Screen failures in clinical trials in retina.

PURPOSE: Disparities in clinical trials are a major problem due to significant underrepresentation of certain gender, racial and ethnic groups. Several factors including stringent eligibility criteria and recruitment strategies hinder our understanding of retinal disease. Thus, we aimed to study the various reasons of screen failures and specific patient and study characteristics among screen failures. DESIGN: This is a cross-sectional retrospective study METHODS: Screening data of 87 trials from 6 centers were analyzed. Study characteristics (disease studied, phase of trial, route of drug administration) and patient demographics (age, gender, race, ethnicity, and employment status) were compared among different causes of screen failures. Screen failures were broadly classified into six categories: exclusion due to vision-based criteria, exclusion due to imaging findings, exclusion due to other factors, patient-related criteria, physician related criteria and miscellaneous. Descriptive statistics, Pearson Chi-square test and ANOVA were used for statistical analysis. MAIN OUTCOME MEASURES: Determine the prevalence of various reasons for screen failures in multiple trials and its trend among different study and patient characteristics. RESULTS: Among 87 trials and 962 patients, 465(48.2%) patients were successfully randomized and 497(51.8%) patients were classified as screen failures. The trials were conducted for various retinal diseases. Mean age was 76.50 ±10.45 years and 59.4% were females. Predominantly whites(93.4%) and unemployed/retired patients(66.6%) were screened. Of the 497 screen failures, most were due to patients not meeting inclusion criteria of imaging findings (n=221[44.5%]) followed by inclusion of vision-based criteria (n=73 [14.7%]), exclusion due to other factors (n=75[15.1%]), patient-related (n=34[6.8%]), physician-related (n=28[5.6%]) and miscellaneous reasons (n= 39[17.8%]). Reason for screen failure was not available for 27(5.4%) patients. A higher proportion of patients screened for surgical trials (15%) declined to participate in the study compared to non-invasive trials involving topical drugs and photobiomodulation (0%).(p=0.02) CONCLUSION: Patients not meeting the imaging and vision-cased criteria were the most common reasons for screen failures. Whites and unemployed patients predominantly participated in clinical trials. Patients are more inclined to continue participation in non-invasive clinical trials compared to surgical trials. Better recruitment strategies and careful consideration of study criteria can aid in decreasing the rate of screen failures.

Effects of hydroxychloroquine therapy on choroidal volume and choroidal vascularity index.

PURPOSE: To determine changes in choroidal volume (CV) and choroidal vascularity index (CVI) in patients on hydroxychloroquine (HCQ) therapy. METHODS: Retrospective analysis of patients on HCQ therapy. CV and CVI were assessed below the central foveal region on spectral-domain optical coherence tomography using an automatic denoising and localization algorithm. CV and CVI were compared with age-matched controls. Regression analyses were performed to generate associations between CV and CVI with demographics and HCQ treatment parameters. Associations were assessed using a generalized estimating equation model adjusted for intra-subject inter-eye correlations. RESULTS: A total of 137 adult patients (23 males and 114 females) were included. Mean age was 45.6 ± 13.7 years and most patients identified as Caucasian (79%). Total duration of HCQ therapy ranged from 3 months to 20 years. Daily HCQ intake varied from 150-600 mg (mean = 304 mg), while cumulative doses ranged from 18-2,800 g. At presentation, the median CV was 0.51 (IQR:0.356-0.747) mm, and median CVI was 0.559 (IQR:0.528-0.578). Increased cumulative HCQ dose was associated with decreased CV (p = 0.006). Compared to age-matched controls, CV, CVI, and luminal area were significantly lower in the study group (p = 0.0003, 0.0001, and 0.0002). CONCLUSION: In this study, we present a novel analysis of key biomarkers which predate the occurrence of HCQ retinopathy. Choroidal volume and vascularity index are significantly reduced in patients on HCQ therapy, especially at higher cumulative doses. These findings suggest new tools to guide medical decision-making for patients receiving HCQ therapy for rheumatologic diseases.

