of 0.4 D. She had a high manifest refraction of –4 D Sph/–7 D Cyl ´ 160 axis, Kmax of 61 D, and topographical astigmatism of 8 D. The area of least corneal thickness in this patient was 420 mm. Based on this information, which I entered in the patient information window, the software recommended the following options starting with the most preferred option:

1. Perform CXL; wait 1 month; advise using contact lenses, or

2. Perform ICR segment(s) implantation; wait 3 months; perform CXL; wait 3 to 6 months until the refraction is stable; correct the residual error by implanting a phakic IOL (PIOL), or

3. Perform lamellar keratoplasty, or

4. Perform intrastromal ring (Myoring,Dioptex GmbH) implantation with same session CXL.

These recommendations were accompanied by a discussion as in the previous case to explain the choice of treatment options proposed and how they are suited to the patient’s parameters. In this case, I proceeded with option 2. Although the patient was tolerant to contact lenses, she had been using them for several years already and was seeking a more radical solution, hence excluding option 1.

PKP was also not a viable option in this case because of the patient’s experience with the graft in her right eye. Although she had good visual acuity in this eye, the graft embarrassed her because it was visible to close friends. In choosing between ICR and Myoring implantation, I prefer the Keraring because it gives more predictable results, especially with low sphere. Furthermore, the software predicted good prognosis with Keraring based on the patient’s topography pattern. Therefore, the patient and I chose to proceed with Keraring implantation.

An additional advantage of the software is that it provides guidelines for the different treatment options suggested based on the patient’s parameters. Therefore, I consulted the software to determine the best size of the Keraring for this patient. Due to the high topographic astigmatism in this case, the software recommended using a 6-mm Keraring instead of a 5-mm Keraring. Three months postoperatively, the patient’s UDVA improved to 0.2++, CDVA improved to 0.9 D, and refraction was –2 D Sph/–1 D Cyl ´ 150.

With such a significant improvement, we were able to avoid PIOL implantation and proceed directly to CXL. Three months post-CXL, we noticed an additional improvement in vision of UDVA 0.4 D, CDVA 1 D, refraction –1 D Sph/–0.5 D Cyl. The patient and I were both very satisfied with the results.

Therefore, the software is able to adapt to different cases and suggest treatment options based on the severity of the patient’s parameters.

Discussion

Contact lenses and spectacles have been the mainstay of keratoconus treatment for most patients. However, there have been several recent developments in other surgical and non-surgical treatment options for keratoconus treatment, including CXL, PRK, ICRs, the Myoring, PIOLs, and deep anterior lamellar keratoplasty. No doubt, future innovations will only add to this list.

Although the availability of a vast number of treatment options is good news for the ophthalmologist and the patient, it also makes the ophthalmologist’s task of finding the optimal treatment modality more challenging. This is especially due to the fact that the choice of treatment modality depends on the patient’s visual and demographic parameters, which do not always suggest the same therapy. Although different parameters are indicative of different treatment options, in general, we know that higher Kmax, thinner cornea, higher refractive error, and lower visual acuity are indications for more aggressive therapy.

The software uses a data-based algorithm that takes into account the various parameters of the patient in order to decide the best treatment options for him/her, thus simplifying the ophthalmologist’s task. A simple user-friendly interface lets the ophthalmologist to enter the patient’s information into the software—information that can be stored long term with the patient’s record and made accessible at future visits.

The software can also detect errors and caution the ophthalmologist to them. For instance, if the ophthalmologist forgets to input a necessary parameter, such as disease stability, the software generates a warning to enter the missing information. Similarly, if there is a logical discrepancy in the entered data, the software picks up on the error and intimates the doctor to correct it. For example, if the ophthalmologist enters a high refractive error into the software but also a high UDVA, the software generates an error message asking the physician to re-check the patient.

An additional advantage of the software, as demonstrated in the second case study, is that it provides the ophthalmologist with general guidelines and topographic patterns suitable for the use of either a single-treatment modality, such as the Myoring or ICRs, or for combination therapy such as with CXL and TG-PRK. Thus, once the ophthalmologist has chosen a preferred treatment option, he or she can consult the software for information on how best to execute the treatment.

Furthermore, this software is easy to install and suitable for use with any topographer. It can also be continually upgraded as new information becomes available and can even be improved to give measurements, locations, and types of ICRs and PIOLs.

The software is in a sense similar to consulting with a colleague, with the added advantage of the software being available at the ophthalmologist’s fingertips. Therefore, the software can help ophthalmologists navigate through the vast amount of information, indications, contraindications, and guidelines for the different keratoconus treatments available in order to choose the best treatment option for their patients based on their patients’ unique needs.

Mazen M. Sinjab, MD, PhD, is an assistant professor at Damascus University, Damascus, Syria. Dr. Sinjab did not indicate a financial interest in the products or companies mentioned. The software is not approved in the United States. Readers may contact Dr. Sinjab via e-mail at mazen.sinjab@yahoo.com.

TAKE HOME:

Chemical enhancement may enable stromal imbibition without epithelial removal. Further study is needed to establish the efficacy of corneal collagen crosslinking with these methods.

By Cheryl Guttman Krader; Reviewed by Jesper Hortjdal, MD, PhD

Aarhus, Denmark—Currently, complete debridement of the corneal epithelium is the most effective technique for ensuring proper imbibition of the corneal stroma with riboflavin when performing collagen crosslinking (CXL).

However, chemical modification of the riboflavin solution is showing promise as an approach for enabling transepithelial CXL, said Jesper Hortjdal, MD, PhD.

“The creation of an epithelial defect to perform CXL is associated with pain along with risks of keratitis and haze,” said Dr. Hjortdal, professor of ophthalmology, Aarhus University Hospital, Denmark. “These drawbacks have generated interest in developing alternative techniques for delivering riboflavin while reducing the epithelial lesion.

“Chemical modifications of the riboflavin solution aim to loosen tight junctions between epithelial cells, and some methods have shown promise,” Dr. Hjortdal said. “However, they should not be used routinely until their safety and efficacy have been studied in further detail.”

Discussing studies on riboflavin penetration into the cornea, Dr. Hjortdal noted that research conducted by his group and others confirm that there is insufficient riboflavin penetration through the intact epithelium when the 0.1% riboflavin solution used in standard CXL is applied. For example, using confocal microscopy to determine riboflavin penetration depth, Dr. Hjortdal and colleagues found that even after complete epithelial removal, a reasonably high concentration of riboflavin was achieved only in the anterior 200 µm of the cornea.

Alternative to epithelial debridement

Scraping of the epithelium has been investigated as an alternative to total epithelial debridement. Results of an in vitro study by Alhamad et al. showed poor penetration into the stroma if the standard riboflavin solution was applied after manual epithelial scraping. However, riboflavin absorption into the stroma was achieved when the applied solution was enhanced with EDTA and trometamol.

Bakke and colleagues conducted a clinical trial evaluating riboflavin solution application to the cornea after incomplete epithelial removal with an excimer laser. Based on examination at the slit lamp to determine riboflavin penetration, they found saturation into the stroma was achieved using the PTK technique.

However, patients who underwent the procedure had more pain than a comparator group treated with mechanical full-thickness epithelial removal, and it took longer to achieve corneal saturation. Additionally, the efficacy of the procedure is unknown as the investigators did not report any postoperative follow-up data.

Preclinical models

Using an animal model and biomechanical testing after CXL to investigate treatment efficacy, Wollensak and colleagues reported that an epithelium-on technique of CXL using a riboflavin solution containing proxymetacaine and benzalkonium chloride (BAC) increased Young’s modulus. However, the effect was only one-fifth that achieved using the standard epithelial-off CXL technique. In contrast, Kissner et al. found the increase in Young’s modulus was similar comparing animal eyes undergoing the standard protocol and those treated with an intact epithelium and riboflavin with 0.02% BAC.

In another preclinical model, Raiskup et al. found a hypoosmolar riboflavin solution containing BAC enhanced riboflavin penetration through the intact epithelium, but the effect was still lower than that achieved with the standard treatment.

Dr. Hjortdal noted there are no randomized controlled clinical trials comparing epithelium-on and epithelium-off techniques of CXL, and cohort studies of epithelium-on techniques report conflicting results. In one trial, Filipello et al. reported good results where eyes were treated with a riboflavin solution containing trometamol and EDTA.

However, in a study using riboflavin solution prepared with proparacaine and a low concentration of BAC (0.005%), Koppen et al. found the outcomes were less effective than what might be achieved with standard CXL.

Jesper Hjortdal, MD, PhD

E: jesper.hjortdal@dadlnet.dk

Dr. Hjortdal has no relevant financial interests to disclose. This article was adapted from Dr. Hjortdal’s presentation during Refractive Surgery 2012 at the annual meeting of the American Academy of Ophthalmology.

Take-Home

A new liquid hydrogel ocular bandage provides improved patient comfort, wound integrity, and closure following cataract surgery.

By Lynda Charters; Reviewed by Matteo Piovella, MD

San Francisco—A new liquid hydrogel ocular bandage (OcuSeal, Beaver-Visitec International) provides improved patient comfort and wound integrity and closure following cataract surgery.

The material is a synthetic hydrogel (85% water) that comes packaged as two separate components—powder and liquid—that are mixed together in a small cylindrical applicator.

“The liquid and powder should be mixed for 5 seconds before use,” said Matteo Piovella, MD, director of the Centro Microchirurgia Ambulatoriale, Monza, Italy. “The solution must be used within 10 seconds.”

When spread over the patient’s wound, the hydrogel film interacts with the underlying tissues and forms a seal that lasts 2 to 3 days. He demonstrated how the hydrogel microstructure comprised holes 2 to 3 µm in size on day 1 postoperatively compared with holes that were 10 µm in size on day 1.

“The epithelium has more room to heal and, eventually, the healed epithelial tissue replaces the [bandage],” he said.

Cross-linked within 20 seconds

Dr. Piovella and co-author, Barbara Kusa, MD, in clinical practice at the Centro Microchirurgia Ambulatoriale, presented their 4-year experience with the product. During that period, they applied the liquid bandage to the clear corneal incisions of 181 patients (246 eyes; 89 men, 92 women). The mean patient age was 68.57 years. The authors found that the ocular bandage cross-linked within 20 seconds of application and formed a smooth, soft, transparent protective film over the incisions.

No patient experienced discomfort; no complications or adverse effects occurred during the first 6 months postoperatively, Dr. Piovella noted.

There is a learning curve attached to use of the product, and in 16 eyes in this series the ocular bandage was applied incorrectly. In these cases, the application was not accomplished quickly enough because the product polymerizes in 15 seconds, he said.

