Visual Outcomes and Risk of Endophthalmitis in Open Globe Injuries without Intraocular Foreign Bodies with Delayed Repair.

OBJECTIVE: To assess and compare the rate of endophthalmitis and visual outcomes in cases of OGI's without intraocular foreign bodies repaired within and greater than 24 hours from the time of injury. DESIGN: A retrospective review of 2,002 cases of OGI's presenting to a single institution. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: Patients with OGI's were admitted and managed according to a standardized protocol. METHODS, INTERVENTION, OR TESTING: The impact of timing of repair was assessed between those undergoing OGI repair within (i) 24 hours, (ii) 25-36 hours, and (iii) greater than 36 hours from the time of injury. MAIN OUTCOME AND MEASURE: Rates of endophthalmitis and postoperative visual acuity of logMAR 1.3, logMAR 1.0, and logMAR 0.3 at 180 days and 1 year following open globe repair. RESULTS: 1,382 patients with OGI's were included, of which 75% were male with an average age of 41 years. Maximal zone of injury was zone 1 for 468 patients, zone 2 for 529 patients and zone 3 for 508 patients. 84% of all OGI's underwent repair within 24 hours from the time of injury, 9% from 25-36 hours, and 7% greater than 36 hours. Average preoperative visual acuity was hand motion. Risk factors associated with repair performed greater than 36 hours from the time of injury included female sex (p=0.042). Endophthalmitis was associated with time to repair greater than 36 hours (p=0.049) but not with 25-36 hours or zone of injury (p=0.111). Time to repair had no significant impact on visual acuity outcomes. CONCLUSIONS: Although repair of OGI's within 24 hours is the current standard of care, this study found no statistically significant difference in rates of endophthalmitis or visual outcomes in eyes undergoing repair within 24 hours of injury compared to repair extending to 25 to 36 hours . Endophthalmitis rates did increase after 36 hours. We recommend urgent repair of open globe injuries, but in certain circumstances, it may be reasonable to delay repair beyond 24 hours to optimize operating conditions.

ENDOGENOUS ENDOPHTHALMITIS DUE TO STREPTOCOCCUS ANGINOSUS IN A HEALTHY, YOUNG WOMAN.

PURPOSE: The purpose of this study was to present a case of indolent endogenous endophthalmitis in a young, seemingly healthy woman. METHODS: This study is a retrospective case report. RESULTS: A 25-year-old woman with no significant medical history presented with vision loss in the left eye over the course of 1 month. Examination showed vitritis and a white-yellow lesion overlying the macula and optic nerve in the left eye. Initial laboratory testing for infectious and inflammatory causes was unrevealing. A diagnostic vitrectomy was performed, and the patient was found to have presumed endogenous endophthalmitis due to Streptococcus anginosus, an extremely uncommon bacterium. Subsequent workup did not reveal evidence of bacteremia, endocarditis, or orbital infection. This case is unique because, unlike the three previously reported cases of S. anginosus endophthalmitis, this patient was seemingly healthy, never had an elevated white blood cell count, never had documented bacteremia, had a normal echocardiogram, and had normal orbital findings on magnetic resonance imaging and computed tomography scans. Further questioning revealed a remote history of facial cellulitis and possible sinusitis treated with oral antibiotics, which are the presumed etiology. CONCLUSION: Streptococcus anginosus endophthalmitis can occur in young, seemingly healthy patients. Endogenous endophthalmitis should be considered in the differential diagnosis even without systemic comorbidities or other risk factors. Detailed questioning about medical history and thorough review of systems, including nonocular symptoms, are essential.

RESCUE INTRAVITREAL METHOTREXATE TREATMENT FOLLOWING EARLY RECOGNITION OF PROLIFERATIVE VITREORETINOPATHY.

PURPOSE: To report a case of proliferative vitreoretinopathy (PVR) in a man with recurrent retinal detachment successfully managed without surgical intervention following the initiation of intravitreal methotrexate injections to arrest progression of PVR. METHODS: Report of a case. RESULTS: A 60-year-old man presented to the retina clinic 4 weeks after undergoing vitrectomy for rhegmatogenous retinal detachment and was found to have an inferior recurrent retinal detachment. He underwent repeat vitrectomy and scleral buckling with successful reattachment of the retina in the immediate postoperative period. At postoperative Week 2, preretinal membranes were noted inferiorly with stretching of the causative retinal break and localized subretinal fluid, consistent with early PVR. The patient underwent immediate laser barricade, and a course of intravitreal methotrexate injections was started. At the final follow-up 7 months later, the retina was fully attached without progression of PVR. CONCLUSION: Intravitreal methotrexate may play a role in arresting progression of early postoperative PVR and obviating the need for surgical intervention.

