MERTK is an essential component of the signaling network that controls phagocytosis in retinal pigment epithelium (RPE), the loss of which results in photoreceptor degeneration. Previous ...proof-of-concept studies have demonstrated the efficacy of gene therapy using human
MERTK
(hMERTK) packaged into adeno-associated virus (AAV2) in treating RCS rats and mice with MERTK deficiency. The purpose of this study was to assess the safety of gene transfer via subretinal administration of rAAV2-VMD2-hMERTK in subjects with
MERTK
-associated retinitis pigmentosa (RP). After a preclinical phase confirming the safety of the study vector in monkeys, six patients (aged 14 to 54, mean 33.3 years) with
MERTK
-related RP and baseline visual acuity (VA) ranging from 20/50 to <20/6400 were entered in a phase I open-label, dose-escalation trial. One eye of each patient (the worse-seeing eye in five subjects) received a submacular injection of the viral vector, first at a dose of 150 µl (5.96 × 10
10
vg; 2 patients) and then 450 µl (17.88 × 10
10
vg; 4 patients). Patients were followed daily for 10 days at 30, 60, 90, 180, 270, 365, 540, and 730 days post-injection. Collected data included (1) full ophthalmologic examination including best-corrected VA, intraocular pressure, color fundus photographs, macular spectral domain optical coherence tomography and full-field stimulus threshold test (FST) in both the study and fellow eyes; (2) systemic safety data including CBC, liver and kidney function tests, coagulation profiles, urine analysis, AAV antibody titers, peripheral blood PCR and ASR measurement; and (3) listing of ophthalmological or systemic adverse effects. All patients completed the 2-year follow-up. Subretinal injection of rAAV2-VMD2-hMERTK was associated with acceptable ocular and systemic safety profiles based on 2-year follow-up. None of the patients developed complications that could be attributed to the gene vector with certainty. Postoperatively, one patient developed filamentary keratitis, and two patients developed progressive cataract. Of these two patients, one also developed transient subfoveal fluid after the injection as well as monocular oscillopsia. Two patients developed a rise in AAV antibodies, but neither patient was positive for rAAV vector genomes via PCR. Three patients also displayed measurable improved visual acuity in the treated eye following surgery, although the improvement was lost by 2 years in two of these patients. Gene therapy for
MERTK
-related RP using careful subretinal injection of rAAV2-VMD2-hMERTK is not associated with major side effects and may result in clinical improvement in a subset of patients.
Purpose
Cases of sudden loss of central vision in eyes with silicone oil in situ and after oil removal have been described. The aim of this review is to present current data on silicone oil toxicity ...to the neuronal aspects of the retina as well as the Cleveland Clinic Abu Dhabi experience with this retinopathy (maculopathy).
Methods
A PubMed review using the terms “silicon oil” and/or “toxicity” and/or “ganglion cell” and/or “nerve fiber” was conducted to identify case reports, case series, and original articles presenting toxicity from silicon oil. Timing of visual loss, as well as SD-OCT data and RNFL/GCC analysis, was collected. Selected cases were pooled from Cleveland Clinic Abu Dhabi Vitreoretinal database to further reinforce the findings.
Results
Twenty-four papers were identified (case/series/articles). The earliest papers that met our criteria seemed to report vision loss at the time of or after silicone oil removal; however, more recent studies have described such toxicity from 1 to 6 months after tamponade with silicone oil in situ. Since the first description of central visual loss from silicone oil, all researchers describe a thinning of perifoveal ganglion cells measured with SD-OCT, while there is no concordance as far as RNFL changes, with some authors describing a thinning and others a thickening, but neither was ever clearly associated with visual loss. The correlation between SD-OCT hyperreflective goblets in the inner retina and histological description of intraretinal oil droplets migration seems to suggest instances of silicone oil penetration in the retinal layers.
Conclusion
In a small percentage of cases who underwent retinal tamponade with silicone oil, ganglion cells can suffer a direct damage either from particles of oil that migrate in the retina or from direct contact with it. Indirect damage may be caused by phototoxicity due to the transparent nature of silicon oil or by inflammatory damage from cytokines sandwiched between oil and retina.
Purpose
To compare the ability of wide-field optical coherence tomography angiography (WF-OCTA) to that of ultra-wide field fluorescein angiography (UWF-FA) and ultra-wide-field color fundus ...photography (UWF-CP) to detect retinal neovascularization (NV) in eyes with proliferative diabetic retinopathy (PDR).
