Intravitreal Pharmacotherapies for Diabetic Macular Edema: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the evidence on the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) and intravitreal corticosteroid pharmacotherapies for the treatment of diabetic macular edema (DME). METHODS: Literature searches were last conducted on May 13, 2020, in the PubMed database with no date restrictions and limited to articles published in English. The combined searches yielded 230 citations, of which 108 were reviewed in full text. Of these, 31 were deemed appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. RESULTS: Only the 21 articles with level I evidence were included in this assessment. Seventeen articles provided level I evidence for 1 or more anti-VEGF pharmacotherapies, including ranibizumab (14), aflibercept (5), and bevacizumab (2) alone or in combination with other treatments for DME. Level I evidence was identified in 7 articles on intravitreal corticosteroid therapy for treatment of DME: triamcinolone (1), dexamethasone (4), and fluocinolone acetonide (2). CONCLUSIONS: Review of the available literature indicates that intravitreal injections of anti-VEGF agents and corticosteroids are efficacious treatments for DME. Elevated intraocular pressure and cataract progression are important potential complications of corticosteroid therapy. Further evidence is required to assess the comparative efficacy of these therapies. Given the limited high-quality comparative efficacy data, choice of therapy must be individualized for each patient and broad therapeutic access for patients is critical to maximize outcomes.

Safety and Efficacy of Anti-Vascular Endothelial Growth Factor Therapies for Neovascular Age-Related Macular Degeneration: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the evidence on the safety and efficacy of anti-vascular endothelial growth factor (VEGF) therapies for the treatment of neovascular age-related macular degeneration (AMD). METHODS: A literature search of the PubMed and Cochrane Library databases was last conducted in February 2017; there were no date restrictions, and the search was limited to studies published in English. The combined searches yielded 191 citations, 28 of which were selected because they were clinical trials and were deemed clinically relevant for the Ophthalmic Technology Assessment Committee Retina/Vitreous Panel to review in full. The panel methodologist then assigned a level of evidence rating to each study. RESULTS: Sixteen of the 28 citations provided level I evidence supporting the use of anti-VEGF agents for neovascular AMD, including intravitreal ranibizumab, aflibercept, and bevacizumab. Eight studies reviewed provided level II evidence, and 4 studies provided level III evidence, but only the level I studies are included in this assessment. There are long-term follow-up data on the efficacy of ranibizumab and bevacizumab (≥5 years), but these data are subject to the bias of incomplete follow-up. CONCLUSIONS: Review of the literature indicates that intravitreal injection of anti-VEGF therapy is safe and effective for neovascular AMD over 2 years, the period for which data are available. Further research is needed to evaluate the long-term safety and comparative efficacy of these agents.

Therapies for Macular Edema Associated with Branch Retinal Vein Occlusion: A Report by the American Academy of Ophthalmology.

PURPOSE: To evaluate the available evidence on the ocular safety and efficacy of current therapeutic alternatives for the management of macular edema (ME) secondary to branch retinal vein occlusion (BRVO). METHODS: Literature searches were last conducted on January 31, 2017, in PubMed with no date restrictions and limited to articles published in English, and in the Cochrane Database without language limitations. The searches yielded 321 citations, of which 109 were reviewed in full text and 27 were deemed appropriate for inclusion in this assessment. The panel methodologist assigned ratings to the selected studies according to the level of evidence. RESULTS: Level I evidence was identified in 10 articles that addressed anti-vascular endothelial growth factor (VEGF) pharmacotherapies for ME, including intravitreal bevacizumab (5), aflibercept (2), and ranibizumab (4). Level I evidence was identified in 6 studies that examined intravitreal corticosteroids, including triamcinolone (4) and the dexamethasone implant (2). Level I evidence also was available for the role of macular grid laser photocoagulation (7) and scatter peripheral laser surgery (1). The inclusion of level II and level III studies was limited given the preponderance of level I studies. The number of studies on combination therapy is limited. CONCLUSIONS: Current level I evidence suggests that intravitreal pharmacotherapy with anti-VEGF agents is effective and safe for ME secondary to BRVO. Prolonged delay in treatment is associated with less improvement in visual acuity (VA). Level I evidence also indicates that intravitreal corticosteroids are effective and safe for the management of ME associated with BRVO; however, corticosteroids are associated with increased potential ocular side effects (e.g., elevated intraocular pressure, cataracts). Laser photocoagulation remains a safe and effective therapy, but VA results lag behind the results for anti-VEGF therapies.

