Outcomes of rhegmatogenous retinal detachment surgery in patients with Stickler syndrome.

PURPOSE: Despite recent developments in vitrectomy technology and instrumentation, rhegmatogenous retinal detachment in Stickler syndrome (RDS) remains a challenge for surgeons. RDSs are associated with a higher rate of complications and surgical failures than those not associated with Stickler syndrome. This study is a report about anatomic and visual outcomes of RDS surgery and describes the surgical techniques associated with the treatment of this specific condition. METHODS: This is a retrospective, interventional, consecutive case series of patients with RDS undergoing retinal reattachment surgery from 1990 to 2020 at the Institute of Ocular Microsurgery (IMO) in Barcelona, Spain. RESULTS: Twenty-four eyes of 18 patients with genetically confirmed Stickler syndrome were included in the study. Ten eyes (41.6%) presented a giant retinal tear. Retinal reattachment was achieved in all cases after an average of 1.21 (range 1-6) surgical interventions. Nineteen eyes (79%) required only one operation to achieve complete retinal reattachment. The most common first surgical procedure was a 4-mm scleral buckle with posterior pars plana vitrectomy and silicone oil endotamponade, performed on 16 (66.6%) of the eyes. The mean follow-up period was 10.2 years. Mean preoperative visual acuity LogMar was 1.10 (Snellen equivalent 20/252), which improved to 0.50 (Snellen equivalent 20/63) at final follow-up (p < 0.05). CONCLUSION: In most RDS cases, anatomic success and visual acuity improvement can be achieved with the first surgical procedure, using a combination of silicone oil tamponade and a 4-mm scleral encircling band. In some early cases of RDS, other less invasive surgical techniques can be used.

Expanding the retinal phenotype of RP1: from retinitis pigmentosa to a novel and singular macular dystrophy.

PURPOSE: This study aimed to identify the underlying genetic cause(s) of inherited retinal dystrophy (IRD) in 12 families of Kuwaiti origin affected by macular dystrophy and four Spanish patients affected by retinitis pigmentosa (RP). METHODS: Clinical diagnoses were based on standard ophthalmic evaluations (best-corrected visual acuity, retinography, fundus autofluorescence imaging, optical coherence tomography, electroretinography and visual field tests). Panel-based whole exome sequencing was used to simultaneously analyse 224 IRD genes in one affected member of each family. The putative causative variants were confirmed by Sanger sequencing and cosegregation analyses. Haplotype analysis was performed using single nucleotide polymorphisms. RESULTS: A homozygous missense mutation c.606C>A (p.Asp202Glu) in RP1 was found to be the molecular cause of IRD in all 12 families from Kuwait. These patients exhibited comparable symptoms, including progressive decline in visual acuity since adolescence. Fundus autofluorescence images revealed bilateral macular retinal pigment epithelium disturbances, with neither perimacular flecks nor peripheral alterations. A shared haplotype spanning at least 1.1 Mb was identified in all families, suggesting a founder effect. Furthermore, RP1 variants involving nonsense and/or frameshifting mutations (three of them novel) were identified in three Spanish autosomal-recessive RP families and one dominant RP pedigree. CONCLUSION: This study describes, for the first time, a macular dystrophy phenotype caused by an RP1 mutation; establishing a new genotype-phenotype correlation in this gene, expanding its mutation spectrum and further highlighting the clinical heterogeneity associated with IRD.

Generation of Best disease-derived induced pluripotent stem cell line (FRIMOi006-A) carrying a novel dominant mutation in BEST1 gene.

Best disease, also known as Best vitelliform macular dystrophy, is an autosomal dominant form of macular degeneration. Here, we have generated an induced pluripotent stem cell (iPSC) line derived from a Best disease patient carrying a new dominant mutation in the BEST1 gene. Skin fibroblasts were reprogrammed to iPSCs by the non-integrative Sendai-virus method. The iPSC line has been characterized preserving the BEST1 mutation, expressing the pluripotency markers and being capable to differentiate to endoderm, mesoderm and ectoderm in vitro.

Generation of an induced pluripotent stem cell line (FRIMOi007-A) derived from an incomplete achromatopsia patient carrying a novel homozygous mutation in PDE6C gene.

