Proof-of-concept calculations to determine the health-adjusted life-year trade-off between intravitreal anti-VEGF injections and transmission of COVID-19.

BACKGROUND: Clinical ophthalmological guidelines encourage the assessment of potential benefits and harms when deciding whether to perform elective ophthalmology procedures during the COVID-19 pandemic, in order to minimize the risk of disease transmission. METHOD: We performed probability calculations to estimate COVID-19 infection status and likelihood of disease transmission among neovascular age-related macular degeneration patients and health-care workers during anti-VEGF procedures, at various community prevalence levels of COVID-19. We then applied the expected burden of COVID-19 illness and death expressed through health-adjusted life-years (HALYs) lost. We compared these results to the expected disease burden of severe visual impairment if sight protecting anti-VEGF injections were not performed. RESULTS: Our calculations suggest a wide range of contexts where the benefits of treatment to prevent progression to severe visual impairment or blindness are greater than the expected harms to the patient and immediate health care team due to COVID-19. For example, with appropriate protective equipment the benefits of treatment outweigh harms when the chance of progression to severe visual impairment is >0.044% for all scenarios where COVID-19 prevalence was 1/1000, even when the attack rate in the clinical setting is very high (5-43%). CONCLUSION: Unless COVID-19 prevalence is very high, the reduced disease burden from avoiding visual impairment outweighs the expected HALYs lost from COVID-19 transmission. This finding is driven by the fact that HALYs lost when someone suffers severe visual impairment for 5 years are equivalent to nearly 400 moderate cases of infectious disease lasting 2 weeks each.

A Multicountry Comparison of Real-World Management and Outcomes of Polypoidal Choroidal Vasculopathy: Fight Retinal Blindness! Cohort.

PURPOSE: To compare the 12-month real-world visual and disease activity outcomes of eyes with polypoidal choroidal vasculopathy (PCV) treated with a combination of photodynamic therapy (PDT) and anti-vascular endothelial growth factor (VEGF) injections (combination group) versus those eyes treated with anti-VEGF monotherapy alone with rescue PDT being used as required (monotherapy group). DESIGN: Database comparative observational study. PARTICIPANTS: Eyes with PCV as graded in the Fight Retinal Blindness! database from Australia, New Zealand, Singapore, and Switzerland. METHODS: Clinical information from a multisite, international registry of neovascular age-related macular degeneration was analyzed with an intention-to-treat approach. MAIN OUTCOME MEASURES: Primary outcome measure was the change in visual acuity in logMAR letters over 12 months between the two groups analyzed with intention-to-treat approach. RESULTS: Forty-one and 152 eyes received combination therapy and anti-VEGF monotherapy, respectively. All anti-VEGF agents were pooled, and bevacizumab represented 66.1% of injections administered. The adjusted mean change in visual acuity between the combination group and monotherapy group at 12 months was +16.9 letters (95% confidence interval [CI], 10.6-23.3 letters) and +8.2 letters (95% CI, 5.2-11.3 letters), respectively (P = 0.02). Proportion of inactive lesions and mean time to inactivity was 85.3% and 80.7 days (95% CI, 62.8-98.5 days), respectively, in the combination group compared with 76.8% and 150.4 days (95% CI, 132.8-168.0 days), respectively, in the monotherapy group (P = 0.01). The mean number of injections of anti-VEGF agent between the combination and monotherapy groups was 4.3 injections (95% CI, 3.6-5.2 injections) and 6.4 injections (95% CI, 5.9-6.9 injections), respectively (P = 0.01). CONCLUSIONS: The real-world outcomes for treatment of PCV showed larger gains in vision, higher proportion of inactive lesions, quicker time to inactivity, and fewer injections administered in the combination group compared with the monotherapy group. These findings are consistent with current evidence reporting the advantages of combination therapy for PCV.

Connexin43 hemichannel block protects against the development of diabetic retinopathy signs in a mouse model of the disease.

