Millena Bittencourt

Ocular tolerability and efficacy of intravitreal and subconjunctival injections of sirolimus in patients with non-infectious uveitis: primary 6-month results of the SAVE Study

BackgroundThe purpose of this study is to evaluate the ocular tolerability and efficacy of sirolimus administered as subconjunctival or intravitreal injections in patients with non-infectious uveitis. Sirolimus as a Therapeutic Approach for Uveitis (SAVE) is a prospective, randomized, open-label, interventional study. Thirty patients were enrolled and randomized in 1:1 ratio to receive either intravitreal injections of 352 μg sirolimus or subconjunctival injections of 1,320 μg at days 0, 60, and 120, with primary endpoint at month 6.ResultsAt month 6, all subjects with active uveitis at baseline showed reduction in vitreous haze of one or more steps. Forty percent of subjects showed reduction of two steps or more of vitreous haze (four in each group), and 60% showed a reduction of one-step vitreous haze (seven in group 1 and five in group 2). Changes in the inflammatory indices were statistically significant (p < 0.05) in both study groups. Thirty percent of patients gained one or more lines of visual acuity, 20% lost one or more lines, and 50% maintained the same visual acuity. There were no statistically significant differences between the two study groups at month 6. No serious adverse events were found to be related to the study drug.ConclusionLocal administration of sirolimus, either intravitreally or subconjunctivally, appears to be safe and tolerable. No drug-related systemic adverse events or serious adverse events were noted. Sirolimus delivered as either an intravitreal or subconjunctival injection has demonstrated bioactivity as an immunomodulatory and corticosteroid-sparing agent in reducing vitreous haze and cells, improving visual acuity, and in decreasing the need for systemic corticosteroids.

Wide-field Retinal Imaging in the Management of Noninfectious Posterior Uveitis

PURPOSE To determine whether the use of ultra wide-field imaging changes the management or determination of disease activity in patients with noninfectious posterior uveitis. DESIGN Prospective, observational case series. METHODS setting: Divisions of Retina and Ocular Immunology at single academic medical center. patient population: Total of 43 patients with noninfectious posterior uveitis seen by 4 investigators at the Wilmer Eye Institute. procedures: Each patient underwent standard clinical examination, followed by ultra wide-field scanning laser ophthalmoscope (SLO) imaging and angiography. Investigators successively determined disease activity and management decisions based on clinical examination, examination plus simulated 30- or 60-degree fluorescein angiography (FA) (obtained by physically narrowing the field of view of the wide-field images), examination plus ultra wide-field SLO images, and examination plus wide-field FA. main outcome measures: The primary outcome was the percentage of patients whose management changed based on the availability of wide-field imaging, compared with standard examination and imaging. The secondary outcome was detection of disease activity with and without wide-angle imaging. RESULTS Management was altered in 7 of 43 patients (16%) based on examination and limited FA, whereas 21 of 43 patients (48%) had management change with the use of the ultra wide-field imaging and angiography (P < .001). Disease activity was detected in 22 of 43 patients (51%) based on examination and simulated conventional imaging, and in 27 of 43 (63%) with wide-field imaging (P = .27). CONCLUSIONS The index study, with several design limitations, has suggested that ultra wide-field imaging may alter management decisions compared to standard-of-care imaging and clinical examination. Additional studies, including longitudinal evaluations, are needed to determine whether these findings, or the subsequent management alterations, may improve patient outcomes.

Characterization of macular lesions in punctate inner choroidopathy with spectral domain optical coherence tomography