In 1% of cases, the hydrogel film cannot be applied to the cornea as a result of imperfect mixing of the two components, he noted.

In the 246 study eyes, the best-corrected visual acuity was 0.47 D 1 hour postoperatively and 0.82 D 1 day postoperatively. Only 10% of patients in whom the ocular bandage was applied reported a foreign body sensation 1 day after surgery compared with 70% of patients in whom the bandage was not used.

Any residual ocular bandage that was inadvertently applied disappeared within 12 hours of surgery in all patients.

Patient comfort

Dr. Piovella believes that patient comfort during the initial period of healing is an important reason to use this product.

In addition, he noted, studies have implicated unsealed clear-corneal incisions as a possible cause of infections postoperatively. Researchers have suggested that rapid fluctuations in IOP, such as might occur with eye rubbing, can cause unhealed cataract wounds to gape, allowing conjunctival fluid and bacteria into the eye.

The ocular bandage may contribute to wound strength following cataract surgery. A comparison performed in human cadaver eyes with and without the ocular bandage indicated that the average pressure at which incisions burst in eyes in which the ocular bandage was not applied was 59.46 mm Hg compared with 221.84 mm Hg in eyes in which the ocular bandage was applied.

Recently, the manufacturer has tightened up the sterilization parameters and is now filling the powder in an oxygen- and humidity-controlled environment to create better bandage consistency to make application easier. The manufacturer also added a blue tint to improve bandage visibility.

Dr. Piovella now uses the ocular bandage routinely after cataract surgery.

“[The ocular bandage] improves wound integrity and closure after cataract surgery and mostly eliminates the postoperative foreign body sensation,” Dr. Piovella concluded. “Our results support [its] routine use . . . after cataract surgery.”

Matteo Piovella, MD

E: piovella@piovella.com

Dr. Piovella receives lecture fees from Beaver-Visitec International. The liquid ocular bandage is not available in the United States.

Take-home

The discovery of a new layer in the cornea has many surgical and clinical implications. This layer can support the endothelium in the procedure of endothelial keratoplasty, making the handling of Descemet’s membrane transplant safer and technically simpler, according to its discoverer Harminder S. Dua, MD, PhD.

Dua's new layer in the cornea: Its discovery is expected to have an effect on posterior corneal surgery and the understanding of corneal biomechanics and posterior corneal pathology (Image courtesy of Harminder S. Dua, MD, PhD)

Nottingham, England—Scientists have discovered a new layer in the cornea.

This previously undetected layer located in the pre-Descemet’s cornea is well-defined, acellular, strong enough to withstand up to 1.5 to 2.0 bars of pressure, and has been named Dua’s layer, after Harminder S. Dua, MD, PhD, who discovered it.

Dr. Dua

“Clinical implications of this layer will emerge with time, but the surgical implications are immediately relevant,” said Dr. Dua, professor of ophthalmology and visual sciences, University of Nottingham, Queens Medical Centre, Nottingham, England.

“This layer can also be used to support the endothelium in the procedure of endothelial keratoplasty, making the handling of the Descemet’s membrane transplant safer and technically simpler,” Dr. Dua said.

To define and characterize the novel pre-Descemet’s layer in the cornea, Dr. Dua and colleagues at the University of Nottingham performed a study, currently in press at Ophthalmology, in which they included 31 human donor sclerocorneal discs and 6 controls.

Big bubble technique

Using the big bubble (BB) technique, they injected air into the stroma of donor whole globes (n = 4) and sclerocorneal discs (n = 21), similar to what is done in the deep anterior lamellar keratoplasty procedure. They then performed the following:

• Creation of BB, followed by peeling of the Descemet’s membrane;

• Peeling off the Descemet’s membrane, followed by creation of the bubble; and

• Creation of the BB and continued inflation until the bubble popped to measure popping pressure.

The tissue they obtained from these experiments also underwent histologic examination.

Three types of BB were obtained:

• Type 1: a well-circumscribed, central, dome-shaped elevation to 8.5-mm diameter (n = 14).

• Type 2: a thin-walled, large BB (maximum: 10.5-mm diameter), which consistently started at the periphery and enlarged centrally (n = 5).

• Type 3: a mixed type of bubble (n = 3).

In Type 1 BB, the Descemet’s membrane could be peeled off without deflating the BB, indicating the presence of another layer of tissue. In Type 2 BB, this was not possible. Type 1 BBs could be created even after initial peeling of the Descemet’s membrane (n = 5), and this confirmed that the Descemet’s membrane was not necessary to create this type of BB.

Popping pressures were 1.45 bar for the Type 1 BB, and 0.6 bar for the Type 2 BB. Histologically confirmed cleavage occurred after the last row of keratocytes. The new layer was found to be acellular, 10.15 μm in diameter, and composed of five to eight lamellae of predominantly type-1 collagen bundles arranged in transverse, longitudinal, and oblique directions.

Feeling the impact

According to Dr. Dua, his discovery will immediately have an effect on surgery in the posterior cornea and the gradual understanding of corneal biomechanics and posterior corneal pathologies, including acute hydrops, Descemetocole, and pre-Descemet’s dystrophies.

Clinically, his discovery will also impact the understanding of several corneal pathologies.

“There are several conditions that affect the back part of the corneal stroma,” Dr. Dua said. “The consequences or sequelae of these could relate to this layer and is something that we are currently investigating.

“For example, it is traditionally believed that a sudden water logging of the cornea (acute hydrops) that occurs in keratoconus (dystrophy of the corneal causing progressive ectasia) is due to a break in the Descemet’s membrane,” he added. “We have hypothesized that this may be due to a break in the Descemet’s membrane and the Dua’s layer. This not proven, but is something we are investigating.”

Surgically, Dr. Dua’s discovery may help explain a few inconsistencies as well.

“Thus far, all surgeons thought that they were separating the Descemet’s membrane from the stroma in . . . deep anterior lamellar keratoplasty,” he said. “We have proved that this is not so, but that this new layer offers the plane of cleavage in most cases (more than 80% of times), and because it is so tough, it keeps the eye much stronger than it would have been if only Descemet’s membrane was left behind or in a PK. Knowledge of this layer will now enable surgeons to understand the operation better and make it safer,” he said.

But is he surprised by his discovery?

“I am pleased by my discovery as it explains a few things that were happening during lamellar corneal surgery that we did not previously understand,” Dr. Dua said. “It will make the operation safer and may also improve our understanding of some corneal diseases.”

Reactions to discovery of new corneal layer

Aside from suggesting the need for medical textbooks to be rewritten, the significance of Dr. Dua’s discovery of a new corneal layer will take time to become realized.

“It will require, in my opinion, some time to see if others can confirm the existence of this ‘new layer’ and its potential significance,” said Peter J. McDonnell, MD, director of the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, and chief medical editor of Ophthalmology Times.

“My view is that this is an interesting and provocative report from a well-respected research group,” he said. “My reading of their paper is that this is not a description of a new layer in the sense of how we think of the corneal layers (epithelium, basement membrane, Bowman’s layer, etc.), in which the composition is distinct and readily appreciated as such on light and electron microscopy (or even at the slit lamp).”

Rather, this is more the suggestion that a region of the deep stromal layer has a somewhat distinct set of physical and mechanical properties from the rest of the more anterior stroma, he noted.

“So, it will be interesting to see how other means of testing for this confirm or refute the finding and to what degree this might prove to have clinical significance,” Dr. McDonnell concluded.

Also weighing in on this new approach is Mark A. Terry, MD, director, Corneal Services, Devers Eye Institute, and professor of clinical ophthalmology, Oregon Health Sciences University, Portland.

“Dr. Dua has taken a new approach to looking at the posterior layers of the cornea and proposes that because the posterior layers of the stroma just anterior to Descemet's membrane react differently to our surgical maneuvers than say, the mid stroma, that this property qualifies this layer as separate anatomical entity,” Dr. Terry said.

This concept of a new layer is seen by some as intellectually “splitting hairs” of terminology, whereas others see it as legitimately “splitting cornea,” he said.

“Dr. Dua’s concept is not without precedent, as Dr. Bowman also recognized the unique qualities of the most anterior layer of the cornea (which bears his name) nearly a century ago,” Dr. Terry concluded. “I applaud the fresh approach to corneal anatomy that Dr. Dua has taken, and I look forward to further documentation of the unique benefits of this layer in the treatment of our patients.”

Harminder S. Dua, MD, PhD

E: harminder.dua@nottingham.ac.uk

Dr. Dua did not indicate any proprietary interest in the subject matter.

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A new layer of the human cornea has been discovered by a researcher at the University of Nottingham in the UK.

Professor Harminder Dua found the 15-micron thick layer between the corneal stroma and Descemet’s membrane. This makes the newly named Dua’s layer the fourth of six layers in the cornea. Dr. Dua shared his discovery in a recent study published in Ophthalmology. <http://www.aaojournal.org/article/S0161-6420(13)00020-1/abstract>

Dr. Dua suggests that this finding will affect corneal surgery, including penetrating keratoplasty, and understanding of corneal dystrophies and pathologies, such as acute hydrops.

This is an interesting finding that needs to be replicated by other labs in much younger eyes, according to Loretta Szczotka-Flynn, OD, PhD, professor of ophthalmology and visual sciences at Case Western Reserve University, and
director of the contact lens service at University Hospitals Eye Institute in Cleveland.

“One possibility is that this may be an artifact occurring in older corneas because the only donor corneas they studied came from donors with a median age of 82 years,” Dr. Szczotka-Flynn says. “If the presence is confirmed, it will be very important in the lamellar types of corneal transplants. For example, in some lamellar transplants, such as DALK, surgeons may not want to bear all the way to Descemet’s. Rather, they may want to retrain their surgical techniques to bear down to this new proposed Dua’s layer, which will potentially keep the post-operative corneal transplant stronger and does not seem to lead to increased corneal haze.”

“This is an interesting read, but not without some controversy,” says Joseph P. Shovlin, OD, FAAO, private practitioner in Scranton, PA, and Optometry Times Editorial Advisory Board member. “Apparently, Binder et al described an acellular posterior stromal matrix layer in an original article in Investigative Ophthalmology and Vision Science.¹ So, this may not be a novel (original) discussion of a sixth layer of the cornea. I am not certain of the clinical significance of this since we've had information on the structure for over a decade from Binder's paper.”