Diabetes Microvascular Disease Diagnosis and Treatment After High-Deductible Health Plan Enrollment.

OBJECTIVE: The Affordable Care Act mandates that primary preventive services have no out-of-pocket costs but does not exempt secondary prevention from out-of-pocket costs. Most commercially insured patients with diabetes have high-deductible health plans (HDHPs) that subject key microvascular disease-related services to high out-of-pocket costs. Brief treatment delays can significantly worsen microvascular disease outcomes. RESEARCH DESIGN AND METHODS: This cohort study used a large national commercial (and Medicare Advantage) health insurance claims data set to examine matched groups before and after an insurance design change. The study group included 50,790 patients with diabetes who were continuously enrolled in low-deductible (≤$500) health plans during a baseline year, followed by up to 4 years in high-deductible (≥$1,000) plans after an employer-mandated switch. HDHPs had low out-of-pocket costs for nephropathy screening but not retinopathy screening. A matched control group included 335,178 patients with diabetes who were contemporaneously enrolled in low-deductible plans. Measures included time to first detected microvascular disease screening, severe microvascular disease diagnosis, vision loss diagnosis/treatment, and renal function loss diagnosis/treatment. RESULTS: HDHP enrollment was associated with relative delays in retinopathy screening (0.7 months [95% CI 0.4, 1.0]), severe retinopathy diagnosis (2.9 months [0.5, 5.3]), and vision loss diagnosis/treatment (3.8 months [1.2, 6.3]). Nephropathy-associated measures did not change to a statistically significant degree among HDHP members relative to control subjects at follow-up. CONCLUSIONS: People with diabetes in HDHPs experienced delayed retinopathy diagnosis and vision loss diagnosis/treatment of up to 3.8 months compared with low-deductible plan enrollees. Findings raise concerns about visual health among HDHP members and call attention to discrepancies in Affordable Care Act cost sharing exemptions.

PYK-1105: Preclinical Evaluation of a Novel Biodegradable Vitreous Substitute for Retinal Tamponade.

Purpose: Current retinal tamponade strategies are limited by anatomic considerations (retinal break location), durability (short-term vs need for removal), and patient adherence (positioning, travel/altitude restrictions). Here we describe the preclinical safety and toxicology of a novel biodegradable hydrogel tamponade agent (PYK-1105) with the potential to improve both patient experience and outcomes after retina surgery. Methods: We studied in vitro performance to assess hydrogel gelation time, modulus, viscosity, degradation time, refractive index, and transmittance. In addition to studying in vitro and in vivo (mice and rabbits) biocompatibility, testing was performed to assess cytotoxicity, intraocular irritation, acute systemic toxicity, genotoxicity, and pyrogenicity. Furthermore, clinical safety was assessed using in vivo (rabbits and minipigs) response to vitrectomy with PYK-1105 insertion with the following measures: clinical examination, multimodal imaging, full-field electroretinography, and histopathology. Results: PYK-1105 met the predefined performance testing criteria for optimal tamponade and demonstrated excellent biocompatibility. Animal studies showed the PYK-1105 formulation to be well tolerated and nontoxic in mice, rabbits, and pigs. Conclusions: PYK-1105 holds promise as a new biodegradable tamponade agent that has the potential to improve both the patient experience and outcomes after retina surgery. Human pilot studies are warranted to further assess for safety and efficacy.

Indications, Findings, and Outcomes of Pars Plana Vitrectomy after Open Globe Injury.

