Corneal Stress Distribution Evolves from Thickness-Driven in Normal Corneas to Curvature-Driven with Progression in Keratoconus.

Purpose: To introduce the novel parameter of Corneal Contribution to Stress (CCS) and compare stress distribution patterns between keratoconus (KCN) and normal corneas. Design: Prospective, observational, cross-sectional study. Participants: The study included 66 eyes of 40 subjects diagnosed with KCN and 155 left eyes from 155 normal control (NRL) subjects. Methods: Tomography was obtained to calculate the newly proposed CCS, defined according to the hoop stress formula without intraocular pressure, R/2t, where R is the radius of curvature and t is the thickness. CCS maps were calculated from pachymetry and tangential curvature maps. Custom software identified the 2-mm-diameter zones of greatest curvature (Cspot-max), thinnest pachymetry (Pach-min), greatest stress (CCSmax), and lowest stress (CCSmin). Stress difference (CCSdiff) was calculated as CCSmax - CCSmin. Distances between Cspot-max vs. Pach-min, vs. CCSmax, and vs. CCSmin, as well as between Pach-min vs. CCSmax and vs. CCSmin, were calculated. t tests were performed between cohorts, and paired t tests were performed within cohorts. Univariate linear regression analyses were performed between parameters and distances. The significance threshold was P < 0.05. Main Outcome Measures: Corneal stress parameters, corneal features of maximum curvature, minimum thickness, and distances between corneal stress parameters and corneal features. Results: CCSmax was significantly closer to Pach-min (0.79 ± 0.92) and Cspot-max (2.04 ± 0.85) than CCSmin (3.17 ± 0.38, 2.73 ± 1.53, respectively) in NRL, P < 0.0001, whereas CCSmin was significantly closer to Cspot-max (1.35 ± 1.43) than CCSmax (2.52 ± 0.72) in KCN, P < 0.0001. Cspot-max (severity) was significantly related to CCSdiff in KCN (P < 0.0001; R2 = 0.5882) with a weak relationship in NRL (P < 0.0080, R2 = 0.0451). Cspot-max was significantly related to the distance from Pach-min to CCSmax (P < 0.0001; R2 = 0.3737) without significance in NRL (P = 0.8011). Conclusions: Corneal stress is driven by thickness in NRL, with greatest stress at thinnest pachymetry and greatest curvature. However, maximum stress moves away from thinnest pachymetry with progression in KCN, and minimum stress is associated with maximum curvature. Severity in KCN is significantly related to greater difference between maximum and minimum stress, consistent with the biomechanical cycle of decompensation. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Strategies for prevention and management of ocular events occurring with mirvetuximab soravtansine.

Mirvetuximab soravtansine (MIRV) is a first-in-class antibody-drug conjugate (ADC) targeting folate receptor alpha (FRα) and is indicated for the treatment of adult patients with FRα-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received 1 to 3 prior systemic treatment regimens. MIRV has demonstrated single-agent anticancer activity in clinical trials, with a differentiated safety profile comprising primarily low-grade, resolvable gastrointestinal and ocular adverse events (AEs). Pooled safety analysis of 464 MIRV-treated patients across 3 trials, including the phase 2 SORAYA study, found that 50% of patients had ≥1 ocular AEs of interest (AEIs) of blurred vision or keratopathy, the majority being grade ≤2. Grade 3 ocular AEIs occurred in 5% of patients, and 1 patient (0.2%) had a grade 4 event of keratopathy. All grade ≥2 AEIs of blurred vision and keratopathy resolved to grade 1 or 0 in patients with complete follow-up data. MIRV-associated ocular AEs were primarily characterized by resolvable changes to the corneal epithelium, with no cases of corneal ulcers or perforations. This reflects the distinctive, milder ocular safety profile for MIRV compared with that of other ADCs with ocular toxicities in clinical use. To maintain a generally low incidence of severe ocular AEs, patients should follow recommendations for maintaining ocular surface health, including daily use of lubricating eye drops and periodic use of corticosteroid eye drops, and should undergo an eye examination at baseline, at every other cycle for the first 8 cycles of treatment, and as clinically indicated. Dose modification guidelines should be followed to maximize patients' ability to remain on therapy. Close collaboration between all care team members, including oncologists and eye care professionals, will help patients benefit from this novel and promising anticancer agent. This review focuses on the etiology, rates, prevention, and management of MIRV-associated ocular events.