Dr. Binder’s paper states:

The attachment of Descemet’s membrane (DM) to the posterior stroma appeared to be accomplished in part by fibers 22.3 nm in diameter that ran perpendicular the DM. The depth of penetration of the fibers into DM was 0.16-0.21 um. They were associated frequently with a dense, amorphous mass at the interface between DM and the posterior stroma.¹

Says Prof. Dua: “Perry Binder’s excellent work on the ultra structure of the cornea related to a different plane. The attachment of Descemet’s membrane to the Dua’s layer has also been studied by Prof. Friedrich Kruse, who refers to it as the inter-fascial layer and mentioned Binder’s paper.²”ODT

Reference

1.  Binder PS, Rock ME, Schmidt KC, Anderson JA. High-voltage electron microscopy of normal human cornea. IOVS. 1991 July; 32: 2234-2243.

2. Schlötzer-Schrehardt U, Bachmann BO, Laaser K, Cursiefen C, Kruse FE. Characterization of the cleavage plane in Descemet’s membrane endothelial keratoplasty. Ophthalmology. 2011 Oct;118(10):1950-1957.

 Take-home

The concept of vision à la carte allows all ophthalmic surgeons to design vision for each patient individually, using all of today’s technologies and techniques.

Dr. Gulani

By Arun C. Gulani, MD

Jacksonville, FL—Vision à la carte is a concept I would like to share with all ophthalmic surgeons wherein we can design vision for each patient individually, using all of today’s technologies and techniques, including combinations of these.

The cornerstone of success is the surgeon’s ability to customize the approach to each patient’s vision goal or best vision potential.

How do we arrange these techniques and pick the ones most suitable for each patient?

My approach has always been that we eye surgeons are all vision-corrective surgeons (irrespective of cornea, LASIK, or cataract specialties).

In this armamentarium of vision-corrective surgery—think of it as an umbrella term with about 48 techniques—there are nearly nine different types of LASIK/laser vision surgery (10 now, with the recent SMILE technique I performed while abroad), four types of implantable contact lenses, six types of premium lens implants, seven types of corneal transplants, five types of intrastromal corneal ring segments, and about three ways of doing corneal collagen crosslinking (CXL).

Combinations for customization

(figure 1) Vision a la carte allows all ophthalmic surgeons to design vision for each patient individually, using all of today's technologies and techniques. (Image courtesy of Arun C. Gulani, MD, and Eyemaginations)

With these approaches at our fingertips, we can try various combinations and have unlimited permutations to tailor to each patient’s vision goal. I introduced this concept of vision à la carte at the Bombay Ophthalmology Association’s conference, held in Mumbai, India, in August.

I like to teach this to surgeons and my patients as “Lego” pieces. Arrange these surgery techniques like Lego pieces on shelves in the mind. Each category should have its own color.

For example, all laser vision techniques could be blue, all cataract surgery lens implant choices and techniques yellow, all corneal techniques green, and adjunct techniques such as CXL (that can be used in combination with practically any surgery) white.

Now, say a surgeon is planning a combination of cataract surgery (yellow piece) with LASIK (blue piece). The surgeon now has a plan that can be visualized, and the colors can be used to explain the plan so much more easily. This approach also empowers the surgeon to pick whatever piece is best suited for the patient or even choose combinations.

Apply this concept to complex and complicated cases. For example, in the case of LASIK ectasia, the surgeon can plan for lamellar corneal transplant (a green piece), followed by laser PRK (a blue piece) 6 months later. This needs to be followed by CXL (a white piece).

Customization further involves the proper consideration of three factors that I call the 3Ts—target, technique, and technology.

• Target. A specific target is a very important piece that I believe was missing from vision corrective surgery until the past few years. Surgeons performed surgeries and hoped for the best (or at least what they thought would be good for patients). Today, we need to plan for specific vision targets. If the patient is a pilot, he or she wants a certain vision at different illuminations—day and night. If the patient is a golfer, he or she wants certain vision at specific distances and often at multiple points. A dental surgeon or an architect’s desire for near vision is usually arm’s length, not 16 inches. We are now making our surgery accountable like never before. Set the target vision with patient counseling and education and work backward to pick the technology and technique to achieve that. This is in sync with patient expectations today.

• Technique. Really raising the bar on surgery to an art, techniques have always been as varied as the surgeons performing them. Today, it means more than individual variances based on training and comfort. Technique now implies how we size, shape, and plan depth for LASIK flaps; Smile LASIK concepts; incisions in cataract surgery; planning for the shape, size, and centration of capsulorhexis; flip/crack/chop and other modifications of cataract consumption; or corneal endothelial transplants in the form of DSAEK/DMEK.

• Technology. Technology in diagnostics provide information about nooks and crannies of the human eye we did not even know existed previously leaving little excuse to “leave vision on the table.” Study of vision impact factors besides refractive errors—including spherical aberration and wavefronts—allows us to aim for our choice of the specific technology in surgery so we can address all adversely affecting vision factors (like aiming for a strike in bowling, and not just settling for a spare.

Understanding universally applicable system

The Gulani 5S Classification System algorithm sets the background to my approach and makes any simple or complex case scenario lucid enough to understand and effectively treat.

This algorithm involves classification according to sight, scar, shape, strength, and site (Figure 1).

• Sight. If the patient has potential vision, we as eye surgeons need to get to work.

• Scar. Is the cornea scarred or clear? If scarred, we need to modify the scar in the interest of vision.

• Shape. All laser vision surgery is based on shape. We flatten myopia, steepen hyperopia, and turn a football-shaped astigmatic cornea into a spherical basketball.

• Strength. Is the cornea tectonically strong (i.e., of a normal thickness)? Is it thicker (Fuchs’ dystrophy, epikeratophakia)? Is it thinner (LASIK ectasia, keratoconus)? The surgeon must remove additional tissue, such as in a case of epikeratophakia in a thick cornea, or add a lamellar corneal transplant in a case of ectasia.

• Site. Peripheral corneal problems are not as visually significant as central problems, unless they indirectly affect vision, such as with induced astigmatism.

Surgeons can address any virgin or complex case with a simplified understanding of the 5S system and a plan that not only surgeons and their patients can understand but they can e-mail this plan to their friends and families as well. (Eyemaginations is working with me toward developing this three-dimensional software prototype).

The time is now

Today, with patient expectations, available technology options, and information resources, patients are literally coming in with their own vision goals, chosen technology, and researched techniques for the surgeon to perform.

With a global patient clientele in my practice, I am seeing patients every day who are willing to travel to a surgeon they have chosen, in their minds, to be the most capable to deliver their “individualized vision goal.”

This concept may serve to relieve surgeons of constantly being under the gun of oncoming technology promises coupled with prohibitive expenses and will not necessitate re-learning techniques and challenging their comfort zone.

Instead, this concept allows us to use all the surgical techniques we already have access to and are capable of performing and put them into a new perspective.

Additionally, this concept of planning with patients invigorates them to the fact that we are personalizing a plan in their best interests, and therefore, the “cost” issue becomes secondary, which otherwise is a confabulating tradeoff toward choice for patients.

Patients are moving from the “burgers-for-everyone” concept and are asking for à la carte treatments. Are we ready to offer a menu of vision-corrective options?

Suggested reading

1. Gulani AC. Femtosecond laser in cataract surgery: Designer cataract surgery. Textbook of Femtosecond Laser: Technology & Techniques. 1st ed. J.P. Publishers 2012;20:152-154.

2. Charters L. Classification system aimed at various corneal refractive surgery complications. Ophthalmology Times. http://ophthalmologytimes.modernmedicine.com/user/login/?destination=node/291988&nid=291988. Accessed Sept. 1, 2013.

3. Gulani AC. Corneoplastique. Video Journal of Ophthalmology. III. 2007

4. Gulani AC. Shaping the future and reshaping the past: The art of vision surgery. Chapter 98. In: Copeland and Afshari’s Principles and Practice of Cornea. New Delhi, India: Jaypee Brothers Medical Publishers. 2013;2:1252-1573.

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Take-home

Point source color LED topography has the potential to offer faster and more accurate corneal measurements than existing Placido disc or Scheimpflug imaging technology.

Dr. Weikert

By Fred Gebhart; Reviewed by Mitchell P. Weikert, MD

Houston—Point source color LED topography (CLT)—though a relatively new technology—has theoretical advantages to provide more accurate, more repeatable measurements of corneal topography compared with Placido disc and Scheimpflug imaging devices.

However, there are few head-to-head comparisons of the three technologies.

“We wanted to take this new point source color LED device and compare it [with] what is already available,” said Mitchell P. Weikert, MD, associate professor, Cullen Eye Institute, Baylor College of Medicine, Houston.

“We wanted to see where it agrees with existing devices and where it disagrees,” Dr. Weikert added. “No two devices are going to agree in all cases, but this will help us understand how this new technology works and the potential clinical utility.”

Comparison study

He presented the initial results of a study comparing three devices: corneal topography based on CLT technology (Cassini, i-optics); Placido disc (Atlas 9000, Carl Zeiss Meditec); and Placido/Scheimpflug (Galilei, Ziemer Ophthalmic Systems).

The study enrolled consecutive patients: 64 normal eyes and 15 post-LASIK/PRK eyes. Similar measurements were obtained from all three devices.

Measurements included keratometry (average and astigmatism) and wavefront aberrations with a 6-mm pupil (total higher-order aberrations [HOAs], third to eighth order; third-order coma; third-order trefoil and fourth-order spherical aberration).

Placido-based topography offers several advantages, including a large number of data points, accuracy to within 0.25 D, and surface quality information.

However, the mires reflect off tear film and provide data on the anterior surface only. Because Placido technology uses concentric rings, it more easily measures changes in the radial direction.

Point source CLT technology projects about 700 red, yellow, and green LED point sources onto the cornea to measure its shape. Each LED is a discrete data point.

The combination of point sources and distinct colors helps ensure that there is no source-image mismatch. The image processing software automatically locates feature points in the reflected images and accounts for smearing and deformation in irregular corneas.

Given the short time required for image capture, results are not affected by motion artifacts caused by eye movement.

“We found good agreement [among results with] the three devices when measuring corneal curvature in normal eyes, which is what we hoped to see,” Dr. Weikert said. “They should all be able to measure normal eyes accurately.

Discovering differences

“When we looked at eyes that had had prior refractive surgery, we found differences,” he said. “As the corneal curvature increased in these post-LASIK/PRK eyes, the differences [among] the devices increased as well.”

The increasing differences in measurement as curvature increases may support the theoretical advantages of point source CLT in the real world. Measuring corneal shape point by point may have greater advantages in more irregular corneal surfaces.

Potential advantages in measuring irregular surfaces were seen again in HOAs. There was good agreement among comparisons of the three devices in normal eyes.