Diagnosis and Treatment of Acute Retinal Necrosis: A Report by the American Academy of Ophthalmology.

PURPOSE: To evaluate the available evidence in peer-reviewed publications about the diagnosis and treatment of acute retinal necrosis (ARN). METHODS: Literature searches of the PubMed and Cochrane Library databases were last conducted on July 27, 2016. The searches identified 216 unique citations, and 49 articles of possible clinical relevance were reviewed in full text. Of these 49 articles, 27 were deemed sufficiently relevant or of interest, and they were rated according to strength of evidence. An additional 6 articles were identified from the reference lists of these articles and included. All 33 studies were retrospective. RESULTS: Polymerase chain reaction (PCR) testing of aqueous or vitreous humor was positive for herpes simplex virus (HSV) or varicella zoster virus (VZV) in 79% to 100% of cases of suspected ARN. Aqueous and vitreous specimens are both sensitive and specific. There is level II and III evidence supporting the use of intravenous and oral antiviral therapy for the treatment of ARN. Data suggest that equivalent plasma drug levels of acyclovir can be achieved after administration of oral valacyclovir or intravenous acyclovir. There is level II and III evidence suggesting that the combination of intravitreal foscarnet and systemic antiviral therapy may have greater therapeutic efficacy than systemic therapy alone. The effectiveness of prophylactic laser or early pars plana vitrectomy (PPV) in preventing retinal detachment (RD) remains unclear. CONCLUSIONS: Polymerase chain reaction testing of ocular fluid is useful in supporting a clinical diagnosis of ARN, but treatment should not be delayed while awaiting PCR results. Initial oral or intravenous antiviral therapy is effective in treating ARN. The adjunctive use of intravitreal foscarnet may be more effective than systemic therapy alone. The role of prophylactic laser retinopexy or early PPV is unknown at this time.

Topical Nonsteroidal Anti-inflammatory Drugs and Cataract Surgery: A Report by the American Academy of Ophthalmology.

OBJECTIVE: To review the available evidence on the effectiveness of prophylactic topical nonsteroidal anti-inflammatory drugs (NSAIDs) in preventing vision loss resulting from cystoid macular edema (CME) after cataract surgery. METHODS: Literature searches of the PubMed and the Cochrane Library databases were last conducted on January 21, 2015, with no date restrictions. The searches retrieved 149 unique citations. The first author reviewed the abstracts of these articles and selected 27 articles of possible clinical relevance for full-text review. Of these 27 articles, 12 were deemed relevant to analyze in full. Two additional articles were identified from the reference list of the selected articles, and another article was identified from a national meeting. The panel methodologist assigned ratings of level of evidence to each of the selected citations. RESULTS: Nonsteroidal anti-inflammatory drug therapy was effective in reducing CME detected by angiography or optical coherence tomography (OCT) and may increase the speed of visual recovery after surgery when compared directly with placebo or topical corticosteroid formulations with limited intraocular penetration. However, the use of NSAIDs did not alter long-term (≥3 months) visual outcomes. Furthermore, there was no evidence that the benefits observed with NSAID therapy could not be obtained similarly with equivalent dosing of a corticosteroid. The reported impression that there is a pharmacologic drug synergy from the use of both an NSAID and a corticosteroid is not supported by the literature. There is no uniform method of reporting CME in the literature, which prevents accurate assessment of its incidence and response to anti-inflammatory therapies. CONCLUSIONS: Cystoid macular edema after cataract surgery has a tendency to resolve spontaneously. There is a lack of level I evidence that supports the long-term benefit of NSAID therapy to prevent vision loss from CME at 3 months or more after cataract surgery. Although dosing of NSAIDs before surgery may hasten the speed of visual recovery in the first several weeks after cataract surgery, there is no evidence that this practice affects long-term visual outcomes. Standardized reporting of CME based on OCT may allow for more uniform quantitation of its incidence and more reliable assessment of treatment outcomes.