High-frequency ultrasound detects biomechanical weakening in keratoconus with lower stiffness at higher grade.

In vivo biomechanical characterization of the cornea remains a challenge. We have developed a high-frequency ultrasound elastography method, the ocular pulse elastography (OPE), to measure corneal axial displacement (CAD) induced by the ocular pulse. Here we compared CAD and a stiffness index derived from CAD between keratoconus patients and normal controls. We also explored the trend of these parameters with keratoconus grade. Twenty normal subjects and twenty keratoconus patients were recruited in this study. Corneal topography, tomography, intraocular pressure (IOP) and ocular pulse amplitude (OPA) were obtained in each measured eye. The cornea's heartbeat-induced cyclic axial displacements were measured by high-frequency (50 MHz) ultrasound. A corneal stiffness index (CSI) was derived from CAD normalized against OPA. CAD and CSI were compared between normal and keratoconus groups, and across keratoconus grades. Keratoconus corneas had significantly greater CAD and lower CSI than normal controls (p's<0.01). Both parameters correlated strongly with grade, in which CAD increased significantly (p = 0.002) and CSI decreased significantly (p = 0.011) with grade. These results suggested a biomechanical weakening in keratoconus which worsens at higher disease severity. This study also demonstrated the ability of high-frequency ultrasound elastography to provide a safe, quick, and accurate evaluation of the cornea's biomechanical condition in vivo. The OPE-measured biomechanical metrics, when integrated with existing diagnostic criteria, may aid the decision-making in the early and definitive diagnosis and staging of keratoconus.

Ultra-wide field imaging to assess the optic nerve and retina in Boston type I and II keratoprosthesis patients.

BACKGROUND: The ability to view the posterior segment in keratoprosthesis (Kpro) implanted patients is limited. The purpose of this retrospective, observational study was to investigate the use of ultra-wide field (UWF) scanning laser ophthalmoscopy imaging and its utility for serial evaluation of the retina and optic nerve in patients with either a Boston type I or II Kpro. METHODS: A retrospective chart review was performed for patients with a Boston type I or II Kpro seen at The Ohio State University Wexner Medical Center. Images were graded for quality by two masked observers on a defined four-point scale ("Poor", "Fair", "Good", or "Very good") and assessed for visible posterior segment anatomy. Interobserver agreement was described using the Kappa statistic coefficient (κ) with 95% confidence intervals. RESULTS: A total of 19 eyes from 17 patients were included in this study. Eighteen eyes had a type I Kpro, while one eye had a type II Kpro. UWF imaging from 41 patient visits were reviewed by two observers. Interobserver agreement between the two graders was fair for image quality (κ = 0.36), moderate for visibility of the macula with discernible details (κ = 0.59), moderate for visibility of the anterior retina with discernable details (κ = 0.60), and perfect agreement for visibility of the optic nerve with discernible details (κ = 1.0). In 6 eyes, UWF imaging was performed longitudinally (range 3-9 individual visits), allowing for long-term follow-up (range 3-46 months) of posterior segment clinical pathology. CONCLUSIONS: UWF imaging provides adequate and reliable visualization of the posterior segment in Kpro implanted patients. This imaging modality allowed for noninvasive longitudinal monitoring of retinal and optic nerve disease in this selected patient population.

Ocular side effects of antirheumatic medications: a qualitative review.