However, in post-LASIK/PRK eyes, the point source CLT device measured higher levels of aberration, except spherical aberration, which was similar across devices.

This makes sense, since spherical aberration and Placido rings are both rotationally symmetric, Dr. Weikert said.

Astigmatic measurement crucial

In measuring astigmatism, Cassini showed increasing differences compared with the Atlas and Galilei devices as astigmatism increased in both normal and post-LASIK/PRK eyes.

Measuring astigmatism has always been important, but it is becoming more important all the time, he said.

“Toric IOL use is steadily increasing and as femtosecond laser use in cataract surgery increases, we will be performing even more astigmatism correction using corneal incisions,” Dr. Weikert said.

“To treat astigmatism accurately, we must first be able to measure it accurately,” he said. “To know where to make our incisions, we have to be able to locate corneal astigmatism accurately.”

Increased precision in measuring and locating astigmatism may be a real benefit of this technology, he said.

Clinical potential

More testing is needed to evaluate the true clinical utility of point source CLT, however.

Though early evidence is positive, just because a new technology produces different results compared with older methods does not automatically mean the newer technique is better or more accurate, Dr. Weikert said.

“We definitely see the potential in this technology,” he said. “We like what we see with point source CLT, but we can’t say at this point this one is better.

“The grid-like point source technology has the potential to improve measurement in corneal curvature and aberrations, but we still need to expand this evaluation, measure more eyes, and more differently shaped eyes,” he said.

It is already known that point source technology can measure manufactured surfaces very accurately compared [with] existing technologies. The next step is to see if it can measure corneas with the same degree of accuracy, Dr. Weikert said.

Mitchell P. Weikert, MD

E: mweikert@bcm.edu

Dr. Weikert receives research support from Optovue.

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Take-home

Repeatability of corneal astigmatism measurement was compared using six different devices.

Dr. Kohnen

By Fred Gebhart; Reviewed by Thomas Kohnen, MD, PhD

Frankfurt, Germany—Given that toric IOLs are driving the need for more precise, more repeatable measurements of corneal astigmatism, the question remains: Which of the competing measurement technologies provide the most effective results?

“What [surgeons] really need is consistent measurement of the astigmatic component of the cornea,” said Thomas Kohnen, MD, PhD, professor and chairman of ophthalmology, Goethe-University, Frankfurt, Germany. “That was why we conducted [a] study of six different devices and four different methods.”

The prospective, randomized study was designed to assess the repeatability of corneal astigmatism measurements using the following technologies:

• Automated keratometry (IOLMaster 500, Carl Zeiss Meditec; Lenstar LS 900, Haag-Streit)

• Manual keratometry (Model G, Carl Zeiss Meditec)

• Placido disc (Keratron Scout, Optikon; Atlas 9000, Carl Zeiss Meditec)

• Scheimpflug imaging (Pentacam HR, Oculus)

Researchers measured 1 eye in each of 45 patients who were aged 18 or more years and who did not have any type of corneal trauma, pathologies, or prior surgery.

The mean age was 53 years; 33 patients were female; and the study included 23 left eyes

Two full standard measurements were made with each of the six devices to test for visual acuity and manifest refraction. The choice of eye to be measured—left or right—and the order in which the six devices were used to measure each eye were both randomized.

Analysis included anterior surface astigmatism and total corneal astigmatism using ray-tracing calculations from the Pentacam measurements of anterior and posterior corneal curvature and pachymetry.

Analysis diameters from 1 to 8 mm were used in 1-mm steps. Measurements were subjected to Bland and Altman analyses of repeatability.

Measure of device performance

The good news was all six instruments delivered very similar results, Dr. Kohnen said.

Manual keratometry had the lowest absolute and relative coefficient of repeatability, 0.619 and 64%, respectively. Scheimpflug imaging delivered the best scores, 0.321 and 39%, respectively.

“Manual keratometry performed the worst, but with very minor differences,” he said. “These differences are very small and we don’t want to make too much of them.

At the same time, clinicians want to get the most precise measurement from a device, Dr. Kohnen noted.

“Repeatability is key—we got the best repeatability from the [Scheimpflug imaging] device,” he said.

The absolute and relative coefficient of repeatability for the other devices—from more repeatable to less repeatable—were:

• Atlas (0.332 and 41%)

• Lenstar (0.424 and 47%)

• Scout (0.448 and 51%)

• IOLMaster (0.512 and 56%)

The study found significant differences between the most repeatable of the automated devices (Pentacam) and the least repeatable (IOLMaster), according to Dr. Kohnen.

The correction for the IOLMaster was 0.51 D compared with 0.32 D for the Pentacam, the relative coefficient of repeatability was 58.06% and 40.16%, and the limits of agreement range was 1.02 D and 0.64 D.

Differences in outcomes to be seen

The study looked only at the repeatability of measurements and did not investigate any possible differences in clinical outcomes using the different devices, Dr. Kohnen said.

Such an outcomes study would require at least 200 eyes, possibly more, with long-term follow-up, he added.

The best correlation was not seen with the IOLMaster, which is what is seen in clinical practice, Dr. Kohnen said.

“We use the IOLMaster in our clinical practice,” he continued. “But experience tells me that when I am using toric IOLs, I like to see a topographer—or, better still, a Scheimpflug device—to get the best measurements possible to correct astigmatism. That is the most important take-home message for me.”

Thomas Kohnen, MD, PhD

E: Kohnen@em.uni-frankfurt.de

Dr. Kohnen has financial relationships with Alcon Laboratories, Oculus, and Carl Zeiss Meditec.

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Take-Home

The Laser Anterior Ciliary Excision procedure uses laser scleral micro-excisions to alter ocular rigidity to rejuvenate aging sclera.

Dr. Waring

By Lynda Charters; Reviewed by AnnMarie Hipsley, DPT, PhD

A new biomedical engineering model may provide more information about the impact of ocular rigidity on loss of accommodation and ultimately may become a model to demonstrate the mechanism of action of how reduced ocular rigidity could facilitate more control over ocular accommodation in humans.

The Laser Anterior Ciliary Excision (LaserACE) procedure (Ace Vision Group) uses a laser to create matrices of micropores in the sclera over the ciliary muscle complex. The group performed a pilot study that showed the impact of this novel procedure on ocular rigidity.

“We have suspected for some time that crosslinking impacts the cornea and the sclera and crystalline lens,” said George Waring IV, MD, assistant professor of ophthalmology, Medical University of South Carolina, and adjunct assistant professor of bioengineering, Clemson University.

“This study induced these changes in a laboratory setting to model aging changes,” he added. “Furthermore, it allows us to undo the aging changes with biomechanical manipulation of the aging eye.”

In a research setting at the National Taiwan University Biomedical Engineering Department, scleral crosslinking was used to alter the ocular rigidity in porcine eyes to a predetermined ocular rigidity coefficient that correlates with a specific age (Pallikaris et al.). This allowed an in vitro assessment of the effects of the LaserACE procedure to enhance ocular resilience, a key factor thought to improve the eye’s ability to accommodate.

Dr. Hipsley

“Lens stiffness has been correlated with loss of accommodation in aging adults,” said AnnMarie Hipsley, DPT, PhD, founder and chief executive of ACE Vision Group, Silver Lake, OH. “However, ocular rigidity also has been correlated with accommodative loss.”

She cited a 2012 Greek study that evaluated the biomechanics of ocular rigidity (Detorakis ET, Pallikaris IG. Ocular rigidity: bio-mechanical role, in vivo measurements and clinical significance. Clin Experiment Ophthalmol. 2012 May 18. doi: 10.1111/j.1442-9071.2012.02809).

Based on the premise of that and other recent studies, the Ace Vision Group researchers hypothesized that decreased ciliary muscle force and increased scleral rigidity resulted in decreased accommodative ability in aging eyes.

The study showed that eyes with induced rigidity mimicking that of an elderly 60-year-old eye had the rigidity of a 30-year-old eye after LaserACE treatment, which was equivalent to controls.

The LaserACE technology is designed to restore dynamic accommodation and does so by increasing scleral resilience, increasing the net forces of the ciliary body, and thereby facilitating accommodation, said Dr. Hipsley, founder of ACE Vision Group.

Laboratory study

She and her colleagues conducted a laboratory study in 50 freshly harvested porcine eyes to develop a method of scleral crosslinking to mimic age-related ocular rigidity, assess the potential effects of the procedure to decrease ocular rigidity, and establish a biomechanical model to test the benefit of intraocular accommodative resultant force efficiency as it relates to decreased ocular rigidity in vitro.

The eyes were separated into four groups:

·      Group A, unablated controls that simulated normal or young eyes.

·      Group B, crosslinked eyes with different degrees of crosslinking to simulate aging eyes.

·      Group C, ablation with LaserACE without crosslinking to simulate young control eyes.

·      Group D, eyes that underwent crosslinking then ablation to simulate aging eyes treated with LaserACE.

In groups C and D, a nine-spot matrix LaserACE pattern was applied to the porcine eyes using a Visiolite 2.94 Er:YAG laser. The laser effects were measured using a pressure transducer, a dosage injector controller, a data computerized reader, and a tissue holding frame. The eyes were fixed in the frame and distilled water was injected into the vitreous chamber at a rate of 8.42 ul/sec.

Scleral crosslinking was performed with 0.8 ml of 2% glutaraldehyde. The eyes were wrapped in cotton gauze and soaked for 5, 10, or 30 minutes. Pressure was plotted against the injected volume curve to estimate the changes in the ocular rigidity from the slope of the linear regression line.

Age, rigidity correlations

The age-versus-rigidity correlations were established from a referenced model for the crosslinked groups, Dr. Hipsley noted.

The collagen crosslinking represented various distinct markers of ocular rigidity over time, she noted. The groups treated with the LaserACE pattern had a significant decrease in ocular rigidity.

“The ocular rigidity was positively correlated with the crosslinking time,” Dr. Hipsley said. “The ocular rigidity in the group that underwent scleral crosslinking for 10 minutes corresponded to the rigidity coefficient of 60-year-old eyes at, and the control unablated group corresponded to the rigidity of the 30-year-old eyes of the referenced model. (Pallikaris IG, et al. Ocular rigidity in living human eyes. Invest Ophthalmol Vis Sci. 2005 Feb;46:409-414.)

“The selected comparison groups—young and old eyes—showed that the rigidity coefficient of the LaserACE-treated old eyes achieved a resultant rigidity that was almost identical to the untreated young eye,” she said.

