Bilateral uveitis, retinal periphlebitis, and optic neuritis associated with non-pineal central nervous system germinoma.

PURPOSE: To report a case of bilateral uveitis, retinal periphlebitis, and optic neuritis associated with a non-pineal central nervous system (CNS) germinoma. METHODS: Case report. RESULTS: A 32-year-old male presented with episodes of acute painless visual disturbance in each eye, and was found to have decreased visual acuity, abnormal color vision, an afferent pupillary defect in the left eye, bilateral optic disc edema, perivenous sheathing, and candle-wax dripping exudates. Optical coherence tomography revealed bilateral intraretinal fluid and posterior vitreous hyperreflective opacities. Fluorescein angiography revealed bilateral optic disc leakage without active small vessel leakage. Magnetic resonance imaging of the brain and orbits revealed enhancing periventricular lesions and enhancement of the left optic nerve and bilateral perioptic nerve sheaths, posterior globes, and optic nerve heads. Brain biopsy was consistent with a CNS germinoma. His ocular signs and symptoms improved with chemotherapy for the germinoma. CONCLUSION: CNS germinomas, including those located outside the pineal region, can be associated with optic neuritis, uveitis, and periphlebitis including characteristic candle-wax dripping exudates. Ocular signs and symptoms typically improve with treatment of the underlying germinoma.

OUTER RETINOPATHY AND MICROANGIOPATHY IN ACUTE MYELOGENOUS LEUKEMIA.

PURPOSE: To describe a patient with acute myelogenous leukemia who presented with a recurrent, bilateral, outer retinopathy, before and after consolidative peripheral blood stem cell transplantation complicated by chronic graft-versus-host disease. METHODS: This is a retrospective review of records from a 23-year-old woman with acute myelogenous leukemia who underwent comprehensive ophthalmic evaluations for over a year including chromatic perimetry and multifocal electroretinograms, imaging with spectral domain optical coherence tomography, near-infrared and short-wavelength fundus reflectance and autofluorescence, fluorescein and optical coherence tomography angiography. RESULTS: The patient presented with recurrent, unilateral paracentral scotomas. There was localized loss of inner segment ellipsoid (EZ) and photoreceptor outer segment signals (IZ) in the pericentral retina of both eyes co-localizing with hyperreflective lesions on near-infrared reflectance. She subsequently lost vision (visual acuity = 20/200) in the right eye a year after consolidative peripheral blood stem cell transplantation complicated by steroid-resistant-chronic graft-versus-host disease. There was loss of the EZ and IZ signals corresponding to a dense central cone scotoma and multifocal electroretinograms depression. Near-infrared autofluorescence, fluorescein and optical coherence tomography angiography were within normal limits. Visual acuity (20/20) and retinal sensitivities improved with restoration of the EZ/IZ signals after oral prednisone and intravenous rituximab, but left a residual photoreceptor loss and paracentral scotoma. CONCLUSION: We propose that an immune-mediated microangiopathy may explain the protracted, recurrent course of primary photoreceptor abnormalities in our patient, which was further complicated by manifestations of chronic graft-versus-host disease following consolidative peripheral blood stem cell transplantation. Outer retinal findings previously documented in leukemia may be explained by a similar mechanism.

Vitreoretinal lymphoma presenting as frosted branch angiitis in a patient with diffuse large B-cell lymphoma.

Purpose: To describe the evaluation, diagnosis, and treatment of vitreoretinal lymphoma presenting as frosted branch angiitis in a patient with diffuse large B-cell lymphoma (DLBCL). Observations: A 57-year-old woman with a history of non-Hodgkin lymphoma and recent DLBCL relapse presented with frosted branch angiitis that raised suspicion for an infectious retinitis but was found to be vitreoretinal lymphoma. Conclusions and Importance: This case primarily highlights the importance of considering vitreoretinal lymphoma on the differential diagnosis of etiologies of frosted branch angiitis. Despite suspicion for vitreoretinal lymphoma, it is also important to treat empirically for infectious etiologies of retinitis in cases of frosted branch angiitis. In this case where the diagnosis was ultimately vitreoretinal lymphoma, weekly alternating intravitreal injections of methotrexate and rituximab led to improvement in visual acuity and retinal infiltration.

