Suppression of Neovascularization by Topical and Subconjunctival Bevacizumab After High-Risk Corneal Transplantation.

Purpose: To assess the effectiveness of topical and subconjunctival bevacizumab in suppressing vascularization in graft and host bed after high-risk corneal transplantation. Design: Secondary analysis of prospective, randomized, double-blind, placebo-controlled multicentric clinical trial. Participants: The study includes patients aged > 18 years who underwent high-risk penetrating keratoplasty, which was defined as corneal vascularization in ≥ 1 quadrants of the corneal graft and host bed, excluding the limbus. Methods: Patients were randomized to treatment and control groups. The patients in the treatment group received subconjunctival injection of bevacizumab (2.5 mg/0.1 ml) on the day of the procedure, followed by topical bevacizumab (10 mg/ml) 4 times per day for 4 weeks. The patients in control group received injection of vehicle (0.9% sodium chloride) on the day of procedure, followed by topical vehicle (carboxymethylcellulose sodium 1%) 4 times a day for 4 weeks. Main Outcome Measures: Vessel and invasion area of vessels in the corneal graft and host beds. Results: This study included 56 eyes of 56 patients who underwent high-risk corneal transplantation, with equal numbers in the bevacizumab and vehicle (control) treatment groups. The mean age of patients who received bevacizumab was 61.2 ± 15.9 years, and the mean age of those treated with vehicle was 60.0 ± 16.1 years. The vessel area at baseline was comparable in the bevacizumab (16.72% ± 3.19%) and control groups (15.48% ± 3.12%; P = 0.72). Similarly, the invasion areas were also similar in the treatment (35.60% ± 2.47%) and control (34.23% ± 2.64%; P = 0.9) groups at baseline. The reduction in vessel area was significantly higher in the bevacizumab-treated group (83.7%) over a period of 52 weeks compared with the control group (61.5%; P < 0.0001). In the bevacizumab-treated group, invasion area was reduced by 75.8% as compared with 46.5% in the control group. The vessel area was similar at 52 weeks postprocedure in cases of first (3.54% ± 1.21%) and repeat (3.80% ± 0.40%) corneal transplantation in patients who received bevacizumab treatment. In the vehicle-treated patients, the vessel area was significantly higher in repeat (9.76% ± 0.32%) compared with first (8.06% ± 1.02%; P < 0.0001) penetrating keratoplasty. In the bevacizumab treatment group, invasion areas at week 52 were comparable in first (11.70% ± 3.38%) and repeat (11.64% ± 1.74%) procedures, whereas invasion area was significantly higher in repeat (27.87% ± 2.57%) as compared with first (24.11% ± 2.17%) penetrating keratoplasty in vehicle-treated patients. Conclusions: In patients undergoing vascularized high-risk corneal transplantation, bevacizumab is efficacious in reducing vascularization of corneal graft and host bed, thereby reducing the risk of corneal graft rejection in vascularized host beds. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Bevacizumab in High-Risk Corneal Transplantation: A Pilot Multicenter Prospective Randomized Control Trial.

PURPOSE: To determine the efficacy of local (subconjunctival and topical) bevacizumab (Avastin) treatment in patients undergoing vascularized high-risk corneal transplantation. DESIGN: Pilot, prospective, randomized, double-blind, placebo-controlled clinical trial conducted at 5 clinical centers in the United States, India, and Brazil. PARTICIPANTS: Patients aged > 18 years undergoing high-risk penetrating keratoplasty, defined as corneal neovascularization (NV) in 1 or more quadrants ≥2 mm from the limbus or extension of corneal NV to the graft-host junction in a previously failed graft. METHODS: Patients were randomized to receive subconjunctival bevacizumab (2.5 mg/0.1 ml) or placebo at the time of surgery, followed by topical bevacizumab (10 mg/ml) or topical placebo, administered 4 times per day for 4 weeks. MAIN OUTCOME MEASURE: The 52-week endothelial immune rejection rate. RESULTS: Ninety-two patients were randomized to receive bevacizumab (n = 48) or control (n = 44). The 52-week endothelial rejection rate was 10% in the bevacizumab group and 19% in the control group (P = 0.20). Post hoc, extended follow-up at the lead study site showed an endothelial rejection rate of 3% in the bevacizumab group and 38% in the control group (P = 0.003). Treatment with bevacizumab was found to have a hazard ratio of 0.15 (95% confidence interval, 0.03-0.65, P = 0.01) in a post hoc Cox regression analysis. CONCLUSIONS: In patients undergoing vascularized high-risk corneal transplantation, there was no statistically significant difference in the rate of endothelial rejection at 1 year in the bevacizumab treatment group compared with the control group. This study may have been underpowered to detect a difference between treatment groups, and taken together, our data suggest that, in the current trial design, bevacizumab has a positive but not (yet) significant effect on endothelial rejection.