Functional and Morphological Characteristics of the Retina of Patients with Drusen-like Deposits and Systemic Lupus Erythematosus Treated with Hydroxychloroquine: A Retrospective Study.

PURPOSE: To evaluate the impact of drusen-like deposits (DLD) on retinal layer integrity and retinal function by optical coherence tomography (OCT) and multifocal electroretinography (mfERG) in patients with systemic lupus erythematosus (SLE). METHODS: We identified 66 eyes of 33 SLE patients treated with hydroxychloroquine (HCQ) that were categorized into two groups according to whether DLDs were present (34 eyes, Group One) or absent (32 eyes, Group Two). The groups were matched for age, sex, HCQ treatment duration, daily, and cumulative dosage. OCT (retinal layer thicknesses, central retinal thickness, CRT) and mfERG concentric ring analysis were analyzed and compared. RESULTS: CRT was significantly thicker in Group One compared to Group Two (273.21 ± 3.96 vs. 254.5 ± 7.62) (p = 0.023). Group One also demonstrated an overall thicker retinal pigment epithelium compared to Group Two; however, the other outer retinal layers, outer nuclear layer, and photoreceptor layer were found to be significantly thinner in Group One compared to Group Two. We found no differences in mfERG parameters between the two groups. CONCLUSIONS: DLDs in SLE patients lead to abnormal central retinal layer thickness, which has no measurable impact on cone-mediated retinal function assessed by mfERG.

A comprehensive review of intravitreal immunosuppressants and biologicals used in ophthalmology.

Systemic immunosuppressants and biologicals have been a valuable tool in the treatment of inflammatory diseases and malignancies. The safety profile of these drugs has been debatable, especially in localized systems, such as the eye. This has led to the search for fairly local approaches, such as intravitreal, subconjunctival, and topical route of administration. Immunosuppressants have been used as a second-line drug in patients intolerable to corticosteroids or those who develop multiple recurrences on weaning corticosteroids. Similarly, biologicals have also been used as the next line of therapy, when adequate control of inflammation could not be attained or immunosuppressants were contraindicated to patients. Intravitreal immunosuppressants, such as methotrexate and sirolimus, have been extensively studied in noninfectious posterior uveitis, whereas limited studies have established the efficacy of intravitreal biologicals, such as infliximab and adalimumab. Most of these drugs have shown good safety profile and tolerability in animal studies alone and have not been studied further in human subjects. However, most of the studies in literature are single-case reports or case series which limits the level of evidence. In this comprehensive review, we discuss the mechanism of action, pharmacodynamics, pharmacokinetics, indications, efficacy, and side effects of different intravitreal immunosuppressants and biologicals that have been studied in literature.

Real-life comparison of three intravitreal antibiotic drug regimens in endophthalmitis.

Purpose: Real-life comparison of three intravitreal drug regimens used in cases of endophthalmitis at a tertiary care center in India. Methods: In this prospective, comparative study, patients of bacterial endophthalmitis were grouped according to intravitreal antibiotic drug regimens into Group 1 (ceftazidime and vancomycin), Group 2 (piperacillin + tazobactam and vancomycin), and Group 3 (imipenem and vancomycin). Forty-eight hours after injection nonresponding/worsening patients underwent vitrectomy. Vitreous samples were subjected to microbiological and pharmacokinetic tests. Results: A total of 64 patients were included and divided into Group 1: 29, Group 2: 20, and Group 3: 15 cases. Also, 75% of patients were post-surgical endophthalmitis, whereas 25% were post-traumatic. Improvement in vision (V90-0) and vision at 3 months (V90) were comparable between the three groups. Visual recovery was poorer in post-traumatic cases. In post-surgical cases, visual recovery was poorer in those presenting beyond 72 h of onset of symptoms (P = 0.0002). Polymerase chain reaction (PCR) positivity (66%) was higher than BACTECTM (33%) and culture (14%). Antibiotic resistance was comparable amongst the three groups. Most patients (62/64) further underwent vitrectomy. Ceftazidime and vancomycin achieved vitreous concentrations more than the minimum inhibitory concentration (MIC) at 48 h after the first injection. Conclusion: The choice of antibiotics did not affect the rate of vitrectomy and final vision in a real-life scenario. Ceftazidime and vancomycin can still be used as first-line intravitreal antibiotics owing to their comparable microbial sensitivity profile and adequate ocular bioavailability.