Incomplete achromatopsia (ACHM) is a disorder in which there is function defect of cone photoreceptors in the retina and individuals with such disease retain residual color vision. Here, we have generated an induced pluripotent stem cell (iPSC) line carrying a homozygous mutation in the PDE6C gene, already related with this vision disorder. Skin fibroblasts from a patient with incomplete ACHM were reprogrammed to iPSCs by the non-integrative Sendai-virus method. Finally, the iPSC line has been characterized expressing the pluripotency markers and being capable to differentiate to endoderm, mesoderm and ectoderm in vitro.

Characterization of the cone-rod dystrophy retinal phenotype caused by novel homozygous DRAM2 mutations.

Cone-rod dystrophies (CRD) are a group of Inherited Retinal Dystrophies (IRD) characterized by the primary involvement of cone photoreceptors, resulting in the degeneration of the central retina, or macula. Although there are more than 55 CRD genes, a considerable percentage of cases remain unsolved. In this context, the present study aimed to describe and characterize the phenoptype and the genetic cause of 3 CRD families from a cohort of IRD cases. Clinical evaluation in each patient was supported by a complete ophthalmological examination, including visual acuity measurement, fundus retinography, fundus autofluorescence imaging, optical coherence tomography and full-field electroretinography. Molecular diagnoses were performed by whole exome sequencing analyzing a group of 279 IRD genes, and cosegregation of the identified pathogenic variants was confirmed by Sanger sequencing. Three novel homozygous mutations in the autophagy gene DRAM2 were identified as the molecular cause of disease in the three families: c.518-1G>A, c.628_629insAG and c.693+2T>A. Clinical data revealed that the 3 patients presented a shared CRD phenotype with adult-onset macular involvement and later peripheral degeneration, although the age of onset, evolution and severity were variable. In order to characterize the transcription effects of these variants, mRNA expression studies were performed. The results showed alterations in the DRAM2 transcription, including alternative splicing forms and lower levels of mRNA, which correlated with the phenotypic variability observed between patients. For instance, frameshift mutations were related to a less severe phenotype, with circumscribed mid-peripheral involvement, and lower levels of mRNA, suggesting an activation of the nonsense-mediated decay (NMD) pathway; while a more severe and widespread retinal degeneration was associated to the inframe alternative splicing variant reported, possibly due to a malfunctioning or toxicity of the resulting protein. Following these findings, DRAM2 expression was assessed in several human tissues by semi-quantitative RT-PCR and two isoforms were detected ubiquitously, yet with a singular tissue-specific pattern in retina and brain. Altogether, although the unique retinal phenotype described did not correlate with the ubiquitous expression, the retinal-specific expression and the essential role of autophagy in the photoreceptor survival could be key arguments to explain this particular DRAM2 phenotype.

Comparative study of penetrating keratoplasty and vitreoretinal surgery with Eckardt temporary keratoprosthesis in ocular trauma versus non-trauma patients.

PURPOSE: To evaluate the effectiveness of temporary keratoprosthesis combined with vitreoretinal surgery and penetrating keratoplasty in patients with or without trauma. METHODS: This retrospective study included 49 eyes in 49 non-trauma patients and 51 eyes in 48 ocular trauma patients who underwent penetrating keratoplasty and vitreoretinal surgery with Eckardt temporary keratoprosthesis between 2009 and 2016, with a follow-up of at least 12 months. Study variables included previous corneal, glaucoma, or retinal surgeries; various intraoperative surgical maneuvers; lens status; vitreoretinal and corneal pathology; functional outcomes; anatomical retinal reattachment; graft clarity; and need for glaucoma surgery or treatment. RESULTS: The mean age was 56 years in the non-trauma group and 42 years in the ocular trauma group. A total of 45% of the non-trauma cases and 24% of the ocular trauma cases had a single functional eye. Pseudophakic and aphakic keratopathy was diagnosed in 41% of the non-trauma group and corneal laceration in 65% of the ocular trauma group. In the ocular trauma group, injuries were open globe injury in 78%, closed globe injury in 12%, and intraocular foreign body in 10%. Retinal detachment with proliferative vitreoretinopathy was present in 39% of patients in the non-trauma group and in 35% of the ocular trauma group. Improvement or stability of visual acuity was higher among ocular trauma patients (86%) than in non-trauma patients (78%). The rate of clear corneal grafts was 49% in both groups. Retinal attachment was achieved in 90% and 78% of patients in the non-trauma and ocular trauma groups, respectively. The use of retinotomy had a positive influence on the final attached retina (p = 0.016). The placement of a scleral buckle significantly increased the risk of glaucoma (p = 0.004). Poor functional outcome was related to persistent retinal detachment (10% versus 16% in the non-trauma and ocular trauma groups, respectively), phthisis (25% versus 12%), hypotony (33% versus 18%), corneal graft end failure (51% in both groups), and secondary glaucoma (18% versus 24%). CONCLUSION: In patients with both vitreoretinal and corneal pathology, the use of Eckardt temporary keratoprosthesis combined with vitreoretinal surgery and penetrating keratoplasty resulted in improvement of visual acuity, particularly in the groups of ocular trauma and monocular patients. The high rate of retinal reattachment and the low rate of graft rejection was probably related to the use of new vitreoretinal techniques, including retinotomy in selected patients.