PURPOSE: To determine the indications, findings, and outcomes of patients with open globe injury (OGI) requiring pars plana vitrectomy (PPV). DESIGN: Retrospective, single-vitreoretinal surgeon case series. PARTICIPANTS: Sixty-one consecutive eyes with OGI that required PPV. METHODS: Retrospective chart review of consecutive patients who underwent PPV after OGI between March 1, 2011, and August 1, 2017, at Massachusetts Eye and Ear by 1 surgeon. MAIN OUTCOME MEASURES: Final visual acuity and rates of recurrent retinal detachment (RD) and proliferative vitreoretinopathy (PVR). RESULTS: Sixty-one eyes of 61 consecutive patients underwent PPV after sustaining OGI. Mean follow-up was 12.8±12.1 months (range, 0.5-65 months). At the time of presentation after OGI, 64% of eyes showed light perception or worse vision. The indications for PPV, which was performed on average of 15 days after injury, included RD without retinal incarceration (39%), RD with retinal incarceration in the scleral or corneal wound or both (13%), media opacity without RD (28%), vitreous traction without RD (11%), intraocular foreign body (5%), and endophthalmitis (3%). At the time of PPV, substantial comorbidities were noted, including corneal trauma (20%), hyphema (41%), iris trauma (62%), lens expulsion (54%), subretinal hemorrhage (51%), and choroidal hemorrhage (30%). Using multivariate analysis, factors associated with RD after initial PPV were preoperative subretinal hemorrhage (odds ratio [OR], 5.73; P = 0.03), PVR found at initial PPV (OR, 11.94; P = 0.021), and retinectomy (OR, 17.88; P = 0.003). No patients were inoperable, because all patients left the operating room with complete retinal reattachment. Of 35 eyes that showed RD, 19 (54%) redetached as a result of PVR. In 80% of eyes with RD at initial presentation (28/35 eyes), the retina remained completely attached at last follow-up, and 5 additional eyes remained partially attached (33/35 [94%]). Of 61 total eyes included in this study, 89% remained completely attached, and 42 (69%) achieved visual acuity of 20/200 or better at last follow-up. CONCLUSIONS: Despite substantial ocular comorbidities, PPV can result in retinal reattachment in even the most severe cases. Good visual outcomes can be achieved for most patients who undergo vitreoretinal surgery after open globe trauma.

Pharmaceutical Formulation Methods for Improving Retinal Drug Delivery.

Clinical pharmacology training for clinicians typically focuses on a drug's Active Pharmaceutical Ingredient. However, pharmaceutical formulation, the process of optimizing manufacturing methods and excipients to make a final drug product, is a critical process in determining whether a potential drug can become a realistic, routinely used therapeutic agent. This review focuses on the formulation methods used in commonly prescribed retina drug products.

Treatment of Refractory Acute Retinal Necrosis with Intravenous Foscarnet or Cidofovir.

PURPOSE: To report use of intravenous foscarnet or cidofovir for the treatment of refractory acute retinal necrosis (ARN). METHODS: Retrospective chart review. RESULTS: Four immunocompetent men aged 45-90 years presented with ARN from 2008-2014. One patient with two prior episodes of herpes simplex virus (HSV) ARN developed ARN after 6 years of antiviral prophylaxis. His condition worsened on acyclovir followed by intravenous foscarnet but responded to intravenous cidofovir (final VA in involved eye 20/20). Another patient with HSV ARN had received prolonged acyclovir prophylaxis for HSV keratitis; ARN improved after switching from acyclovir to intravenous foscarnet (final VA 20/125). Two patients with varicella zoster virus (VZV) ARN initially responded to acyclovir but developed fellow eye involvement 2-8 weeks later that worsened on acyclovir but responded to intravenous foscarnet (fellow eye final VA 20/20, 20/40). CONCLUSIONS: Cases of HSV or VZV ARN that worsen despite intravenous acyclovir treatment may respond to intravenous foscarnet or cidofovir.

Severe corneal ulcer with progression to endophthalmitis and high-grade bacteremia.

PURPOSE: Bacterial sepsis is a common consequence of many infectious processes. Here, we describe a case of a woman with a corneal ulcer who went on to develop group B streptococcal (GBS) endophthalmitis, bacteremia, and eventual loss of the eye. OBSERVATIONS: A previously healthy, immunocompetent, middle aged, contact lens wearing female who, after freshwater boating in her contact lenses, developed a red, painful eye. She was initially prescribed an hourly topical steroid by an outside optometrist but worsening of her condition prompted her to present to our Emergency Department. Despite aggressive initial management, the patient went on to develop GBS endophthalmitis, sepsis with high-grade bacteremia, and eventual loss of the eye. CONCLUSIONS AND IMPORTANCE: Eye care providers should exercise caution when prescribing frequent, potent corticosteroids when an infectious etiology is in the differential diagnosis.

Effect of Methotrexate on an In Vitro Patient-Derived Model of Proliferative Vitreoretinopathy.