PurposePunctate inner choroidopathy (PIC) is an ocular inflammatory disease. Spectral domain optical coherence tomography (SD-OCT) allows detailed visualization of retinal and choroidal structures. We aimed to describe the retinal changes on SD-OCT associated with PIC lesions localized in the macula.MethodsRetrospective case series: PIC lesions not associated with choroidal neovascularization (CNV) and captured by macular SD-OCT scans were identified and characterized.ResultsTwenty-seven PIC lesions from seven patients (eight eyes) were identified and classified into four categories according to disease activity and temporal changes. Among clinically inactive patients, two main patterns were noted on OCT: (1) retinal pigment epithelium (RPE) elevation with sub-RPE hyper-reflective signals and (2) localized disruption of outer retinal layers with choroid and Bruchs membrane (BM) generally spared. Clinically active patients demonstrated lesions with intact BM with RPE elevation that fluctuated with disease activity and sub-RPE hyper-reflective signals. Photoreceptor-associated bands on SD-OCT (PRs) were not visible during active disease, but returned to normal visibility when lesions were clinically stable. Seven lesions in patients without clinically detected activity demonstrated alteration of RPE elevation.ConclusionSD-OCT can provide detailed structural characteristics of PIC lesions. RPE elevation is noted in many lesions while BM and choroid are spared. Photoreceptor-associated bands on SD-OCT appear compressed during clinically active stages and are visible during stabilization. OCT may provide information on activity not detected clinically.

Ultra-wide-field retinal imaging in the management of non-infectious retinal vasculitis.

BackgroundThe purpose of this study is to describe and quantify the benefit of ultra-wide-field imaging and fluorescein angiography (FA) in the management of non-infectious retinal vasculitis. In this prospective observational cohort series, patients with non-infectious retinal vasculitis were evaluated and enrolled by four investigators from the Divisions of Retina and Ocular Immunology at the Wilmer Eye Institute. In each patient, disease activity and the need for management changes were assessed, based on clinical examination with or without standard (60°) imaging and then with the addition of ultra-wide-field pseudo-color scanning laser ophthalmoscope (SLO) images and FA using the Optos ultra-wide-field SLO (Optos Panoramic 200MA™, Optos PLC, Dunfermline, Scotland, UK). A standardized questionnaire was completed by each investigator at the time of the clinical evaluation.The primary outcome was the percentage of patients whose management was changed by clinical examination and standard FA, compared with clinical examination plus ultra-wide-field imaging. The secondary outcome was the percentage of patients whose disease was determined to be active based on each modality.ResultsSeventy-one visits from 23 patients were reviewed and analyzed. Based on examination plus ultra-wide-field imaging and ultra-wide-field angiography, disease activity was detected in 48/71 (68%) compared with 32/71 (45%) based on examination and standard FA (P = 0.0095). Based on the clinical examination alone, the decision to alter management was made in 4 of 71 visits (6%), and an additional 3 of 71 (4%) based on simulated standard FA. The addition of ultra-wide-field SLO pseudo-color images altered management in an additional 10/71 visits (14%), and 36/71 (51%) with the addition of ultra-wide-field FA.ConclusionsUltra-wide-field fluorescein imaging and angiography can provide additional information that may be important and relevant in the management of retinal vasculitis.

Association of Retinal Sensitivity to Integrity of Photoreceptor Inner/Outer Segment Junction in Patients with Diabetic Macular Edema

PURPOSE To evaluate the relationship between retinal sensitivity and the photoreceptor inner segment/outer segment (IS/OS) layer status in patients with diabetic macular edema (DME). DESIGN Cross-sectional study. PARTICIPANTS Twenty-five adult patients (37 eyes) diagnosed with DME and managed at the Wilmer Eye Institute, Johns Hopkins University (Baltimore, MD). METHODS We obtained simultaneous fundus microperimetry (MP) and optical coherence tomography (OCT) of patients with DME using a combined MP/OCT system. The device recorded retinal sensitivity and retinal thickness on a 3-dimensional tomography map, and we performed a point-by-point analysis of the IS/OS layer integrity at every MP point. We also reviewed OCT scans to determine the type of DME, cystoid macular edema, or diffuse macular edema (absence of any cysts). In addition, fixation stability and fixation location were analyzed. MAIN OUTCOME MEASURES Retinal point sensitivity measured by MP. RESULTS Twenty-five patients (37 eyes: 29 male and 8 female; mean age, 64.16 years) with DME were enrolled. Fixation was centric in 30 eyes (81%), paracentric in 3 eyes (8%), and eccentric in 4 eyes (11%). Twenty-seven eyes had cystoid macular edema, and 10 eyes had diffuse macular edema. Mean central subfield thickness was 325 μm. We analyzed a total of 1036 individual MP points. Mean point sensitivity was 10.51 dB. A total of 793 points (76.5%) had IS/OS layer present, and 243 points (23.5%) had IS/OS layer disrupted. A mixed linear model, constructed to adjust for potential confounders and account for dependence between retinal points, revealed that the absence of the IS/OS junction was significantly associated with a 3.28-dB decrease in retinal point sensitivity (P<0.001). CONCLUSIONS This novel index study demonstrates that disruption of the IS/OS junction is correlated with a significant decrease in point sensitivity in eyes with DME. Further studies are indicated to confirm and validate this relationship. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Spectral- and time-domain optical coherence tomography measurements of macular thickness in normal eyes and in eyes with diabetic macular edema