Diagnosis and management of postrefractive surgery ectasia.

Postrefractive surgery ectasia is a serious, sight-threatening complication seen after the following procedures: laser in situ keratomileusis, photorefractive keratectomy, small-incision lenticule extraction, radial keratotomy, and/or arcuate keratotomy. Specific risk factors may include age, corneal thickness, degree of refractive error, corneal topographic changes including irregular astigmatism, percent tissue ablation, and residual stromal bed. Biomarkers may be a new option to help indicate who is at greatest risk for ectasia. Visual aids including spectacles or contacts lenses are often required to achieve optimal vision. Collagen crosslinking is the only treatment believed to stop progression of ectasia and prevent keratoplasty. Other surgical options may include topography-guided phototherapeutic keratectomy and intrastromal corneal ring segments. Ultimately, an "ounce of prevention is a pound of cure," so careful preoperative screening and ultimately offering the safest and most effective treatments for patients is arguably the most important job of the refractive surgeon.

Corneal confocal microscopy: Neurologic disease biomarker in Friedreich ataxia.

OBJECTIVE: Friedreich ataxia (FRDA), an autosomal recessive neurodegenerative disease caused by mutations in the gene encoding for the mitochondrial protein frataxin, is characterized by ataxia and gait instability, immobility, and eventual death. We evaluated corneal confocal microscopy (CCM) quantification of corneal nerve morphology as a novel, noninvasive, in vivo quantitative imaging biomarker for the severity of neurological manifestations in FRDA. METHODS: Corneal nerve fiber density, branch density, and fiber length were quantified in individuals with FRDA (n = 23) and healthy age-matched controls (n = 14). All individuals underwent genetic testing and a detailed neurological assessment with the Scale for the Assessment and Rating of Ataxia (SARA) and Friedreich's Ataxia Rating Scale (FARS). A subset of individuals with FRDA who were ambulatory underwent quantitative gait assessment. RESULTS: CCM demonstrated a significant reduction in nerve fiber density and length in FRDA compared to healthy controls. Importantly, CCM parameters correlated with genotype, SARA and FARS neurological scales, and linear regression modeling of CCM nerve parameter-generated equations that predict the neurologic severity of FRDA. INTERPRETATION: Together, the data suggest that CCM quantification of corneal nerve morphology is a rapid, sensitive imaging biomarker for quantifying the severity of neurologic disease in individuals with FRDA. Ann Neurol 2018;84:893-904.

Revisiting monovision for presbyopia.

PURPOSE OF REVIEW: Presbyopia is an inevitable age-related loss of accommodation that results in spectacle dependence with common everyday near-vision tasks. Many surgical approaches to presbyopic correction have been investigated, with monovision correction being amongst the most common and attractive options. In this article, we will review the advantages and disadvantages of the new modalities of presbyopic monovision correction. RECENT FINDINGS: New methods such as mini-monovision, corneal inlays, and multifocal corneal ablation aim to maximize stereopsis and decrease the anisometropic side effects of conventional monovision. These include inlays such as the KAMRA and Raindrop, and phakic intraocular lenses such as the hole ICL. Newer corneal laser refractive procedures such as small incision lenticule extraction have also shown good outcomes with monovision. Pseudophakic monovision using standard monofocal lenses still provides good results. SUMMARY: Monovision for presbyopic correction continues to provide promising results. There are a number of new devices and techniques that have shown good visual acuity outcomes, patient satisfaction and spectacle independence.

