Understanding Ocular Graft-Versus-Host Disease to Facilitate an Integrated Multidisciplinary Approach.

Ocular Graft-versus-Host Disease (oGVHD) remains a challenging and potentially devastating complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). It significantly impacts the quality of life of affected survivors, however, is often underrecognized particularly during the early stages. Targeting all providers in the HSCT community who see patients regularly and frequently for their post-allo-HSCT care, this review and opinion piece introduces the basic concepts of ocular surface pathophysiology, dissects the different stages of clinical presentation of oGVHD, explains why the current diagnostic criteria tend to capture the late disease stages, highlights the warning signs of early disease development, in hope to facilitate prompt referral of oGVHD suspects for ocular specialist care. In addition to introducing a comprehensive list of treatment options, this review emphasizes basic therapeutic strategy and options that are safe and effective to be initiated by any care provider. We believe in empowering the patients as well as the care providers beyond disciplinary boundaries, in order to provide the most cohesive and integrated care to our patients in a multidisciplinary approach.

Active Learning to Characterize the Full Contrast Sensitivity Function in Cataracts.

Background: To characterize contrast sensitivity function (CSF) in cataractous and pseudophakic eyes compared to healthy control eyes using a novel quantitative CSF test with active learning algorithms. Methods: This is a prospective observational study at an academic medical center. CSF was measured in eyes with visually significant cataract, at least 2+ nuclear sclerosis (NS) and visual acuity (VA) ≥ 20/50, in pseudophakic eyes and in healthy controls with no more than 1+ NS and no visual complaints, using the Manifold Contrast Vision Meter. Outcomes included Area under the Log CSF (AULCSF) and CS thresholds at 1, 1.5, 3, 6, 12, and 18 cycles per degree (cpd). A subgroup analysis as performed on cataract eyes with VA ≥ 20/25. Results: A total of 167 eyes were included, 58 eyes in the cataract group, 77 controls, and 32 pseudophakic eyes with respective median AULCSF of 1.053 (0.352) vs 1.228 (0.318) vs 1.256 (0.360). In our multivariate regression model, cataract was associated with significantly reduced AULCSF (P= 0.04, ß= -0.11) and contrast threshold at 6 cpd (P= 0.01, ß= -0.16) compared to controls. Contrast threshold at 6 cpd was significantly reduced even in the subgroup of cataractous eyes with VA ≥ 20/25 (P=0.02, ß=-0.16). Conclusion: The novel qCSF test detected disproportionate significant contrast deficits at 6 cpd in cataract eyes; this remained significant even in the cataractous eyes with VA ≥ 20/25. CSF testing may enhance cataract evaluation and surgical decision-making, particularly in patients with subjective visual complaints despite good VA.

Ocular Graft-versus-Host Disease Underdiagnosis: A Survey Study.

Purpose: To understand the degree and explore the possible causes of ocular graft-versus-host disease (oGVHD) underdiagnosis in patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients and Methods: A 15-question survey was emailed to 6032 subscribers to the Blood and Marrow Transplant Information Network. A total of 371 respondents confirmed the history of allo-HSCT, of which 335 were symptomatic. Their self-reported symptoms, onset, treatments tried, degree of symptom control and established diagnoses of systemic chronic graft-versus-host disease (cGVHD) and oGVHD were analyzed. Results: Among the 335 symptomatic survey respondents, 306 reported their ocular symptom onset was after allo-HSCT, with only 170 [55.6% (170/306)] ever receiving a diagnosis of oGVHD; 23 reported worsening pre-existing ocular symptoms after allo-HSCT, with only 5 [21.7% (5/23)] ever receiving a diagnosis of oGVHD; 6 reported stable symptoms before and after allo-HSCT, with 1 ever receiving a diagnosis of oGVHD. Of the 176 respondents carrying the diagnosis of oGVHD, 167 [94.9% (167/176)] also had the diagnosis of cGVHD. Logistic regression analysis showed that the diagnosis of oGVHD was highly correlated with the number of symptoms and treatments one reported. Furthermore, 35% of the respondents with new onset ocular symptoms reported onset within the first 6 months after allo-HSCT (previously reported), as well as 39% of the respondents with worsened existing symptoms. Conclusion: oGVHD underdiagnosis is likely associated with the previous diagnostic criteria, in which cGVHD of another organ system was required. The correct notion that oGVHD commonly causes severe dry eye disease has likely led to its underdiagnosis in patients with fewer number of symptoms and/or who tried fewer treatments.