PurposeTo report macular thickness values in normal eyes and eyes with diabetic macular edema (DME) using time-domain (TD) and spectral-domain (SD) optical coherence tomography (OCT), and to derive a conversion equation.MethodsThe index study was a prospective investigation conducted on 80 eyes from 40 normal subjects and 130 eyes from 118 patients with DME seen in our clinic. Retinal thickness values from the central 1 mm of the macula and surrounding four ETDRS subfields were acquired using TD-OCT (Stratus OCT) and SD-OCT (SPECTRALIS HRA+OCT). Measurements of the central (C) subfield from both devices were used to derive a conversion equation. The equation was used to predict SD-OCT values using measurements from TD-OCT. Agreement between predicted and actual SD-OCT measurements was assessed.ResultsIn normal eyes, the mean difference between TD-OCT and SD-OCT measurements of the C subfield was 76 μm (CI95=74 and 77, respectively). The conversion equation, y=1.029x+72.49, was derived. In eyes with DME, using the equation, SPECTRALIS-predicted values were 5% higher than actual measurements, with 95% of predicted values falling within 9% of the actual measurements. Relocating SD-OCT grids to match the location on TD-OCT resulted in predicted values falling within 7% of actual measurements.ConclusionsThe percent difference between actual thickness measurements from SPECTRALIS and predicted thickness measurements, using the conversion equation, was within reported limits of repeatability of Stratus in eyes with DME. Our equation may help correlate OCT values from both devices in standard care and clinical trials for DME.

New Treatment Options for Noninfectious Uveitis

Autoimmune uveitis is a group of sight-threatening inflammatory diseases associated with an exacerbated immunological response to ocular proteins. The Standardization of Uveitis Nomenclature Working Group Guidelines have recommended the use of corticosteroids as the first line of therapy for patients who present with active uveitis. However, long-term use of corticosteroids is associated with numerous adverse effects including cataract, glaucoma and metabolic disorders. In this context, new drugs developed to treat rheumatic diseases, and other autoimmune diseases, are being employed often as monotherapy or combined with other immunosuppressive drugs in order to decrease the corticosteroid burden on patients and to manage refractive uveitis. These drugs are currently being evaluated in the framework of uveitis and may open a new horizon with less side effects and more responsiveness for chronic cases. Among others, calcineurin inhibitor voclosporin, mammalian target of rapamycin inhibitor sirolimus, and the IL-1 trap rilonacept, are among these new agents and will be scrutinized in detail in this chapter. More efficient modes of drug delivery are also being employed to deliver high concentration of drug locally and to minimize systemic side effects. The new modes of drug delivery that we will describe in the index chapter include nanoparticles and iontophoresis.

Comparison of time domain and spectral domain optical coherence tomography in measurement of macular thickness in macular edema secondary to diabetic retinopathy and retinal vein occlusion.