Analysis of patient outcomes following proton radiation therapy for retinoblastoma.

PURPOSE: Proton radiotherapy (PRT) is used in the treatment of retinoblastoma (RB) and has the potential to minimize exposure of normal tissue to radiation and thus decrease risk of toxicity and second malignancies. However, comprehensive analyses of long-term patient outcomes are not available. METHODS: RB patients treated with PRT at our institution between 1986 and 2012 were invited to return for participation in a study designed to assess long-term outcomes. Enrolled patients underwent comprehensive analysis including oncologic, ophthalmic, endocrine, cephalometric, and quality of life (QOL) assessments. RESULTS: A total of 12 patients were enrolled in this study, and the average length of follow-up among enrolled patients was 12.9 years (range 4.8-22.2 years). All enrolled patients had bilateral disease, and the disease and visual outcomes for enrolled patients were similar to outcomes for all RB patients treated with PRT over the same time period at our institution. Endocrine evaluation revealed no growth abnormalities or hormonal deficiencies across the cohort. Based on MRI and external cephalometry, PRT was associated with less facial hypoplasia than enucleation. Patient and parent-proxy QOL assessments revealed that RB treatment did not appear to severely impact long-term QOL. CONCLUSIONS: In addition to providing an opportunity for long-term disease control and functional eye preservation, PRT does not appear to be associated with unexpected late visual, endocrine, or QOL effects in this cohort.

Resident and young physician experience with complex cataract surgery and new cataract and refractive technology: Results of the ASCRS 2016 Young Eye Surgeons survey.

A survey was offered to attendees of the 2016 annual meeting of the American Society of Cataract and Refractive Surgery (ASCRS) as well as online to ASCRS members. Of the 429 self-identified surgeons in training or those with fewer than 5 years in practice, 83% had performed complex cataract surgery using iris expansion devices or capsular tension rings (63%) and 70% had implanted a toric intraocular lens (IOL). A minority of respondents had performed laser-assisted cataract surgery (27%) or implanted presbyopia-correcting IOLs (39%), and only half (50%) had performed laser vision correction (LVC). Comfort with complex cataract and IOL procedures improved with increasing number of cases performed until greater than 10 cases. From this we can conclude that young surgeons have adequate exposure to complex cataracts but lack experience in refractive surgery and new IOL technology. Reported surgeon confidence improved with increased experience and exposure.

Tear film assessments for the diagnosis of dry eye.

PURPOSE OF REVIEW: Dry eye disease (DED) is a complex, multifactorial condition that is challenging to diagnose and monitor clinically. To date, diagnosis has consisted largely of self-reported symptom questionnaires and a collection of clinical tests including vital dye staining, estimation of tear breakup time and Schirmer's testing, as no gold standard exists. As the dry eye field has made progress in understanding disease pathogenesis, new methods for assessment of this condition have been developed. RECENT FINDINGS: DED is now known to be characterized by tear hyperosmolarity and ocular surface inflammation, and there are now commercially available devices that accurately and reliably measure tear osmolarity and matrix metalloproteinase 9, a marker of inflammation and tissue breakdown. In addition, there are a variety of imaging modalities that have shown promise in their ability to identify patients with DED by assessing tear film dimensions and tear film instability. SUMMARY: There is a significant need for the development of tear film assessments for accurate diagnosis and monitoring of dry eye. There are a number of new devices and techniques that have shown promise in their ability help clinicians manage patients with DED.

Cicatrizing Conjunctivitis in a Patient Diagnosed With Drug Reaction With Eosinophilia and Systemic Symptoms/Drug-Induced Hypersensitivity Syndrome but With Features of Stevens-Johnson Syndrome.

