Faculty Bibliography

The initial published clinical report on riboflavin/ultraviolet A corneal cross-linking (CXL) for treatment of progressive keratoconus dates back to 2003. CXL has since then been widely used outside the United States for treatment of progressive keratoconus and post-laser in situ keratomileusis ectasia. The Food and Drug Administration (FDA) approved Avedro Inc.'s corneal cross-linking system (KXL) for treatment of patients with progressive keratoconus and post-laser in situ keratomileusis ectasia in April 2016. The procedure is not currently approved for stable keratoconus. There are 2 FDA-approved topical ophthalmic solutions for use in CXL. Riboflavin 5'-phosphate in 20% dextran ophthalmic solution 0.146% (Photrexa Viscous) and Riboflavin 5'-phosphate ophthalmic solution 0.146% (Photrexa) are intended for use with the KXL system. Photrexa Viscous is used in all CXL procedures, whereas Photrexa is indicated for use when the corneal stroma is thinner than 400 µm after completion of the Photrexa Viscous induction period. The FDA-approved procedure using the Dresden protocol (UV-A, 3 mW/cm for 30 min) induces cytologic and morphologic changes in the anterior 250 to 300 µm of the corneal stroma. It has been believed that a minimum thickness of 400 μm was necessary to protect the corneal endothelium from potential damage. The CXL procedure using the standard Dresden protocol is established as the gold standard for treatment of progressive keratoconus. CXL treatment is indicated for a list of conditions ranging from corneal ectasia to infectious keratitis. Newer protocols, treatment regimens, and expanded indications will require further refinements, investigations, and long-term studies.

PURPOSE/OBJECTIVE:To describe a new surgical technique where corneal cross-linking (CXL) (to treat corneal ectasias) and photo-activated chromophore for keratitis-CXL (PACK-CXL) are performed while the patient is seated in an upright position at the slit lamp. METHODS:Topical anesthesia is applied in the waiting room, 10 minutes before the procedure. Once in the office or procedure room, eyelids and periorbital areas are disinfected with chloramphenicol and the patient is seated at the slit lamp. Epithelial debridement is performed with a cotton swab soaked in freshly prepared 40% ethanol, using 70 seconds of tapping, followed by gentle pressure to remove the epithelium. The patient is placed in the supine position for riboflavin application for 10 minutes. Stromal thickness is assessed using ultrasound pachymetry after 5 and 10 minutes. Finally, the patient is returned to the slit lamp to receive ultraviolet irradiation. RESULTS:CXL at the slit lamp is an easy-to-perform technique that substantially reduces the infrastructure needed to perform CXL and PACK-CXL procedures. CONCLUSIONS:A significant advantage of allowing CXL treatment at the slit lamp is that CXL technology can now be used in clinics that do not have easy access to an operating room infrastructure. Slit-lamp CXL can also reduce procedure costs by eliminating the technical fees related to the use of an operating room, making this treatment not only more accessible for patients, but also affordable. [J Refract Surg. 2021;37(2):78-82.].

PURPOSE:To determine whether corneal cross-linking (CXL) with individualized fluence ("sub400 protocol") is able to stop keratoconus (KC) progression in ultrathin corneas with 12-month follow-up. DESIGN:Retrospective, interventional case series. METHODS:with irradiation times individually adapted to stromal thickness. Pre- and postoperative examinations included corrected distance visual acuity (CDVA), refraction, Scheimpflug, and anterior segment optical coherence tomography imaging up to 12 months after CXL. Outcome measures were arrest of KC progression at 12 months postoperatively and stromal demarcation line (DL) depth. RESULTS:(-2.06 ± 3.66 D) and densitometry (+2.00 ± 2.07 GSU). No significant changes were found in CDVA (P = .611), sphere (P = .077), or cylinder (P = .915). CONCLUSIONS:The "sub400" individualized fluence CXL protocol standardizes the treatment in ultrathin corneas and halted KC progression with a success rate of 90% at 12 months. The sub400 protocol allows for the treatment of corneas as thin as 214 μm of corneal stroma, markedly extending the treatment range. The DL depth did not predict treatment outcome. Hence, the depth is unlikely related to the extent of CXL-induced corneal stiffening but rather to the extent of CXL-induced microstructural changes and wound healing.

