Arie L. Marcovich

Clinical and corneal biomechanical changes after collagen cross-linking with riboflavin and UV irradiation in patients with progressive keratoconus: results after 2 years of follow-up.

Purpose: To assess the biomechanical and keratometric effects and the safety of treatment of progressive keratoconus with UV–riboflavin collagen cross-linking (CXL). Methods: This is a prospective clinical controlled study. Fourteen eyes of 14 patients with progressive keratoconus were treated with CXL after corneal deepithelization. Patients were assessed preoperatively, at week 1 and at months 1, 3, 6, 9, 12, and 24 after treatment. We measured uncorrected visual acuity (UCVA) and best spectacle–corrected visual acuity (BSCVA) (logarithm of the minimum angle of resolution), refraction, biomicroscopy and fundus examination, intraocular pressure, axial length, endothelial cell density, corneal topography, minimal corneal thickness, macular optical coherence tomography, and corneal biomechanics with the ocular response analyzer. Results: Comparing the preoperative results with 24-month postoperative results, we observed significant improvement in BCVA (0.21 ± 0.1 to 0.14 ± 0.1, P = 0.002) and stability in UCVA (0.62 ± 0.5 and 0.81 ± 0.49, P = 0.475). We observed a significant decrease in steepest-meridian keratometry (diopters) (53.9 ± 5.9 to 51.5 ± 5.4, P = 0.001) and in mean cylinder (diopters) (10.2 ± 4.1 to 8.1 ± 3.4, P = 0.001). Significant elongation of the eyes was observed, from 24.39 ± 1.7 mm to 24.71 ± 1.9 mm (P = 0.007). No significant change was observed in mean simulated keratometry, minimal corneal thickness, endothelial cell density, corneal hysteresis, and corneal resistance factor or foveal thickness. Conclusions: Two years after CXL, the observation of stable UCVA, improved BCVA, and reduced keratometry suggests stabilization in progression of keratoconus. Unchanged corneal thickness, endothelial cell density, and foveal thickness suggest the long-term safety of this procedure. The observed increase in axial length and stability in corneal biomechanical parameters measured with the ocular response analyzer require further study for verification and explanation.

Topical tetracaine versus topical tetracaine plus intracameral lidocaine for cataract surgery

Purpose: To compare topical tetracaine 0.5% alone and with intracameral lidocaine 1% as a local anesthetic agent in phacoemulsification with intraocular lens (IOL) implantation. Setting: The Toronto Hospital—Western Division; Toronto, Canada. Methods: Fifty‐trine consecutive patients (60 eyes) having phacoemulsification with implantation of a foldable acrylic IOL (AcrySot) were randomized into 1 of 2 groups: The‐intracameral balanced salt solution (BSS) group received topical tetracaine 0.5% plus intracameral BSS;‐the intracameral lidocaine group received topical tetracaine 0.5.% with preservabve‐free intracameral lidocaine 1%. The patients’ subjective experience of pain, vvas measured at 4 points during surgery using a 4‐point pain scale. Patient and surgeon satisfaction with the anesthesia used was measured using a 5‐point satisfaction scale. Central endothelial cell counts were obtained preoperatively and 1 month postoperatively. Best corrected visual acuity (BCVA) was measured pfeoperatively and 1 hour, i day, 1 week, and 1 month postoperatively. Results: The mean pain score after phaccemulsfication was significantly higher in the intracameral BSS group than in the intracameral lidocaine group (0.63 ± 0.7 [SD] and 0.23 ± 0.4, respectively,‐ P < .019). The mean pain score at the end of surgery was also significantly higher in the intracameral BSS group than in the intracameral lidocaine group (0.60 ± 0.6 and 0.21 ± 0.4, respectively; P < .014). The surgeon satisfaction score was significantly lower for the intracameral BSS group than for’ the intracameral lidocaine group (3.90 1.2 and 4.73 ± 0.8, ’ respectively; P < .0007). There was no difference in patient satisfaction between the intracameral BSS and intracameral lidocaine groups (4.60 ± 0.6 and 4.70 0.8). Endothelial cell loss 1 month postoperatively was similar between the 2 groups (,6:1% ± 8% and 6.7% ± 6%) Ninety‐seven percent of patients (29/30) in each group noted BCVA improvement from preoperatively. The rate of potential visual acuity recovery was similar in both groups. Conclusion: Topical tetracaine 0.5% with intracameral lidocaine was safe and effective in patients having phacoemulsifcation with IOL implantation. The advantage of using intracameral lidocaine 1% over a placebo was a significant decrease in the patients’ subjective experience of pain and in the surgeon’s satisfaction with the anesthesia used. None of the other parameters measured in this study differed significantly between the 2 groups.