Improved ocular resilience may be beneficial to decrease the mechanical resistance of the ocular wall to improve the resultant centripetal forces of mechanical accommodation. Collagen crosslinking may be a novel tool to evaluate the effect of ocular rigidity on the globe and it may be a method to determine the mechanism of action of the LaserACE procedure and its impact on accommodative resultant force efficiency, she said.

The investigators concluded that the scleral crosslinking method might be a useful model to correlate age with ocular rigidity.

When performed on porcine eyes in a laboratory setting, the LaserACE procedure reduced ocular rigidity and improved ocular resilience.

This study could be a first indicator of the mechanism of action and an early indicator of the potential value of ocular rejuvenation solutions for restoring accommodation without manipulating the visual axis or using implants.

Further studies will investigate additional modeling, characteristics and further applications.

AnnMarie Hipsley, DPT, PhD

E: ahipsley@acevisiongroup.com

Dr. Hipsley is the founder and chief executive of ACE Vision Group.

George Waring IV, MD

E: georgewaringiv@gmail.com

Dr. Waring is director of Ace Vision Group’s scientific advisory board.

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Take-Home

There are many causes of limbal stem cell deficiency and it is important to know how to recognize them and how to intervene.

Dr. Holland

By Fred Gebhart; Reviewed by Edward Holland, MD

Cincinnati, OH— limbal stem cell deficiency is a growing problem that is often not recognized and not treated in the early stages, said Edward Holland, MD.

When recognized and treated early, the loss of limbal epithelial stem cells can usually be halted or reversed, but if allowed to progress to total limbal deficiency, there are few viable treatment options short of surgery, he said.

“Ophthalmologists typically understand acute causes of limbal stem cell deficiency, like chemical or thermal trauma, and some of the congenital causes, such as congenital aniridia,” said Dr. Holland, director, cornea service, Cincinnati Eye Institute and professor of ophthalmology, Cincinnati University. “But we are also seeing an increased incidence of limbal stem cell deficiency (LSCD) in patients with chronic ocular surface disease and in patients who have had mitomycin for pterygium and glaucoma surgery. The most notable increase in LSCD is coming in patients who have worn long term contact lenses.”

One of the biggest surprises to many clinicians, he said, is the incidence of LSCD associated with common restorative and curative procedures, such as contact lenses and ocular surgery for cataracts and glaucoma.

“There are many more common causes of LSCD than ophthalmologists and optometrists realize,” Dr. Holland said. “If not recognized and treated, LSCD progresses to total limbal deficiency. At that point, we have a challenging surgical management to undertake.”

Complications

LSCD may lead to persistent epithelial defects, corneal ulceration and scarring, conjunctivalization of the cornea, severe vision loss, chronic pain, and keratoplasty failure.

This cascade of events is often initiated by acute insult to the eye, such as alkali or acid injury, multiple ocular surface surgeries, thermal injury, or radiation.

Inflammatory eye diseases—such as Sjögren’s syndrome, vernal keratoconjunctivitis, mucous membrane pemphigoid, and others—are widely recognized to affect limbal stem cells.

Any number of bacterial, viral and parasitic pathogens can affect limbal function and regeneration.

But it is the slow and chronic insults, such as contact lens use, dry eye, or toxicity from topical medications that can be difficult, even counterintuitive, to diagnose, Dr. Holland said.

“The noncorneal specialist needs to recognize that there are numerous causes of limbal deficiency besides some of the devastating injuries and diseases that we all know about,” he said. “If you recognize a patient with progressive severe ocular surface disease and you eliminate that surface inflammation, you can probably stop the development of limbal deficiency.”

The single most important intervention in the contact lens-wearing patient is closer attention to the limbus and peripheral epithelium, Dr. Holland said. Any sign of chronic peripheral epithelial abnormality in a contact lens wearer is reason to suspect limbal insufficiency.

“I don’t want to imply that contact lenses are bad,” he said. “LSCD is a rare complication. There are over 30 million contact lens wearers in the United States and the vast majority are doing great. But limbal complications should be part of your differential every time you are working up an abnormal epithelium in a contact lens wearer.”

Combating the problem

Convincing patients to stop wearing contacts can be tough, Dr. Holland said, as most contact wearers like the visual improvement that contacts bring. But in patients with early limbal deficiency, wearing contacts relieves ocular discomfort even as it contributes to inflammation and limbal damage.

“You have to explain the potentially devastating problem they could have with contact lenses and limbal deficiency,” he said. “If the contacts are stopped, the patient will do fine. But if the patient continues to wear contacts over the next few years, the rest of the limbus can become affected and progress to permanent limbal deficiency.”

The growing use of mitomycin in ocular surgery is another contributing factor to the increasing prevalence of limbal stem cell deficiency.

Patients who undergo a single procedure that involves mitomycin may be at relatively low risk if the surgeon takes appropriate steps to protect the limbus.

However, patients who undergo multiple surgeries with mitomycin or use the agent to manage ocular surface squamous neoplasia are at much higher risk for limbal involvement.

“Early recognition of limbal involvement means you have an opportunity to arrest progression,” Dr. Holland said. “Once you get to the severe stage, treatment is much more difficult. We typically start with supportive care to reduce inflammation, most often topical steroids or cyclosporine.

“Sometime agents such as autologous serum are helpful,” he continued. “In some patients, a temporary soft bandage contact lens is helpful or maybe a scleral contact lens. But once you have progressed to total limbal deficiency with total corneal involvement, you have to consider surgical management.”

Edward Holland, MD           

E: eholland@holprovision.com

Dr. Holland reported no financial conflicts of interest.

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Take-Home

A corneal presbyopia inlay seems to have overcome two obstacles to patient satisfaction by providing good near vision without glare and halos.

Dr. Steinert

By Lynda Charters; Reviewed by Roger F. Steinert, MD

Irvine, CA—Corneal inlays for presbyopia are a treatment modality worthy of consideration, according to Roger Steinert, MD.

The demand for surgical correction of presbyopia has been increasing, and LASIK and multifocal IOLs have provided limited success for patients with presbyopia, explained Dr. Steinert, the Irving H. Leopold Professor and Chair, professor of biomedical dngineering, and director, Gavin Herbert Eye Institute, University of California, Irvine.

One such investigational corneal inlay—which has the same refractive index as the cornea—works by reshaping Bowman’s layer and the anterior cornea to create smooth transition zones for near, intermediate, and distance vision. The hydrogel inlay (Raindrop Near Vision Inlay, ReVision Optics) is a cross-linked methylmethacrylate/vinyl pyrrolidone) copolymer with a high-water content (78%) when fully hydrated.

The device—which currently is implanted monocularly in the United States—is positioned in the cornea at about a depth of 200 µm. The inlay provides plus power with a profocal shape in the corneal center, he explained.

Study of the inlay

Dr. Steinert and his colleagues conducted a multicenter, prospective, non-randomized case series that included 45 patients who underwent implantation of the corneal inlay in the non-dominant eye.

Patients were evaluated preoperatively and at 1, 3, 6, 9, and 12 months postoperatively. Among the main factors measured were uncorrected distance visual acuity (UDVA), uncorrected near visual acuity (UNVA), patients’ self-reported symptoms, and patients’ satisfaction with near and distance visual acuity and overall.

Investigators performed univariate, multivariate, and longitudinal analyses of the data amassed from study of the corneal implant to determine which factors were associated with patient satisfaction with corneal inlay refractive surgery to correct presbyopia.

Univariate and multivariate analyses showed that visual acuity and visual symptoms are the main drivers of patient satisfaction, according to Dr. Steinert.

For example, glare and halos are associated with multifocal IOL implantation, and visual dysphotopsias cause the greatest dissatisfaction. The presence of glare and halos seem to have a greater impact on patients’ perceptions of visual outcomes than the visual acuity at any distance.

Patients who expressed satisfaction with the corneal inlay were found to have a mean UNVA at all postoperative evaluations that was almost 20/20. Patients who expressed dissatisfaction had a postoperative UNVA of about 20/25 to about 20/30.

The data showed a smaller difference in the UDVA (about 20/32) between patients who were satisfied and those who were not.

“Better near acuity in the eye with the inlay was associated with higher near and overall patient satisfaction,” Dr. Steinert said. “Better distance acuity in the eye with the inlay was not associated with greater distance vision or overall patient satisfaction.”

Patient satisfaction

Patients graded their symptoms—which included glare, halos, visual fluctuations, and diplopia—on a scale of 0 to 4, with 0 indicating no symptoms and 4 indicating severe symptoms. The maximal possible score was 16.

When the cumulative intensity score was evaluated regarding distance vision, most patients who were satisfied with near vision had a cumulative intensity symptom score that was near the preoperative score. The cumulative intensity score of the unsatisfied patients peaked at 1 month postoperatively at about 5 and by month 12 was 2.

Stronger visual symptoms were associated with lower odds of near, distance, and overall patient satisfaction, Dr. Steinert noted.

“The big drivers of patient satisfaction are uncorrected near vision and the lack of symptoms, especially halos and glare,” he said. “Interestingly, the mild reduction in distance vision was the least important issue related to patient satisfaction with the procedure.

“This runs counter to concerns that people have had regarding corneal inlays and shows that if patients achieve good reading vision without glare and halos—which [this corneal inlay] seems to accomplish in well over 90% of patients—they are very happy with the procedure,” Dr. Steinert concluded.

Roger F. Steinert, MD

E: steinert@uci.edu

Dr. Steinert is a consultant and medical monitor for ReVision Optics.

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TAKE HOME:

There is no current justification for considering routine corneal crosslinking for primary prevention of postLASIK ectasia—considering the many unknowns about the efficacy and safety of combining procedures—relates one ophthalmologist.

By Cheryl Guttman Krader; Reviewed by Perry S. Binder, MS, MD

Irvine, CA—An assessment of current knowledge on the potential risks and benefits of performing corneal crosslinking (CXL) at the time of primary LASIK indicates there is no current justification for routine application of the combined procedure, according to Perry S. Binder, MS, MD.

“The idea of performing CXL on every LASIK case is based on the hope of preventing ectasia,” said Dr. Binder, clinical professor of ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine. “However, peer-reviewed studies of CXL at the time of primary LASIK are very limited, and there are alternatives to LASIK that can be used successfully in cases deemed at risk for ectasia.”

“In addition, I don’t believe we can defend the increased cost of CXL to patients in lieu of what we know about the current risk/incidence of ectasia,” Dr. Binder added. “Therefore, my recommendation is that CXL should not be performed at the time of LASIK until research is published or presented that tips the risk:benefit ratio in favor of the combined procedure.”