QUANTITATIVE ASSESSMENT OF AUTOMATED OPTICAL COHERENCE TOMOGRAPHY IMAGE ANALYSIS USING A HOME-BASED DEVICE FOR SELF-MONITORING NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate a prototype home optical coherence tomography device and automated analysis software for detection and quantification of retinal fluid relative to manual human grading in a cohort of patients with neovascular age-related macular degeneration. METHODS: Patients undergoing anti-vascular endothelial growth factor therapy were enrolled in this prospective observational study. In 136 optical coherence tomography scans from 70 patients using the prototype home optical coherence tomography device, fluid segmentation was performed using automated analysis software and compared with manual gradings across all retinal fluid types using receiver-operating characteristic curves. The Dice similarity coefficient was used to assess the accuracy of segmentations, and correlation of fluid areas quantified end point agreement. RESULTS: Fluid detection per B-scan had area under the receiver-operating characteristic curves of 0.95, 0.97, and 0.98 for intraretinal fluid, subretinal fluid, and subretinal pigment epithelium fluid, respectively. On a per volume basis, the values for intraretinal fluid, subretinal fluid, and subretinal pigment epithelium fluid were 0.997, 0.998, and 0.998, respectively. The average Dice similarity coefficient values across all B-scans were 0.64, 0.73, and 0.74, and the coefficients of determination were 0.81, 0.93, and 0.97 for intraretinal fluid, subretinal fluid, and subretinal pigment epithelium fluid, respectively. CONCLUSION: Home optical coherence tomography device images assessed using the automated analysis software showed excellent agreement to manual human grading.

TRIANGULAR SIGN OF AMALRIC IN INTRAVASCULAR LYMPHOMA.

PURPOSE AND METHODS: To report a case of bilateral ocular ischemia caused by intravascular lymphoma with the presence of bilateral triangular sign of Amalric. RESULTS: A 67-year-old woman was admitted to our hospital for progressive paraplegia and a 6-month history of acute painless vision loss in the right eye. Initial examination showed vision of counting fingers in the right eye and 20/20 in the left eye with normal anterior examination. Fundus examination revealed a likely previous central retinal artery occlusion in the right eye with pale nerve and attenuated vessels. Both fundi had triangular regions of pigmentary change known as the triangular sign of Amalric, indicative of choroidal ischemia. However, the left eye was asymptomatic. Neuroimaging revealed multifocal enhancing lesions throughout the central nervous system of unclear etiology. An extensive neurologic and systemic workup was unrevealing, including a brain biopsy, and empiric treatment for an unspecified inflammatory condition with intravenous corticosteroids was initiated. During her hospitalization, she developed acute painless vision loss in the left eye, and examination showed no light perception vision in both eyes with signs of acute retinal and choroidal ischemia in the left eye. A subsequent brain biopsy revealed intravascular lymphoma. CONCLUSION: Triangular pigmentary changes indicate choroidal ischemia and can be seen in many conditions. This patient presented with the triangular sign of Amalric in both eyes, including her asymptomatic left eye. Intravascular lymphoma should be considered in cases of concomitant inflammatory brain lesions and chorioretinal ischemia.

Risk of non-infectious uveitis or myasthenia gravis in patients on checkpoint inhibitors in a large healthcare claims database.

AIM: To determine if checkpoint inhibitors (CPIs) confer an increased risk of non-infectious uveitis or myasthenia gravis (MG) compared to patients on non-checkpoint inhibitor (N-CPI) chemotherapy. METHODS: A retrospective cohort study was performed comparing patients in a large commercial and Medicare advantage database exposed to CPI compared to N-CPI. All patients who initiated a CPI (ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, cemiplimab and durvalumab) were eligible. Date of earliest CPI in the exposure group and N-CPI chemotherapy in the comparator group was considered the index date. Exclusion occurred in both cohorts for any history of uveitis or MG diagnosis and having <1 year in the insurance plan prior to the index date, and <6 months in plan following the index date. Every exposed patient was matched up to 1:10 based on demographics and index year to patients on N-CPI chemotherapy. Multivariate Cox proportional hazards regression modelling was performed. RESULTS: For evaluation of incidence of non-infectious uveitis, 26 (0.3%) of 8678 patients on CPI and 123 (0.2%) of 76 153 N-CPI comparators were found to have non-infectious uveitis. After multivariate analysis, CPIs showed an increased hazard for uveitis compared to N-CPI (HR=2.09; 95% CI 1.36 to 3.22, p=0.001). For the MG analysis, 11 (0.1%) of 9210 patients developed MG in the CPI group and 36 (0.04%) of 80 620 comparators. The CPI cohort had a higher hazard of developing MG (HR=2.60; 95% CI 1.34 to 5.07, p=0.005) compared to controls in multivariate analysis. CONCLUSIONS: Exposure to CPI confers a higher risk for non-infectious uveitis and MG compared to N-CPI chemotherapy.