Therapies for macular edema associated with central retinal vein occlusion: a report by the American Academy of Ophthalmology.

PURPOSE: To review the available evidence regarding the safety and efficacy of therapies for the treatment of macular edema (ME) associated with central retinal vein occlusion (CRVO). METHODS: A literature search of the PubMed database was last conducted in March 2014 with no date restrictions but limited to articles published in English. A literature search of the Cochrane Library was also conducted in March 2014 with no date restrictions and without a language limitation. The combined searches yielded 108 citations, of which 20 were deemed clinically relevant for the Ophthalmic Technology Assessment Committee Retina/Vitreous panel to review in full text. Three additional studies were also identified for panel review. The level of evidence of these selected studies was reviewed by the panel methodologist. RESULTS: There were 7 citations representing 4 clinical trials that provided level I evidence supporting the use of anti-vascular endothelial growth factor (VEGF) pharmacotherapies for ME associated with CRVO, including intravitreal ranibizumab (2), aflibercept (3), and bevacizumab (2). There were 3 citations representing 2 studies with level I evidence for intravitreal corticosteroid injection with dexamethasone intravitreal implant (2 citations) or triamcinolone (1 citation), although cataract and glaucoma were observed in these studies. Level I evidence is available on the limited benefit of macular grid-pattern laser photocoagulation (1 citation). Eight other citations reviewed were rated as level II, and 4 citations were rated as level III. Long-term efficacy results (≥2 years of follow-up) are limited to intravitreal ranibizumab at this time, and few studies have evaluated combination therapy with anti-VEGF and corticosteroid versus monotherapy of either class of drug. CONCLUSIONS: Level I evidence indicates that intravitreal anti-VEGF pharmacotherapy is safe and effective over 2 years for ME associated with CRVO and that delay in treatment is associated with worse visual outcomes. In addition, level I evidence demonstrates short-term efficacy of intravitreal corticosteroid but also an association with a higher frequency of adverse events.

A novel mutation at the N-terminal domain of the TIMP3 gene in Sorsby fundus dystrophy.

PURPOSE: To report a novel mutation occurring in the N-terminal domain of the tissue inhibitor of metalloproteinase 3 (TIMP3) gene in Sorsby fundus dystrophy. METHODS: Retrospective review of medical records of two patients who had clinical features consistent with Sorsby fundus dystrophy. Genetic testing confirmed a mutation in the TIMP3 gene in both patients. RESULTS: Both patients had findings of drusenlike deposits, retinal pigment epithelial and photoreceptor atrophy, and bilateral, recurrent choroidal neovascularization. A strong family history of early onset macular degeneration was present in both. The patients developed choroidal neovascularization at the age of 45 and 48 years, and both had multiple recurrences in both eyes. Genetic testing in both patients confirmed a heterozygous nucleotide change of C113G, causing a Ser38Cys change in Exon 1 of the N-terminal domain of the TIMP3 gene. CONCLUSION: All previously reported mutations in Sorsby fundus dystrophy occur at Exon 5 in the C-terminal domain. We report 2 patients with novel mutations in Exon 1 of the N-terminal domain. Although the mutation occurs at a different location on the TIMP3 gene, the clinical features are similar to other reported patients with Sorsby fundus dystrophy. This finding assists in understanding the pathogenesis of this disorder.

Reduction of vitreous prostaglandin E2 levels after topical administration of ketorolac 0.45%.

