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Inherited retinal diseases can result from various genetic defects and are one of the leading causes for blindness in the working-age population. The present study aims to provide a comprehensive description of changes in retinal structure associated with phenotypic disease entities and underlying genetic mutations. Full macular spectral domain optical coherence tomography scans were obtained and manually segmented in 16 patients with retinitis pigmentosa, 7 patients with cone−rod dystrophy, and 7 patients with Stargardt disease, as well as 23 age- and sex-matched controls without retinal disease, to assess retinal layer thicknesses. As indicated by generalized least squares models, all IRDs were associated with retinal thinning (p < 0.001), especially of the outer nuclear layer (ONL, p < 0.001). Except for the retinal nerve fiber layer, such thinning was associated with a reduced visual acuity (p < 0.001). These advances in our understanding of ultrastructural retinal changes are important for the development of gene-, cell-, and optogenetic therapy. Longitudinal studies are warranted to describe the temporal component of those changes.
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Degeneração Retiniana , Retinose Pigmentar , Humanos , Tomografia de Coerência Óptica/métodos , Retina/diagnóstico por imagem , Retinose Pigmentar/genética , Doença de Stargardt/genéticaRESUMO
PURPOSE: Missing heritability in human diseases represents a major challenge, and this is particularly true for ABCA4-associated Stargardt disease (STGD1). We aimed to elucidate the genomic and transcriptomic variation in 1054 unsolved STGD and STGD-like probands. METHODS: Sequencing of the complete 128-kb ABCA4 gene was performed using single-molecule molecular inversion probes (smMIPs), based on a semiautomated and cost-effective method. Structural variants (SVs) were identified using relative read coverage analyses and putative splice defects were studied using in vitro assays. RESULTS: In 448 biallelic probands 14 known and 13 novel deep-intronic variants were found, resulting in pseudoexon (PE) insertions or exon elongations in 105 alleles. Intriguingly, intron 13 variants c.1938-621G>A and c.1938-514G>A resulted in dual PE insertions consisting of the same upstream, but different downstream PEs. The intron 44 variant c.6148-84A>T resulted in two PE insertions and flanking exon deletions. Eleven distinct large deletions were found, two of which contained small inverted segments. Uniparental isodisomy of chromosome 1 was identified in one proband. CONCLUSION: Deep sequencing of ABCA4 and midigene-based splice assays allowed the identification of SVs and causal deep-intronic variants in 25% of biallelic STGD1 cases, which represents a model study that can be applied to other inherited diseases.
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Degeneração Macular , Transcriptoma , Transportadores de Cassetes de Ligação de ATP/genética , Genômica , Humanos , Íntrons , Degeneração Macular/genética , Mutação , Linhagem , Doença de StargardtRESUMO
Autosomal recessive bestrophinopathy (ARB) has been reported as clinically heterogeneous. Eighteen patients (mean age: 22.5 years; 15 unrelated families) underwent ophthalmological examination, fundus photography, fundus autofluorescence, and optical coherence tomography (OCT). Molecular genetic testing of the BEST1 gene was conducted by the chain-terminating dideoxynucleotide Sanger methodology. Onset of symptoms (3 to 50 years of age) and best-corrected visual acuity (0.02-1.0) were highly variable. Ophthalmoscopic and retinal imaging defined five phenotypes. Phenotype I presented with single or confluent yellow lesions at the posterior pole and midperiphery, serous retinal detachment, and intraretinal cystoid spaces. In phenotype II fleck-like lesions were smaller and extended to the far periphery. Phenotype III showed a widespread continuous lesion with sharp peripheral demarcation. Single (phenotype IV) or multifocal (phenotype V) vitelliform macular dystrophy-like lesions were observed as well. Phenotypes varied within families and in two eyes of one patient. In addition, OCT detected hyperreflective foci (13/36 eyes) and choroidal excavation (11/36). Biallelic mutations were identified in each patient, six of which have not been reported so far [c.454C>T/p.(Pro152Ser), c.620T>A/p.(Leu207His), c.287_298del/p.(Gln96_Asn99del), c.199_200del/p.(Leu67Valfs*164), c.524del/p.(Ser175Thrfs*19), c.590_615del/p.(Leu197Profs*26)]. BEST1-associated ARB presents with a variable age of onset and clinical findings, that can be categorized in 5 clinical phenotypes. Hyperreflective foci and choroidal excavation frequently develop as secondary manifestations.