Comparison of United States and International Ophthalmic Drug Pricing.

PURPOSE: To compare United States and international drug pricing for commonly prescribed intravitreal and topical ophthalmic medications. DESIGN: Cross-sectional observational study. METHODS: For 25 commonly used ophthalmic medications (3 intravitreal, 22 topical), we obtained 2017 third quarter United States average wholesale price (AWP), drug acquisition cost, or consumer pricing through United States government health insurance plans (Veterans Affairs [VA], Medicaid, Medicare Part B, and Medicare Part D) and commercial drug plans (CVS Caremark and Navitus Health Solutions), online pricing without insurance through a large United States warehouse retailer (Costco), and international drug pricing through government-sponsored health plans in Italy, Spain, Turkey, Canada, and Japan. MAIN OUTCOME MEASURES: Drug acquisition costs and consumer pricing of ophthalmic drugs through various payment systems. All prices were converted to United States dollars. RESULTS: For intravitreal medications in the United States, aflibercept and ranibizumab were priced similarly to each other and were more expensive than dexamethasone implants. Pricing of aflibercept and ranibizumab through government health insurance plans in Italy, Spain, Turkey, Canada, and Japan were less expensive by as much as 84.3% compared with the United States. For topical medications in the United States, pricing varied significantly both across different classes of medications and also between nonbranded and branded medications. Drug acquisition costs through the VA and Medicaid were inexpensive on average, but pricing through a hospital-employee drug insurance plan offered the smallest range (between $2.35 and $60.00). In all 5 non-United States countries studied, each topical medication with the exceptions of cyclosporine emulsion and difluprednate was less than $100, and 94.4% of topical medications in these countries had a nonbranded or branded option that was less than $50. CONCLUSIONS: In the United States, for topical more than intravitreal medications, significant price variation exists across both different drug pricing systems and different medications. Price differentials between nonbranded and branded medications can be significant. Internationally, topical medications exhibited a more limited and lower price range compared with drug pricing in the United States.

Establishment of an induced pluripotent stem cell line (FRIMOi005-A) derived from a retinitis pigmentosa patient carrying a dominant mutation in RHO gene.

Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by the progressive degeneration of photoreceptors. In the present study, we have generated an induced pluripotent stem cell (iPSC) line derived from a RP patient with a dominant mutation in the RHO gene, responsible for the synthesis of rhodopsin. The reprogramming of these iPSCs was performed from skin fibroblasts by the Sendai-virus based approach. Characterization of the iPSC line showed a normal karyotype carrying the RHO mutation, expressed pluripotency markers and could be differentiated to endoderm, mesoderm and ectoderm in vitro.

Generation of two iPS cell lines (FRIMOi003-A and FRIMOi004-A) derived from Stargardt patients carrying ABCA4 compound heterozygous mutations.

Recessive Stargardt disease (STGD1) is an autosomal recessive retinal dystrophy, caused by mutations in the retina-specific ATP-binding cassette transporter (ABCA4) gene, which plays a role as a retinaldehyde flippase in the photoreceptor outer segments. In this work, two human induced pluripotent stem cell (iPSC) lines were generated from STGD1 patients carrying compound heterozygous mutations in ABCA4. Skin fibroblasts were reprogrammed with the Yamanaka factors using a non-integrating, Sendai virus-based approach. Both iPSC lines displayed typical embryonic stem cell morphology, had normal karyotype, expressed several pluripotency markers and were able to differentiate into all three germ layers. Resource table.