PURPOSE: Severe cutaneous adverse reactions to drugs (SCARs) such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS) serve as one of the main reasons for inpatient ophthalmic consultation. Although it is well-recognized that SJS/TEN is associated with severe ocular mucosal inflammation and cicatrizing, potentially blinding, sequelae, this association has not been described in relation to other SCARs. We present a patient fulfilling the diagnostic criteria for probable DRESS/DIHS but not for SJS/TEN, yet exhibiting the severe ocular surface involvement characteristic of SJS/TEN. METHODS: Case report. RESULTS: A 64-year-old man presented with bilateral pseudomembranous conjunctivitis and conjunctival denudation (sloughing) in the setting of a maculopapular rash, fever, liver dysfunction, and hematologic abnormalities 1 month after initiating several medications. A skin biopsy was not consistent with SJS/TEN. The patient was diagnosed with probable DRESS/DIHS and treated with high-dose systemic corticosteroids. The ocular surface inflammation was addressed with intensive topical corticosteroid ointment. The pseudomembranes resolved over a 6-week period, but the patient exhibited residual conjunctival scarring of all palpebral surfaces. CONCLUSIONS: The development of severe ocular surface mucosal inflammation and denudation with cicatrizing sequelae in a patient carrying a diagnosis of DRESS/DIHS has diagnostic and therapeutic implications for the ophthalmologist. Careful ophthalmic assessment is indicated in any SCAR patient with ophthalmic symptoms, regardless of formal diagnosis. Furthermore, the early therapeutic interventions recently recommended in SJS/TEN to limit the ophthalmic cicatricial sequelae, such as systemic or topical corticosteroids, may be indicated.

Clinical Experience With PROSE Fitting: Significance of Diagnosis and Age.

OBJECTIVE: To compare ease of adoption of the BostonSight Prosthetic Replacement of the Ocular Surface Ecosystem device, a custom-fit scleral lens, by patients in different age and diagnosis groups. METHODS: In this prospective study, patients were categorized by age as younger than 60 or 60 years and older and by diagnosis as corneal irregularity (CI) or ocular surface disease (OSD). Ease of adoption of the scleral device was assessed by (1) number of devices and visits required to complete the fitting process, (2) time needed for device insertion and removal, (3) adaptation to the device, as assessed by daily wear time and by time needed to achieve full-time wear (defined as 8 hours per day), and (4) patients' subjective rating of ease of device insertion and removal. The length of the fitting process was also assessed. RESULTS: There was no significant difference in the number of devices and visits needed between age group younger than 60 and age group of 60 and older or between CI and OSD groups. Patients in all groups achieved full-time wear in less than 2 weeks. Average wear time per week did not differ significantly between age or diagnosis groups. Similarly, the time needed for daily insertion and removal during the fitting period, as well as patients' subjective rating of ease of device insertion and removal, did not differ between age or diagnosis categories. The length of the fitting process was significantly longer in the OSD group compared with the CI group (P<0.001); however, factors not related to ease of adoption of the scleral device may be responsible for this difference. CONCLUSIONS: Patients in both younger and older patient groups adopted the use of a scleral device with equal ease, as did patients in the CI and OSD diagnosis groups.

Corneal nerve structure and function after long-term wear of fluid-filled scleral lens.