Efficacy and Safety of 1% Progesterone Gel to the Forehead for Ocular Chronic Graft-versus-Host Disease.

There is no Food and Drug Administration-approved treatments for ocular chronic graft-versus-host disease (oGVHD) to date, and current therapeutic options are limited. Forehead application of 1% progesterone gel provides corneal antinociception in preclinical models, suggesting it may be useful in alleviating ocular irritations. This study was conducted to evaluate the efficacy and safety of 1% progesterone gel in treating moderate to severe symptomatic oGVHD. Thirty-three patients with oGVHD following allogeneic stem cell transplantation were enrolled in this single-center, sponsor-initiated, prospective exploratory randomized double-masked placebo-controlled phase II clinical trial. The inclusion criteria included a National Institutes of Health consensus score of ≥2, moderate to severe ocular discomfort level, and receipt of a stable immunosuppression regimen. Twenty-one of the 22 patients in the progesterone arm and all 11 patients in the placebo arm completed the course of twice-daily forehead drug application for 10 weeks. The changes from baseline of self-reported ocular symptom scores and physician-recorded cornea fluorescein staining scores were analyzed using mixed-model repeated-measures regression model in an intention-to-treat population. The 33 patients included 12 women and 21 men, with a median age of 66 years (range, 24 to 75 years). At 10 weeks, there was a significant reduction in ocular symptoms from baseline in the progesterone group compared with the placebo group in symptom frequency (-30.7 versus -2.2; P < .001) and severity (-19.8 versus +1.6; P = .005). At 10 weeks, there was also greater reduction of cornea fluorescein staining centrally (-1.2 versus +.1; P = .001) and inferiorly (-1.4 versus -0.2; P = .005). No difference was noted in superior cornea staining. There were no severe adverse events in the progesterone group. Forehead application of 1% progesterone gel significantly improved ocular signs and symptoms within 10 weeks. It appears to be a safe and effective new therapy for oGVHD, and a novel mechanism for neuroaxis drug delivery. A multicenter phase III clinical trial is planned for further validation.

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIa. The 2020 Clinical Implementation and Early Diagnosis Working Group Report.

Recognition of the earliest signs and symptoms of chronic graft-versus-host disease (GVHD) that lead to severe manifestations remains a challenge. The standardization provided by the National Institutes of Health (NIH) 2005 and 2014 consensus projects has helped improve diagnostic accuracy and severity scoring for clinical trials, but utilization of these tools in routine clinical practice is variable. Additionally, when patients meet the NIH diagnostic criteria, many already have significant morbidity and possibly irreversible organ damage. The goals of this early diagnosis project are 2-fold. First, we provide consensus recommendations regarding implementation of the current NIH diagnostic guidelines into routine transplant care, outside of clinical trials, aiming to enhance early clinical recognition of chronic GVHD. Second, we propose directions for future research efforts to enable discovery of new, early laboratory as well as clinical indicators of chronic GVHD, both globally and for highly morbid organ-specific manifestations. Identification of early features of chronic GVHD that have high positive predictive value for progression to more severe manifestations of the disease could potentially allow for future pre-emptive clinical trials.

Novel Method to Determine Target Refraction in Cataract Surgery for Patients Dependent on Therapeutic Scleral Lenses.