Establishment and characterization of an iPSC line (FRIMOi001-A) derived from a retinitis pigmentosa patient carrying PDE6A mutations.

Retinitis pigmentosa (RP) refers to a clinical and genetic heterogeneous group of inherited retinal degenerations characterized by photoreceptor cell death. In this work, we have generated an induced pluripotent stem cell (iPSC) line derived from a RP patient with two heterozygous mutations in the cGMP-specific phosphodiesterase 6A alpha subunit (PDE6A) gene. Skin fibroblasts were generated and reprogrammed by using a Sendai virus-based approach. The iPSC line had a normal karyotype, carried the two PDE6A mutations, expressed pluripotency markers and could generate endoderm, mesoderm and ectoderm in vitro. Resource table.

Generation of an induced pluripotent stem cell line (FRIMOi002-A) from a retinitis pigmentosa patient carrying compound heterozygous mutations in USH2A gene.

A human induced pluripotent stem cell (iPSC) line was generated from a female patient affected by autosomal recessive retinitis pigmentosa with two mutations in the USH2A gene: c.2209C > T (p.Arg737Ter) and c.8693A > C (p.Tyr2898Ser). Skin fibroblasts were infected with Sendai virus containing the Yamanaka factors and the resulting cells were fully characterized to confirm successful reprogramming. The iPSC line expressed several pluripotency markers, could generate the three germ layers, had a normal karyotype, carried the two USH2A mutations and was free of Sendai virus. This cell line will serve as a model to unravel the pathogenic mechanisms underlying USH2A-associated retinal degeneration.

A new instrument to simplify encircling buckle placement.

PURPOSE: The purpose of this study is to describe a new surgical instrument that simplifies 360° silicone band placement, alone or in combination with pars plana vitrectomy, for the treatment of rhegmatogenous retinal detachment. METHODS: The instrument has a straight shank and a curved component in the form of a partial helix, whose purpose is to encircle the perimeter of the eye globe below the rectus muscles. The distal tip of the helix is inserted through a small conjunctival incision in the superior temporal quadrant, and the shank is rotated 360° on its axis until the tip emerges from the insertion point. One end of the silicone band is sutured to the tip, and the instrument is rotated in the opposite direction until both ends of the band are positioned in the same scleral quadrant. The band is sutured to the sclera and the conjunctival incision is closed. Pars plana vitrectomy can then be performed using transconjunctival microincision techniques through the intact conjunctiva. RESULTS: Our experience using the instrument in more than 100 procedures has shown that the new technique considerably reduces surgical trauma: wide opening of the conjunctiva is obviated, there is little manipulation of the extraocular musculature, and only a few sutures are needed. The duration of the procedure is considerably shorter because of the smaller number of surgical maneuvers. CONCLUSION: We describe a new scleral technique facilitated by this surgical instrument, whose objective is safe and effective placement of an encircling silicone band with minimum trauma and a reduction in operating time.

Update on Diagnosis and Treatment of Diabetic Retinopathy: A Consensus Guideline of the Working Group of Ocular Health (Spanish Society of Diabetes and Spanish Vitreous and Retina Society).

A group of members of the Spanish Retina and Vitreous Society (SERV) and of the Working Group of Ocular Health of the Spanish Society of Diabetes (SED) updated knowledge regarding the diagnosis and treatment of diabetic retinopathy (DR) based on recent evidence reported in the literature. A synthesis of this consensus forms the basis of the present review, which is intended to inform clinicians on current advances in the field of DR and their clinical applicability to patients with this disease. Aspects presented in this article include screening procedures of DR, new technologies in the early diagnosis of DR, control of risk factors in the different stages of the disease, indications of panretinal laser photocoagulation, efficacy of intravitreal antiangiogenic agents and steroids, and surgical options for treating DR-related complications. Practical information regarding periodicity of screening procedures in patients with type 1 and type 2 diabetes, ophthalmological controls according to the stage of retinopathy and complications, and criteria and degree of urgency for referral of a DR patient to the ophthalmologist are also presented.

