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.

Dexmedetomidine promotes the functional recovery of mice after acute ischemic stroke via activation of the α2-adrenoceptor.

Ischemic stroke (IS) is a well-known acute cerebrovascular disease characterized by high disability, morbidity, and recurrence rates with no effective treatments. Dexmedetomidine (DEX), a selective a2-adrenoceptor agonist used in anaesthesiology and pain management, has been found to exhibit neuroprotective effects in various diseases. However, its role in IS and the underlying mechanisms remains to be determined. Hence, the aim of the present study was to investigate the neuroprotective role of DEX in the recovery of mice following middle cerebral artery occlusion (MCAO). Mice were used to establish the animal model, and then DEX was injected. Behavioural tests (neurological function assessments, grip test, and rotarod test), brain water content measurement, ELISA, and measurement of oxidative stress were performed. DEX activated a2-adrenoceptor and resulted in reduced brain injury, as indicated by the decreased brain water content, S100 Calcium Binding Protein B (S100B) content, and neuron-specific enolase (NSE) content, whilst also inhibiting oxidative stress, as indicated by the increased total antioxidant capacity, catalase, glutathione, and superoxide dismutase levels, and decreased malondialdehyde and glutathione oxidized levels. Neuroinflammation was also reduced as indicated by the decrease in IFN-g, IL-1a, IL-1b, IL-6, TNF-a, and MMP levels, improved the recovery of neurological function, as indicated by the decreased neurological function score and mNSS, and increased grip strength and rotarod performance in MCAO mice. These combined results suggest that DEX may be a novel strategy for the treatment of IS.

Successful Management of Infectious Crystalline Keratopathy with Intrastromal Antibiotic Injections.

Purpose. To report the successful treatment of a case of presumed infectious crystalline keratopathy with repeated intrastromal antibiotic injections in a cornea graft in the setting of severe ocular graft-vs.-host-disease (GVHD). Observations. A 62-year-old man with a history of ocular GVHD and tectonic penetrating keratoplasty (PK) for corneal melt from herpes zoster keratopathy developed presumed infectious crystalline keratopathy (ICK) in the corneal graft. Given the patient's complicated ocular history, chronic immunosuppression and new cardiac comorbidities, a therapeutic PK would most likely fail. Efforts were then directed to rescue the graft with minimally invasive approaches. Two separate intrastromal injections of cefuroxime and moxifloxacin successfully treated his ICK. Conclusions and Importance. This case supports a role for repeated intrastromal antibiotic injections in patients with ICK refractory to topical antibiotic therapy, which might eliminate the need for therapeutic PK and preserve vision.

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.

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report.

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.

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.

Scleral Lens and Prosthetic Replacement of the Ocular Surface Ecosystem Utilization in Ocular Graft-versus-Host Disease: A Survey Study.

PURPOSE: To evaluate the utilization of scleral lenses and prosthetic replacement of the ocular surface ecosystem devices (SL/PDs) in the management of ocular graft-versus-host disease (oGVHD). PATIENTS AND METHODS: A survey of 15 questions was sent via email to 6032 subjects registered with the Blood and Marrow Transplant Information Network. The survey reviewed transplant history, graft-versus-host disease history, as well as oGVHD symptoms and onset. Additional questions surveyed treatments used for oGVHD, as well as the degree of ocular symptom control and experience with SL/PDs. A total of 306 respondents met the eligibility requirements to be part of the analyzed cohort. RESULTS: The mean number of symptoms reported from the analyzed cohort was 4.79 ± 2.44, median (IQR) of 5.0 (3.0 to 7.0), with the most common symptom being gritty, dry eyes (87%). The mean number of treatments utilized across the analyzed cohort was 3.21 ± 2.55, median (IQR) of 2.5 (1.0 to 5.0), with the most common treatment being artificial tears (86%). Wearing scleral lenses resulted in a mean of 5.42 ± 1.86, median (IQR) of 6.0 (4.0 to 7.0) symptoms improving, with improved dryness/grittiness of the eyes (94%), improved eye pain (92%) and improved quality of life (89%) being the most commonly improved symptoms. Fifty-six percent of those wearing scleral lenses wished the lenses had been recommended sooner. The most common reason patients cited for not wearing scleral lenses was that they had never heard of them (63%). CONCLUSION: SL/PDs help to control the symptoms of oGVHD. With their use, clinicians are able to improve the quality of life of this patient population. Despite the known benefits, SL/PDs still remain underutilized in oGVHD care. A majority of current SL/PD wearers wish that they had been recommended sooner as a treatment option. SL/PDs should be considered a component of comprehensive oGVHD management.

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.

A Comprehensive Surgical Curriculum Reduced Intra-operative Complication Rates of Resident-performed Cataract Surgeries.