Purpose. To evaluate macular thickness, agreement, and intraclass repeatability in three optical coherence tomography (OCT) devices: the time domain (TD) Stratus OCT and two spectral domain (SD) OCTs, Spectralis and Cirrus SD-OCT, in eyes with macular edema secondary to diabetic retinopathy (DR) and retinal vein occlusion (VO). Methods. In a prospective observational study at a university-based retina practice, retinal thickness tomography was performed simultaneously for fifty-eight patients (91 eyes) with DR and VO employing a time domain and two spectral domain OCTs. Agreement in macular measurements was assessed by constructing Bland-Altman plots. Intraclass repeatability was assessed by intraclass correlation coefficients (ICCs). Results. Based on the Bland-Altman plots for central macular thickness, there was low agreement between the measurements of Cirrus SD-OCT and Stratus OCT, Spectralis OCT and Stratus OCT, as well as Spectralis OCT and Cirrus SD-OCT among DR and RVO patients. All three devices demonstrated high intraclass repeatability, with ICC of 98% for Stratus OCT, 97% for Cirrus SD-OCT, and 100% for Spectralis OCT among DR patients. The ICC was 97% for Stratus OCT, 79% for Cirrus SD-OCT, and 91% for Spectralis OCT among RVO patients. Conclusion. There are low agreements among interdevice measurements. However, intraclass repeatability is high in both TD and SD-OCT devices.

Aflibercept: a Potent Vascular Endothelial Growth Factor Antagonist for Neovascular Age-Related Macular Degeneration and Other Retinal Vascular Diseases

IntroductionIn the western hemisphere, age-related macular degeneration (AMD) is the leading cause of visual loss in the elderly. Currently approved therapies for AMD include argon laser, photodynamic therapy, and antivascular endothelial growth factor (VEGF) therapy. The index review discusses aflibercept (VEGF Trap-Eye) in the context of current anti-VEGF therapies for neovascular AMD and other retinal vascular diseases. It highlights important differences between VEGF Trap-Eye and currently used anti-VEGF therapies for neovascular AMD; and discusses the efficacy of these treatments utilizing information from landmark clinical trials.MethodsA systematic search of literature was conducted on PubMed, Science Direct, and Scopus with no limitations of language or years of publication.ResultsPreclinical studies have shown that VEGF Trap-Eye binds to VEGF-A with a higher affinity than other anti-VEGF molecules; and that it also binds to placental growth factor (PlGF). In clinical trials, VEGF Trap-Eye has been shown to be as effective in the treatment of neovascular AMD as other anti-VEGF therapies and possibly to have a longer duration of drug activity.ConclusionVEGF Trap-Eye has enhanced the treatment options currently available for the management of neovascular AMD. The comparable efficacy of VEGF Trap-Eye (to other anti-VEGF agents) coupled with its longer dosing interval may decrease the number of annual office visits for patients with AMD and their caregivers.

Assessment of estimated retinal atrophy progression in Stargardt macular dystrophy using spectral- domain optical coherence tomography

Aims To estimate disease progression based on analysis of macular volume measured by spectral-domain optical coherence tomography (SD-OCT) in patients affected by Stargardt macular dystrophy (STGD1) and to evaluate the influence of software errors on these measurements. Methods 58 eyes of 29 STGD1 patients were included. Numbers and types of algorithm errors were recorded and manually corrected. In a subgroup of 36 eyes of 18 patients with at least two examinations over time, total macular volume (TMV) and volumes of all nine Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields were obtained. Random effects models were used to estimate the rate of change per year for the population, and empirical Bayes slopes were used to estimate yearly decline in TMV for individual eyes. Results 6958 single B-scans from 190 macular cube scans were analysed. 2360 (33.9%) showed algorithm errors. Mean observation period for follow-up data was 15 months (range 3–40). The median (IQR) change in TMV using the empirical Bayes estimates for the individual eyes was −0.103 (−0.145, −0.059) mm3 per year. The mean (±SD) TMV was 6.321±1.000 mm3 at baseline, and rate of decline was −0.118 mm3 per year (p=0.003). Yearly mean volume change was −0.004 mm3 in the central subfield (mean baseline=0.128 mm3), −0.032 mm3 in the inner (mean baseline=1.484 mm3) and −0.079 mm3 in the outer ETDRS subfields (mean baseline=5.206 mm3). Conclusions SD-OCT measurements allow monitoring the decline in retinal volume in STGD1; however, they require significant manual correction of software errors.