TOPIC: This paper reviews the ocular side effects of medications used in the treatment of rheumatological conditions. CLINICAL RELEVANCE: Rheumatic diseases are inflammatory conditions that may affect the skin, blood vessels, joints, muscles and internal organs. Immunosuppressive agents are often used as treatment and while powerful, they carry side effects and toxicities that need careful monitoring. Ophthalmic complications have been reported with the use of antirheumatic medications; however, there is a lack of literature synthesising these reports. This paper addresses this gap and hopes to inform both rheumatologists and ophthalmologists as they work together on the management of patients with rheumatological conditions. METHODS: PubMed literature search was conducted from November to September 2019 searching for ocular side effects with the use of 25 rheumatological drugs. RESULTS: A total of 111 papers were included in this review. Adverse side effects were divided into non-infectious and infectious causes. Traditional disease-modifying antirheumatic drugs (DMARDs) were associated with pruritus, irritation and dryness of the conjunctiva while biologic DMARDS showed reports of new-onset/recurrent uveitis and demyelinating conditions. Infectious side effects included episodes of cytomegalovirus retinitis, toxoplasmic chorioretinitis and endophthalmitis. Other serious side effects were encountered and included in this review. CONCLUSION: The goal of this paper is to inform healthcare providers about potential ocular side effects from rheumatological medications. Healthcare providers are encouraged to learn more about these ophthalmic complications and find relevance within their clinical practice.

Heartbeat-Induced Corneal Axial Displacement and Strain Measured by High Frequency Ultrasound Elastography in Human Volunteers.

Purpose: The purpose of this study was to establish in vivo data acquisition and processing protocols for repeatable measurements of heartbeat-induced corneal displacements and strains in human eyes, using a high-frequency ultrasound elastography method, termed ocular pulse elastography (OPE). Methods: Twenty-four volunteers with no known ocular diseases were recruited for this study. Intraocular pressure (IOP) and ocular pulse amplitude (OPA) were measured using a PASCAL Dynamic Contour Tonometer (DCT). An in vivo OPE protocol was developed to measure heartbeat-induced corneal displacements. Videos of the central 5.7 mm of the cornea were acquired using a 50-MHz ultrasound probe at 128 frames per second. The radiofrequency data of 1000 frames were analyzed using an ultrasound speckle tracking algorithm to calculate corneal displacements and quantify spectral and temporal characteristics. The intrasession and intersession repeatability of OPE- and DCT-measured parameters were also analyzed. Results: The in vivo OPE protocol and setup were successful in tracking heartbeat-induced corneal motion using high-frequency ultrasound. Corneal axial displacements showed a strong cardiac rhythm, with good intrasession and intersession repeatability, and high interocular symmetry. Corneal strain was calculated in two eyes of two subjects, showing substantially different responses. Conclusions: We demonstrated the feasibility of high-frequency ultrasound elastography for noninvasive in vivo measurement of the cornea's biomechanical responses to the intrinsic ocular pulse. The high intrasession and intersession repeatability suggested a robust implementation of this technique to the in vivo setting. Translational Relevance: OPE may offer a useful tool for clinical biomechanical evaluation of the cornea by quantifying its response to the intrinsic pulsation.

Known and novel ocular toxicities of biologics, targeted agents, and traditional chemotherapeutics.