Methods
In this cross-sectional study, naïve patients with active PDR underwent UWF-FA and UWF-CP using the Optos 200Tx and WF-OCTA with 12 × 12 mm fields of five visual fixations using the PLEX Elite 9000. NV was defined on OCTA when the co-registered B-scan with flow overlay of the vitreoretinal interface (VRI) segmentation showed extraretinal proliferation. Three masked readers examined the UWF-FA, UWF-CP, and WF-OCTA independently for the presence of NV. Statistical analysis was performed to compare the diagnostic accuracy of the 3 wide-field imaging modalities using OCT B-scan as the reference standard.
Results
In 82 eyes with PDR, neovascularization of the disc (NVD) was detected in 13 eyes by UWF-CP, 35 eyes with UWF-FA, and 37 eyes with OCTA using the VRI slab. Upon review of the 2500 OCT B-scans with superimposed flow overlay of each eye, NVD was confirmed in 37 eyes. The sensitivity and specificity of NVD detection were 35.1% and 97.8%, respectively for UWF-CP; 94.6% and 100%, respectively, for UWF-FA; and 100% and 100% for WF-OCTA. One hundred ninety-six foci of neovascularization elsewhere (NVE) were identified with the OCT B-scan with superimposed flow overlay. UWF-CP analysis was able to detect 62 foci of NVE of the 196 confirmed by B-scan (31.6% detection rate). An additional 11 foci of NVE seen on UWF-CP were not confirmed by B-Scan (15% false positive rate). There were 182 foci of NVE identified by UWF-FA (detection rate 91.3%), while WF-OCTA detected 196 retinal NVEs (detection rate 100%). The rate of false positives for both UWF-FA and WF-OCTA was low (< 2%).
Conclusion
WF-OCTA can identify NV that is not evident in UWF-CP and represents a faster and safer alternative to UWF-FA for surveillance of PDR with comparable diagnostic accuracy.
Fundus autofluorescence (FAF) is a non‐invasive retinal imaging modality used in clinical practice to non‐invasively map changes at the level of the retinal pigment epithelium (RPE)/photoreceptor ...complex and alterations of macular pigment distribution. This imaging method is based on the visualization of intrinsic fluorophores and may be easily and rapidly used in routine patient care. Excessive accumulation of lipofuscin granules in the lysosomal compartment of RPE cells represents a common downstream pathogenic pathway in various hereditary and complex retinal diseases. The clinical applications of FAF continue to expand. It is now an essential tool for evaluating macular dystrophies and various hereditary retinal disorders. Fundus autofluorescence (FAF) may detect abnormalities beyond those detected on funduscopic examination, fluorescein angiography (FA) or optical coherence tomography (OCT). Fundus autofluorescence (FAF) imaging is particularly helpful for differential diagnosis, detection and extent delineation of involved retinal areas, genotype‐phenotype correlations and monitoring of changes overtime. Given its ease of use, non‐invasive nature and value in characterizing retinal disease, FAF enjoys increasing clinical relevance. This review summarizes basic principles and FAF findings in various hereditary retinal diseases.
Insulin-like growth factor binding proteins (IGFBPs) play important physiological functions through the modulation of IGF signaling as well as IGF-independent mechanisms. Despite the established role ...of IGFs in development, a similar role for the seven known IGFBPs has not been established in humans. Here, we show that an autosomal-recessive syndrome that consists of progressive retinal arterial macroaneurysms and supravalvular pulmonic stenosis is caused by mutation of IGFBP7. Consistent with the recently established inhibitory role of IGFBP7 on BRAF signaling, the BRAF/MEK/ERK pathway is upregulated in these patients, which may explain why the cardiac phenotype overlaps with other disorders characterized by germline mutations in this pathway. The retinal phenotype appears to be mediated by a role in vascular endothelium, where IGFBP7 is highly expressed.
Retinal arteriolar macroaneurysms with supravalvular pulmonic stenosis (RAMSVPS) is a rare syndrome that to date has only been reported in Saudi Arabian families. All tested patients have been ...homozygous for a single
splice variant (NM_001553.2:c.830-1G>A). We report our experience with RAMSVPS in the United Arab Emirates.
Retrospective case series.