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Bestrofinas/genética , Oftalmopatias Hereditárias/genética , Fenótipo , Doenças Retinianas/genética , Adulto , Alelos , Criança , Pré-Escolar , Oftalmopatias Hereditárias/diagnóstico por imagem , Oftalmopatias Hereditárias/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Doenças Retinianas/diagnóstico por imagem , Doenças Retinianas/patologiaRESUMO
PURPOSE: To classify and characterize AMN lesions with SD-OCT during a follow-up as long as 5 years. METHODS: Retrospective study of 14 patients (18 eyes) with special focus on SD-OCT. We measured thickness of inner nuclear layer (INL), outer retinal layer (ONL), and hyperreflective band at baseline and during follow-up. AMN lesions were classified as type 1 and type 2. RESULTS: Of 14 patients (six males, eight females, mean age 29.7 years), three patients (four eyes) had type 1 and nine (12 eyes) had type 2. Two patients did not meet the criteria for AMN type 1 or 2 and were therefore classified as new subtype of AMN. In all patients, statistically significant thinning of ONL and INL was observable. Mean ONL of all patients was 90.2 ± 7.81 and 72.3 ± 15.64 µm (p < 0.05) during follow-up; mean INL was 54.4 ± 10.71 and 37.5 ± 6.18 µm (p < 0.05) in the course. In the subgroup analysis in AMN type 2, the thinning of both ONL and INL was also statistically significant (mean ONL: 87.4 ± 6.02 and 71.6 ± 12.7 µm (p < 0.05); mean INL: 48.5 ± 5.04 and 38.5 ± 5.6 µm (p < 0.05)) in the course. CONCLUSION: SD-OCT allows for classification, characterization, and further understanding of AMN lesions. Up to now, this is one of the largest AMN case series differentiating into different subtypes and following up for up to 5 years. Furthermore, we describe a new AMN subtype characterized by initially clinically visible yellowish parafoveal lesions, subtle pigmentary changes at late stage, lack of classic dark appearance on IR reflectance, involvement of RPE/Bruch's complex, and disruption of ellipsoid zone and interdigitation zone. The patients suffered from a prolonged visual impairment and paracentral scotomata. We propose the term AMN type 3 or "paracentral acute outer maculopathy."
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Macula Lutea/diagnóstico por imagem , Doenças Retinianas/classificação , Doenças Retinianas/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Adulto , Feminino , Humanos , Macula Lutea/patologia , Masculino , Pessoa de Meia-Idade , Doenças Retinianas/patologia , Estudos Retrospectivos , Adulto JovemRESUMO
A primary skeletal muscle cell culture, in which myoblasts derived from newborn rabbit hindlimb muscles grow on gelatin bead microcarriers in suspension and differentiate into myotubes, has been established previously. In the course of differentiation and beginning spontaneous contractions, these multinucleated myotubes do not detach from their support. Here, we describe the development of the primary myotubes with respect to their ultrastructural differentiation. Scanning electron microscopy reveals that myotubes not only grow around the surface of one carrier bead but also attach themselves to neighboring carriers, forming bridges between carriers. Transmission electron microscopy demonstrates highly ordered myofibrils, T-tubules, and sarcoplasmic reticulum. The functionality of the contractile apparatus is evidenced by contractile activity that occurs spontaneously or can be elicited by electrostimulation. Creatine kinase activity increases steadily until day 20 of culture. Regarding the expression of isoforms of myosin heavy chains (MHC), we could demonstrate that from day 16 on, no non-adult MHC isoform mRNAs are present. Instead, on day 28 the myotubes express predominantly adult fast MHCIId/x mRNA and protein. This MHC pattern resembles that of fast muscles of adult rabbits. In contrast, primary myotubes grown on matrigel-covered culture dishes express substantial amounts of non-adult MHC protein even on day 21. To conclude, primary myotubes grown on microcarriers in their later stages exhibit many features of adult skeletal muscle and characteristics of fast type II fibers. Thus, the culture represents an excellent model of adult fast skeletal muscle, for example, when investigating molecular mechanisms of fast-to-slow fiber-type transformation.