Whole exome sequencing using Ion Proton system enables reliable genetic diagnosis of inherited retinal dystrophies.

Inherited retinal dystrophies (IRD) comprise a wide group of clinically and genetically complex diseases that progressively affect the retina. Over recent years, the development of next-generation sequencing (NGS) methods has transformed our ability to diagnose heterogeneous diseases. In this work, we have evaluated the implementation of whole exome sequencing (WES) for the molecular diagnosis of IRD. Using Ion ProtonTM system, we simultaneously analyzed 212 genes that are responsible for more than 25 syndromic and non-syndromic IRD. This approach was used to evaluate 59 unrelated families, with the pathogenic variant(s) successfully identified in 71.18% of cases. Interestingly, the mutation detection rate varied substantially depending on the IRD subtype. Overall, we found 63 different mutations (21 novel) in 29 distinct genes, and performed in vivo functional studies to determine the deleterious impact of variants identified in MERTK, CDH23, and RPGRIP1. In addition, we provide evidences that support CDHR1 as a gene responsible for autosomal recessive retinitis pigmentosa with early macular affectation, and present data regarding the disease mechanism of this gene. Altogether, these results demonstrate that targeted WES of all IRD genes is a reliable, hypothesis-free approach, and a cost- and time-effective strategy for the routine genetic diagnosis of retinal dystrophies.

Scleral buckling in phakic uncomplicated primary rhegmatogenous retinal detachment: long-term outcomes.

PURPOSE: Scleral buckling (SB) is a surgical technique that has been used successfully to treat retinal detachments for the last 6 decades. The aim of this study was to report the long-term anatomical and functional outcomes of SB surgery in phakic patients with uncomplicated primary rhegmatogenous retinal detachment (PRRD). This article also outlines the benefits of SB compared to pars plana vitrectomy, such as reducing the risk of developing cataract, high intraocular pressure, and glaucoma, in addition to reducing surgical cost. METHODS: We retrospectively reviewed the clinical notes of 90 phakic eyes with PRRD treated with SB surgery that had a minimum of 5 years follow-up. Preoperative and postoperative characteristics were recorded. Main outcome measures were reattachment rate, best-corrected visual acuity (BCVA) improvement, and complications. RESULTS: A total of 90 eyes (88 patients) with phakic PRRD repaired through SB surgery were included. Mean age was 49.2 ± 14.6 years (range 20-80). Primary and final anatomic success was 96.7% and 100%, respectively. Mean preoperative BCVA was 0.3 ± 0.31 logMAR (6/12) and mean postoperative BCVA 0.1 ± 0.2 logMAR (p<0.001) (6/7.5). There were no cataract or primary open-angle glaucoma cases after 1 year of follow-up. Mean follow-up was 8.5 ± 2.6 years (range 5-13). CONCLUSIONS: We report a high single operation success rate over time in phakic PRRD, repaired through SB surgery. Functional and anatomical success was maintained throughout the follow-up without complications. Therefore, the authors recommend the use of this technique in selected cases in order to reduce morbidity and the incidence of reoperations.

A multicenter, 12-month randomized study comparing dexamethasone intravitreal implant with ranibizumab in patients with diabetic macular edema.