IMPORTANCE: Inhibition of proinflammatory prostaglandins in the retina may have therapeutic effects for retinal disease. OBJECTIVE: To determine vitreous levels of ketorolac and prostaglandin E2 (PGE2) in eyes treated with topical ketorolac tromethamine 0.45% (Acuvail). DESIGN, SETTING, AND PARTICIPANTS: A prospective comparative interventional study, performed in a university academic hospital, included 24 eyes in 22 consecutive patients undergoing pars plana vitrectomy. INTERVENTION: Application of topical ketorolac 0.45%, 4 times daily, for 3 days before pars plana vitrectomy in the first 12 consecutive eyes. The next 12 eyes were untreated and served as controls. Undiluted vitreous samples were obtained at the time of surgery and immediately frozen at -80 °C. MAIN OUTCOMES AND MEASURES: Vitreous ketorolac and PGE2 levels. RESULTS: Seven of the 12 eyes (58%) had ketorolac levels above the lower limit of quantitation. All 7 were in pseudophakic eyes, and 4 of the 5 below this limit were phakic (P = .01). The mean ketorolac level in the 7 eyes was 7.55 ng/mL (range, 5.0-14.9 ng/mL). The mean (SD) PGE2 levels were 13.8 (3.8) pg/mL in control eyes and 11.7 (4.4) pg/mL in ketorolac-treated eyes (P = .04). Treatment with ketorolac resulted in a 15% reduction in PGE2 levels. When only pseudophakic eyes were analyzed, mean (SD) PGE2 levels were 14.1 (4.1) pg/mL in control eyes and 11.6 (4.5) pg/mL in ketorolac-treated eyes (P < .05). CONCLUSIONS AND RELEVANCE: Topical ketorolac 0.45% can obtain a vitreous level that exceeds its median inhibitory concentration and can significantly decrease vitreous PGE2 levels. Vitreous levels of ketorolac were significantly higher in pseudophakic eyes than in phakic eyes. The results of this study suggest that topically administered ketorolac 0.45% may allow meaningful inhibition of prostaglandins in the retina. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01609881.

Reduction of interleukin 8 and platelet-derived growth factor levels by topical ketorolac, 0.45%, in patients with diabetic retinopathy.

IMPORTANCE: Inhibition of inflammatory cytokines may have therapeutic effects in diabetic retinopathy (DR). OBJECTIVE: To compare aqueous and vitreous levels of 17 inflammatory cytokines in patients treated preoperatively with topical ketorolac tromethamine, 0.45%, or placebo before pars plana vitrectomy for complications related to proliferative DR (PDR). DESIGN, SETTING, AND PARTICIPANTS: A prospective, randomized, placebo-controlled, patient-masked interventional study performed in a university academic hospital included 20 eyes from 20 patients undergoing pars plana vitrectomy for complications of PDR. INTERVENTIONS: Eyes were randomized to ketorolac tromethamine, 0.45% (Acuvail), or placebo 4 times daily for 3 days before pars plana vitrectomy. Undiluted aqueous and vitreous samples were taken at the time of surgery and immediately frozen at -80°C. MAIN OUTCOMES AND MEASURES: Aqueous and vitreous levels of prostaglandin E2 and 16 other inflammatory cytokines implicated in the pathogenesis of DR. RESULTS: Prostaglandin E2, platelet-derived growth factor (PDGF) AA, eotaxin, vascular endothelial growth factor, interferon γ-inducible protein of 10 kDa, monocyte chemoattractant protein 1, growth-related oncogene, interleukin 6, interleukin 8 (IL-8), and tumor necrosis factor were detectable in the aqueous and vitreous of at least half of the eyes, and these cytokines were analyzed further. Aqueous levels were lower in the ketorolac group for all cytokines detected, but only the difference in IL-8 was statistically significant (52% reduction; P = .04). Levels of IL-8 (41% reduction; P = .002) and PDGF-AA (21% reduction; P = .009) were significantly lower in the vitreous of patients treated with ketorolac. CONCLUSIONS AND RELEVANCE: Topical ketorolac tromethamine, 0.45%, significantly lowered aqueous IL-8 levels and vitreous IL-8 and PDGF-AA levels in this series of eyes, suggesting that it may cause meaningful inhibition of inflammatory cytokines implicated in the pathogenesis of DR. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01609881.