Safety of corneal collagen cross-linking with UV-A and riboflavin in progressive keratoconus.

Purpose: To assess the possible damage to ocular tissues during treatment of keratoconus with UV-A-riboflavin corneal collagen cross-linking (CXL). Design: Single center, prospective, interventional study. Methods: Fourteen eyes of 14 patients aged 28.2 ± 5.9 (mean ± SD) years with progressive keratoconus were treated with UV-A-riboflavin CXL. Corneal endothelium was assessed with the endothelial specular microscope. Central retina was assessed with biomicroscopy fundus examination and with optical coherence tomography using macular thickness protocol. Patients were assessed preoperatively, at week 1, month 1, 3, 6, 9, and 12 after treatment. Results: Comparative preoperative and postoperative results showed stable endothelial cell density (2730 cells/mm2, 2793 cells/mm2, and 2640 cells/mm2, preoperatively, at month 6, and at month 12, respectively) and stable foveal thickness (203, 202, and 205 μm, preoperatively, at month 6, and at month 12, respectively). No morphological abnormalities were noted. Conclusions: UV-A-riboflavin CXL seems to be a safe procedure that does not cause damage to the corneal endothelium and central retina.

Penetrating keratoplasty for keratoconus: long-term results.

Purpose: To study central corneal endothelial cell density and morphology and corneal topography in transplanted corneas for keratoconus 10 to 17 years postoperatively. Methods: Retrospective, noncomparative case series including all keratoconus patients who underwent penetrating keratoplasty by one surgeon, at the same center, between January 1986 and December 1994. Seventeen patients (22 eyes) met the criteria. Four patients (5 eyes) with unchanged visual acuity during the follow-up period did not agree to return for the last follow-up examination, 1 patient (1 eye) had graft failure, and 3 patients (4 eyes) were lost to follow-up. We reviewed the charts of 9 patients (12 eyes), and collected data including manifest refraction, best corrected visual acuity (BCVA), endothelial cell density, cell morphology, and corneal topography. Results: The mean follow-up period for all eyes evaluated was 13.3 ± 2.4 years (range 10-17 years). At the last follow-up, 91.7% of eyes achieved BCVA of 20/40 or better, and mean endothelial cell density was 695 ± 113.6 cells/mm2. Pleomorphism was detected in 5 eyes. Keratoconus pattern, by corneal topography, was not detected in any eye at the final examination. Conclusions: Endothelial cell count 10-17 years post-PKP for keratoconus is very low with pleomorphism and viable grafts, indicating continued endothelial instability.

Prediction of refractive outcomes with toric intraocular lens implantation

Purpose To evaluate and compare the accuracy of different methods to measure and predict postoperative astigmatism with toric intraocular lens (IOL) implantation. Setting Ein‐Tal Ophthalmology Center, Tel‐Aviv, Israel. Design Retrospective case series. Methods Postoperative corneal astigmatism was measured with 3 devices (IOLMaster 500; optical low‐coherence reflectometry [OLCR]–based Lenstar LS 900; Atlas topographer) and compared with the manifest astigmatic refractive outcome in patients with toric IOLs. The error in the predicted residual astigmatism was calculated by vector analysis according to the measurement and calculation method used to predict the required toric IOL cylinder power. Results The centroid errors in predicted residual astigmatism were against the rule with the Alcon and Holladay toric calculators (0.53 to 0.56 diopter [D]), were lower with the Baylor nomogram (0.21 to 0.26 D), and were lowest for the Barrett toric calculator (0.01 to 0.16 D) (P <.001). The Barrett toric calculator had the lowest median absolute error in predicted residual astigmatism (0.35 to 0.54 D, all devices) compared with the Alcon and Holladay toric calculators with or without the Baylor nomogram (P <.021). The Barrett toric calculator and the OLCR device achieved the most accurate results; 75.0% and 97.1% of eyes were within ±0.50 D and ±0.75 D of the predicted residual astigmatism, respectively. Conclusion Prediction of astigmatic outcomes with toric IOLs can be improved with appropriate measuring devices and methods to establish the required toric IOL power. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.