PURPOSE: The aim of this study was to determine whether long-term wear of a fluid-filled scleral lens alters basal tear production, corneal sensation, corneal nerve density, and corneal nerve morphology in 2 disease categories. METHODS: Patients recruited from the Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) treatment program at the Weill Cornell Medical College were categorized into 2 groups: distorted corneas (DC) or ocular surface disease (OSD). We measured tear production, central corneal sensation, subbasal nerve density and tortuosity, and stromal nerve thickness before and after long-term wear of the prosthetic device used in PROSE treatment, defined as at least 60 days of wear for a minimum of 8 hours a day. RESULTS: Twenty patients were included in the study. After long-term wear of the prosthetic device, tear production decreased in patients with DC (21.2 ± 8.5 to 10.4 ± 4.6 mm; P < 0.0001) but did not change in patients with OSD (7.5 ± 5.2 to 8.7 ± 7.2 mm; P = 0.71). Corneal sensation increased in the DC group (45.6 ± 9.2 to 55.0 ± 5.6 mm; P < 0.05). There was no significant change in sensation in patients with OSD (45.0 ± 8.7 to 49.1 ± 14.8 mm; P = 0.37). Subbasal nerve density, subbasal nerve tortuosity, and stromal nerve thickness remained unchanged in both DC and OSD groups after long-term wear (P > 0.05). CONCLUSIONS: Patients with DC had significantly reduced basal tear production and increased corneal sensation after long-term wear of the scleral lens, but patients with OSD did not show any changes in tear production or corneal sensation.

Treatment of Refractory Persistent Corneal Epithelial Defects: A Standardized Approach Using Continuous Wear PROSE Therapy.

PURPOSE: To evaluate continuous wear of a fluid-ventilated, gas-permeable scleral PROSE device using a standardized protocol as treatment for refractory persistent corneal epithelial defects in patients with severe ocular surface disease. METHODS: Retrospective review of eight eyes of seven consecutive patients with persistent epithelial defects refractory to traditional therapies. The standardized treatment regimen consisted of: (1) 24-hour-a-day PROSE wear until re-epithelialization was achieved, (2) brief daily device removal, cleaning, disinfection, and reservoir fluid replacement, (3) addition of a benzalkonium chloride (BAK)-free fourth-generation fluoroquinolone antibiotic drop to the reservoir, and (4) transition to long-term, daytime PROSE wear upon re-epithelialization. RESULTS: All eight eyes exhibited resolution of the persistent epithelial defect. No eyes developed microbial keratitis. Four eyes exhibited recurrences; all recurrences promptly responded to reinstitution of continuous wear. CONCLUSIONS: Continuous wear of a PROSE device, using a strictly standardized regimen, constitutes an effective, safe treatment option for refractory persistent epithelial defects.

Ultraviolet-blocking intraocular lenses: fact or fiction.

PURPOSE OF REVIEW: Ultraviolet-blocking intraocular lenses (IOLs) are used routinely in cataract surgery and are widely accepted. Blue-blocking IOLs, however, have been much debated since their inception. In this article, we will review the advantages and disadvantages of blue-blocking IOLs. RECENT FINDINGS: In experimental and animal studies, acute blue light exposure induces retinal damage and the use of blue-blocking IOLs lessens this damage. Many large epidemiologic studies have further investigated this relationship between blue light exposure and the development of age-related macular degeneration, and have shown conflicting results. Visual performance and circadian rhythm disturbances have also been explored in patients with blue-blocking IOLs; no significant negative effects have been shown. SUMMARY: The current literature on blue-blocking IOLs is contradictory. Studies have failed to conclusively prove that blue-blocking lenses provide photoprotection against age-related macular degeneration or cause any significant detrimental effects on visual function or circadian rhythms.

Prompt versus delayed amniotic membrane application in a patient with acute Stevens-Johnson syndrome.

BACKGROUND: Stevens-Johnson syndrome is often associated with blinding ocular surface cicatricial sequelae. Recent reports have described markedly improved clinical outcomes with the application of amniotic membrane to the ocular surface during the acute phase. Here we describe the clinical outcome of a patient with acute Stevens-Johnson syndrome and severe ocular surface involvement in whom the evolving medical condition and family consent resulted in amniotic membrane application to each eye at differing intervals from disease onset. METHODS: We undertook a retrospective chart review of a woman with Stevens-Johnson syndrome who presented within hours of disease onset. She underwent application of amniotic membrane to the ocular surface of the left eye during the hyperacute phase (<72 hours after disease onset) and to the right eye at a later time point during the acute phase (six days after disease onset). The clinical outcomes of the two eyes, as well as associated ocular symptoms, were compared over a one-year postoperative period. RESULTS: The right eye, treated later in the course of the disease, required additional surgical procedures and ultimately exhibited significantly more advanced ocular surface pathology than the left. Further, the patient reported more pronounced issues of chronic eye pain and visual difficulties in the right eye. CONCLUSION: Earlier intervention with application of amniotic membrane to the ocular surface in this patient with severe ocular involvement secondary to Stevens-Johnson syndrome proved superior. Application of amniotic membrane as soon as possible after disease onset, preferably in the hyperacute phase, appears to result in a significantly better clinical outcome than application later in the disease course.