Diabetic retinopathy (DR) is a vascular disease of the neuroretina characterised by hyperglycaemia and inflammation. Current DR therapies target late-stage vascular defects and there is evidence to suggest that they contribute to geographic atrophy and retinal ganglion cell death long term. Therefore, alternative treatments that target common upstream disease mechanisms are needed. Recent studies have shown that connexin43 hemichannel blockers can reduce inflammation and prevent vessel leak in brain and spinal cord lesions. The aim of this study was to evaluate the effectiveness of a connexin43 hemichannel blocker (Peptide5) in a mouse model of DR in which pro-inflammatory cytokines, IL-1ß and TNF-α, were intravitreally injected into non-obese diabetic (NOD, hyperglycaemic) mice. Fundus and optical coherence tomography images were taken to evaluate vessel dilation and beading as well as retinal and vitreous hyper-reflective foci (HRF). Immunohistochemistry was performed to assess levels of astrogliosis, microgliosis and inflammasome activation. Results showed that Peptide5 injection lowered the incidence of vessel dilation and beading, decreased the severity of vitreous and retinal HRF, and reduced sub-retinal fluid accumulation compared to the vehicle group. Furthermore, Peptide5 led to reduced connexin43 and GFAP upregulation, inhibited microglial infiltration into the outer nuclear layer and prevented upregulation of inflammasome markers compared to vehicle. The present study provides evidence in support of Peptide5, and connexin43 hemichannel block in general, as a potential upstream approach for the treatment of DR. KEY MESSAGES: Connexin43 is upregulated in a novel mouse model of diabetic retinopathy (DR). Connexin43 hemichannel block inhibits inflammation and inflammasome activation. Connexin43 hemichannel block prevents the development of clinical DR signs. Connexin43 hemichannel block is a potential upstream approach for DR treatment.

Intravitreal pro-inflammatory cytokines in non-obese diabetic mice: Modelling signs of diabetic retinopathy.

Diabetic retinopathy is a vascular disease of the retina characterised by hyperglycaemic and inflammatory processes. Most animal models of diabetic retinopathy are hyperglycaemia-only models that do not account for the significant role that inflammation plays in the development of the disease. In the present study, we present data on the establishment of a new animal model of diabetic retinopathy that incorporates both hyperglycaemia and inflammation. We hypothesized that inflammation may trigger and worsen the development of diabetic retinopathy in a hyperglycaemic environment. Pro-inflammatory cytokines, IL-1ß and TNF-α, were therefore injected into the vitreous of non-obese diabetic (NOD) mice. CD1 mice were used as same genetic background controls. Fundus and optical coherence tomography images were obtained before (day 0) as well as on days 2 and 7 after intravitreal cytokine injection to assess vessel dilation and beading, retinal and vitreous hyper-reflective foci and retinal thickness. Astrogliosis and microgliosis were assessed using immunohistochemistry. Results showed that intravitreal cytokines induced vessel dilation, beading, severe vitreous hyper-reflective foci, retinal oedema, increased astrogliosis and microglia upregulation in diabetic NOD mice. Intravitreal injection of inflammatory cytokines into the eyes of diabetic mice therefore appears to provide a new model of diabetic retinopathy that could be used for the study of disease progression and treatment strategies.

Hypertensive iridocyclitis associated with delayed onset biopsy proven Cytomegalovirus retinitis.

We describe a case of primary hypertensive iridocyclitis with biopsy-proven Cytomegaloviral retinitis. It is an observational case report of a 69-year-old diabetic gentleman on azathioprine for Crohn's disease who presented with recurrent episodes of hypertensive iridocyclitis. On the 4 th attendance in 5 months, a granular white lesion was noted in the temporal periphery of the mid-peripheral fundus and a chorioretinal and vitreous biopsy performed. Vitreous PCR was positive for Cytomegalovirus (CMV). Hematoxylin and eosin staining revealed cytomegalic-like inclusions within necrotic neural retina. Transmission electron microscopy revealed herpes family virus particles and immunohistochemistry demonstrated CMV protein. This case provides further evidence implicating CMV infection in the etiology of hypertensive iridocyclitis. With hindsight, the cumulative effect of diabetes and azathioprine on the immune surveillance system proved sufficient to render the patient susceptible to CMV retinitis.

Visual outcome after intravitreal ranibizumab for wet age-related macular degeneration: a comparison between best-corrected visual acuity and microperimetry.

PURPOSE: The purpose of this study was to compare the observed change in best-corrected visual acuity (BCVA) with the change in central retinal sensitivity pretreatment and 1 month after 3 consecutive treatments with ranibizumab in patients with wet age-related macular degeneration. METHODS: Ten consecutive patients with untreated age-related macular degeneration underwent microperimetric and BCVA assessment before and 1 month after 3 consecutive treatments with ranibizumab. Best-corrected visual acuity was assessed at 2 m by using the Early Treatment Diabetic Retinopathy Study chart. Threshold microperimetry was performed using a Goldman III stimulus to 45 points over the central 12 degrees of the macula. Significant visual improvement after treatment was defined as a change in BCVA >/=10 letters or, on microperimetry, a change in mean retinal sensitivity > or = 2 dB. RESULTS: One month after treatment, the median change in BCVA was +6 letters (range, -15 to +12), and the mean change in the mean retinal sensitivity was +2.86 dB (standard deviation, 1.55 dB). One patient recorded a significant improvement in BCVA compared with 8 patients who recorded a significant improvement in mean retinal sensitivity (P = 0.016). CONCLUSION: Compared with microperimetry, BCVA seems to significantly underestimate the change in visual function experienced by patients treated with ranibizumab.

