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To assess the relationship of demographics, clinical characteristics and structural optical coherence tomography (OCT) findings to long-term visual outcomes in patients with Leber hereditary optic neuropathy (LHON) treated with idebenone.Retrospective, interventional, noncomparative clinical cohort study.In this study, a total of 17 participants (34 eyes) with LHON treated with idebenone therapy within 1 year after disease onset and 2 years (24 months) of regular follow-ups were retrospectively enrolled. At baseline, structural OCT volume scans of the macula and optic nerve were reviewed to measure metrics reflecting neuronal loss (ie, macular ganglion cell and inner plexiform layer [GC-IPL] and peripapillary retinal nerve fiber layer [RNFL] thicknesses). Stepwise multiple regression analyses were computed to assess associations between final best-corrected visual acuity (BCVA) at 2 years and change in BCVA from baseline at 2 years as dependent variables with demographics, clinical characteristics, and OCT metrics at baseline (visit before the initiation of treatment).The BCVA was 1.6±0.8 logMAR (Snellen VA of ∼20/800) at baseline (visit before the initiation of treatment) and 1.0±0.7 logMAR (Snellen VA of 20/200) at the 2-year follow-up visit (P.0001). Mean±SD change in BCVA from baseline at 2 years was -51.9%±35.9%. In multivariable analysis, the strongest associations with final BCVA were with baseline BCVA (P = .012), superior macular GC-IPL thickness (P = .044), superotemporal macular GC-IPL thickness (P = .010), and inferotemporal macular GC-IPL thickness (P = .015). Similarly, the strongest associations with delta BCVA were with superior macular GC-IPL thickness (P = .045), superotemporal macular GC-IPL thickness (P = .047), and inferotemporal macular GC-IPL thickness (P = .030).We identified OCT biomarkers associated with long-term (ie, 2-year) visual outcomes in patients with LHON treated with idebenone therapy in the first year after disease onset. Thinning of the GC-IPL in the superior and temporal parafoveal regions was associated with worse long-term visual outcomes in these patients.

(1) Purpose: To determine the “retinal thickness deviation” (RTD) in diabetic macular edema (DME) eyes treated with intravitreal therapy and to establish associations between RTD and best-corrected visual acuity (BCVA). (2) Methods: We conducted a retrospective study, including consecutive patients with DME eyes undergoing intravitreal therapy with two years of follow-up. BCVA and central subfield thickness (CST) were collected at baseline and at 12 months and 24 months of follow-up. RTD was calculated as the absolute difference between measured and normative CST values at each time point. Linear regression analyses were performed between RTD and BCVA and between CST and BCVA. (3) Results: One hundred and four eyes were included in the analysis. The RTD was 177.0 (117.2) μm at baseline, 97.0 (99.7) μm at 12 months and 89.9 (75.3) μm at 24 months of follow-up (p < 0.001). RTD showed a moderate association with BCVA at baseline (R2 = 0.134, p < 0.001) and 12 months (R2 = 0.197, p < 0.001) and a substantial association at 24 months (R2 = 0.272, p < 0.001). The CST showed a moderate association with BCVA at baseline (R2 = 0.132, p < 0.001) and 12 months (R2 = 0.136, p < 0.001), while the association was weak at 24 months (R2 = 0.065, p = 0.009). (4) Conclusions: RTD showed a good association with visual outcome in patients with DME eyes undergoing intravitreal treatment.

The purpose of the study was to determine the “retinal thickness deviation” (RTD) in diabetic macular edema (DME) eyes treated with intravitreal therapy and to establish associations be-tween RTD and best-corrected visual acuity (BCVA). We conducted a retrospective study, in-cluding consecutive DME eyes undergoing intravitreal therapy with two years of follow-up. BCVA and central subfield thickness (CST) were collected at baseline, 12 months and 24 months of follow-up. RTD was calculated as the absolute difference between measured and normative CST values at each time point. Linear regression analyses were performed between RTD and BCVA and between CST and BCVA. One hundred and four eyes were included in the analysis. The RTD was 177.0 (117.2) μm at baseline, 97.0 (99.7) μm at 12 months and 89.9 (75.3) μm at 24 months of follow-up (P < .001). RTD showed a moderate association with BCVA at baseline (R2=0.134, p

Introduction: The aim of our study was to investigate factors associated with diabetic retinopathy (DR) severity fluctuations in patients undergoing intravitreal injections for diabetic macular edema and to explore risk factors for proliferative DR (PDR). Methods: We graded ultra-widefield fundus photography imaging at each visit using the Early Treatment Diabetic Retinopathy Study severity scale (DRSS). We calculated the deviation from the mode (DM) of DRSS values as a proxy of DR severity fluctuations, and we analyzed its clinical associations with linear models. We computed risk factors for PDR with Cox hazard models. We included the DRSS area-under-the-curve (AUC) of DRSS scores as a covariate in all analyses. Results: We included 111 eyes with median follow-up of 44 months. Higher DRSS-AUC values (=+0.03 DRSS DM for unitary DRSS/month increase, p=0.01) and a higher number of anti-VEGF injections (=+0.07 DRSS DM for injection, p=0.045) were associated with wider DR severity fluctuations. Higher DRSS-AUC values (HR=1.45 for unitary DRSS/month increase, p=0.001) and wider DR severity fluctuations (HR=22.35 4th quartile vs. 1st-3rd quartile of DRSS DM, p=0.01) were risk factors for PDR. Discussion/Conclusion: Patients with larger DR variability in response to intravitreal injections may be at higher risk of DR progression. We advocate attentive follow-up in these patients to recognize PDR early.