Current ophthalmologic treatment strategies for acute and chronic Stevens-Johnson syndrome and toxic epidermal necrolysis.

PURPOSE OF REVIEW: To review the newer, effective ophthalmologic treatments for acute Stevens-Johnson syndrome (SJS) as well as the emerging treatment options for patients with chronic, severe ocular surface damage from the disease. RECENT FINDINGS: Amniotic membrane transplantation (AMT) applied to the eyes and eyelids in the acute phase of SJS can prevent the devastating scarring and visual problems that characterize the chronic phase of the disease. The severity of ocular inflammation in the acute phase does not always correlate to the severity of skin and systemic involvement. Thus, it is crucial that all patients with SJS be evaluated by an ophthalmologist familiar with the current management of the disease, the potential urgency of the situation and the option of AMT. Although challenging, the severe, chronic ocular problems of SJS can be at least partially alleviated with autologous serum drops, mucous membrane grafting to replace scarred tarsal conjunctiva, specialized contact lenses (PROSE), conjunctival replacement surgery (COMET), limbal stem cell transplantation and kerotoprostheses. SUMMARY: Early AMT is an effective treatment of acute SJS. Emerging treatments offer increased hope for those who have already suffered damage from SJS, but emphasis on the prevention of damage in the acute phase is most crucial.

Boston type I keratoprosthesis-donor cornea interface evaluated by high-definition spectral-domain anterior segment optical coherence tomography.

BACKGROUND: The purpose of this study was to assess whether the resolution offered by two different, recently commercially available high-resolution, spectral-domain anterior segment optical coherence tomography (AS-OCT) instruments allows for detailed anatomic characterization of the critical device-donor cornea interface in eyes implanted with the Boston type I permanent keratoprosthesis. METHODS: Eighteen eyes of 17 patients implanted with the Boston type I keratoprosthesis were included in this retrospective case series. All eyes were quantitatively evaluated using the Cirrus HD-OCT while a subset (five eyes) was also qualitatively imaged using the Spectralis Anterior Segment Module. Images from these instruments were analyzed for evidence of epithelial migration onto the anterior surface of the keratoprosthesis front plate, and presence of a vertical gap between the posterior surface of the front plate and the underlying carrier donor corneal tissue. Quantitative data was obtained utilizing the caliper function on the Cirrus HD-OCT. RESULTS: The mean duration between AS-OCT imaging and keratoprosthesis placement was 29 months. As assessed by the Cirrus HD-OCT, 83% of eyes exhibited epithelial migration over the edge of the front plate. Fifty-six percent of the keratoprosthesis devices displayed good apposition of the device with the carrier corneal donor tissue. When a vertical gap was present (44% of eyes), the mean gap was 40 (range 8-104) microns. The Spectralis Anterior Segment Module also displayed sufficient resolution to allow for similar characterization of the device-donor cornea interface. CONCLUSION: Spectral-domain AS-OCT permits high resolution imaging of the keratoprosthesis device-donor cornea interface. Both the Cirrus HD-OCT and the Spectralis Anterior Segment module allowed for visualization of epithelial coverage of the device-donor cornea interface, as well as identification of physical gaps. These imaging modalities, by yielding information in regard to integration of the keratoprosthesis with surrounding corneal tissue, may help identify those at risk for keratoprosthesis-related complications, such as extrusion and endophthalmitis, and hence guide clinical management.