Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in TREX1, which was termed 'retinal vasculopathy with cerebral leukodystrophy'. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder. We identified five different TREX1 mutations in 78 members from 11 unrelated families and by using a standardized study protocol we retrospectively reviewed and aggregated the associated clinical, neuroimaging, and pathology data. Findings were similar across mutations and families. Sixty-four mutation carriers had vascular retinopathy. Neuroimaging revealed (i) punctate, hyperintense, white matter lesions with or without nodular enhancement in 97% of them; (ii) rim-enhancing mass lesions in 84%; and (iii) calcifications in the white matter in 52%. Ninety per cent had clinical manifestations of brain disease, including focal neurological deficits (68%), migraine (59%), cognitive impairment (56%), psychiatric disturbances (42%), and seizures (17%). One mutation carrier had enhancing brain lesions and neurological features but unknown retinopathy status. Additional systemic features included liver disease (78%), anaemia (74%), nephropathy (61%), hypertension (60%), mild Raynaud's phenomenon (40%), and gastro-intestinal bleeding (27%). Mean (AE standard deviation) age at diagnosis was 42.9 AE 8.3 years and at death 53.1 AE 9.6 years. Pathological examination revealed systemic vasculopathy with luminal narrowing and multi-laminated basement membranes. The 13 mutation carriers without retinopathy or brain lesions were on average 8 years younger (mean age: 35.1 AE 10.6 years). Of them, 54% had mild Raynaud's phenomenon, 42% had migraine, and 23% had psychiatric disturbances. Retinal vasculopathy with cerebral leukodystrophy is an autosomal dominant systemic small-vessel disease due to specific TREX1 mutations and clinically primarily characterized by (i) visual impairment from vascular retinopathy; and (ii) neurological decline and premature death due to progressive enhancing cerebral white matter lesions. Impaired liver and kidney function, anaemia sometimes associated with gastrointestinal bleeding, hypertension, migraine, and Raynaud's phenomenon appear to be part of the clinical spectrum as well. Penetrance

Objective To evaluate the association of subretinal hyper-reflective material (SHRM) with visual acuity (VA), geographic atrophy (GA) and scar in the Comparison of Age related Macular Degeneration Treatments Trials (CATT) Design Prospective cohort study within a randomized clinical trial. Participants The 1185 participants in CATT. Methods Participants were randomly assigned to ranibizumab or bevacizumab treatment monthly or as-needed. Masked readers graded scar and GA on fundus photography and fluorescein angiography images, SHRM on time domain (TD) and spectral domain (SD) optical coherence tomography (OCT) throughout 104 weeks. Measurements of SHRM height and width in the fovea, within the center 1mm2, or outside the center 1mm2 were obtained on SD-OCT images at 56 (n=76) and 104 (n=66) weeks. VA was measured by certified examiners. Main Outcome Measures SHRM presence, location and size, and associations with VA, scar, and GA. Results Among all CATT participants, the percentage with SHRM at enrollment was 77%, decreasing to 68% at 4 weeks after treatment and 54% at 104 weeks. At 104 weeks, scar was present more often in eyes with persistent SHRM than eyes with SHRM that resolved (64% vs. 31%; p<0.0001). Among eyes with detailed evaluation of SHRM at weeks 56 (n=76) and 104 (n=66), mean [SE] VA letter score was 73.5 [2.8], 73.1 [3.4], 65.3 [3.5], and 63.9 [3.7] when SHRM was absent, present outside the central 1mm2, present within the central 1mm2 but not the foveal center, or present at the foveal center (p=0.02). SHRM was present at the foveal center in 43 (30%), within the central 1mm2 in 21 (15%) and outside the central 1mm2 in 19 (13%). When SHRM was present, the median maximum height in microns under the fovea, within the central 1 mm2 including the fovea and anywhere within the scan was 86; 120; and 122, respectively. VA was decreased with greater SHRM height and width (p<0.05). Conclusions SHRM is common in eyes with NVAMD and often persists after anti-VEGF treatment. At 2 years, eyes with scar were more likely to have SHRM than other eyes. Greater SHRM height and width were associated with worse VA. SHRM is an important morphological biomarker in eyes with NVAMD.