PERSISTENT PLACOID MACULOPATHY IN A PATIENT WITH HIGH MYOPIA.

PURPOSE: To describe a case of persistent placoid maculopathy in a patient with high myopia. METHODS: Interventional case report. RESULTS: A 59-year-old white man with high myopia presented with blurriness in the left eye. Vision was 20/20 bilaterally. Optical coherence tomography showed subretinal thickening and fluid without definitive leakage on fluorescein angiography after which anti-vascular endothelial growth factor (anti-VEGF) therapy was initiated. The patient was diagnosed with persistent placoid maculopathy based on multimodal imaging and clinical response. His disease course was characterized by multiple bilateral recurrences despite active treatment. At final visit (23 months after presentation), the vision was 20/20 in the right eye and 20/25 in the left eye, and the disease remained quiescent on immunomodulating therapy. CONCLUSION: Prompt initiation of anti-VEGF injections and immunosuppression resulted in disease control and preservation of vision in both eyes for almost 2 years.

PERSISTENT PLACOID MACULOPATHY: A Systematic Review.

PURPOSE: To review the literature on persistent placoid maculopathy. METHODS: Several databases were searched for all years for "persistent placoid maculopathy." RESULTS: A total of 21 unique patients were identified (most commonly Caucasian men in their 50s and 60s). Mean ± SD age at time of presentation was 58.6 ± 6.9 years of age, and follow-up time was 29.2 ± 51.9 months. Thirty-three (79%) eyes had subjective symptoms on presentation. Five (24%) patients presented with a prodrome, and four (19%) patients had vitreous cell. Mean ± SD logarithm of minimal angle of resolution presenting versus final vision was 0.48 ± 0.50 (Snellen equivalent, 20/60) versus 0.63 ± 0.52 (Snellen equivalent, 20/84). Systemic inflammation and autoimmune disease were associated with worse presenting and final vision. Persistent placoid maculopathy characteristic imaging features that aid in diagnosing this rare clinical entity include the following: 1) plaque-like hypopigmented, white/yellowish foveal/perifoveal lesions on color fundus photography; 2) early hypofluorescence and late "fill-in" or staining on fluorescein angiography; 3) persistent hypocyanescence on indocyanine green angiography; and 4) choriocapillaris hyposignal on optical coherence tomography angiography. Choroidal neovascularization was present in 50% of eyes, with 62% diagnosed at presentation. Although choroidal neovascularization is typically responsive to anti-vascular endothelial growth factor injections, it is associated with poor visual outcome. Systemic steroids are generally used as first-line agents with addition of other immunomodulatory medications if the disease is refractory or recurrent. CONCLUSION: Precise disease pathophysiology of persistent placoid maculopathy has not been elucidated but most probably relates to selective choriocapillaris hypoperfusion/ischemia/vasculitis. Combination of anti-vascular endothelial growth factor injections and immunosuppressive medications may be effective in controlling disease activity and limiting development of sight-threatening complications.

Accuracy of Billing Codes Used in the Therapeutic Care of Diabetic Retinopathy.