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Gelatina/química , Fibras Musculares Esqueléticas/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Colágeno/química , Creatina Quinase/metabolismo , Combinação de Medicamentos , Laminina/química , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Contração Muscular , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/ultraestrutura , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteoglicanas/química , RNA Mensageiro/metabolismo , Coelhos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
PURPOSE: To analyze changes in demographic parameters and retreatment patterns over a 10-year period in a clinical routine setting of infants with retinopathy of prematurity (ROP) requiring treatment documented in the German Retina.net ROP registry. DESIGN: Multicenter, noninterventional, observational registry study recruiting patients treated for ROP. SUBJECTS: A total of 692 eyes of 353 infants treated for ROP were documented in the Retina.net ROP registry over a 10-year period between 2011 and 2020. These cases cover about 15% of all infants treated for ROP in Germany. METHODS: The Retina.net ROP registry was established in 2012 to jointly collect information on infants treated for ROP. The database collects information on demographic parameters (gestational age [GA], birth weight, neonatal comorbidities) as well as treatment parameters (type of treatment, weight and age at treatment, and stage of ROP). A total of 19 centers contributed to the analysis. This is the 10-year analysis of data from 2011 to 2020, in which we focus on changes over time regarding the respective parameters. MAIN OUTCOME MEASURES: Changes over time in demographic parameters and treatment patterns for ROP in Germany. RESULTS: The overall incidence of treatment requiring ROP was 3.5% of all infants screened for ROP at participating centers. Gestational age, weight at birth, and weight at treatment remained stable over the 10-year period, whereas postmenstrual and postnatal age at treatment increased moderately but statistically significantly over the years. The most prevalent ROP severity stage at treatment was stage 3+ in zone II (76.6% of all treated eyes). Treatment patterns changed considerably from predominantly laser treatments in 2011 (75% of all treated eyes) to predominantly ranibizumab treatments in 2020 (60.9% of all treated eyes). The overall retreatment rate was 15.6%. Retreatment rates differed between initial treatment modalities (14.1% after laser coagulation, 12% after bevacizumab and 24.5% after ranibizumab). Treatment-associated systemic or ophthalmic complications were rare. CONCLUSIONS: This data analysis represents one of the largest documented cohorts of infants treated for ROP. The data on demographic parameters and treatment patterns provide useful information for further improvement of ROP management. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Inibidores da Angiogênese , Idade Gestacional , Sistema de Registros , Retinopatia da Prematuridade , Humanos , Retinopatia da Prematuridade/epidemiologia , Retinopatia da Prematuridade/diagnóstico , Alemanha/epidemiologia , Recém-Nascido , Masculino , Feminino , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/uso terapêutico , Fotocoagulação a Laser/métodos , Incidência , Seguimentos , Injeções Intravítreas , Estudos Retrospectivos , LactenteRESUMO
BACKGROUND: The goal of this study was to evaluate macular microvascular changes in patients with Fabry disease (FD) using optical coherence tomography angiography (OCTA) and to explore their correlation with laboratory and ocular findings. METHODS: A total of 76 eyes (38 patients) and 48 eyes of 24 healthy controls were enrolled in this prospective study. Vessel Area Density (VAD) and Foveal Avascular Zone (FAZ) area were calculated on 2.9 × 2.9 mm OCTA images scanned with the Heidelberg Spectralis II (Heidelberg, Germany). VAD was measured in three layers: Superficial Vascular Plexus (SVP), Intermediate Capillary Plexus (ICP), and Deep Capillary Plexus (DCP). All scans were analyzed with the EA-Tool (Version 1.0), which was coded in MATLAB (The MathWorks Inc, R2017b). FAZ area was manually measured in full-thickness, SVP, ICP and DCP scans. RESULTS: Average VAD in SVP, ICP and DCP was higher in Fabry disease patients than in controls (49.4 ± 11.0 vs. 26.5 ± 6.2, 29.6 ± 7.4 vs. 20.2 ± 4.4, 32.3 ± 8.8 vs. 21.7 ± 5.1 respectively, p < 0.001). Patients with cornea verticillata (CV) had a higher VAD in ICP and DCP compared to patients without CV (p < 0.01). Patients with increased lysoGb3 concentration had a higher VAD in DCP when compared to patients with normal lysoGb3 concentration (p < 0.04). There was no difference in VAD in patients with and without vascular tortuosity. However, a significantly higher VAD was observed in patients with vascular tortuosity compared to controls (p < 0.03). CONCLUSIONS: Increased lysoGb3 and VAD in DCP could be reliable biomarkers of disease activity. Cornea verticillata could be adopted as a predictive biomarker for VAD changes and disease progression. The combination of cornea verticillata and increased VAD may serve as a diagnostic biomarker for Fabry disease, however due to the discrepancies in VAD values in various studies, further research has to be done to address this claim.