Outlining his arguments against performing primary CXL to prevent postLASIK ectasia, Dr. Binder highlighted the current low risk for that complication and explained the underlying factors.

“Improved surgeon awareness has resulted in better screening efforts,” he said.

In addition, we have better methods for screening, more reliable technology for achieving predictable flap thickness, and more ways to measure postoperative flap and residual stromal bed thickness, according to Dr. Binder.

Performing CXL routinely can add risks, particularly corneal ulcers, corneal infiltrates, risks associated with epithelial removal, and corneal endothelial damage, he noted.

In addition, there are a variety of unknowns accompanying simultaneous CXL-LASIK.

Unanswered questions

One of the most basic questions that must be answered is whether CXL at the time of primary LASIK is effective in preventing ectasia.

With all of the clinical variables that would need to be accounted for in stratifying treatment groups, a study would need to enroll a minimum of 300 to 400 eyes to detect a benefit of CXL for reducing the risk of ectasia after primary LASIK, Dr. Binder noted.

Considering the multiple differences between CXL performed with LASIK versus using the standard Dresden protocol that is used to treat keratoconus provides reason to question the safety and efficacy of combining CXL with LASIK.

“We don’t know how riboflavin or UVA penetration into the cornea is affected by a healthy LASIK epithelium or how riboflavin diffuses from the LASIK interface in either direction,” Dr. Binder said. “In addition, it is not known how CXL might affect primary and enhancement excimer laser ablation rates or the stability of refraction postLASIK.

“How would one determine the contribution of CXL versus routine wound healing to the outcomes, and knowing that the effects of CXL can continue for many years, when would it be appropriate to perform an enhancement procedure?” he asked.

Other questions remaining to be answered include whether the CXL procedure might affect LASIK flap adhesion, have long-term adverse effects on the crystalline lens, or affect calculations for subsequent pseudophakic IOL implantation.

In addition to the need for studies addressing these many issues to understand the risks and benefits of the combination procedure, Dr. Binder called for research toward improving the predictability, efficacy, and safety of CXL.

A variety of CXL protocols are being used without any laboratory data or clinical studies to support their efficacy or safety, he explained.

In addition, more information is needed to establish the best method for riboflavin delivery, and investigations of other photosensitizers would also be worthwhile.

Considering the potential for UVA toxicity to the conjunctiva, corneal stem cells, and corneal endothelium, there is also a need to develop systems for delivering focal irradiation to the affected cornea and for more accurately determining the depth of treatment and its effects on corneal biomechanics, Dr. Binder noted.

Perry S. Binder, MS, MD

E: garrett23@aol.com

Dr. Binder has no relevant financial interests to disclose.

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Take-home

An investigational small aperture corneal inlay (Karma, AcuFocus) may improve near and intermediation vision in patients with presbyopia without compromising stereopsis, like other current treatment options, such as LASIK monovision or contact lens monovision.

By Nancy Groves; Reviewed by Jay Stuart Pepose, MD, PhD

St. Louis—Findings from several studies of the Kamra small aperture corneal inlay (AcuFocus)—an investigational device in the United States—suggest that it is an effective alternative to other treatments for presbyopia, according to Jay S. Pepose, MD, PhD.

Recent studies, Dr. Pepose said, found that binocular and monocular mesopic and photopic contrast scores showed a reduction—although results remained well within normal limits—and that stereopsis scores are unaffected by the presence of the inlay. In addition, patients reported that they could easily perform near, intermediate, and distance tasks without glasses in different lighting conditions and had a low incidence of visual symptoms 24 months after implantation.

Dr. Pepose, is the founder and medical director of the Pepose Vision Institute, St. Louis. He also serves as professor of clinical ophthalmology at Washington University School of Medince and Barnes-Jewish Hospital, St. Louis.

The inlay is designed to improve functional near and intermediate vision, as well as reducing dependence on reading glasses while maintaining distance vision. It is 3.8 mm in diameter and works by blocking unfocused light and expanding depth of field through its fixed 1.6 -mm central aperture.

Made of polyvinylidene fluoride—a biocompatible material commonly used in intraocular lens haptics—the inlay is 5 mµ thick. It received CE Mark approval for use in Europe in 2005, and a pre-market approval application was submitted to the FDA in December 2012.

Examining the study

Dr. Pepose said the objective and subjective results were from a prospective, non-randomized clinical trial that was conducted at 24 sites in the United States, Europe, and the Asia-Pacific region. The study enrolled and implanted 507 subjects who were naturally occurring presbyopic emmetropes aged 45 to 60 years old with a spherical equivalent between +0.50 and -0.75D. Uncorrected near visual acuity was worse than 20/40 and better than 20/100 preoperatively.

Binocular photopic contrast sensitivity remained within normal limits at 24 months post-operatively, although there was a statistically significant decrease from preoperative levels (p < 0.001) at certain spatial frequencies.

Similarly, monocular and binocular mesopic contrast sensitivity were also within the normal range at 24 months.

Stereopsis was evaluated pre-operatively and at 6 months post-operatively in a sub study of 60 patients treated by Phillip C. Hoopes, MD, in Salt Lake City, Utah.

The difference in mean pre-operative and post-operative distance stereoacuity was not statistically significant (36.1 ± 31.3 vs. 35.5 ± 34.7 arc sec).

Dr. Pepose compared treatment with the Kamra inlay to alternative procedures for presbyopic vision correction.

Further investigations

Monovision with LASIK resulted in a 2.75-fold increase in arc seconds (p < 0.05) between pre-operative and post-operative examinations (165.55 ± 138.25 vs. 451.74 ± 286.97) in a study of 25 patients. These findings were reported by Alarcon et al. (J Cataract Refract Surg 2011;37:1629-1635).

In a study of increasing amounts of contact lens monovision, statistically significant changes from baseline (32 ± 33 arc sec) occurred at all levels (+0.75 D: 44 ± 38, 1.38-fold increase; +1.5 D, 77 ± 76, 2.41-fold increase; +2.5 D, 182 ± 142, 5.7-fold increase. p < 0.01).

This prospective study was performed by Durrie (Trans Am Ophthalmol Soc 2006:104:366-401).

“The Kamra inlay is in marked contrast to the findings of monovision’s loss of stereopsis after pseudophakic LASIK and contact lens monovision,” Dr. Pepose said.

He also reported the results for near vision tasks, as data was obtained from a questionnaire in which patients were asked how easy it was to perform a series of near vision tasks with both eyes without their glasses.

The scale ranged from 1, “not easy at all,” to 7, “very easy.”  At 24 months, statistically significant improvement was seen in mean scores for performing near tasks in both dim and bright light conditions (p< 0.001). These included intermediate vision tasks such as viewing a computer and near tasks such as reading a book or newspaper.

Mean scores for viewing a computer improved significantly from 2.74 ± 1.42 pre-operatively to 5.09 ± 1.72 at 24 months, and mean scores for reading a book improved significantly from 1.73 ± 1.04 to 4.66 ±` 1.76 over the same time period.

“This is impressive, especially given that the mean MRSE (mean refraction spherical equivalent) in the inlay-implanted eye was +0.18 D ± 0.79, and we have learned commercially that having a small amount of myopia further enhances near and intermediate vision,” Dr. Pepose said. “I think we shouldn’t minimize the need of good intermediate vision for our patients who now are using many handheld devices.”

The ease of distance task performance remained stable at 24 months post-operatively, and there was little or no change in patients’ ranking of the ease of performing the tasks (p = 0.016).

Patients reported a very low incidence of visual symptoms post-operatively, such as glare, halo, and night vision problems. All mean symptom scores were reported between 0.2 and 1.6 on a scale of 1 to 7 at 24 months. There was no indication of the photopsia sometimes associated with multifocal lens implants, Dr. Pepose said.

Jay Stuart Pepose, MD, PhD

E: jpepose@peposevision.com

Dr. Pepose is a consultant for AcuFocus.

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Take-Home

Results from preclinical studies and early clinical experience show that iontophoresis is an efficient and effective method for delivering riboflavin into the cornea, while CXL performed after the procedure is associated with good results in early follow-up.

By Cheryl Guttman Krader; Reviewed by Paolo Vinciguerra, MD 

Milan, Italy—Early experience with corneal crosslinking (CXL) using iontophoresis-assisted riboflavin imbibition shows it is a promising technique for treating eyes with progressive keratoconus, said Paolo Vinciguerra, MD.

“Reliable delivery of riboflavin into the cornea is critical to the safety and success of CXL,” said Dr. Vinciguerra, professor of ophthalmology, Humanitas University of Milan, Italy. “We have found that the iontophoresis-assisted method results in immediate strong corneal fluorescence after UVA irradiation comparable to that achieved with the standard epi-off technique, and in vivo OCT imaging shows a visible demarcation line representing riboflavin penetration depth at 200 to 250 mµ.

“Patient follow-up demonstrates the technique results in keratometric flattening by 3 months post-CXL, which is sooner than what is seen using other CXL techniques,” he continued. “In addition, we have documented improvements in corneal biomechanical properties . . . these are only preliminary results from a limited number of eyes with short follow-up, however, they are very promising.”

About the procedure

Iontophoresis is a non-invasive approach that uses electrical current to enhance tissue penetration by an ionized compound. Riboflavin is well suited for use in iontophoresis, Dr. Vinciguerra explained, because it is negatively charged at physiological pH, has high aqueous solubility, and has a relatively low molecular weight that enables its transport into the cornea.

The procedure involves placement of the 8-mm ionotophoresis device onto the cornea using a 9-mm annular suction ring. The suction ring is fixed onto the cornea with low suction and is connected to a battery-powered DC generator emitting a current of 1 mA (I-ON XL, Sooft Italia). A second grounding electrode is placed on the patient’s forehead, and the suction ring is filled with 0.5 mL of a hypotonic 0.1% riboflavin solution (Ricrolin +, Sooft Italia).

After just 5 minutes of iontophoresis, the concentration of riboflavin in the cornea is close to 2/3 that achieved following the standard 30-minute protocol of topical administration to a debrided cornea. Ultraviolet A (UVA) irradiation is then performed using 10 mW/cm² for 9 minutes.

Dr. Vinciguerra—along with colleagues in collaboration with Eberhard Spoerl, PhD, University of Dresden, Germany—obtained proof of principle for iontophoresis-assisted riboflavin delivery in preclinical studies using human cadaver eyes.

An initial investigation compared biomechanical changes (increase in Young’s modulus) occurring with different methods of riboflavin impregnation and UVA irradiation protocols.