Five affected individuals (two males and three females) from two unrelated Emirati families were known to our institution (age of first signs 6 months to 10 years of age, with one asymptomatic 6-year-old boy identified by sibling screening examination). Initial ophthalmic diagnoses had been Coats disease or traumatic retinal bleeding. Characteristic retinal arteriolar trunk beading and macroaneurysms led to the actual diagnosis of RAMSVPS. One child with esotropia at 6 months of age seemed to have unilateral Coats disease until retinal signs became apparent in the contralateral eye at 4 years old. One family consented to genetic testing, and both affected siblings were homozygous for the Saudi
splice variant (c.830-1G>A). The three children who underwent echocardiography were all confirmed to have cardiac valvular abnormalities (two supravalvular pulmonic stenosis and one tricuspid stenosis).
The distinct ophthalmic phenotype of RAMSVPS is important to recognize because of systemic implications. Retinal findings can be misinterpreted as sequelae of trauma or Coats disease and can seem unilateral in very young children until changes in the contralateral eye become apparent years later. The homozygous
splice variant associated with the disease likely represents an ancestral founder effect for the Arabian Peninsula.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Purpose
Editorial to De Giacinto et al case report on free autologous neurosensory retina patch.
Methods
Literature review and experts’ opinion
Results
In the present issue, De Giacinto et al ...describe a free autologous neurosensory retina patch to close a chronic macular hole. This new technique was made necessary by an extended internal limiting membrane peeling during the first surgery, that prevented grafting a patch of internal limiting membrane when the hole did not close. We hereby review pros and cons of patching a chronic macular hole with an internal limiting membrane patch, as well as the importance of not over-enlarging a peeling.
Discussion
Internal limiting membrane patch can be considered in chronic macular holes. It may not be an option in cases of over-enlargement of a previous peel; free autologous neurosensory retina patch may be a valid alternative in such cases.
To study the multimodal imaging findings of a large series of eyes with cilioretinal artery obstruction (CILRAO) and describe the systemic associations.
Multicentre, retrospective chart review from ...12 different retina clinics worldwide of eyes with CILRAO, defined as acute retinal whitening in the distribution of the cilioretinal artery, were identified. The clinical, systemic information and multimodal retinal imaging findings were collected and analysed.
A total of 53 eyes of 53 patients with CILRAO were included in the study. In 100% of eyes, fundus photography illustrated deep retinal whitening corresponding to the course of the cilioretinal artery. Twenty-eight patients (52.8%) presented with isolated CILRAO (baseline best-corrected visual acuity (BCVA) 20/50, final BCVA 20/25) associated with nocturnal hypotension, 23 patients (43.4%) with CILRAO secondary to central retinal vein occlusion (CRVO) (baseline BCVA 20/40, final BCVA 20/20) and two patients with CILRAO due to biopsy-proven giant cell arteritis (GCA) (baseline BCVA 20/175, final BCVA 20/75). With spectral domain optical coherence tomography (SD-OCT), a hyper-reflective band involving the inner nuclear layer (ie, paracentral acute middle maculopathy or PAMM) was noted in 51 eyes (28/28 eyes with isolated CILRAO and 23/23 eyes with CILRAO+CRVO) corresponding to the retinal whitening. In the two eyes with CILRAO+GCA, SD-OCT illustrated hyper-reflective ischaemia of both the middle and inner retina.
Isolated CILRAO and CILRAO secondary to CRVO are the result of hypoperfusion or insufficiency, rather than occlusion, of the cilioretinal artery and are associated with PAMM or selective infarction of the the inner nuclear layer. With GCA, there is complete occlusion of the cilioretinal artery producing ischaemia involving both the middle and inner retina associated with worse visual outcomes.
Retinal dystrophies (RD) are heterogeneous hereditary disorders of the retina that are usually progressive in nature. The aim of this study was to clinically and molecularly characterize a large ...cohort of RD patients.
We have developed a next-generation sequencing assay that allows known RD genes to be sequenced simultaneously. We also performed mapping studies and exome sequencing on familial and on syndromic RD patients who tested negative on the panel.
Our panel identified the likely causal mutation in >60% of the 292 RD families tested. Mapping studies on all 162 familial RD patients who tested negative on the panel identified two novel disease loci on Chr2:25,550,180-28,794,007 and Chr16:59,225,000-72,511,000. Whole-exome sequencing revealed the likely candidate as AGBL5 and CDH16, respectively. We also performed exome sequencing on negative syndromic RD cases and identified a novel homozygous truncating mutation in GNS in a family with the novel combination of mucopolysaccharidosis and RD. Moreover, we identified a homozygous truncating mutation in DNAJC17 in a family with an apparently novel syndrome of retinitis pigmentosa and hypogammaglobulinemia.
Our study expands the clinical and allelic spectrum of known RD genes, and reveals AGBL5, CDH16, and DNAJC17 as novel disease candidates.
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