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Distrofias Hereditárias da Córnea , Doença de Fabry , Humanos , Angiofluoresceinografia/métodos , Vasos Retinianos , Estudos Prospectivos , Doença de Fabry/diagnóstico , Acuidade Visual , BiomarcadoresRESUMO
INTRODUCTION: In this work, we provide a detailed characterization of a rare complication-subconjunctival cyst formation after strabismus surgery-in a large German cohort. METHODS: We conducted a retrospective analysis of 822 consecutive patients who underwent strabismus surgery between 2015 and 2022. The patients received comprehensive eye and orthoptic examinations preoperatively, at 1 day, and at 3 months postoperatively. Cysts were analyzed with slit-lamp examination, anterior segment optical coherence tomography (AS-OCT), and histopathological subsumption. RESULTS: Nineteen cases of postoperative cysts were observed (2.3%), 12 of which underwent surgical revision. Clinical evaluation including slit-lamp and AS-OCT as well as histological analysis resulted in a classification of three types of cysts: type 1, which is a single hyporeflective cyst, type 2, which is a multilobular hyporeflective cyst, and type 3, a dense hyperreflective granulomatous-like cyst. Eta (η) correlation ratio analysis could show a correlation between time of clinical appearance and type of cyst (Eta = 0.63). Most cysts developed within 20 days after surgery. Not only did cysts more frequently affect the medial rectus muscle, which in most cases underwent a shortening procedure (11/19 tucks, 4/19 resections) for intermittent exotropia (X(T)), but the cyst also formed earlier than in the lateral rectus muscle (Eta = 0.45). No correlation could be shown between the type of surgical procedure and time of cyst occurrence (Eta = 0.1). Patient age and cyst type correlated strongly (Eta = 0.47). The underlying type of strabismus did not correlate with the type of cyst observed. CONCLUSIONS: Our cases showed a strong positive correlation to the type of strabismus (X(T)), age (young patients), and the procedure (tuck/resection). We introduce a grading system for postoperative cysts after strabismus surgery, complementing histopathology and slit-lamp aspects with AS-OCT information.
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INTRODUCTION: Retinal microvasculature is known to be altered in patients with Fabry disease (FD). We aimed to investigate the long-term changes in macular microvasculature and explore a reliable retinal biomarker for treatment monitoring in FD. METHODS: Prospective study of 26 eyes with FD followed up to 48 months (mean 24, range 8-48). OCT angiography (OCTA) images (2.9 × 2.9 mm) were obtained using Heidelberg Spectralis II at baseline and follow-up. Macular vessel area density (VAD, %) was measured in three layers: superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) in three peri-macular circular sectors (c1, c2, c3). Additionally, foveal avascular zone (FAZ) area (mm2) and horizontal and vertical diameters (µm) were assessed. RESULTS: VAD decreased over time in SVP, ICP (in sectors c2 and c3) and DCP (all sectors) (p < 0.04). VAD reduction was predominantly seen in treated FD patients. FAZ and horizontal diameters increased at follow-up in FD patients compared to baseline (p ≤ 0.025). Correlation analysis showed a moderate to strong negative correlation between VAD of SVP and DCP in the innermost circle and FAZ in treated patients (r = - 0.6; p < 0.0001). CONCLUSIONS: This is the first long-term follow-up OCTA study in FD to our knowledge. A decrease in VAD, pronounced in the peripheral circle and deeper layers, as well as an enlargement of the FAZ could be observed over time. These changes reflect the vascular remodelling during the course of the disease. Interestingly, the reduction of VAD was more pronounced in treated patients. This could be a result of enzyme replacement therapy and could be potentially used as a reliable biomarker for monitoring the treatment of the disease. A baseline examination of VAD and FAZ before treatment initiation is meaningful. Larger studies are needed to establish the use of VAD and FAZ as biomarkers for treatment monitoring.
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More than 10 disease-modifying therapies (DMT) are approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for the treatment of multiple sclerosis (MS) and new therapeutic options are on the horizon. Due to different underlying therapeutic mechanisms, a more individualized selection of DMTs in MS is possible, taking into account the patient's current situation. Therefore, concomitant treatment of various comorbid conditions, including autoimmune mediated disorders such as rheumatoid arthritis, should be considered in MS patients. Because the pathomechanisms of autoimmunity partially overlap, DMT could also treat concomitant inflammatory diseases and simplify the patient's treatment. In contrast, the exacerbation and even new occurrence of several autoimmune diseases have been reported as a result of immunomodulatory treatment of MS. To simplify treatment and avoid disease exacerbation, knowledge of the beneficial and adverse effects of DMT in other autoimmune disorders is critical. Therefore, we conducted a literature search and described the beneficial and adverse effects of approved and currently studied DMT in a large number of comorbid autoimmune diseases, including rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel diseases, cutaneous disorders including psoriasis, Sjögren´s syndrome, systemic lupus erythematosus, systemic vasculitis, autoimmune hepatitis, and ocular autoimmune disorders. Our review aims to facilitate the selection of an appropriate DMT in patients with MS and comorbid autoimmune diseases.