OBJECTIVES: To evaluate the impact of a comprehensive cataract surgery curriculum on the incidence of intraoperative complications. DESIGN: We retrospectively compared the total number of cataract surgeries that the residents performed in all of the teaching sites, and the incidences of intraoperative complications (anterior capsule tear, posterior capsule rent, vitreous loss, anterior vitrectomy, zonular dialysis, iris trauma, hemorrhage, dropped lens fragment, corneal wound burn, incorrect intraocular lens) for the surgeries performed at Massachusetts Eye & Ear by residents in the pre-intervention group (residents graduating in 2004 and 2005), before the implementation of a surgical curriculum, and the residents in the post-intervention group (residents graduating in 2014 and 2015). SETTING: Ophthalmology residency program at a major academic institution. PARTICIPANTS: Residents graduating in 2004, 2005, 2014, and 2015. RESULTS: We reviewed 4373 charts. 2086 of those surgeries were performed at Massachusetts Eye & Ear. The incidence of posterior capsule rent/vitreous loss/anterior vitrectomy was lower in the post-intervention group (1.4% versus 7.7%, p < 0.0001). Other complications were also lower in the post-intervention group. CONCLUSIONS: Implementation of a comprehensive cataract surgery curriculum focusing on pre-operative, intra-operative and post-operative interventions, with an emphasis on patient outcomes resulted in a decrease in the rate of intraoperative complications.

Primary implantation of type I Boston keratoprosthesis in nonautoimmune corneal diseases.

PURPOSE: The aim of this study was to report outcomes of type I Boston keratoprosthesis (KPro) as primary corneal surgery in nonautoimmune corneal disorders. METHODS: In this retrospective, observational, large single-center case series of 43 eyes (37 patients) that were followed for an average of 39 months (1-6 years), primary implantation of the type I Boston KPro was performed in all patients. Visual acuity at year 1, visual acuity at last follow-up, and postoperative complication rates were examined for all eyes. RESULTS: Preoperative best-corrected visual acuity ranged from 20/60 to light perception, with vision of 20/200 or worse in 88%. Vision was ≥20/200 at 1 year in 77% of eyes (P < 0.0001). Complications included retroprosthetic membrane formation (51%), glaucoma progression (47%), corneal melt (19%), and sterile vitritis (14%). CONCLUSIONS: In a large series with long follow-up, primary Boston KPro effectively restored vision. Close follow-up is needed to manage the known complications after Boston KPro.

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.

The incidence of intraocular foreign bodies and other intraocular findings in patients with corneal metal foreign bodies.

PURPOSE: To review the findings of dilated fundus examinations (DFEs) in patients with the diagnosis of corneal metal foreign body (CMFB) and to assess the likelihood of concomitant intraocular foreign body (IOFB) in this clinical setting. DESIGN: Retrospective, case review series. PARTICIPANTS: All 288 cases with a new diagnosis of CMFB that had a documented DFE in the emergency department at Massachusetts Eye and Ear Infirmary from January 1, 2008, to December 31, 2008. In addition, all 9 separate cases of metal IOFB seen in the same time period were also reviewed. METHODS: The medical records of all patients were individually reviewed. MAIN OUTCOME MEASURES: The DFE findings of each visit were analyzed in addition to mechanism of injury, visual acuity and anterior segment abnormalities. RESULTS: Of the 288 CMFB cases, all but 1 presented without corneal or conjunctival laceration. The etiologies of the injuries included low- and high-velocity impact. Best-corrected visual acuity ranged between 20/15 and 20/150. The anterior chamber (AC) reaction ranged from quiet to 4+ cells. None of the DFEs revealed an IOFB. Only 1 case had a posterior segment abnormality related to the injury-commotion retinae in the setting of an explosion. There were 14 cases with unrelated DFE findings. Among the separate 9 cases of metal IOFB reviewed, all had a history of high-velocity injury and evidence of corneal or conjunctival laceration. In 1 of the 9 cases, the IOFB was protruding from the cornea; in 2 cases, IOFBs were seen on DFE. Six cases were diagnosed by computed tomography. All documented AC examinations for this group of patients had significant findings such as 4+ cells, hyphema, or lens fragments. CONCLUSIONS: The finding of IOFB on a DFE for patients with a CMFB without clinical evidence of penetrating injury is very rare. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

H3 trimethyl K9 and H3 acetyl K9 chromatin modifications are associated with class switch recombination.

Class switch recombination (CSR) involves a DNA rearrangement in the Ig heavy chain (IgH) gene that allows the same variable (V) region to be expressed with any one of the downstream constant region (C) genes to encode antibodies with many different effector functions. One hypothesis for how CSR is targeted to different C region genes is that histone modifications increase accessibility and/or recruit activation-induced cytosine deaminase (AID) and its associated processes to particular donor and recipient switch regions. In this work, we identified H3 acetyl K9 and H3 trimethyl K9 as histone modifications that correlate with the recombining pair of donor and recipient switch regions. The appearance of H3 trimethyl K9 is surprising because usually it is thought to mark silent genes and heterochromatin. Nevertheless, the time course of appearance of these histone modifications, the regions in IgH they associate with, and their appearance independent of AID damage suggest that both modifications play a role in targeting CSR.

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.