To investigate the prevalence of polypoidal choroidal vasculopathy in presumed age-related peripapillary subretinal neovascular membranes.

BACKGROUND: To investigate the prevalence and angiographic appearances of polypoidal choroidal vasculopathy (PCV) masquerading as age-related peripapillary subretinal neovascular membranes (PSRNVM). METHODS: A consecutive case series of all patients investigated for presumed age-related PSRNVM in our tertiary referral centre over the period September 2006-2007. The presenting clinical features and fundus fluorescein angiographic (FFA) characteristics of each patient's lesion were identified. Any accompanying Indocyanine Green Angiogram (ICGA) was also reviewed, and on the basis of this investigation patients were classified into one of three groups: proven PCV, probable PCV and PSRNVM. RESULTS: Thirty patients with presumed age-related PSRNVM were identified. The FFA leakage pattern was occult in 21 patients and classic in nine patients. Sixteen patients also had ICGA performed. In 14 of these patients the original FFA leakage pattern was occult, and in two it was classic. Of the 14 patients with occult leakage on FFA who subsequently underwent ICGA all were found to have PCV. CONCLUSIONS: PCV is important and underrecognized in presumed age-related PSRNVMs. In such cases, particularly when the pattern of leakage on the fluorescein angiogram is occult, ICGA should be performed to identify the site of the polyps and if required to direct treatment.

Large-spot subthreshold infrared laser to treat diabetic macular edema.

PURPOSE: To evaluate the efficacy of a large-spot subthreshold infrared laser protocol to treat diabetic maculopathy. METHODS: In a prospective, fellow eye, controlled case series, all patients had clinically significant diabetic macular edema (DME) treated with a single application of subthreshold infrared (810 nm) laser. If bilateral disease was present, the fellow eye was treated with conventional macular laser. The study was to include 20 patients. Visual acuity and central macular thickness (CMT) measured by optical coherence tomography (OCT) were assessed in the study and fellow eyes at baseline and 6 months, and any changes were compared. RESULTS: The 11th patient developed a choroidal infarct with subsequent profound loss of vision immediately after treatment. The study was terminated prematurely at this point. For the remaining 10 patients, there was a trend toward improvement in visual acuity in the study eye compared with the fellow eye at the 6-month follow-up (median change: +1.5 letters for study eye vs -6.5 letters for fellow eye; P = 0.08). There was also significant improvement in OCT-measured CMT in the study eye (mean decrease, 117 microm) compared with deterioration in OCT-measured CMT in the fellow eye (mean increase, 24 microm; P = 0.02). CONCLUSION: This subthreshold infrared laser protocol led to improvement in OCT-measured CMT and stabilization of vision in most subjects. The current protocol is however unpredictable and should not be used in the treatment of DME without further modification.

Reexploration and inferior oblique myectomy temporal to the inferior rectus to treat persistent inferior oblique overaction.

PURPOSE: Persistent symptomatic inferior oblique (IO) muscle overaction (IOOA) after IO muscle weakening surgery is a common problem. We describe the results of reexploration and myectomy of the IO muscle using a standard inferotemporal approach to treat this clinical entity. METHODS: A retrospective noncomparative consecutive series of patients referred for treatment of persistent IOOA. The following preoperative and postoperative measurements were recorded in each case: (1) the ductions and versions of the overacting IO muscle and its antagonist superior oblique (SO) muscle; and (2) alternate prism cover test, using loose prisms at 6 m, in primary position and right- and leftgaze. The preoperative and longer term postoperative findings were compared. RESULTS: Eight patients were identified. Three had previously undergone a standard IO myectomy, and five had undergone a standard IO muscle recession. The median period of postoperative follow-up was 12 months (range, 7 months to 2 years). The IOOA was eliminated in three patients and a reduction of IOOA of at least 1 unit was achieved in all patients. Seven patients showed improvement of their SO muscle underaction on versions, postoperatively. All patients achieved a marked improvement in their alignment across the three standard horizontal positions of gaze. The mean vertical deviations pre- and postoperatively was 23(Delta) versus 7(Delta) in contralateral gaze, 17(Delta) versus 4(Delta) in primary gaze, and 7(Delta) versus 1(Delta) in ipsilateral gaze. CONCLUSIONS: Reexploration and myectomy of the IO muscle near to the temporal border of the inferior rectus muscle is a reliable and effective way of treating persistent IOOA.