Unusual presentation of cornea verticillata with intravitreal methotrexate in a case of primary intraocular lymphoma.

A 56-year-old woman presented with floaters and diminution of vision in the right eye for 1 week. On examination, visual acuity was 20/400 in the right eye and 20/60 in the left eye. Indirect ophthalmoscopy revealed vitritis in the right eye and subretinal deposits in both eyes. Vitreous biopsy of the right eye revealed large B-cell-type primary intraocular lymphoma and the patient underwent multiple intravitreal methotrexate injections (400 µg/0.1 mL) in the right eye and systemic chemotherapy for bilateral disease. Following biweekly injections of methotrexate, her visual acuity improved considerably from 20/400 to 20/60 with resolution of vitritis. However, following eighth dose of intravitreal methotrexate, she experienced visual decline to 20/120 along with photophobia, redness and watering. Whorl-shaped opacities, limbitis and corneal haze were noted on slit-lamp examination. Intravitreal methotrexate was stopped, and the patient was started on frequent topical lubricants, loteprednol, topical folinic acid and oral folic acid. Complete resolution of corneal toxicity was observed at 3 weeks and the injections were suspended as there was no recurrence at 6 months follow-up.

Demography, clinical profile and surgical outcomes of paediatric giant retinal tear related retinal detachments.

OBJECTIVE: To determine the demographic profile, clinical features and surgical outcomes of giant retinal tear (GRT) related retinal detachments (RD) in children. METHODS: In this retrospective study, medical records of children aged 14 years and below, who underwent surgery for RD at our centre in the last 5 years were reviewed. Among these, we selected medical records of children with RDs with GRT, and examined the coloured retinal drawings, ultrawidefield photographs and/or surgical videos. RESULTS: Out of 1536 medical records, 91 eyes of 87 children (5.6% of all RDs) were included. Mean age was 10.21 ± 3.08 years with male:female ratio of 8.6:1. The most common aetiologies for GRTs were high myopia (28 cases-32.18%) and trauma (25 cases-28.73%). Bilateral RD were possibly present in 29/87 (33.3%) cases. Six months follow up data was available for 82/91 eyes. Overall retinal re-attachment was achieved in 52/82 (63.41%) eyes; in 33/82 (40.24%) eyes retinal attachment could be achieved by a single surgery. Absence of proliferative vitreoretinopathy (PVR) (OR: 2.44, p-value:0.03, 95%CI: 1.21-5.08) or PVR-A (OR: 3.62, p-value: 0.03, 95%CI: 1.52-12.26) and presence of preexisting posterior vitreous detachment (OR: 7.14, p-value: 0.02, 95%CI: 1.31-38.73) were associated with successful retinal re-attachment after single surgery. Median time to presentation of cases succeeding after 1 surgery was 10 days. Ambulatory vision (1/60 and better) at final followup could be achieved in 45/82 (54.88%) eyes. CONCLUSION: GRT relatedRDs constitute a significant proportion of paediatric RDs. Anatomical success can currently be achieved in a large number of cases. Early surgery, absence of PVR and presence of PVD are associated with higher surgical success.

Optical Coherence Tomography Angiography following Scleral Buckling Surgery.

INTRODUCTION: The retinal changes following scleral buckling surgery (SBS) for rhegmatogenous retinal detachment (RRD) have been rarely evaluated with optical coherence tomography angiography (OCTA). METHODS: A 40 years old male presented with subtotal RD involving the macula and had best corrected visual acuity of logmar 2.3 in the affected right eye. Five months after applying 120 degree scleral buckle, swept source optical coherence tomography (SSOCT) and swept source optical coherence tomography angiography (SS-OCTA) were done. RESULT: At five months post-surgery, despite a settled retina in the operated eye, the patient had vision of logmar 1 and thin retinal nerve fibre layer (115 micrometer). The SSOCT showed inner segment-outer segment (IS-OS) junction disruption, thinned retinal pigment epithelium, central macular thickness of 275 micrometer and subfoveal choroidal thickness of 222 micrometer. A 3x3 mm macular OCTA scan showed a normal foveal avascular zone along with higher values for vascular density in superficial capillary plexus in all quadrants except temporal quadrant in operated eye as compared to fellow eye. CONCLUSION: The SBS with 120 degree buckle did not lead to a reduced vascular density in superficial capillary plexus in the operated eye with respect to fellow eye.