Low-dose pulsed intravenous cyclophosphamide for severe ocular cicatricial pemphigoid in elderly patients.

Purpose: Ocular cicatricial pemphigoid (OCP) is a relatively rare autoimmune disease affecting elderly patients and causing severe symptoms that may culminate in blindness. Treatment is based on immunosuppression, but optimal regimens have not been established. Methods: A prospective unmasked case series of all patients with severe OCP who gave consent and completed treatment and ≥6 months of follow-up in the cornea and immunomodulation outpatient clinics of an academic hospital. Monthly pulses of intravenous cyclophosphamide (IVC; 500 mg) were administered with ondansetron and adjusted according to response. Results: Over 14 years, 13 patients (median age 77 years) met inclusion criteria. All had bilateral OCP (2 eyes were previously blind), but extraocular involvement was rare (1/13). Three to 28 pulses were given, and the patients were followed up for a median of 32 (range, 6–167) months. Remission of inflammation in both eyes was achieved in 12 patients (92%). Vision improved in 5 of 13 patients, stabilized in another 5 (combined, 77%), and worsened in only 3 patients. One patient’s condition flared up during treatment that responded to steroids and increasing IVC frequency. In 4 patients and 6 eyes (25%), cicatrization progressed (usually, Foster stages 1–3). Two late relapses occurred and responded to retreatment. IVC was generally well tolerated, although nausea led to modification in 2 patients. One patient developed candida keratitis. Conclusions: Compared with other treatment modalities, low-dose monthly pulse IVC is found to be a relatively safe, simple, and usually effective alternative immunosuppressive treatment in severe OCP.

Surgical management of pterygium.

Pterygium is a triangular fibrovascular growth that extends from the conjunctiva in the interpalpebral fissure and encroaches on the cornea. It occurs usually on the nasal side, but can grow nasally and temporally, or infrequently, only on the temporal side. The pterygium consists of a cap, head, and body. The cap is a gray subepithelial opacity at the leading edge of the pterygium. Behind the cap, the head of the pterygium is a thickened vascular area that is tightly attached to the cornea. The body of the pterygium is the fleshy, vascular area of bulbar conjunctiva, with folds that mark its edges. Pterygia may be markedly vascular and encroach toward the central cornea, or remain stationary and become flat and atrophic with time. The pterygium may induce irregular corneal astigmatism, owing to abnormal pooling of tears in advance of the apex of the pterygium. This tear film causes topographic horizontal flattening, that results in astigmatism with the rule. The pterygium may cause irritation, inflammation, and foreign body sensation.

Homologous scleral graft for corneal perforation in a child.

Purpose: To show the emergency use of preserved homologous sclera for the repair of a perforated cornea in a young child. Methods: Our case was a 3.5-year-old boy who presented with an acute corneal ulcer and endophthalmitis, which was complicated by a developing corneal melting and perforation of 2.5-mm diameter during pars plana vitrectomy. Because no donor cornea was available, a full-thickness preserved donor sclera was used to close the corneal defect. Results: During the next 8 months, scar tissue formed underneath the scleral graft. The graft was removed, revealing mild opacification at the site of corneal perforation. Three years after surgery, best-corrected visual acuity was 20/60. Conclusions: In the absence of a corneal button for grafting, preserved homologous sclera may be used for closing a corneal defect.