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Artrite Reumatoide , Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Esclerose Múltipla , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Autoimunidade , Doenças Autoimunes/complicações , Doenças Autoimunes/tratamento farmacológicoRESUMO
INTRODUCTION: Myopia is a major cause of degenerative eye disease and increases the risk of secondary visual impairment. Mitigating its progression therefore has great potential of clinically relevant benefit as shown by using highly diluted atropine eye drops in children of Asian origin. However, limited evidence is available regarding the efficacy and safety of low-dose atropine therapy in non-Asian populations. Hence, the Low-dose AtropIne for Myopia Control in Children (AIM) study will test the efficacy and safety of 0.02% atropine vs placebo in a German population. METHODS AND ANALYSIS: AIM is a national, multicentre, prospective, randomised, placebo-controlled, double-blind trial with two parallel arms. The primary objective is to assess the efficacy of atropine 0.02% eyedrops for myopia control in children of Caucasian origin. The primary outcome is the change in cycloplegic refraction after 1 year of treatment (D/year). Secondary and tertiary outcome measures comprise the change in axial length (mm/year) in children treated with 0.02% atropine compared with placebo, the myopic progression of participants treated with 0.01% compared with 0.02% atropine (D/year and mm/year), and the safety profile of both 0.02% and 0.01% atropine. Furthermore, the myopic progression 1 year after cessation of therapy with 0.02% atropine will be evaluated. Inclusion criteria are an age of 8-12 years and myopia of -1 D to -6 D with an estimated annual myopia progression of ≥0.5 D. After randomisation, patients will receive either atropine 0.02% (arm A) or placebo eye drops (arm B) in the first year of treatment. In the second year, they will continue to receive atropine 0.02% (arm A) or switch to atropine 0.01% (arm B). In the third year, they will switch to placebo (arm A) or continue with atropine 0.01% (arm B). To achieve a statistical power of 80%, the calculated sample size is 300. The trial has started in October 2021 with a planned recruitment period of 18 months. ETHICS AND DISSEMINATION: AIM has been approved by the Central Ethics Committee of the University Medical Center Freiburg (21-1106), local ethics committees of each participating centre and the German Federal Institute for Drugs and Medical Devices (61-3910-4044659). It complies with the Declaration of Helsinki, local laws and ICH-GCP. Results and underlying data from this trial will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: NCT03865160.
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Atropina , Miopia , Humanos , Criança , Atropina/uso terapêutico , Estudos Prospectivos , Miopia/tratamento farmacológico , Testes Visuais , Método Duplo-Cego , Soluções Oftálmicas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como AssuntoRESUMO
An unintentional embolization of retinal arteries is rare and has been documented as a complication after embolization of arteries supplying head and neck tumors. However, occlusion of the central retinal artery with severe loss of vision has never been reported to be a complication from embolization of tumor-supplying ethmoidal branches of the ophthalmic artery. A 40 year-old male patient with a history of right nephrectomy for renal cell carcinoma underwent preoperative radiological embolization of an ethmoidal metastasis after having experienced a life-threatening sinus bleeding. Repeated probing of the ophthalmic artery with an endovascular microcatheter for particle embolization of the tumor-supplying arteries was performed under anticoagulation with heparin. Postoperatively, a standard ophthalmological examination including extended vascular evaluation by angiography was performed. After extended probing of the ophthalmic artery a marked reduction in its blood flow occurred. Despite post-interventional imaging showing persisting perfusion of the central retinal and ciliary arteries, the patient developed complete loss of vision on this side four days later. At this time fundoscopy and fluorescein angiography revealed a recanalized central artery occlusion, while indocyanin angiography showed infarctions of the choroid. Radiological intervention via the ophthalmic artery can result in complete loss of vision, even after limited and transient obstruction of the vessel.