To investigate demographic and clinical factors influencing the longitudinal changes of retinal pigment epithelium (RPE) dehiscence area after RPE tears, including the presence of RPE tear-associated repair proliferation (TARP), and identify factors associated with TARP development over follow-up.Retrospective, single-center, observational cohort study of patients with a history of macular neovascularization and RPE tear. The area of RPE dehiscence was measured on repeated short-wavelength fundus autofluorescence imaging. Associations between covariates and RPE dehiscence areas were tested with multivariable linear mixed models. Associations between TARP development and clinical variables were investigated with Cox regression models. Factors associated with visual acuity changing rates were explored with linear mixed models.Thirty-seven eyes of 36 patients were included in this study and followed for a median time of 18 months. Tear-associated repair proliferation was identified in 27 eyes (73%). The median time for TARP detection was 112 days; none of the investigated factors was significantly associated with TARP occurrence. The presence of TARP (estimate: -0.042 mm2/month; P = 0.001) and female gender (estimate: -0.035 mm2/month; P = 0.006) were associated with slower rates of RPE dehiscence enlargement over time. Faster rates of visual improvement were observed in eyes with TARP compared with those without TARP (estimate = -0.010 logarithm of the minimum angle of resolution/month if TARP was present; P = 0.008).Retinal pigment epithelium tear repair with TARP and female gender were associated with slower RPE degeneration after RPE tears. The presence of TARP was associated better visual prognosis. Additional research on factors promoting TARP development may have therapeutic and prognostic implications.

BACKGROUND: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing =20 kg) or 0·25 mg/kg (for individuals weighing

Introduction Macular neovascularization (MNV) is a common complication of age-related macular degeneration (AMD). Although several biomarkers may help to estimate the risk of MNV onset, neovascular complication is difficult to predict. Previous studies showed that the quantitative assessment of choroidal and choriocapillaris changes is useful for the assessment of atrophy expansion. On the other hand, scant data are available regarding the role of this kind of assessment in the setting of MNV. The aim of the study is to analyze choroidal and choriocapillaris changes occurring before the onset of MNV in patients affected by AMD using quantitative optical coherence tomography (OCT) and OCT angiography (OCTA). Methods The study was designed as a retrospective case series. Patients affected by AMD, categorized in eyes complicated by MNV and eyes not developing MNV, were retrospectively analyzed for 1 year of follow-up. Choroidal thickness (CT), Sattler layer thickness (SLT) and Haller layer thickness (HLT) were measured on OCT scans. Vessel density (VD) and choriocapillaris (CC) porosity were quantified on OCTA reconstructions. The main outcome measure was the relationship between choroidal and CC parameters, and MNV onset. Results We included 50 eyes of 50 AMD patients (28 male; mean age 74 ± 5 years). Over the 1-year follow-up, 15/50 eyes developed MNV (9 type 1; 3 type 2; 3 mixed type 1–2). Mean best-corrected visual acuity (BCVA) was 0.15 ± 0.15 logMAR at baseline, remaining stable in eyes not developing MNV (0.15 ± 0.12 logMAR; p > 0.05), and worsening to 0.38 ± 0.20 logMAR in eyes developing MNV (p

To quantitatively evaluate the inner and outer choroidal changes in the fellow eyes of patients with unilateral central serous chorioretinopathy (CSC).We analyzed data from patients with a diagnosis of unilateral CSC who had structural optical coherence tomography (OCT) and swept-source OCT angiography obtained. An additional group of age-matched healthy patients was included for comparison. The main outcome measures were: (1) choriocapillaris flow deficits' quantitative metrics; (2) choroidal luminal (LCA) and stromal (SCA) areas; and (3) choroidal vascularity index.Fellow unaffected eyes from 60 patients with unilateral CSC and 30 healthy subjects were included in the analysis. Mean ± SD age was 47.5 ± 9.9 years in the unilateral CSC group and 50.7 ± 10.8 years in the control group (P = 0.410). In the structural OCT assessment, both the LCA and SCA were increased in the unilateral CSC group (0.33 ± 0.11 and 0.29 ± 0.10 mm2) compared with healthy controls (0.28 ± 0.08 and 0.27 ± 0.05 mm2), although only differences in LCA reached a statistical significance (P = 0.041 and P = 0.286 for LCA and SCA, respectively). The choroidal vascularity index was higher in CSC patients (53.7 ± 3.6 and 50.9 ± 5.5%, P = 0.045). In the OCT angiography evaluation, the choriocapillaris flow deficits' percentage and number were increased in those patients affected by unilateral CSC. In multiple regressions, the strongest association with choriocapillaris percentage of flow deficits was with the presence of pachychoroid pigment epitheliopathy signs in the study eye (P0.0001).Our results corroborate the hypothesis that inner and outer choroidal changes affect both eyes of patients with unilateral disease.