Importance: Insurance billing claim databases represent a growing field of scientific inquiry within ophthalmology. Validating the accuracy of billing claim codes used during the care of diabetic retinopathy is a necessary precursor to fully understanding the underlying data and subsequent results of these types of studies. Objective: To determine the accuracy of diagnostic, procedural, and therapeutic billing codes used in the treatment of diabetic retinopathy. Design, Setting, and Participants: This retrospective medical record review was conducted at 3 clinical practices (1 academic and 2 private). Insured patients with diabetic retinopathy were seen by the practices between 2011 and 2013. Each patient then had every visit for 2 years reviewed twice, once for billing data and the second for data from the medical record. Data were collected and analyzed from October 2015 to July 2016. Main Outcomes and Measures: The positive predictive value (PPV) and negative predictive value (NPV) for each code of interest. Sensitivity and specificity were secondary outcomes. Results: A total of 146 patients (mean [SD] age, 60.3 [12.5] years) from 11 physicians had 1072 encounters reviewed over 2 calendar years. Among the included patients, 49.3% were female (n = 72), 48.6% were white (n = 71), 37.0% were black (n = 54), and 18.5% had type 1 diabetes and a mean (SD) hemoglobin A1C level of 7.7% (1.8) (n = 27). Nearly all codes of interest that were used frequently also had a high PPV (range, 89.5%-100%) and NPV (88.6%-100%) including billing codes for intravitreal injection, focal laser, panretinal photocoagulation, laterality of procedure, ranibizumab, bevacizumab, fundus photographs, fluorescein angiography, and optical coherence tomography. Codes that were used infrequently (<20 instances) but still had a high PPV (all 100%) and NPV (99.7%-100%) were codes for aflibercept, triamcinolone, and the dexamethasone implant. Only the codes for infrequently used B-scan ultrasonography (PPV, 69.6%) and subtenon injection (PPV, 100%; NPV, 99.7%, but sensitivity of only 40%) were found to be of questionable accuracy. Other than subtenon injection (40%), all codes were also found to have a high sensitivity (range, 87.6%-100%) and a high specificity (range, 97.2%-100%). Conclusions and Relevance: These data suggest diagnostic, procedure, and therapeutic codes derived from insurance billing claims accurately reflect the medical record for patients with diabetic retinopathy.

Intravitreal Bevacizumab for the Treatment of Vitreous Hemorrhage Due to Proliferative Diabetic Retinopathy.

PURPOSE: To evaluate the outcomes of intravitreal bevacizumab (IVB) use in patients with a vitreous hemorrhage (VH) secondary to proliferative diabetic retinopathy (PDR). DESIGN: Retrospective, interventional case series. METHODS: Patients who presented to Scheie Eye Institute between January 2008 and January 2015 with a new VH secondary to PDR and treated with IVB were included. Exclusion criteria consisted of IVB treatment prior to the study, a history of pars plana vitrectomy (PPV), and less than 1 year of follow-up. Outcomes of interest were additional treatments including PPV, injections, and panretinal photocoagulation (PRP), as well as visual acuity at baseline and at 1 year. RESULTS: Of the 111 eligible eyes, 55 (49.5%) had PRP, 35 (31.6%) were managed with injections alone, and 21 (18.9%) had PPV after 1 year. The overall average number of injections during this time was 2 (range, 1-9), and 13 (11.7%) eyes were managed with a single injection alone. Of the 69 eyes with 2 years of follow-up, 43 (62.3%) had PRP, 16 (23.2%) were treated with injections alone, and 10 (14.5%) had PPV. CONCLUSIONS: This study underscores the potentially important role that IVB injections have in the management of patients with VH secondary to PDR. The results indicate that a proportion of patients may be treated with a minimal amount of intervention requiring 1 or 2 anti-vascular endothelial growth factor injections only. Also, the rate of PPV at 2 years (27.9%, n = 31) suggests that most patients may be managed nonsurgically.

Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial.