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Cegueira/etiologia , Carcinoma de Células Renais/terapia , Embolização Terapêutica/efeitos adversos , Seio Etmoidal/irrigação sanguínea , Neoplasias Renais/patologia , Artéria Oftálmica , Neoplasias dos Seios Paranasais/terapia , Doença Aguda , Adulto , Carcinoma de Células Renais/diagnóstico por imagem , Carcinoma de Células Renais/secundário , Seio Etmoidal/diagnóstico por imagem , Angiofluoresceinografia , Fluordesoxiglucose F18 , Humanos , Masculino , Nefrectomia , Neoplasias dos Seios Paranasais/diagnóstico por imagem , Neoplasias dos Seios Paranasais/secundário , Tomografia por Emissão de Pósitrons , Acuidade Visual/fisiologiaRESUMO
Retinal angiomatous proliferation (RAP) is a variant of exudative age-related macular degeneration with particularly bad prognosis. The purpose of this work is to describe the long-term functional and morphological outcome of patients treated with intravitreal bevacizumab and ranibizumab. Retrospective case series of 16 eyes treated with bevacizumab and 19 eyes treated with ranibizumab. All patients received initially three intravitreal injections of bevacizumab (1.25 mg/0.05 ml) or ranibizumab (0.5 mg/0.05 ml) every 4 weeks. Follow-up ranged from 1 to 7 months after the third injection. Complete ophthalmologic examination including best-corrected visual acuity (VA), optical coherence tomography, fluorescein angiography, and in selected cases, indocyanine green angiography was performed. Triple intravitreal injections resulted in improvement of VA in bevacizumab-treated as well as in ranibizumab-treated patients; logarithm of the minimal angle of resolution (logMAR) 0.84 before treatment and 0.67 at month 9, and logMAR 0.75 before treatment and 0.59 at month 9, respectively. Central macular thickness (CMT) in the bevacizumab group improved from 363.67 ± 47.4 µm at baseline to 328 ± 49.77 µm at month 6 (p = 0.03) and 301 ± 129.69 at month 9 (p = 0.35). CMT in the ranibizumab group improved from 545.62 ± 167.39 µm at baseline to 395.88 ± 169.37 µm at month 6 and 411.83 ± 212.41 µm at month 9 (p = 0.03, p = 0.05, respectively). Patients with RAP might benefit from both intravitreal bevacizumab and ranibizumab treatments with stabilization of VA over a longer period of time. Close follow-up should nevertheless be performed in this special subgroup because of the high recurrence rate.
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Inibidores da Angiogênese/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Degeneração Macular/tratamento farmacológico , Retina/patologia , Neovascularização Retiniana/tratamento farmacológico , Acuidade Visual/fisiologia , Idoso , Idoso de 80 Anos ou mais , Bevacizumab , Exsudatos e Transudatos , Feminino , Angiofluoresceinografia , Humanos , Verde de Indocianina , Injeções Intravítreas , Degeneração Macular/diagnóstico , Degeneração Macular/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ranibizumab , Neovascularização Retiniana/diagnóstico , Neovascularização Retiniana/fisiopatologia , Retratamento , Estudos Retrospectivos , Tomografia de Coerência Óptica , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
PURPOSE: Transforming growth factor-beta (TGFB)-mediated epithelial-mesenchymal transition (EMT) plays a crucial role in the pathogenesis of retinal fibrosis, which is one of the leading causes of impaired vision. Current approaches to treating retinal fibrosis focus, among other things, on inhibiting the TGFB signaling pathway. Transient expression of microRNAs (miRNAs) is one way to inhibit the TGFB pathway post-transcriptionally. Our previous study identified the miRNA miR-302d as a regulator of multiple TGFB-related genes in ARPE-19 cells. To further explore its effect on primary cells, the effect of miR-302d on TGFB-induced EMT in primary human retinal pigment epithelium (hRPE) was investigated in vitro. METHODS: hRPE cells were extracted from patients receiving enucleation. Transfection of hRPE cells with miR-302d was performed before or after TGFB1 stimulation. Live-cell imaging, immunocytochemistry staining, Western blot, and ELISA assays were utilized to identify the alterations of cellular morphology and EMT-related factors expressions in hRPE cells. RESULTS: hRPE cells underwent EMT by TGFB1 exposure. The transfection of miR-302d inhibited the transition with decreased production of mesenchymal markers and increased epithelial factors. Meanwhile, the phosphorylation of SMAD2 activated by TGFB1 was suppressed. Moreover, miR-302d expression promoted TGFB1-induced fibroblast-like hRPE cells to revert towards an epithelial stage. As confirmed by ELISA, miR-302d reduced TGFB receptor 2 (TGFBR2) and vascular endothelial growth factor A (VEGFA) levels 48 hours after transfection. CONCLUSIONS: The protective effect of miR-302d might be a promising approach for ameliorating retinal fibrosis and neovascularization. MiR-302d suppresses TGFB-induced EMT in hRPE cells via downregulation of TGFBR2, even reversing the process. Furthermore, miR-302d reduces the constitutive secretion of VEGFA from hRPE cells.