The results showed the best outcome was achieved in the iontophoresis group, which was only 1 of 5 experimental groups, and they were confirmed in a second experiment.

Based on this experience, a clinical trial was initiated enrolling patients aged 18 to 45 years with progressive keratoconus and no previous ocular surgery. In addition to showing keratometric flattening, data collected in the study indicated that patients experience less pain with the ionotophoresis riboflavin delivery versus with the standard technique, although some patients did develop an epithelial defect.

Follow-up showed good recovery of BCVA with improvements in higher order aberrations. There is no evidence of endothelial toxicity.

Paolo Vinciguerra, MD

E: paolo.vinciguerra@humanitas.it

Dr. Vinciguerra has no relevant financial interests to disclose.

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Take-home:

Corneal confocal microscopy may be a useful tool for physicians performing corneal collagen crosslinking.

Dr. Touboul

By Nancy Groves; Reviewed by David Touboul, MD

Bordeaux, France—Conventional corneal collagen crosslinking (C-CXL) has become the gold standard to halt keratoconus. Several new CXL procedures, however, have been developed.

Corneal confocal microscopy (CCM) appears to be a useful tool for noninvasive CXL titration and follow-up in patients with keratoconus treated with these protocols, said David Touboul, MD, French National Reference Center for Keratoconus, Bordeaux, France.

Based on a study Dr. Touboul and colleagues performed at the center, he concluded that keratocyte loss is probably a relevant parameter to make comparisons between different CXL protocols.

He also suggested that incorporation of data from biomechanics and topography could lead to better optimization of the compromise between safety and efficacy in CXL.

The new trends in CXL include improving safety with transepithelial protocols (T-CXL) and decreasing operating time with accelerated protocols (A-CXL), Dr. Touboul said.

T-CXL is similar to C-CXL, but in the newer protocol the epithelium is not removed and 0.1 tromethamine is used to enhance riboflavin uptake in the cornea, while dextran is not used.

The main differences between the accelerated protocol and the others are the times and fluency. In A-CXL, riboflavin is administered for 10 minutes instead of 30, and UVA time is only 3 minutes versus 30, reducing the overall time of the procedure to less than one-quarter of that required for the conventional protocol, 13 minutes versus 60. The fluency in A-CXL is 30 mW/cm² compared to 3 mW/cm² in C-CXL and T-CXL.

The study used CCM to compare conventional CXL with the two newer protocols.

Dr. Touboul and colleagues evaluated 24 eyes of 24 patients with progressive keratoconus and corneal thickness > 400 µm. They were divided into three groups of eight each: Group 1, C-CXL; Group 2, A-CXL; group 3, T-CXL.

In vivo CCM was performed on each patient preoperatively and at 1, 3, and 6 months postoperatively.

“The main confocal findings after C-CXL were nerve plexus loss, keratocyte loss with a decrease of keratocyte density and decrease of nuclear reflectivity, and also a stromal honeycomb-like pattern,” Dr. Touboul said. “All of these signs decreased with stromal depth and with time.”

At 1 month, the control eyes (no CXL) and the T-CXL eyes were similar, while there was a huge loss of keratocytes in the stroma in the C-CXL and A-CXL eyes. In eyes treated with A-CXL, the loss of keratocytes in the anterior stroma was even more pronounced than in the eyes treated with conventional CXL.

At month 3, there were signs of regression of the keratocyte loss, and at month 6 the trend was confirmed with minimal loss of keratocytes in the entire population.

There was no significant endothelial cell loss in any of the CXL protocols at any point during the follow-up (p> 0.05) The preoperative and 6-month counts were, respectively: C-CXL, 2995 ± 367 and 3013 ± 366; T-CXL, 3445 ± 250 and 3594 ± 260; A-CXL, 3591 ± 483 and 3577 ± 516.

Finally, the investigators found that the epi-off CXL protocols exhibited long-term anterior nerve plexus loss.

“For the same amount of photons, based on confocal findings there were very different reactions to the crosslinking in the stroma,” Dr. Touboul said.

He hypothesized that T-CXL did not exhibit changes with CCM. One theory to explain this is that the epithelium was soaked with riboflavin, preventing stomal crosslinking by acting as a UVA light shield, but this is probably wrong because riboflavin cannot enter the epithelial cells and natural UVA epithelial absorption is very low.

The more plausible option to explain the lack of visible changes on CCM is that there was insufficient riboflavin in the stroma at the end of the soaking time. With no riboflavin, there is no effect, Dr. Touboul added.

Another question is why A-CXL was located more anteriorly. Among several possibilities, the most likely is that the shorter soaking and UVA time caused the difference. The less likely choices are that higher fluency was used (30 versus 3 mW/cm²), which is unlikely because at the end, the same dose of photons was used in this study as in others, or that the riboflavin was somehow different.

The study also raised questions about the relationship between keratocyte loss, corneal stiffening, and CXL efficacy, Dr. Touboul said. Two key issues are whether collagen bonding remains possible and effective without killing keratocytes and whether the keratocyte, epithelium, and nerve plexus renewal play a role in keratoconus stabilization.

“Today, nobody knows,” he concluded.

The study was published in the Journal of Refractive Surgery (2012;28:769-776).

David Touboul, MD

E: david.touboul@chu-bordeaux.fr

Dr. Touboul did not report any disclosures.

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Take-Home

Children and adolescents with keratoconus may have rapid progression between the ages of 8 and 19 years and immediate treatment with corneal crosslinking may stop that progression.

By Lynda Charters; Reviewed by Farhad Hafezi, MD, PhD

Geneva, Switzerland—Ophthalmologists have struggled with decisions about whether to treat subpopulations of patients with keratoconus differently from the currently accepted approach.

The answer may be “yes,” based on a study that found that the vast majority of children and adolescents aged 8 to 19 years have rapid keratoconic progression after the initial diagnosis is established. To avoid this, immediate treatment may be required.

When corneal crosslinking (CXL) technology was first introduced, clinicians approached its use conservatively.

“When CXL initially began to be used, we always determined that the patient was progressing before CXL was applied to be sure that an emerging technology was used carefully to avoid unnecessary complications,” said Farhad Hafezi, MD, PhD, who was part of the Swiss team that developed the first CXL device.

“However, it is now time to re-visit this strategy considering that CXL is used clinically in more than 100 countries worldwide,” said Dr. Hafezi, professor and chairman, Department of Ophthalmology, Geneva University Hospital, Geneva, Switzerland, and clinical professor of ophthalmology, Doheny Eye Institute, University of Southern California, Los Angeles.

Progression was defined as an increase of more than 1 D of Kmax of the anterior corneal curvature within a 12-month period.

Keratoconus can progress extremely rapidly in young patients and reported a 4-diopter progression in a 15-year-old boy over a period of 12 weeks, he noted.

“If we wait for progression over a very short interval, it might still be too long to wait,” he emphasized. He noted that he re-examines his young patients after only 4 weeks to avoid missing any immediate progression.

To address the question about adjusting treatment strategies for these children, Dr. Hafezi and his colleagues conducted a retrospective interventional cohort study of 42 patients, 36 boys and 16 girls (average age, 16.6 years; range, 9 to 19 years). Of 59 eyes examined, 52 eyes showed keratoconus progression and were included.

Informed consent from parents was received. Forty-six eyes underwent treatment after the patients provided informed consent. The patients had been followed for up to 3 years (mean, 26.3 months; range, 3 to 36 months).

“Interestingly, we found that when we looked at the arrested progression and the flattening effect of treatment, the children and adolescents behaved similarly to what we expect to see in adults,” he said. “In some cases, the children and adolescents reacted faster and we observed arrested progression in as soon as 3 months after treatment compared to at least 6 months in adults.”

Two different findings

Two other findings in this study differed from those in adults, Dr. Hafezi noted.

During the first 2 years of follow-up, Dr. Hafezi and colleagues found that children and adolescents behaved like adults, with more than 1-D flattening of the Kmax readings. However, during the third year of follow-up, there was no additional flattening and the eyes stabilized.

When these results were compared with two other studies on the same topic, one study by Paolo Vinciguerra, MD, et al. (Am J Ophthalmol. 2012;154:520-526) showed the same results for the first 2 years of follow-up (no data were provided on the third year of follow-up) in a larger number of patients. However, a second study by Aldo Caporossi, MD, et al. (Cornea. 2012;35:233-235) found that there was significant flattening during the first 2 years and additional flattening during the third year.

“The results of these studies indicated that we must pay particular attention to children with keratoconus after year 2,” Dr. Hafezi said. “It seems sensible that during a period in their lives when they are susceptible to aggressive progression, cross-linking might not be the cure forever, but might be effective for a time, that is, perhaps limited to 2, 3, or 4 years. This requires closer study.”

The second result that he found interesting involved the number of eyes of patients who initially presented with keratoconus between the ages of 8 and 19 years and showed keratoconic progression.

“Of the 59 eye that were diagnosed with keratoconus at the initial visit, 52 (88%) showed progression,” he said. “About nine of 10 children will progress between ages 8 and 19 once keratoconus has been diagnosed.”

CXL seems to be efficient in pediatric and adolescent patients, Dr. Hafezi said.

However, the long-lasting effect of the flattening is controversial and particular attention must be paid to year 3 after treatment. If almost 90% of children and adolescents have progression of keratoconus, treatment should be addressed immediately when the diagnosis is made.

“Once the diagnosis is made, this age group should be treated without waiting for progression,” said Dr. Hafezi, noting this attitude was adopted as a general recommendation at the 9th International CXL Congress in Dublin, Ireland, in December 2013.

Farhad Hafezi, MD, PhD

E: farhad@hafezi.ch

Dr. Hafezi has no financial interest in this subject matter.

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Take-home

In vivo confocal microscopy has enormous potential to be used in a large number of physiological and pathological ocular conditions.

Anterior Segment Techniques By Pedram Hamrah, MD, and Ahmad Kheirkhah, MD

Editor’s Note: In vivo confocal microscopy is no longer only a research tool. It has important potentially sight-saving clinical applications. Confocal microscopy must be done if Acanthamoeba keratitis or fungal keratitis is being considered in the differential diagnosis. Culture results take too long. Early diagnosis is the key to a favorable result.

—Ernest W. Kornmehl, MD

Ophthalmologists face the challenge of differentiating among multiple clinical entities, with clinical suspicion initially often guiding treatment. Patient history and slit lamp examination are often the only tools available for diagnosis and monitoring of treatment.

A number of new imaging technologies have emerged in research and clinical ophthalmology.