OBJECTIVES: To evaluate a novel approach to determine the refractive target for patients undergoing cataract surgery who are dependent on therapeutic scleral lenses, to avoid the need for postoperative scleral lens replacement. METHODS: Retrospective single-surgeon case series. The target refraction for intraocular lens selection was determined by considering the effective scleral lens system power. This was calculated by adding the known scleral lens spherical power to the difference between the scleral lens base curve and the average keratometry value. RESULTS: Six eyes from three patients with moderate myopia or emmetropia with ocular graft versus host disease dependent on therapeutic scleral lenses underwent cataract surgery with intraocular lens selection based on this method. All six eyes had corrected visual acuities of 20/30 or better while wearing their previous scleral lenses at the postoperative week 1 visit. All six eyes resumed full-time scleral lens use 1 week after phacoemulsification and did not require scleral lens replacement. CONCLUSIONS: Using this method, patients requiring therapeutic scleral lenses can quickly experience optimal vision, comfort, and ocular surface protection 1 week after cataract surgery. These patients can continue to use their existing scleral lenses and avoid the costs and burdens associated with lens replacement.

Current and potential applications of anterior segment optical coherence tomography in contact lens fitting.

Optical coherence tomography (OCT) is a non-invasive, high-resolution and high-speed imaging modality that has enjoyed rapid growth in ophthalmology since its development 20 years ago. Contact lens fitting is traditionally based on trial lenses, which is expensive and time-consuming. Modern anterior segment OCT is capable of generating three-dimensional ocular surface maps of the cornea and sclera with potential application in contact lens fitting. This paper reviewed the history, the ophthalmic applications, and the most recent advancement in three-dimensional anterior segment OCT. There is very limited literature of OCT in contact lens fitting to date. This review anticipates an increase in this application in the near future.

Levels of vascular endothelial growth factor-A165b (VEGF-A165b) are elevated in experimental glaucoma.

PURPOSE: Although ischemia has previously been suggested to contribute to the pathogenesis of glaucoma, neovascularization is not implicated in glaucoma. Because vascular endothelial growth factor-A (VEGF-A) is a key mediator in neovascularization response, we investigated the levels of the major pro-angiogenic (VEGF-A164) and anti-angiogenic VEGF-A subtypes (VEGF-A165b) in the retina during experimental glaucoma. METHODS: Glaucoma was induced unilaterally in rats by injecting 1.9 M hypertonic saline solution in the episcleral veins. The contralateral eye served as the control. The intraocular pressure (IOP) of each eye was measured via Tonopen in conscious rats. Eyes were enucleated either on the 5th or the 10th day of elevated IOP. Whole retinal lysates were separated by SDS-PAGE and transferred to PVDF membranes. Levels of VEGF-A164 and VEGF-A165b were analyzed by western blotting using specific antibodies. In a different group of rats, retinal ganglion cells were retrogradely labeled by injecting Fluorogold in the superior colliculus a week before the induction of glaucoma. After the eyes were enucleated on the fifth day of elevated IOP, posterior eye cups were sectioned using a cryostat. Levels and localization of VEGF-A164 and VEGF-A165b were examined in retinal sections by immunohistochemistry. RESULTS: VEGF-A164 levels remained unchanged between the control and glaucomatous retinas after five days (p=0.341) and 10 days of elevated IOP (p=0.117). The presence of the anti-angiogenic VEGF-A isoform has not been previously reported in the rat. An antibody specific to VEGF-A165b detected the anti-angiogenic protein in the rat retina. VEGF-A165b levels were significantly increased (2.33+/-0.44 fold, p=0.014) in the glaucomatous retinas compared to those in controls after five days of elevated IOP. VEGF-A165b levels were not different (p=0.864) between the control and glaucomatous retinas following 10 days of elevated IOP. Expression of both VEGF-A164 and VEGF-A165b were observed in the retinal ganglion cells (RGC) and inner nuclear layer (INL). CONCLUSIONS: Five day elevation of IOP leads to an increase in the anti-angiogenic VEGF-A165b levels but not in the pro-angiogenic VEGF-A164 levels in the glaucomatous retina. VEGF-A165b levels return to baseline after 10 days of elevated IOP, and VEGF-A164 levels remain unchanged. We speculate that the short-term elevation of VEGF-A165b levels and/or the unchanged levels of VEGF-A164 contribute to the lack of neovascularization in the glaucomatous retina.