Geographic chorioretinal atrophy in pseudoxanthoma elasticum.

PURPOSE: To describe a series of patients with geographic atrophy independent of choroidal neovascularization (CNV) in pseudoxanthoma elasticum and to report progression over time. DESIGN: Retrospective observational case series. METHODS: Records of all Vanderbilt Eye Institute patients with pseudoxanthoma elasticum and at least 1 set of color fundus photographs were reviewed (41 eyes of 21 patients). Fluorescein angiography, fundus autofluorescence, and optical coherence tomography images were reviewed, when available. In patients with geographic atrophy and at least 1 year of follow-up, atrophy was measured using fundus photographs. Main outcome measures included incidence of geographic atrophy, progression over time, and macular features associated with development or progression of geographic atrophy. RESULTS: Eight eyes (20%) of 5 patients had geographic atrophy independent of CNV. Progression was documented in 6 eyes of 4 patients followed for at least 1 year (mean 3.5 years). Mean initial and final area was 2.9 and 9.5 mm(2), respectively, and growth rate was 1.7 mm(2) per year. Of the 6 eyes, 3 had a final visual acuity of 20/20 and the other 3 ranged from 20/150 to 20/400. All 8 eyes had pattern dystrophy, and 5 had linear pigment deposits that appeared to predict development or growth of atrophy. CONCLUSIONS: Isolated geographic atrophy independent of CNV can develop in pseudoxanthoma elasticum, causing significant vision loss. Linear pigmented pattern dystrophy appears to predate geographic atrophy. Progression is similar to age-related macular degeneration. Recognition of this feature is important, especially if therapies to slow or reverse geographic atrophy become available.

Nonsteroidal anti-inflammatory drugs for retinal disease.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively in ophthalmology for pain and photophobia after photorefractive surgery and to reduce miosis, inflammation, and cystoid macular edema following cataract surgery. In recent years, the US Food and Drug Administration has approved new topical NSAIDs and previously approved NSAIDs have been reformulated. These changes may allow for greater drug penetration into the retina and thereby offer additional therapeutic advantages. For example, therapeutic effects on diabetic retinopathy and age-related macular degeneration may now be achievable. We provide an updated review on the scientific rationale and clinical use of NSAIDs for retinal disease.

Bilateral Multifocal Central Serous-Like Chorioretinopathy due to MEK Inhibition for Metastatic Cutaneous Melanoma.

Newer chemotherapeutic agents target extracellular signaling, including the mitogen-activated protein kinase kinase (MEK) pathway. We present a case of a 54-year-old female who developed bilateral multifocal central serous-like chorioretinopathy shortly after starting MEK inhibition for metastatic cutaneous melanoma. There was a complete resolution of findings after drug stoppage. After resuming a lower dose of the MEK inhibitor, the findings recurred again but resolved after drug stoppage. Other etiologies were unlikely given the clinical course. The presumed mechanism involves toxicity to the retinal pigment epithelium, with breakdown of the blood-retinal barrier. Recognition of this side effect is important with this new class of chemotherapy.

Acute macular neuroretinopathy: an atypical case.

PURPOSE: The purpose of this report is to describe extensive acute macular neuroretinopathy lesions with atypical features. METHODS: Retrospective case report. RESULTS: A patient developed acute macular neuroretinopathy in the setting of multiple previously described associations including a flu-like illness, sympathomimetic exposure, overdose of norepinephrine reuptake inhibitors, anemia, thrombocytopenia, and hypotensive shock. The fundus lesions superficially resembled retinal hemorrhages in color and fluorescein angiography pattern. The lesions could be detected on autofluorescence and infrared imaging. Optical coherence tomography revealed outer plexiform layer opacification and photoreceptor abnormalities. CONCLUSION: This case suggests a compounding effect of factors associated with acute macular neuroretinopathy, possible exacerbating insults and outer plexiform layer abnormalities that may correlate with the temporal course of this condition.

Circumscribed outer foveolar defects in spinocerebellar ataxia type 7.