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MicroRNAs , Fator de Crescimento Transformador beta , Humanos , Transição Epitelial-Mesenquimal/genética , Receptor do Fator de Crescimento Transformador beta Tipo II , Epitélio Pigmentado da Retina , Fator A de Crescimento do Endotélio Vascular/genética , MicroRNAs/genética , FibroseRESUMO
Proper treatment of the two-wall fractured orbit is still controversial. Specifically, there is no consensus on the issue of the necessity of medial orbital wall repair. With anatomically critical structures at risk during the surgical approach, surgeons' view on the necessity of medial orbital wall repair often is restricted and an aesthetically disturbing enophthalmos is more likely to be accepted. Therefore, treatment options range from leaving the medial wall without repair to reconstruction with autogenous tissue or alloplastic materials, which can lead to moderate to severe side effects. However, emerging technologies such as patient-specific implants (PSI) offer a reliable and anatomically correct reconstruction of the bony orbit. This study aimed to evaluate the outcome of full orbital reconstruction using PSIs compared to only orbital floor repair using PDS (bioresorbable polydioxanone) foils leaving the medial orbital wall untouched in traumatic two-wall orbital fractures. Of all patients treated at the University Hospital of Düsseldorf between 2017 and 2019 who suffered from traumatic orbital fracture, only patients with a two-wall orbital fracture involving both the orbital floor and the medial wall (n = 68) were included. Patients were treated either with a PSI (n = 35) or a PDS foil (n = 33). Primary outcome parameters were ophthalmological disturbances analyzed via clinical investigation and intra-orbital angles, volumes and implant position analyzed with radiological 3D-datasets. While a two-wall reconstruction using PSIs led to a significant improvement of the enophthalmos, the rate of postoperative enophthalmos was significantly increased in cases of only orbital floor repair with PDS foils. Radiologically, a significant reconstruction of the three-dimensional bony orbit succeeded with the simple use of PSIs leading to a significant reduction in the traumatically enlarged orbital volume. PSI also led to a significant reduction in the traumatically enlarged medial angle of the orbit. This was not the case for single-floor repair with PDS foil. The results of this study suggest that complex orbital fractures can be reconstructed at an even higher degree of accuracy with selective laser-melted PSIs than PDS foils. In order to achieve a true to original reconstruction of the bony orbit, surgical treatment of the medial orbital wall can be advocated for in the long term depending on the indication.
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Contemporary advances in technology have allowed the transfer of knowledge from industrial laser melting systems to surgery; such an approach could increase the degree of accuracy in orbital restoration. The aim of this study was to examine the accuracy of selective laser melted PSIs (patient-specific implants) and navigation in primary orbital reconstruction. Ninety-six patients with orbital fractures were included in this study. Planned vs. achieved orbital volumes (a) and angles (b) were compared to the unaffected side (n = 96). The analysis included the overlay of post-treatment on planned images (iPlan 3.0.5, Brainlab®, Feldkirchen, Germany). The mean difference in orbital volume between the digitally planned orbit and the postoperative orbit was 29.16 cm3 (SD 3.54, presurgical) to 28.33 cm3 (SD 3.64, postsurgical, t = 5.00, df = 95.00; p < 0.001), resulting in a mean volume difference (planned vs. postop) of less than 1 cm3. A 3D analysis of the color mapping showed minor deviations compared to the mirrored unaffected side. The results suggested that primary reconstruction in complex orbital wall fractures can be routinely achieved with a high degree of accuracy by using selective laser melted orbital PSIs.
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BACKGROUND: The Retina.net ROP registry documents data of preterm infants developing stages of retinopathy of prematurity (ROP) that need ROP treatment. The aim of this analysis was to investigate data regarding epidemiology, therapy and changes over time (15 years) in a single participating center (Hannover Medical School, MHH). METHODS: Analysis of data of infants treated for ROP at a single center over time (birth 2001-2016, ROP treatment in 2002-2017). RESULTS: Overall, 65 infants were treated (23 female). In 11 infants (16.9%) ROP screening was conducted externally and infants were transferred to the MHH for ROP treatment. Between 2006 and 2016, incidence of ROP requiring treatment among infants screened for the development of ROP was 4.1%. Mean gestational age was 25.7 weeks (standard deviation, SD 1.8), mean birth weight 763â¯g (SD 235), postmenstrual age at treatment 38.2 weeks (SD 3.2), postnatal age 12.4 weeks (SD 3.2). There was no significant change in parameters over time. ROP zone II, stage 3+ was most frequently treated (57 eyes of 31 infants). 58 infants were treated with laser (114 eyes), 7 infants were treated with anti-VEGF (bevacizumab, bilateral, 14 eyes) from 2014 onwards. Retreatment due to recurrence of ROP was necessary in one infant after initial laser coagulation. Infants with ROP requiring treatment often presented with neonatal comorbidities, ventilation in more than 90%, bronchopulmonary dysplasia, and received transfusions. CONCLUSION: This is the first monocentric analysis over 15 years originating from the Retina.net ROP registry. In this cohort we see a change in ROP therapy from laser coagulation to anti-VEGF (bevacizumab) from 2014 onwards, demographic data and treatment parameters remained relatively stable over time.