Purpose: The purpose of this study was to develop a method for isolating, culturing, and characterizing cells from patient-derived membranes in proliferative vitreoretinopathy (PVR) to be used for drug testing. Methods: PVR membranes were obtained from six patients with grade C PVR. Membrane fragments were analyzed by gross evaluation, fixed for immunohistologic studies to establish cell identity, or digested with collagenase II to obtain single cell suspensions for culture. PVR-derived primary cultures were used to examine the effects of methotrexate (MTX) on proliferation, migration, and cell death. Results: Gross analysis of PVR membranes showed presence of pigmented cells, indicative of retinal pigment epithelial cells. Immunohistochemistry identified cells expressing α-smooth muscle actin, glial fibrillary acidic protein, Bestrophin-1, and F4/80, suggesting the presence of multiple cell types in PVR. Robust PVR primary cultures (C-PVR) were successfully obtained from human membranes, and these cells retained the expression of cell identity markers in culture. C-PVR cultures formed membranes and band-like structures in culture reminiscent of the human condition. MTX significantly reduced the proliferation and band formation of C-PVR, whereas it had no significant effect on cell migration. MTX also induced regulated cell death within C-PVR as assessed by increased expression of caspase-3/7. Conclusions: PVR cells obtained from human membranes can be successfully isolated, cultured, and profiled in vitro. Using these primary cultures, we identified MTX as capable of significantly reducing growth and inducing cell death of PVR cells in vitro.

Verteporfin inhibits growth of human glioma in vitro without light activation.

Verteporfin (VP), a light-activated drug used in photodynamic therapy for the treatment of choroidal neovascular membranes, has also been shown to be an effective inhibitor of malignant cells. Recently, studies have demonstrated that, even without photo-activation, VP may still inhibit certain tumor cell lines, including ovarian cancer, hepatocarcinoma and retinoblastoma, through the inhibition of the YAP-TEAD complex. In this study, we examined the effects of VP without light activation on human glioma cell lines (LN229 and SNB19). Through western blot analysis, we identified that human glioma cells that were exposed to VP without light activation demonstrated a downregulation of YAP-TEAD-associated downstream signaling molecules, including c-myc, axl, CTGF, cyr61 and survivin and upregulation of the tumor growth inhibitor molecule p38 MAPK. In addition, we observed that expression of VEGFA and the pluripotent marker Oct-4 were also decreased. Verteporfin did not alter the Akt survival pathway or the mTor pathway but there was a modest increase in LC3-IIB, a marker of autophagosome biogenesis. This study suggests that verteporfin should be further explored as an adjuvant therapy for the treatment of glioblastoma.

Validation of the Retinal Detachment after Open Globe Injury (RD-OGI) Score as an Effective Tool for Predicting Retinal Detachment.

PURPOSE: The Retinal Detachment after Open Globe Injury (RD-OGI) Score is a clinical prediction model that was developed at the Massachusetts Eye and Ear Infirmary to predict the risk of retinal detachment (RD) after open globe injury (OGI). This study sought to validate the RD-OGI Score in an independent cohort of patients. DESIGN: Retrospective cohort study. PARTICIPANTS: The predictive value of the RD-OGI Score was evaluated by comparing the original RD-OGI Scores of 893 eyes with OGI that presented between 1999 and 2011 (the derivation cohort) with 184 eyes with OGI that presented from January 1, 2012, to January 31, 2014 (the validation cohort). METHODS: Three risk classes (low, moderate, and high) were created and logistic regression was undertaken to evaluate the optimal predictive value of the RD-OGI Score. A Kaplan-Meier survival analysis evaluated survival experience between the risk classes. MAIN OUTCOME MEASURES: Time to RD. RESULTS: At 1 year after OGI, 255 eyes (29%) in the derivation cohort and 66 eyes (36%) in the validation cohort were diagnosed with an RD. At 1 year, the low risk class (RD-OGI Scores 0-2) had a 3% detachment rate in the derivation cohort and a 0% detachment rate in the validation cohort, the moderate risk class (RD-OGI Scores 2.5-4.5) had a 29% detachment rate in the derivation cohort and a 35% detachment rate in the validation cohort, and the high risk class (RD-OGI scores 5-7.5) had a 73% detachment rate in the derivation cohort and an 86% detachment rate in the validation cohort. Regression modeling revealed the RD-OGI to be highly discriminative, especially 30 days after injury, with an area under the receiver operating characteristic curve of 0.939 in the validation cohort. Survival experience was significantly different depending upon the risk class (P < 0.0001, log-rank chi-square). CONCLUSIONS: The RD-OGI Score can reliably predict the future risk of developing an RD based on clinical variables that are present at the time of the initial evaluation after OGI.

SMOKING IS A RISK FACTOR FOR PROLIFERATIVE VITREORETINOPATHY AFTER TRAUMATIC RETINAL DETACHMENT.