SUMMARY1. Intracellular voltage recordings using conventional and double-barrelled chloride-selective microelectrodes have been used to identify several transport mechanisms at the apical and basolateral membranes of the isolated bovine retinal pigment epithelium (RPE)-choroid preparation. Intracellular recordings were obtained from two cell populations, melanotic (pigmented) and amelanotic (nonpigmented). The electrical properties of these two populations are practically identical. For melanotic cells the average apical resting membrane potential (VA) is -61 + 2 mV (mean + S.E.M., n = 49 cells, thirty-three eyes). For these cells the ratio of apical to basolateral membrane resistance (a) was 0-22 + 0-02. The mean transepithelial voltage and resistance were 6 + 1 mV and 138 + 7 Ql cm2, respectively.2. The apical membrane, which faces the distal retina, contains a Ba2+-inhibitable K+ conductance and a ouabain-inhibitable, electrogenic Na+-K+ pump. In addition it contains a bumetanide-sensitive mechanism, the putative Na+-K+Cl-cotransporter. The basolateral membrane contains a DIDS (4,4'-diisothiocyanostilbene-2,2'-disulphonic acid)-inhibitable chloride channel. The relative conductances of the apical and basolateral membranes to K+ and Cl-are TK t 09 and TC 0-7, respectively. 3. The ouabain-induced fast phase of apical membrane depolarization (0-30 s) was used to calculate the equivalent resistances of the apical (RA) and basolateral (RB) cell membranes, as well as the paracellular or shunt resistance (R.). They are: 3190 + 400, 17 920 + 2730 and 2550 + 200 Q (mean ± S.E.M., n = 9 tissues), respectively. From these data the equivalent electromotive forces (EMF) at the apical (EA) and basolateral (EB) membranes were also calculated. They are: -69+ 5-0 and -24 + 5 0 mV, respectively.4. Intracellular Cl-activity (a' 1) was measured using double-barrelled ionselective microelectrodes. In the steady state a' =61 + 4-0 mm and the Nernst potential Ec1 =-13-5+1-5 mV (mean+S.E.M., n = 4).5. In the intact eye or in retina, RPE-choroid preparations it has been shown that the transition between light and dark alters the K+ concentration in the extracellular (or subretinal) space between the photoreceptors and the apical membrane of the RPE. These light-induced changes in subretinal [K+]o were qualitatively simulated in vitro by altering apical K+ between 5 and 2 mm. This produced a sequence of MS 8333 D. P. JOSEPH AND S. S. MILLER voltage changes at the apical and basolateral membranes that had three operationally distinct phases. Phase 1 is generated by the combination of an apical membrane K+ diffusion potential and inhibition of the electrogenic Na+-K+ pump. Phase 2 is a delayed hyperpolarization of the basolateral membrane. Phase 3 is most probably caused by a decrease in [K+]i and a decrease in apical membrane K+ conductance. These voltage changes were accompanied by a monotonic decrease in an ail of 26+3-0 mm (n = 4).6. The second of the three phases that is produced following apical K+ reduction from 5 to 2 mm is c...

Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

Purpose: Anatomically similar rhegmatogenous retinal detachments (RRDs) can be treated with scleral buckle (SB), pars plana vitrectomy (PPV), or SB combined with PPV (PPV/SB). This study compares moderately complex phakic primary RRD treated with SB, PPV, or PPV/SB to review anatomic and visual outcomes.Design: Multicenter, retrospective, interventional cohort study.Participants: Data were gathered on all patients from multiple retina practices in the United States with RRD in 2015 and >90 days of follow-up. The cohort of phakic patients with moderately complex RRD was analyzed.Methods: A large and detailed database was generated. Eyes with findings that would bias toward PPV (vitreous hemorrhage, dense cataract, proliferative vitreoretinopathy, giant retinal tear, among others) were excluded. Age <40 years (bias toward SB) was excluded. Comparable cases of moderately complex RRD were then chosen naive to surgeon, surgery, and outcome for subgroup analysis.Main Outcome Measures: Single surgery anatomic success (SSAS), defined as retinal attachment with no other RRD surgery within 90 days, is the main outcome measure. Final visual acuity is the secondary outcome measure. Pearson's chi-square and analysis of variance were used to test treatment effect of surgery type on SSAS and vision.Results: Single surgery anatomic success was noted in 155 of 169 SB cases (91.7%), 207 of 249 PPV cases (83.1%), and 271 of 297 PPV/SB cases (91.2%). Scleral buckle and PPV/SB were superior to PPV for SSAS (P ¼ 0.0041). For macula-on or split cases, SB had significantly better visual outcomes than PPV or PPV/SB even after controlling for cataract (cases with minimal cataract at final follow-up or after cataract surgery) (P < 0.001).Conclusions: For phakic moderately complex primary RRDs in this study of PPV versus SB versus PPV/SB, SB had the best visual outcomes, and PPV had the worst SSAS outcomes.