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Retinopatia da Prematuridade , Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Feminino , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Injeções Intravítreas , Fotocoagulação a Laser , Masculino , Sistema de Registros , Retina , Retinopatia da Prematuridade/diagnóstico , Retinopatia da Prematuridade/epidemiologia , Retinopatia da Prematuridade/terapia , Estudos Retrospectivos , Fator A de Crescimento do Endotélio VascularRESUMO
Leber congenital amaurosis caused by mutations in the RPE65 gene belongs to the most severe early-onset hereditary childhood retinopathies naturally progressing to legal blindness. The novel gene therapy voretigene neparvovec is the first approved causative treatment option for this devastating eye disease and is specifically designed to treat RPE65-mediated retinal dystrophies. Herein, we present a follow-up of the youngest treated patients in Germany so far, including four pre-school children who received treatment with voretigene neparvovec at a single treatment center between January 2020 and May 2022. All patients underwent pars plana vitrectomy with circumferential peeling of the internal limiting membrane at the injection site and subretinal injection of voretigene neparvovec. Pre- and postoperative diagnostics included imaging (spectral domain optical coherence tomography, fundus autofluorescence, fundus wide-angle imaging), electrophysiologic examination (ERG), retinal light sensitivity measurements (FST) and visual acuity testing. Behavioral changes were assessed using a questionnaire and by observing the children's vision-guided behavior in different levels of illumination. All children showed marked increase in vision-guided behavior shortly after therapy, as well as marked increase in visual acuity in the postoperative course up to full visual acuity in one child. Two eyes showed partial electrophysiological recovery of an ERG that was undetectable before treatment-a finding that has not been described in humans before.
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In patients with central visual field scotomata a large part of visual cortex is not adequately stimulated. Over time this lack of input could lead to a reduction of gray matter in the affected cortical areas. We used Voxel Based Morphometry to investigate structural brain changes in patients with central scotomata due to hereditary retinal dystrophies and compared their results to those of normal sighted subjects. Additionally we correlated clinical and demographic characteristics like duration of disease, scotoma size, visual acuity, fixation stability and reading speed to the amount of gray matter in whole brain analyses within the patient group. We found a decrease in gray matter around the lesion projection zone in visual cortex of patients in comparison to controls. Gray matter loss along the posterior and middle portions of the calcarine sulcus is also correlated with scotoma size, indicating that indeed the lack of functional input provokes the gray matter alterations. In whole brain regression analyses within the patient group we found an additional cluster in the right superior and middle frontal gyri, slightly anterior to the frontal eye fields, where gray matter correlated positively with fixation stability. This could be regarded as a consequence of oculomotor learning.
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Distrofias Retinianas/genética , Distrofias Retinianas/patologia , Escotoma/patologia , Córtex Visual/patologia , Adolescente , Adulto , Idoso , Comportamento/fisiologia , Criança , Feminino , Fixação Ocular , Humanos , Processamento de Imagem Assistida por Computador , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Leitura , Análise de Regressão , Escotoma/psicologia , Acuidade Visual/fisiologia , Campos Visuais/fisiologia , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: Presentation and application of a method for pachymetry with the slit lamp based on the concept of a defined optical section. METHODS AND PATIENTS: The visible width of an optical section on slit lamp examination with a 45° angle between the slit beam and the central corneal surface was determined in 103 eyes (68 with glaucoma and 35 in patients with keratoconus). The measurements were compared to the pachymetric values previously determined elsewhere for these eyes in order to establish a proportionality factor for calculation of corneal thickness from slit lamp measurements. RESULTS: From a linear regression between the external pachymetry and visible width of the optical section in the split lamp, 1.71 was determined to be the factor of proportionality. Applying this factor to single measurements, 82 out of 103 eyes had a maximum difference of 40⯵m compared to the external pachymetric values. CONCLUSION: Based on a defined optical section at the slit lamp, clinically relevant estimates can be made for central corneal thickness in diseases, such as glaucoma or keratoconus. The difference to the externally measured pachymetric values was within the range of diurnal changes in corneal thickness for 80% of the eyes. Similar to other pachymetric procedures, the reliability of determination of the corneal thickness with the slit lamp also increases when applied intraindividually or for the same eye in the course of time.