Heads-up 3D viewing system in rhegmatogenous retinal detachment with proliferative vitreoretinopathy - A prospective randomized trial.

Purpose: To compare the outcomes of vitreoretinal surgery in patients with primary and recurrent rhegmatogenous retinal detachment (RRD) with proliferative vitreoretinopathy (PVR) on 3 dimensional digitally assisted visualization system (3D-DAVS) and conventional analogue microscope (CAM). Methods: 68 patients with primary (50) and recurrent (18) RRD with PVR > C1 were included. One group underwent surgery on 3D-DAVS while the other on CAM. The parameters studied included detachment rate, best-corrected visual acuity (BCVA), duration of surgery, mean endo-illumination levels of 23 G (Gauge) micro incision vitrectomy system (MIVS) and microscope and satisfaction of surgeon and observers based on a framed questionnaire. The mean duration of follow up was three months. Results: 68 eyes of 68 patients with median age 52.5 (range 18-68) years were included. 50 had primary RRD and 18 had recurrent RRD. Detachment rate at the end of three months was comparable in both groups of primary (P > 0.99) and recurrent (P = 0.21) RRD. Mean duration of surgery in minutes for 3D DAVS and CAM group was 61.8 (±22.07) and 58.04 (±12.33), respectively, in primary RRD and 37.22 (±10.27) and 36.55 (±5.92), respectively, in recurrent RRD group. Mean endo-illumination in 3D DAVS (14.5%) group was half of that in CAM (34.17%) group. Surgeon and observer satisfaction scores were significantly higher for 3D DAVS group. Conclusion: 3D DAVS is a safe and effective modality or performing VR surgery in RRD with PVR. 3D DAVS allows lower endo-illumination levels provides superior surgeon ergonomics and offers better learning opportunities to the trainees.

Three-years follow-up swept source optical coherence tomography angiography findings in post-fever retinitis.

Post fever retinitis (PFR), characterized by multiple cotton wool spot like lesions in the posterior pole, is commonly reported following viral and bacterial infections. Retinal perfusion defects have been documented with the help of optical coherence tomography angiography (OCTA) in cases of PFR. But long term changes in such cases have not been reported earlier. In the following report, we have described the swept-source OCTA findings of two PFR patients at initial presentation and three years follow-up. Initial OCTA scans may not provide accurate information regarding the perfusion status due to associated retinal edema and inflammation. However, persisting perfusion defects at the superficial and deep retinal capillary plexus were noted on long term follow-up in both the cases.

Optical coherence tomography angiography-guided photodynamic therapy for extrafoveal choroidal neovascularization.

Type 1 extrafoveal choroidal neovascularization (CNV) secondary to neovascular age-related macular degeneration was diagnosed in a 68-year-old woman using optical coherence tomography angiography (OCT-A) alone. The entire network of vessels was clearly visible on a 12 × 12 mm OCT-A scan segmented below the retinal pigment epithelium. The patient was initially treated with intravitreal ranibizumab followed by photodynamic therapy (PDT) guided by OCT-A. Complete resolution of subretinal fluid with shrinkage of the neovascular complex was noted 1 month after PDT.

Intraoperative optical coherence tomography-guided subretinal cocktail injection in a case of ruptured retinal artery macro-aneurysm with multilevel bleed.