PURPOSE:To compare the elastic modulus of thin corneal lamellas using 2D stress-strain extensometry in healthy ex vivo human corneal lamellas with or without the presence of Bowman layer. SETTING:Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Switzerland; ELZA Institute, Dietikon, Switzerland; Department of Ophthalmology, Philipps University of Marburg, Germany. DESIGN:Prospective experimental laboratory study. METHODS:Healthy human corneas were stripped of Descemet membrane and the endothelium for Descemet membrane endothelial keratoplasty. After epithelium removal, corneas were divided into 2 groups. In Group 1, Bowman layer was ablated with an excimer laser (20 μm thick, 10 mm). In Group 2, Bowman layer was left intact. Then, a lamella was cut from the anterior cornea with an automated microkeratome. Elastic and viscoelastic material properties were analyzed by 2D stress-strain extensometry between 0.03 and 0.70 N. RESULTS:Twenty-six human corneas were analyzed. The mean lamella thickness was 160 ± 37 μm in corneas with Bowman layer and 155 ± 22 μm in corneas without. No statistically significant differences between flaps with and without Bowman layer were observed in the tangential elastic modulus between 5% and 20% strain (11.5 ± 2.9 kPa vs 10.8 ± 3.7 kPa, P > .278). CONCLUSIONS:The presence or absence of Bowman layer did not reveal a measurable difference in corneal stiffness. This may indicate that the removal of Bowman layer during photorefractive keratectomy does not represent a disadvantage to corneal biomechanics.

BACKGROUND:Infectious keratitis is a major cause of global blindness. We tested whether standalone photoactivated chromophore corneal cross-linking (PACK-CXL) may be an effective first-line treatment in early to moderate infectious keratitis, compared with standard antimicrobial treatment. METHODS:This is a randomized, controlled, multinational phase 3 clinical trial. Participants in five centers in Egypt, India, Iran, Israel, and China, aged ≥ 18 years, with infectious keratitis of presumed bacterial, fungal, or mixed origin, were randomly assigned (1:1) to PACK-CXL, or antimicrobial therapy. Outcomes measures included healing, defined as time to re-epithelialization of the corneal epithelial defect in the absence of inflammatory activity in the anterior chamber and clearance of stromal infiltrates. Treatment success was defined as the complete resolution of signs of infection. RESULTS:Between July 21, 2016, and March 4, 2020, participants were randomly assigned to receive PACK-CXL (n = 18) or antimicrobial therapy per American Academy of Ophthalmology (AAO) guidelines (n = 21). No participants were lost to follow-up. Four eyes were excluded from the epithelialization time analysis due to treatment failure: two in the antimicrobial therapy group, and two in the PACK-CXL group. Success rates were 88.9% (16/18 patients) in the PACK-CXL group and 90.5% (19/21 patients) in the medication group. There was no significant difference in time to complete corneal re-epithelialization (P = 0.828) between both treatment groups. CONCLUSIONS:PACK-CXL may be an alternative to antimicrobial drugs for first-line and standalone treatment of early to moderate infectious keratitis of bacterial or fungal origin. Trial registration This trial is registered at ClinicalTrials.gov, trial registration number: NCT02717871.

PURPOSE/UNASSIGNED:The purpose of this study was to determine if concurrent riboflavin/UV-A light (RF/UV-A) and rose Bengal/green light (RB/green) epi-off PACK-CXL enhances corneal resistance to enzymatic digestion compared to separate chromophore/light treatments. METHODS/UNASSIGNED:Ex vivo porcine corneas were allocated as follows. Group A corneas were soaked with riboflavin (RF) and were either not irradiated (A1, controls) or were irradiated with 10 (A2) or 15 J/cm² (A3) UV-A light at 365 nm, respectively. Group B corneas were soaked with RB and either not irradiated (B1, controls) or were illuminated with 10 (B2) or 15 J/cm² (B3) green light at 525 nm, respectively. Corneas in group C were soaked with both RF and RB and were either not irradiated (C1, controls) or were subjected to the same session consecutive 10 J/cm2 (C2) or 15 J/cm2 (C3) UV-A and green light exposure. Following treatment, all corneas were exposed to 0.3% collagenase A to assess digestion time until corneal button dissolution. RESULTS/UNASSIGNED:A1 to A3 digestion times were 21.38, 30.5, and 32.25 hours, respectively, with A2 and A3 showing increased resistance to A1. B1-3 had digestion times of 31.2, 33.81, and 34.38 hours, with B3 resisting more than B1. C1 to C3 times were 33.47, 39.81, and 51.94 hours; C3 exhibited superior resistance to C1 and C2 (both P < 0.05). CONCLUSIONS/UNASSIGNED:Same-session combined RF/UV-A and RB/green PACK-cross-linking significantly increases corneal enzymatic digestion resistance over standalone treatments. TRANSLATIONAL RELEVANCE/UNASSIGNED:Combining RF-based and RB-based PACK-CXL considerably increases corneal collagenase digestion resistance, potentially minimizing ulcer size in clinical contexts.