Among these, in vivo confocal microscopy (IVCM) is a novel, noninvasive, high-resolution tool that allows imaging of the living ocular structures at the cellular level. Provision of images comparable to histochemical methods by IVCM, enables clinicians to study epithelial cells, keratocytes, endothelial cells, nerves, and immune cells in different ocular and systemic diseases, many of which are not visible by slit lamp examination (Figure 1).

Recently, the indications for IVCM have been significantly expanded beyond an adjunct tool in diagnosis of Acanthamoeba and fungal keratitis, and there have been numerous publications showing the utility of IVCM in various conditions, some of which have been summarized below.

Infectious keratitis

Although cultures remain the gold standard for the diagnosis of causative microorganisms in infectious keratitis, they suffer from high false-negative rates and a significant delay in obtaining the results, particularly in cases of slow-growing organisms, such as fungi and Acanthamoeba. Given the importance of timing in diagnosis and initiation of anti-microbial therapy, there is an exciting emerging role for IVCM evolving not only for the diagnosis of microbial keratitis, but also potentially in the management of this disease.

The initial presentation of Acanthamoeba keratitis (AK) is typically nonspecific, often leading to misdiagnosis of patients and delay in appropriate therapy, in part due to poor yield and delay of positive cultures.

However, both cyst and trophozoite forms of this parasite can be identified by IVCM, allowing for possible early diagnosis early in the course of disease. Cysts are 15 to 28 µm with a double-walled spherical structure. Trophozoites are usually 25 to 40 µm in diameter, are hyperreflective, and surrounded by hyporeflective edema (Figure 2).

These structures may be difficult to differentiate from leukocytes, epithelial cells, as well as debris, and expert readers should be consulted for image analysis. According to several studies, IVCM has had a sensitivity of 91% and a specificity of 100% for diagnosis of AK.

In addition, during the prolonged course of treatment, IVCM could be used to demonstrate the presence or absence of cysts and trophozoites and thereby help judge the efficacy of the treatment.

The rate of fungal keratitis has recently increased in the United States. The initial presentation of fungal keratitis is indolent and non-specific. Cultures may be delayed for weeks and have a low sensitivity. IVCM can directly demonstrate the presence of fungal elements and their depth and distribution within the cornea. In filamentous fungal keratitis, such as with Aspergillus and Fusarium species, hyphae can be visualized by IVCM as branching hyper-reflective elements (Figure 2).

Fungi, however, must be differentiated subbasal corneal epithelial nerves.

In addition, yeasts such as Candida Albicans have round, budding bodies that may develop pseudohyphae. IVCM has had a sensitivity of 94% and a specificity of 78% in patients with fungal keratitis, according to several studies.

As with AK, IVCM can be applied for monitoring and guidance of treatment to show the resolution of fungal elements or conversely increased depth of their invasion, potentially mandating therapeutic modification or need for surgical intervention in unresponsive cases.

In all forms of infectious keratitis, IVCM has shown a significant increase in corneal immune dendritic cells and a significant decrease in corneal nerves not only in the involved eye but also in the contralateral apparently normal eyes—suggesting that measurement of corneal sensation may not be helpful to determine the etiology of diseases and that subjective comparison between eyes may yield inaccurate results.

Dry eye disease

Due to symptom-sign disparity in dry eye disease, there are various efforts to employ new diagnostic tools for this very common condition. Among these, IVCM is actively being studied for this purpose. By showing the inflammatory and immunologic cellular changes in the cornea and conjunctiva (Figure 3), IVCM may be used as a tool to determine the level of inflammation.

Though inflammation is not specific to dry eye disease, IVCM would potentially allow stratification for therapeutic strategies and monitoring of therapeutic response to anti-inflammatory therapy in the clinic and for clinical trials for dry eye disease.

Neurotrophic keratopathy

Neurotrophic keratopathy (NK) is a corneal disease caused by reduced corneal nerves and thus decreased sensation. It is characterized by impaired function of the corneal epithelial cells and delayed wound healing.

Although the function of corneal nerves can be evaluated using esthesiometers, their density can be quantitatively assessed by IVCM. As corneal sensation is only reduced when the corneal nerve density decreases to less than 50% of the normal range, IVCM is a more accurate tool to detect the nerve loss early in the disease course and has been utilized as such particularly in monitoring diabetic patients.

Moreover, it can be used to evaluate the course of nerve regeneration postsurgically or with therapeutic intervention, such as with autologous serum tears.

Corneal dystrophies

IVCM is helpful in evaluating the morphological characteristics of corneal dystrophies at the histological level and may be helpful in diagnosis, determination of progression, and understanding the pathophysiology of disease. The use of IVCM may be valuable in the differential diagnosis of corneal dystrophies, especially when diagnosis is otherwise uncertain, as observations obtained using IVCM may be unique to each dystrophy.

This modality is a useful technique to differentiate corneal dystrophies in vivo, bypassing the dependence on genetic studies and histopathology.

Corneal surgery

IVCM has been extensively used to evaluate the effects of various surgeries on the corneal structures. Among these, the effects of corneal laser refractive procedures and corneal transplantation on the subbasal nerve plexus have been studied.

Subbasal corneal nerves are clearly visible in IVCM and they can be easily quantified and morphologically described. Following photorefractive keratectomy, subbasal corneal nerves are undetectable by IVCM in the treatment area, but slowly returning to near normal density within 2 years.

In contrast, after LASIK, low subbasal nerve density has been observed at 2 to 3 years and even at 5 years following surgery.

More recently, IVCM has been used to monitor recovery after collagen crosslinking.

Other conditions

Additional clinical indications for IVCM are its potential utility for detection of ocular surface squamous neoplasia (OSSN), with the results comparable to the impression cytology. Moreover, in patients with corneal neuropathy, IVCM may aid in the determination of abnormal underlying nerve alterations (Figure 4).

These patients, who may have significant corneal neuralgia, pain, or photoallodynia, may not demonstrate abnormal findings on slit lamp examination, which may lead to the diagnosis of non-somatic pain.

However, IVCM demonstrates nerve alterations, such as significant reduction of nerve density and abnormal morphology of nerves.

IVCM may also provide additional information at the limbus in patients with limbal stem cell deficiency, and may serve as an adjunct noninvasive diagnostic tool in the future.

In conclusion, IVCM is an emerging clinical tool for the study of ocular structures at the cellular level. It has enormous potential to be used in a large number of physiological and pathological ocular conditions and its utility is currently moving from research into the clinic.

Ernest W. Kornmehl, MD, editor of the “Anterior Segment Techniques” column and associate medical editor on Ophthalmology Times’ Editorial Advisory board, reviewed this article. He is medical director, Kornmehl Laser Eye Associates, Boston; clinical instructor at Harvard Medical School, and associate clinical professor in ophthalmology, Tufts School of Medicine.

Pedram Hamrah, MD, is affiliated with the Ocular Surface Imaging Center, Cornea and Refractive Surgery Service, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston.

Ahmad Kheirkhah, MD, is affiliated with the Ocular Surface Imaging Center, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston.

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Take Home

Pre-Descemet’s endothelial keratoplasty is a new corneal transplantation technique using a graft consisting of the pre-Descemet’s layer (Dua’s layer), Descemet’s membrane, and endothelium.

By Cheryl Guttman Krader; Reviewed by Amar Agarwal, MD and Priya Narang, MS

Chennai, India—Pre-Descemet’s endothelial keratoplasty (PDEK) is a new corneal transplantation technique that is expected to offer the visual recovery benefits of Descemet’s membrane endothelial keratoplasty, but with advantages of easier tissue handling and expanded donor availability, according to Amar Agarwal, MD, and Harminder Dua, MD, who developed it.

The procedure involves transplantation of a graft consisting of endothelium, Descemet’s membrane, and the pre-Descemet’s layer (PDL)—also named Dua’s layer after Harminder Dua, MD, who discovered the sixth layer of the cornea between the stroma and Descemet’s membrane.

Since Dua’s layer is more fibrous than Descemet’s membrane, it adds rigidity to the graft, which limits scrolling and thus facilitates intraoperative handling and manipulation. In addition, a PDEK graft may be harvested from donors of any age, unlike DMEK grafts for which only eyes from donors aged 50 and above are considered suitable based on endothelial cell density.

Background on procedure

Dr. Agarwal, chairman and managing director, Dr. Agarwal’s Group of Eye Hospitals, performed the first PDEK case in September at his Hospital in Chennai, India. The patient was a 64-year-old man with pseudophakic bullous keratopathy. On the first day after surgery, the patient had a clear graft, and he achieved rapid visual recovery with BCVA of 20/30 after 3 weeks.

By mid-February, Dr. Agarwal had performed 45 PDEK procedures with similarly good early results.

“Now, data from ongoing follow-up is needed to determine rates of endothelial cell loss, graft detachment, graft failure, visual acuity, and visual quality over the long-term,” said Dr. Agarwal.

About PDEK

Procurement of the PDEK graft is performed with the donor corneal scleral button positioned endothelial side up. Using a 30-gauge needle introduced from the limbus into the mid-peripheral stroma (Figure 1A), air is injected between the PDL and posterior stroma in order to create a type 1 big bubble (Figure 1B).

Trephination is performed (Figure 1C) around the margins of the big bubble (diameter of about 8 mm). After injecting trypan blue into the big bubble (Figure 1D) to stain the Descemet’s membrane, the donor button is dissected with corneoscleral scissors (Figure 1E) and stored in MK medium while waiting insertion into the host eye (Figure 1F).

The epithelium of the recipient eye (Figure 2A) is removed to aid visualization. After marking the cornea with a trephine, the anterior chamber is entered with a knife, trypan blue is injected to stain the Descemet’s membrane and then excess dye is washed from the anterior chamber. The margin of the Descemet’s membrane that will be removed is first scored and then stripped from the endothelial side using a reverse Sinskey hook (Figure 2 B). After the peeled Descemet’s membrane is removed from the eye (Figure 2C), the PDEK graft is inserted using a specialized injection system that is an IOL injector minus the spring.

The graft is injected with the rolled up margins of the graft towards the cornea (Figure 2D), and then the entry site is sutured to prevent the graft from slipping out. Unrolling of the graft is achieved with slow injection of air and fluid beneath the graft (Figure 2E) while stroking the corneal surface over the graft.

Once the graft is unrolled, air is injected into the anterior chamber to achieve its firm adhesion to the Descemet’s bed of the recipient eye (Figure 2F).

Amar Agarwal, MD

E: aehl19c@gmail.com

Dr. Agarwal has no financial interest in the subject matter.

Priya Narang, MS

E: narangpriya19@gmail.com

Dr. Narang has no financial interest in the subject matter.

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