PURPOSE: To determine the incidence of retinal redetachment due to proliferative vitreoretinopathy after open-globe trauma in smokers and nonsmokers. METHODS: A total of 892 patients comprising 893 open-globe injuries, in whom 255 eyes were diagnosed with a retinal detachment, and 138 underwent surgical repair were analyzed in a retrospective case-control study. Time to redetachment was examined using the Kaplan-Meier method and analysis of risk factors was analyzed using Cox proportional hazards modeling. RESULTS: Within one year after retinal detachment surgery, 47% (95% CI, 39-56%) of all 138 repaired retinas redetached because of proliferative vitreoretinopathy. Being a smoker was associated with a higher rate of detachment (adjusted hazard ratio 1.96, P = 0.01). As shown in previous studies, the presence of proliferative vitreoretinopathy at the time of surgery was also an independent risk factor for failure (adjusted hazard ratio 2.13, P = 0.005). Treatment with vitrectomy-buckle compared favorably to vitrectomy alone (adjusted hazard ratio 0.58, P = 0.04). Only 8% of eyes that redetached achieved a best-corrected visual acuity of 20/200 or better, in comparison to 44% of eyes that did not redetach (P < 0.001). CONCLUSION: Proliferative vitreoretinopathy is a common complication after the repair of retinal detachment associated with open-globe trauma, and being a smoker is a risk factor for redetachment. Further study is needed to understand the pathophysiologic mechanisms underlying this correlation.

Multimodal Imaging of Elschnig Spots: A Case of Simultaneous Hypertensive Retinopathy, Choroidopathy, and Neuropathy.

A 65-year-old woman with chronic hypertension, chronic renal insufficiency, and schizophrenia self-discontinued her medications and presented complaining of decreased vision; she was found to have a blood pressure of 256/156 and visual acuity 20/70 OD. In the emergency department, her blood pressure was rapidly lowered to a nadir of 134/104. During the course of her hospitalization, her visual acuity declined from 20/70 to 20/200 OD in parallel with a decline in her renal function. Multi-modal imaging revealed simultaneous hypertensive retinopathy, choroidopathy, and optic neuropathy. Autofluorescence can play an important role in the diagnosis of hypertensive choroidopathy.

The Impact of Institutional Review Boards (IRBs) on Clinical Innovation: A Survey of Investigators and IRB Members.

We conducted a survey to assess the perspectives of principal investigators and Institutional Review Board (IRB) members on the impact of the IRB structure on the conduct of research and innovative therapy, defined as a nonstandard treatment intended to enhance the well-being of an individual patient. Although investigators and IRB members agreed that the IRB provides adequate protection to study subjects (97% vs. 100%) and an ethically insightful review (88% vs. 100%), a third of clinical investigators felt that the IRB review process limits clinical innovation, in comparison with only 4% of IRB representatives. Limitations of the current IRB review process were explored. We propose several measures to improve the IRB review process while maintaining the protection of human research subjects, including the use of centralized IRBs, the opening of IRB meetings to investigators, the development of metrics and outcome measures for the IRB, and the promotion of guidelines that distinguish research and innovative therapy.

Effect of Massachusetts health reform on chronic disease outcomes.

OBJECTIVE: To determine whether Massachusetts Health Reform improved health outcomes in uninsured patients with hyperlipidemia, diabetes, or hypertension. DATA SOURCE: Partners HealthCare Research Patient Data Registry (RPDR). STUDY DESIGN: We examined 1,463 patients with hyperlipidemia, diabetes, or hypertension who were uninsured in the 3 years before the 2006 Massachusetts Health Reform implementation. We assessed mean quarterly total cholesterol, glycosylated hemoglobin, and systolic blood pressure in the respective cohorts for five follow-up years compared with 3,448 propensity score-matched controls who remained insured for the full 8-year study period. We used person-level interrupted time series analysis to estimate changes in outcomes adjusting for sex, age, race, estimated household income, and comorbidity. We also analyzed the subgroups of uninsured patients with poorly controlled disease at baseline, no evidence of established primary care in the baseline period, and those who received insurance in the first follow-up year. PRINCIPAL FINDINGS: In 5 years after Massachusetts Health Reform, patients who were uninsured at baseline did not experience detectable trend changes in total cholesterol (-0.39 mg/dl per quarter, 95 percent confidence interval [-1.11 to 0.33]), glycosylated hemoglobin (-0.02 percent per quarter [-0.06 to 0.03]), or systolic blood pressure (-0.06 mmHg per quarter [-0.29 to 0.18]). Analyses of uninsured patients with poorly controlled disease, no evidence of established primary care in the baseline period, and those who received insurance in the first follow-up year yielded similar findings. CONCLUSIONS: Massachusetts Health Reform was not associated with improvements in hyperlipidemia, diabetes, or hypertension control after 5 years. Interventions beyond insurance coverage might be needed to improve the health of chronically ill uninsured persons.