Digoxin derivatives with selectivity for the α2β3 isoform of Na,K-ATPase potently reduce intraocular pressure

Significance Glaucoma is associated with increased pressure in the eye, which can be alleviated by increasing outflow from the eye or reducing inflow of aqueous humor produced in the ciliary epithelium. A special form of Na,K-ATPase (α2β3 isoform), the ion pump that maintains electrochemical gradients of Na+ and K+ across animal cell membranes, powers production of aqueous humor. We describe derivatives of a classical Na,K-ATPase inhibitor, digoxin, with selectivity for the α2β3 isoform over the common α1β1 isoform and show that topical application of α2β3-selective derivatives to rabbit eyes efficiently reduces either pharmacologically raised or basal intraocular pressure. This work confirms the importance of α2β3 in production of aqueous humor and may provide a novel approach for glaucoma drug therapy. The ciliary epithelium in the eye consists of pigmented epithelial cells that express the α1β1 isoform of Na,K-ATPase and nonpigmented epithelial cells that express mainly the α2β3 isoform. In principle, a Na,K-ATPase inhibitor with selectivity for α2β3 that penetrates the cornea could effectively reduce intraocular pressure, with minimal systemic or local toxicity. We have recently synthesized perhydro-1,4-oxazepine derivatives of digoxin by NaIO4 oxidation of the third digitoxose and reductive amination with various R-NH2 substituents and identified derivatives with significant selectivity for human α2β1 over α1β1 (up to 7.5-fold). When applied topically, the most α2-selective derivatives effectively prevented or reversed pharmacologically raised intraocular pressure in rabbits. A recent structure of Na,K-ATPase, with bound digoxin, shows the third digitoxose approaching one residue in the β1 subunit, Gln84, suggesting a role for β in digoxin binding. Gln84 in β1 is replaced by Val88 in β3. Assuming that alkyl substituents might interact with β3Val88, we synthesized perhydro-1,4-oxazepine derivatives of digoxin with diverse alkyl substituents. The methylcyclopropyl and cyclobutyl derivatives are strongly selective for α2β3 over α1β1 (22–33-fold respectively), as determined either with purified human isoform proteins or intact bovine nonpigmented epithelium cells. When applied topically on rabbit eyes, these derivatives potently reduce both pharmacologically raised and basal intraocular pressure. The cyclobutyl derivative is more efficient than Latanoprost, the most widely used glaucoma drug. Thus, the conclusion is that α2β3-selective digoxin derivatives effectively penetrate the cornea and inhibit the Na,K-ATPase, hence reducing aqueous humor production. The new digoxin derivatives may have potential for glaucoma drug therapy.

Digoxin derivatives with enhanced selectivity for the α2 isoform of Na,K-ATPase: effects on intraocular pressure in rabbits.

Background: The α2 isoform of Na,K-ATPase may play a major role in aqueous humor production. Results: We have chemically modified digoxin and obtained derivatives with enhanced selectivity for α2. When applied topically, they effectively reduce intraocular pressure in rabbits. Conclusion: α2 is crucial for aqueous humor production. Significance: Potentially, the derivatives may be useful for control of intraocular pressure. In the ciliary epithelium of the eye, the pigmented cells express the α1β1 isoform of Na,K-ATPase, whereas the non-pigmented cells express mainly the α2β3 isoform of Na,K-ATPase. In principle, a Na,K-ATPase inhibitor with selectivity for α2 could effectively reduce intraocular pressure with only minimal local and systemic toxicity. Such an inhibitor could be applied topically provided it was sufficiently permeable via the cornea. Previous experiments with recombinant human α1β1, α2β1, and α3β1 isoforms showed that the classical cardiac glycoside, digoxin, is partially α2-selective and also that the trisdigitoxose moiety is responsible for isoform selectivity. This led to a prediction that modification of the third digitoxose might increase α2 selectivity. A series of perhydro-1,4-oxazepine derivatives of digoxin have been synthesized by periodate oxidation and reductive amination using a variety of R-NH2 substituents. Several derivatives show enhanced selectivity for α2 over α1, close to 8-fold in the best case. Effects of topically applied cardiac glycosides on intraocular pressure in rabbits have been assessed by their ability to either prevent or reverse acute intraocular pressure increases induced by 4-aminopyridine or a selective agonist of the A3 adenosine receptor. Two relatively α2-selective digoxin derivatives efficiently normalize the ocular hypertension, by comparison with digoxin, digoxigenin, or ouabain. This observation is consistent with a major role of α2 in aqueous humor production and suggests that, potentially, α2-selective digoxin derivatives could be of interest as novel drugs for control of intraocular pressure.