PURPOSE: To report circumscribed outer foveolar defects in a 40-year-old man with a history of spinocerebellar ataxia type 7. METHODS: A 40-year-old man with genetically confirmed spinocerebellar ataxia type 7 presented with progressive vision loss and decreased color perception for 3 years. He underwent a full ocular examination, fundus photography, autofluorescence, spectral-domain optical coherence tomography imaging, and a full-field electroretinogram. RESULTS: The patient's ocular examination and fundus autofluorescence were both normal except for mild temporal pallor of both optic discs. Spectral-domain optical coherence tomographic imaging showed foveal thinning with an outer foveolar defect because of focal loss of photoreceptors, disruption of the inner segment-outer segment junction but preservation of the external limiting membrane, and thinning of the outer plexiform layer in both eyes. Electroretinography showed severely reduced cone function with mildly reduced rod function. CONCLUSION: Spinocerebellar ataxia type 7 should be included in the differential diagnosis for "outer retinal holes" or "foveal cavitation," which also includes solar retinopathy, juxtafoveal telangiectasia, Welder maculopathy, tamoxifen retinopathy, Stargardt disease, amyl nitrate abuse, and cone or cone-rod degeneration syndromes.

Reliability of grading retinal hemorrhages in abusive head trauma.

PURPOSE: To study the intra- and inter-observer reliability of pediatric ophthalmologists in grading retinal hemorrhages in abusive head trauma. METHODS: Pediatric ophthalmologists attending the 2009 annual meeting of the American Association for Pediatric Ophthalmology and Strabismus participated in an onsite survey. The participants were required to compare a collection of fundus photographs of patients with abusive head trauma to two standardized photographs, A and B. Participants graded photographs as normal (no retinal hemorrhages), better than A but not normal, same as A, between A and B, same as B, or worse than B. The survey was divided into four parts: part 1 consisted of 20 photographs to be graded; part 2 was a questionnaire about participant's professional experience; part 3 consisted of 20 photographs to be graded (including 15 graded in part 1 but reordered); and part 4 asked about the criteria used to grade the photographs. RESULTS: Of the 95 participants, 92 (97%) were licensed physicians with a mean of 14 years in practice. The intra-rater reliability was found to be high, with overall average of 85% pre- and post-agreement on the common pictures. Kendall's coefficient of concordance was used as the statistical measure of inter-rater reliability and had a high value (0.82). CONCLUSIONS: Pediatric ophthalmologists showed high intra- and inter-observer reliability in grading retinal hemorrhages in abusive head trauma.

Profound postoperative hypotony with globe collapse after 25-gauge pars plana vitrectomy.

PURPOSE: To report a series of cases of profound hypotony with globe collapse on postoperative day 1 after sutureless 25-gauge pars plana vitrectomy and to identify common risk factors for this complication. METHODS: Retrospective chart review of three patients. Ocular history and surgeries, preoperative diagnosis, operative technique, postoperative and final visual acuities, reformation intervention, and need for additional surgery were reviewed. RESULTS: Three cases were reviewed. Patient ages were 22, 53, and 53 years. All patients had a history of a rhegmatogenous retinal detachment repaired by surgery and all had at least one vitrectomy. Two had a prior scleral buckle and two had pathologic myopia. All patients underwent sutureless 25-gauge pars plana vitrectomy. No patient had intraocular air, gas, or silicone oil tamponade. All patients presented on postoperative day 1 with globe collapse, hand motion vision, and scleral infolding. All patients underwent office-based injection of sterile balanced salt solution or air. One patient required an additional procedure-operative closure of sclerotomies and intraocular gas tamponade. All three patients attained a final Snellen visual acuity of 20/50 or 20/60. CONCLUSION: These cases represent a small fraction (0.12%) of patients who underwent 25-gauge pars plana vitrectomy by one surgeon. Patients had several risk factors, including severe eye disease, prior retinal detachment repair, prior vitrectomy, pathologic myopia, and lack of intraocular tamponade. In patients with several risk factors, consideration should be given for intraocular gas or air injection or sclerotomy closure.