PURPOSE OF REVIEW/OBJECTIVE:The aim of this study was to summarize the recent developments in corneal cross-linking (CXL) and its indications, including corneal ectasias, refractive surgery and infectious keratitis. RECENT FINDINGS/RESULTS:Advances in CXL technology, such as the use of higher-intensity LED ultraviolet (UV) light sources and a better understanding of the UV-riboflavin photochemical reaction, have enabled safer and more effective methods of cross-linking thin and ultra-thin corneas, and more effective accelerated transepithelial/'epi-on' CXL procedures that are beginning to supplant the Dresden protocol as the 'gold standard' CXL method. CXL is also being used in combination with laser surgery, not only to expand the patient base who can receive refractive surgery, but also to help rehabilitate vision in patients with ectasia. CXL, and CXL combined with photorefractive keratectomy (PRK), can result in corneal flattening of 1-2 D, and corneal regularization of 4-5 D, respectively. Finally, photoactivated chromophore for keratitis-corneal cross-linking (PACK-CXL) has been shown to be an effective therapy for infectious keratitis, both alone, and in combination with antimicrobial drugs. SUMMARY/CONCLUSIONS:CXL has evolved from a single technique to treat a single corneal ectasia, keratoconus, to several techniques with several indications, spanning a spectrum of corneal ectasias, as well as visual rehabilitation, refractive procedures and infectious keratitis treatment.

The word "elective" refers to medications and procedures undertaken by choice or with a lower grade of prioritization. Patients usually use elective medications or undergo elective procedures to treat pathologic conditions or for cosmetic enhancement, impacting their lifestyle positively and, thus, improving their quality of life. However, those interventions can affect the homeostasis of the tear film and ocular surface. Consequently, they generate signs and symptoms that could impair the patient's quality of life. This report describes the impact of elective topical and systemic medications and procedures on the ocular surface and the underlying mechanisms. Moreover, elective procedures performed for ocular diseases, cosmetic enhancement, and non-ophthalmic interventions, such as radiotherapy and bariatric surgery, are discussed. The report also evaluates significant anatomical and biological consequences of non-urgent interventions to the ocular surface, such as neuropathic and neurotrophic keratopathies. Besides that, it provides an overview of the prophylaxis and management of pathological conditions resulting from the studied interventions and suggests areas for future research. The report also contains a systematic review investigating the quality of life among people who have undergone small incision lenticule extraction (SMILE). Overall, SMILE seems to cause more vision disturbances than LASIK in the first month post-surgery, but less dry eye symptoms in long-term follow up.

PURPOSE/OBJECTIVE:To determine whether combinations of devices with different measuring principles, supported by artificial intelligence (AI), can improve the diagnosis of keratoconus (KC). METHODS:Scheimpflug tomography, spectral-domain optical coherence tomography (SD-OCT), and air-puff tonometry were performed in all eyes. The most relevant machine-derived parameters to diagnose KC were determined using feature selection. The normal and forme fruste KC (FFKC) eyes were divided into training and validation datasets. The selected features from a single device or different combinations of devices were used to develop models based on random forest (RF) or neural networks (NN) trained to distinguish FFKC from normal eyes. The accuracy was determined using receiver operating characteristic (ROC) curves, area under the curve (AUC), sensitivity, and specificity. RESULTS:271 normal eyes, 84 FFKC eyes, 85 early KC eyes, and 159 advanced KC eyes were included. A total of 14 models were built. Air-puff tonometry had the highest AUC for detecting FFKC using a single device (AUC = 0.801). Among all two-device combinations, the highest AUC was accomplished using RF applied to selected features from SD-OCT and air-puff tonometry (AUC = 0.902), followed by the three-device combination with RF (AUC = 0.871) with the best accuracy. CONCLUSION/CONCLUSIONS:Existing parameters can precisely diagnose early and advanced KC, but their diagnostic ability for FFKC could be optimized. Applying an AI algorithm to a combination of air-puff tonometry with Scheimpflug tomography or SD-OCT could improve FFKC diagnostic ability. The improvement in diagnostic ability by combining three devices is modest.