Submacular hemorrhage (SMH) following ruptured retinal artery macro aneurysm (RRAM) has better prognosis as compared to other etiologies. Timely intervention from as early as 24 h to less than 7 days is known to provide better visual outcomes in such cases. A variety of surgical techniques have been described in the treatment of RRAM. In this case report, we describe the advantages of intraoperative optical coherence tomography-guided sub-retinal injection of a cocktail mixture consisting of recombinant tissue plasminogen activator, bevacizumab, and air. Faster visual recovery with an immediate displacement of sub-macular bleed can be achieved with this technique in cases of RRAM-associated SMH.

Age-related changes in macular vessels and their perfusion densities on optical coherence tomography angiography.

Purpose: To evaluate age-related changes in macular vessels and their perfusion densities using optical coherence tomography angiography (OCTA). Methods: A total of 108 eyes of 54 healthy subjects between the age group of 11 to 60 years having unaided visual acuity of 20/20 were studied on spectral domain OCTS using 3 * 3 mm macula protocol. These subjects were divided into 5 groups; Group 1: 11-20 years, Group 2: 21-30 years, Group 3: 31-40 years, Group 4: 41-50 years, and Group 5: 51-60 years. An early treatment diabetic retinopathy study (ETDRS) grid overlay at the macula was used to calculate changes in different quadrants of the superficial retinal plexus. Results: A total of 98 eyes of 49 patients were considered for the final analysis. The vessel density values decreased from the second to the sixth decade in all four quadrants (except the third decade, where a slight increase was noted). The total vessel density decreased from 168 ± 78 mm-1 (group 1) to 131.47 ± 18.32 mm-1 (group 5). A similar reduction pattern in perfusion density was seen in each quadrant from the second to the sixth decade. The total perfusion density reduced from 309 ± 15.63% (group 1) to 283.05 ± 45.23% (group 5). The foveal avascular zone area was 0.18 ± 0.09 mm2 in group 1, 0.33 ± 0.13 mm2 in group 2, 0.30 ± 0.10 mm2 in group 3, 0.38 ± 0.05 mm2 in group 4, and 0.46 ± 0.06 mm2 in group 5. Conclusion: In our population, macular vessel density appears to decrease noticeably from the fourth decade onwards but a statistically significant decrease was observed only from the fifth decade onwards. However, it was not uniform along with all the quadrants. Similarly, the percentage of perfusion density dropped from the fourth decade but these values also varied among the different quadrants.

Clinical features, optical coherence tomography findings and treatment outcomes of post-fever retinitis.

OBJECTIVES: To study the clinical features, optical coherence tomography (OCT) findings, treatment options and follow-up outcomes of post-fever retinitis (PFR). SUBJECTS: A total of 19 eyes of 13 patients, diagnosed with PFR (retinitis following febrile episode) over 2 years were retrospectively studied. METHODS: Documented history, baseline clinical features and systemic investigations performed for PFR were reviewed. Fundus findings, foveal architecture on swept-source OCT, the treatment options and the follow-up outcomes including best-corrected visual acuity (BCVA) and central foveal thickness (CFT) were reviewed and analyzed. RESULTS: Common fundus findings included whitish retinitis lesions (100%), macular star (95%, 18eyes), retinal flame-shaped hemorrhages (63%, 12 eyes), inflammatory retinal vessels (30%, 6 eyes), vitreous hemorrhage (one eye) and OCT findings included neuro-sensory detachment (79%, 15 eyes), intraretinal white dots (89.5%,17 eyes). The baseline median log MAR BCVA and CFT were 1.30 (interquartile range (IQR):0.8-1.8) and 423 microns (IQR:182-555). Overall, nine patients (12 eyes) received a combination of oral doxycycline and oral steroids and four patients (7 eyes) received a combination of oral doxycycline, oral steroid and intravitreal anti-vascular endothelial growth factor (IVA). Significant improvement was evident at 8 weeks in median BCVA (0.50, IQR: 0.3-0.8, p < 0.05) and median CFT (223 micron, IQR: 170-256, p < 0.05) though only 26% (5 eyes) attained BCVA > = 6/12. CONCLUSION: Our study puts forth certain characteristic fundus and OCT features of PFR. A combination of oral doxycycline and oral steroids as a treatment option showed improvement in BCVA and CFT. Additional IVA helps in faster visual recovery in patients presenting with severe macular edema at onset.