PURPOSE: Increases in cancer with an aging population and the rapid development of new chemotherapeutics underscore the need for ophthalmologists to identify and manage potential ocular toxicities. This retrospective case series reports the ocular side effects of traditional and novel chemotherapeutic agents from a large center. METHODS: The medical records of 3537 adult patients 18 years and older who presented to an academic ophthalmology department on high-risk medications identified by ICD-9 search between January 2010 and February 2015 were reviewed. A cancer diagnosis, as well as a temporal association with chemotherapeutic use and ocular side effect, was deemed necessary for inclusion in the study. The main measures were ocular side effects in cancer patients taking chemotherapy, ocular imaging abnormalities, and the outcome of each side effect. RESULTS: Of the 161 oncology patients referred to the ophthalmology clinic for chemotherapeutic screening or ocular side effect, 31 (19.3%) were identified as having an ocular adverse reaction due to a novel or traditional chemotherapeutic medication. A novel flattening of the corneal curvature with hyperopic shift and corneal microcysts was identified in a patient taking the antibody-drug conjugate mirvetuximab soravtansine and was reversible with topical steroids. A bilateral medium-vessel choroidal vasculopathy with serous retinal detachment was seen with ipilimumab. The most frequent medication with ocular toxicity was interferon-α(2b) (IFN-α(2b)) (6/31, 19.4%); headache was typical in these patients (83.3%). Ibrutinib ocular toxicity was second most common (5/31, 16.1%), usually causing red or dry eye, while one patient developed branch retinal artery occlusion. Retinal abnormalities documented on OCT imaging occurred with IFN-α(2b), ipilimumab, binimetinib, and docetaxel, while rod-cone ERG abnormality was seen with cisplatin. Inflammatory conditions included anterior scleritis with zoledronic acid, focal eyelid inflammation with veliparib, bilateral chemosis with R-CHOP, iritis, and blepharospasm with IFN-α(2b). AION occurred with pemetrexed, and transient vision loss with hyperemic disc OS was seen with FOLFOX. Two patients (2/31, 6.5%) developed permanent vision loss. Six patients were lost to follow-up, and the clinical course was unknown (6/31, 19.4%). CONCLUSIONS AND RELEVANCE: Cases of permanent visual loss were observed; yet, in the majority of side effects, they improved with topical therapy and/or holding the medication. Further research is needed to elucidate the incidence and the pathophysiology of these side effects and maximize patient quality of life.

Tear lipid layer thickness with eye drops in meibomian gland dysfunction.

PURPOSE: The aim of this study was to evaluate the efficacy of a lipid containing emollient eye drop, Soothe XP, which was reformulated in 2014 with a more stable preservative and buffer system, compared to a control, non-emollient, eye drop (Systane Ultra) in improving lipid layer thickness (LLT) in subjects with dry eye due to meibomian gland dysfunction (MGD). PATIENTS AND METHODS: This prospective single-center, open-label, cross-over, examiner masked-study enrolled subjects aged 30-75 years with lipid-deficient dry eye and a clinical diagnosis of MGD as determined by a slit lamp examination, an evaluation of meibomian gland drop out with meibography, and a standard patient evaluation of eye dryness questionnaire of >5. Eligibility was then determined by a LLT of <75 nm at baseline and the inability to increase LLT ≥15 nm with three blinks, as determined by interferometric methods. Subjects were randomized to receive a single emollient or non-emollient eye drop at Visit 1 and were crossed over for the alternate treatment at Visit 2. At each visit, LLT was measured prior to and 15 minutes following the instillation of the assigned eye drop. The primary endpoint was the change in LLT from baseline. RESULTS: Subjects (n=40) were enrolled and 35 completed the two study arms. Mean (±SD) patient age was 55.7 years (10.9) and 69% were female. Mean (±SD) LLT at baseline was 49.5 nm (9.2). Instillation of Soothe XP resulted in an increase in LLT to 77.5 nm (29.3) 15 minutes following drop instillation, which is an increase of 28.0 nm (27.4) (P<0.001). In contrast, LLT 15 minutes after the instillation of Systane Ultra was 50.8 nm (14.1), which was not statistically significant when compared to the baseline LLT. CONCLUSION: In this study of subjects with MGD, the emollient, or lipid containing eye drop, increased the LLT of tears when measured 15 minutes after instilling a single eye drop.

Bilateral optic neuropathy following bite from brown recluse spider (Loxosceles reclusa).

A 63-year-old female with history of a resected frontal lobe meningioma presented with bilaterally decreased vision after a bite from a brown recluse spider. The exam was significant for a left relative afferent pupillary defect, bilateral optic nerve pallor, decreased foveal sensitivity in the left eye and new bilateral visual field defects, despite stability of her meningioma. The findings remained stable at 1-year follow-up. To our knowledge, this is the first reported case of optic neuropathy secondary to a brown recluse spider bite. Visual field tests performed prior to the bite allowed us to compare and localize changes related to the bite.