PURPOSE: To provide 2-year results comparing anti-vascular endothelial growth factor (VEGF) agents for center-involved diabetic macular edema (DME) using a standardized follow-up and retreatment regimen. DESIGN: Randomized clinical trial. PARTICIPANTS: Six hundred sixty participants with visual acuity (VA) impairment from DME. METHODS: Randomization to 2.0-mg aflibercept, 1.25-mg repackaged (compounded) bevacizumab, or 0.3-mg ranibizumab intravitreous injections performed up to monthly using a protocol-specific follow-up and retreatment regimen. Focal/grid laser photocoagulation was added after 6 months if DME persisted. Visits occurred every 4 weeks during year 1 and were extended up to every 4 months thereafter when VA and macular thickness were stable. MAIN OUTCOME MEASURES: Change in VA, adverse events, and retreatment frequency. RESULTS: Median numbers of injections were 5, 6, and 6 in year 2 and 15, 16, and 15 over 2 years in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P = 0.08). Focal/grid laser photocoagulation was administered in 41%, 64%, and 52%, respectively (aflibercept vs. bevacizumab, P < 0.001; aflibercept vs. ranibizumab, P = 0.04; bevacizumab vs. ranibizumab, P = 0.01). At 2 years, mean VA improved by 12.8, 10.0, and 12.3 letters, respectively. Treatment group differences varied by baseline VA (P = 0.02 for interaction). With worse baseline VA (20/50 to 20/320), mean improvement was 18.1, 13.3, and 16.1 letters, respectively (aflibercept vs. bevacizumab, P = 0.02; aflibercept vs. ranibizumab, P = 0.18; ranibizumab vs. bevacizumab, P = 0.18). With better baseline VA (20/32 to 20/40), mean improvement was 7.8, 6.8, and 8.6 letters, respectively (P > 0.10, for pairwise comparisons). Anti-Platelet Trialists' Collaboration (APTC) events occurred in 5% with aflibercept, 8% with bevacizumab, and 12% with ranibizumab (global P = 0.047; aflibercept vs. bevacizumab, P = 0.34; aflibercept vs. ranibizumab, P = 0.047; ranibizumab vs. bevacizumab, P = 0.20; global P = 0.09 adjusted for potential confounders). CONCLUSIONS: All 3 anti-VEGF groups showed VA improvement from baseline to 2 years with a decreased number of injections in year 2. Visual acuity outcomes were similar for eyes with better baseline VA. Among eyes with worse baseline VA, aflibercept had superior 2-year VA outcomes compared with bevacizumab, but superiority of aflibercept over ranibizumab, noted at 1 year, was no longer identified. Higher APTC event rates with ranibizumab over 2 years warrants continued evaluation in future trials.

Branch retinal artery occlusion after coil embolization of a paraclinoid aneurysm.

The authors report a case of a 48-year-old woman with a branch retinal artery occlusion after the neurosurgical coiling of a paraclinoid aneurysm. Clinical examination revealed a Hollenhorst plaque at the bifurcation of the inferior arcade and at a branch of the superior arcade with associated retinal whitening in the right eye. Follow-up examination at 8 months demonstrated improved visual acuity with near complete resolution of the retinal infarction but a persistent inferior Hollenhorst plaque. This case illustrates a retinal artery occlusion as a possible complication of paraclinoid aneurysmal coiling procedure.

Seven new loci associated with age-related macular degeneration.

Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10(-8). These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10(-8) for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.

A lack of delayed intraocular pressure elevation in patients treated with intravitreal injection of bevacizumab and ranibizumab.

PURPOSE: The purpose of this study was to report the rate of intraocular pressure (IOP) elevation after intravitreal injections of anti-vascular endothelial growth factor agents for exudative age-related macular degeneration. METHODS: Retrospective chart review of all patients receiving intravitreal ranibizumab and/or bevacizumab injections for exudative age-related macular degeneration from November 2005 to June 2010. Delayed ocular hypertension (OHT) was defined as either an IOP ≥22 mmHg on 2 consecutive visits (with an increase from baseline >6 mmHg) or an IOP >26 mmHg on a single visit with a concomitant initiation or augmentation of IOP-lowering treatment. Noninjected fellow eyes served as controls. Incidence of delayed OHT was analyzed using survival analyses, with risk assessed by Cox proportional hazards regression models. Eyes with glaucoma were evaluated separately. RESULTS: Three hundred and two treated eyes and 226 control eyes met inclusion criteria. In eyes with exudative age-related macular degeneration without glaucoma, 3 of 270 injected eyes (0.51% incidence per eye-year) developed delayed OHT compared with 4 of 195 control eyes (1.00% incidence per eye-year), a difference that was not statistically significant (hazard ratio = 0.48; 95% confidence interval: 0.11-2.23). In eyes with exudative age-related macular degeneration and glaucoma, 2 of 32 injected eyes developed delayed OHT (3.1% incidence per eye-year) compared with 3 of 31 control eyes (5.7% incidence per eye-year), a difference that was not statistically significant (hazard ratio = 0.59; 95% confidence interval: 0.10-3.60). CONCLUSION: The incidence of delayed OHT after intravitreal anti-vascular endothelial growth factor injections was low and did not differ between injected and control eyes, including eyes with glaucoma. These results argue against a significant risk of IOP elevation because of repeated anti-vascular endothelial growth factor therapy.