Background: Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment. Methods: FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing. Findings: Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p

To provide a review of the salient histological and imaging features in neovascular age-related macular degeneration (AMD) that will be integrated in order to have a better comprehension of the pathogenesis and clinical aspects of this disease.A literature review of histology and imaging features in neovascular AMD was conducted.Histology has granted a detailed characterization of neovascular AMD ex vivo. In details, histological features in these eyes have offered important insights into the pathogenesis of neovascular AMD. In addition, histology donated a detailed characterization of the different types of macular neovascularization (MNV) that may complicate AMD. The introduction of optical coherence tomography angiography (OCTA) has enormously amplified our knowledge of neovascular AMD through in vivo assessment of the anatomical and pathological characteristics of this disease. New insights elucidating the morphological features of the choriocapillaris confirmed that this vascular structure plays a crucial role in the pathogenesis of neovascular AMD. OCTA also offered a detailed visualization of MNV complicating neovascular AMD.New imaging technologies offer a remarkable chance to build a bridge between histology and clinical findings in neovascular AMD.

BACKGROUND Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood. METHODS We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. RESULTS A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P

Background: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. Methods: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. Results: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. Conclusions: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.).

The purpose of this study was to investigate a confocal scanning laser ophthalmoscopy (cSLO) ultra-widefield (UWF) swept-source optical coherence tomography (S-SOCT) in assessment of diabetic choroidopathy and to evaluate the agreement of measurements with a spectral-domain OCT (SD-OCT) instrument.We conducted a cross-sectional study of patients with diabetes evaluating the choroidal vascularity index (CVI) in the nasal, temporal, and central macula segments of a UWF SS-OCT scan centered to the fovea. UWF pseudocolored fundus images were used for diabetic retinopathy (DR) severity staging. The CVI values were compared between different degrees of severity of DR and different posterior-pole sectors with linear mixed models. Central macula CVI measurements were repeated on SD-OCT scans; the interobserver intraclass coefficient (ICC) was calculated between SS-OCT and SD-OCT.A total of 151 eyes of 85 patients were included. The CVI values decreased from nonproliferative DR to proliferative DR, with high-risk proliferative DR having significantly lower CVI values than moderate to severe nonproliferative DR (P = 0.03). The central macula region was the most evidently affected; the nasal sector was the least affected. The agreement between SS-OCT and SD-OCT was moderate (ICC = 0.50).Diabetic choroidopathy progresses with worsening of DR toward proliferative disease; choroidal depletion is more prominent in the macula. Caution is recommended in comparing CVI values between different devices.Choroidal vascularity informs about the severity of DR and its complications, such as macular edema. The agreement between readers and between instruments may be suboptimal in certain cases.

Purpose To investigate the relationship between retinal structure and macular function in eyes screened for hydroxychloroquine (HCQ) toxicity. Methods Participants referred for hydroxychloroquine retinopathy screening with spectral domain optical coherence tomography (SD-OCT) and multifocal electroretinogram (mfERG) testing were included in the analysis. Amplitude and implicit time of mfERG N1 and P1 responses were included in the analysis. Ring ratios were computed for amplitude values as the ratio of rings 1–3:5 (R1–3:R5). A control group of healthy participants was included for comparison of SD-OCT metrics. Results Sixty-three eyes screened for HCQ retinopathy and 30 control eyes were analyzed. The outer nuclear layer (ONL) was significantly thinner in HCQ patients in the foveal (P = 0.008), parafoveal (P < 0.0001), and perifoveal (P < 0.0001) regions. The HCQ cohort was further divided into two subgroups according to the presence of structural clinically detectable retinopathy (i.e., structural damage as detected by multimodal imaging). HCQ eyes without retinopathy had a thinner ONL thickness in the foveal (P = 0.032), parafoveal (P < 0.0001), and perifoveal (P < 0.0001) regions and a thinner inner nuclear layer (INL) in the parafoveal region (P = 0.045 versus controls). Structural changes in HCQ patients without retinopathy were significantly associated with macular function as R2:R5 ring ratio of mfERG P1 amplitude was associated with INL (P = 0.002) and ONL (P = 0.044) thicknesses, and R3:R5 ring ratio of P1 amplitude was associated with ONL thickness (P = 0.004). Conclusions Our results suggest that structural alterations secondary to HCQ toxicity may occur in the absence of clinically detectable retinopathy, and this may reflect in an impaired macular function.