PURPOSE: To evaluate whether treatment with dexamethasone intravitreal implant (DEX implant) 0.7 mg every 5 months provides a similar average change in best-corrected visual acuity (BCVA) from baseline as ranibizumab 0.5 mg administered as per its European Summary of Product Characteristics in patients with diabetic macular edema (DME). METHODS: This was a multicenter, open-label, 12-month, randomized, parallel-group, noninferiority study in patients with DME (one eye/patient). The primary efficacy measure was BCVA using the Early Treatment Diabetic Retinopathy Study (ETDRS) method. Secondary efficacy measures included area of leakage on fluorescein angiography and central retinal thickness (CRT) on optical coherence tomography. RESULTS: Baseline patient characteristics were similar in the two treatment groups (DEX implant, n = 181; ranibizumab, n = 182); mean DME duration was ∼33 months. The mean average BCVA change from baseline over 12 months was 4.34 letters with DEX implant and 7.60 letters with ranibizumab. The lower limit of the 95 % confidence interval of the between-group difference was -4.74 letters, and therefore, DEX was demonstrated to be noninferior to ranibizumab based on the prespecified noninferiority margin of 5 letters. At monthly follow-up visits, the percentage of patients with ≥15-letter BCVA gain from baseline ranged from 7.2 to 17.7 % with DEX implant and 4.4 to 26.9 % with ranibizumab. Both DEX implant and ranibizumab effectively reduced CRT and reduced the area of fluorescein leakage. Between-group differences in change from baseline CRT favored DEX implant at 1, 2, 6, and 7 months (p ≤ 0.007) and ranibizumab at 4, 5, 9, and 10 months (p < 0.001); the decrease in fluorescein leakage area was greater with DEX implant than ranibizumab at month 12 (p < 0.001). Ocular adverse events in the study eye were more frequent in the DEX implant group because of the occurrence of intraocular pressure (IOP) increases and cataract. IOP increases were transient and generally managed with topical medication. CONCLUSIONS: Both DEX implant and ranibizumab were well tolerated and improved BCVA and anatomic outcomes in patients with DME. DEX implant met the a priori criterion for noninferiority to ranibizumab in average change from baseline BCVA over 12 months. Noninferiority was achieved with an average of 2.85 DEX implant injections and 8.70 ranibizumab injections per patient.

Effect of intravitreal injection of dexamethasone 0.7 mg (Ozurdex®) on intraocular pressure in patients with macular edema.

BACKGROUND: To evaluate the effect of Ozurdex® on intraocular pressure in patients with macular edema alone (group 1) or associated with glaucoma or ocular hypertension (group 2). METHODS: A clinical, retrospective, observational, comparative study included 92 eyes with macular edema treated with a single injection of Ozurdex®; 27 eyes were previously diagnosed with glaucoma or ocular hypertension. RESULTS: The mean intraocular pressure (group 1 vs. group 2) after injection was 12.1 versus 19.9 mm Hg, (p < 0.05; day 1); 17.5 versus 19.7 mm Hg (p < 0.05; month 1); 18.4 versus 20.9 mm Hg (p < 0.05; month 2); 15 versus 17.4 mm Hg (p < 0.05; month 3); 13.9 versus 16.7 mm Hg (p > 0.05; month 6); 13.8 versus 15.1 mm Hg (p > 0.05; month 9) and 13.1 versus 16.4 mm Hg (p > 0.05; month 12). Thirty eyes (32.6%) showed ocular hypertension (intraocular pressure >21 mm Hg) after the injection: 21.5% of group 1 and 59.3% of group 2. In group 2, 27 eyes (100%) needed medical treatment to reduce intraocular pressure in comparison to 8 patients (12.3%) in group 1 (p < 0.001). CONCLUSIONS: Intravitreal injection of Ozurdex® was associated with ocular hypertension in 32.6% of the eyes. Previous glaucoma or ocular hypertension are risk factors for this increase.

Management of Vision-Threatening Complications of Vasoproliferative Tumors of the Retina.

AIMS: To report the management of vision-threatening complications of vasoproliferative tumors of the retina. METHODS: Clinical records of 31 eyes of 30 patients treated at our centers from 1998 through 2013 were reviewed. The main outcome measures included: type of treatment, tumor regression, tumor relapse and final visual acuity. RESULTS: Seventeen patients (57%) underwent vitrectomy for epimacular membranes (n = 10), rhegmatogenous retinal detachment (n = 2), vitreous hemorrhage (n = 2), tractional retinal detachment (n = 1), serous retinal detachment (n = 1) and subhyaloid hemorrhage (n = 1). After the initial treatment, 10 additional surgeries were performed for vitreoretinal complications. Tumor activity was treated in all eyes either with photocoagulation or cryotherapy. Control of tumor activity was achieved in all cases, after treatment of recurrences. There were no statistically significant differences between initial and final visual acuity (p = 0.437). Recurrence showed a statistically significant association with the presence of proliferative vitreoretinopathy (p = 0.024), tumor thickness (p = 0.026), basal diameter (p = 0.031), and use of photocoagulation alone as initial treatment (p = 0.006, logistic regression). CONCLUSION: In our series, more than half of vasoproliferative tumors of the retina required surgery as the initial treatment. Recurrence was associated with tumor size, presence of proliferative vitreoretinopathy, and use of photocoagulation alone as the initial treatment.