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The Centre for European Nuclear Research (CERN) uses large and complex scientific instruments to study the basic constituents of matter by operating a network of underground particle accelerators and appurtenant tunnels. Long-term safety and structural health of this critical infrastructure highlighted the need for a sensing plan that could provide remote monitoring and resistance to high radiation. A pilot Distributed Fibre-Optic Sensing (DFOS) system using Brillouin scattering was used to instrument 8 tunnel sections and obtain a first set of short-term readings. These preliminary readings show minor tunnel ovalisation and will be used as baseline for future long-term readings. [ABSTRACT FROM AUTHOR]

Biallelic mutations in the RPE65 gene affect nearly 8% of Leber Congenital Amaurosis and 2% of Retinitis Pigmentosa cases. Voretigene neparvovec (VN) is the first gene therapy approach approved for their treatment. To date, real life experience has demonstrated functional improvements following VN treatment, which are consistent with the clinical trials outcomes. However, there is currently no consensus on the characteristics for eligibility for VN treatment. We reviewed relevant literature to explore whether recommendations on patient eligibility can be extrapolated following VN marketing. We screened 166 papers through six research questions, following scoping reviews methodology, to investigate: (1) the clinical and genetic features considered in VN treatment eligibility; (2) the psychophysical tests and imaging modalities used in the pre-treatment and follow-up; (3) the potential correlations between visual function and retinal structure that can be used to define treatment impact on disease progression; (4) retinal degeneration; (5) the most advanced testing modalities; and (6) the impact of surgical procedure on treatment outcomes. Current gaps concerning patients' eligibility in clinical settings, such as pre-treatment characteristics and outcomes are not consistently reported across the studies. No upper limit of retinal degeneration can be defined as the univocal factor in patient eligibility, although evidence suggested that the potential for function rescue is related to the preservation of photoreceptors before treatment. In general, paediatric patients retain more viable cells, present a less severe disease stage and show the highest potential for improvements, making them the most suitable candidates for treatment., (© 2024. The Author(s).)

Purpose : We report the successful surgical treatment of a case of spontaneous complete anterior crystalline lens luxation in a patient affected by retinitis pigmentosa (RP), associated with elevated intraocular pressure and pupillary block. Additionally, we review the current literature regarding the association between ectopia lentis and RP. Case description : A 44-year-old female RP patient presented to our emergency department reporting severe ocular pain in her left eye (LE) and sickness. She had no history of ocular trauma and did not report systemic disorders. The best corrected visual acuity at presentation was 1/20 in her LE, the intraocular pressure was 60 mmHg, and slit lamp examination showed in her LE a complete dislocation of the lens in the anterior chamber, with mydriasis, atalamia, and a pupillary block. The patient had been administered intravenous mannitol 18% solution and dorzolamide-timolol eye drops and was hospitalized for urgent lens extraction. Anterior segment optical coherence tomography and ultrasound biomicroscopy were performed before surgery. Decompressive 23-gauge pars plana vitrectomy and phacoemulsification were performed, and the capsular bag was removed due to marked zonular weakness, with deferred intraocular lens implant. Conclusions : Acute angle closure glaucoma in patients with RP may be rarely caused by spontaneous anterior lens dislocation. To our knowledge, this is the first report of spontaneous anterior lens dislocation in an RP patient, documented through photographs, anterior segment optical coherence tomography, and ultrasound biomicroscopy.

Purpose: To report a case of macular hole and detachment occurring after the subretinal injection of Voretigene Neparvovec (VN) in a patient affected by atypical RPE65 retinal dystrophy with high myopia and its successful surgical management., Case Description: We report a case of a 70-year-old man treated with VN in both eyes. The best corrected visual acuity (BCVA) was 0.7 LogMar in the right eye (RE) and 0.92 LogMar in the left eye (LE). Axial length was 29.60 mm in the RE and 30.28 mm in the LE. Both eyes were pseudophakic. In both eyes, fundus examination revealed high myopia, posterior staphyloma, and extended retinal atrophy areas at the posterior pole, circumscribing a central island of surviving retina. Both eyes were treated with VN subretinal injection, but a full-thickness macular hole and retinal detachment occurred in the LE three weeks after surgery. The patient underwent 23-gauge vitrectomy with internal limiting membrane (ILM) peeling and the inverted flap technique with sulfur hexafluoride (SF6) 20% tamponade. Postoperative follow-up showed that the macular hole was closed and the BCVA was maintained., Conclusions: Our experience suggests that patients with atypical RPE65 retinal dystrophy and high myopia undergoing VN subretinal injection require careful management to minimize the risk of macular hole and detachment occurrence and promptly detect and address these potential complications.

Purpose : To describe an atypical phenotypic pattern of late-onset retinitis pigmentosa (RP) due to the same specific c.425A>G (p.Tyr142Cys) heterozygous mutation in the cone-rod homeobox gene ( CRX gene) in two unrelated Italian patients. Case 1 : A 67-year-old woman (P.P.) was incidentally diagnosed with sector RP at the age of 50. The patient was initially asymptomatic and did not have any family history of retinal dystrophy. Fundus examination showed the presence of typical retinal pigmentary deposits with a peculiar pericentral/sector distribution. Genomic sequencing disclosed the missense mutation c.425A>G (p.Tyr142Cys) in the CRX gene. During the follow-up period of 7 years, the patient maintained good visual acuity and complained only of mild symptoms. Case 2 : A 76-year-old man (P.E.) presented with nyctalopia and visual field constriction since the age of 50. Fundus examination showed the presence of retinal pigment deposits with a concentric pericentral and perimacular pattern. A full-field electroretinogram (ffERG) showed extinguished scotopic responses and reduced abnormal photopic and flicker cone responses. Genomic sequencing identified the same missense mutation, c.425A>G (p.Tyr142Cys), in the CRX gene. Similarly to the first case, during the whole follow-up of 7 years, the visual acuity remained stable, as did the visual field and the patient's symptoms. Conclusions : We report the first cases of late-onset retinitis pigmentosa related to a specific heterozygous CRX gene mutation in exon 4. We also report two atypical phenotypic RP patterns related to mutations in the CRX gene.

Purpose: To compare non-syndromic and syndromic forms of USH2A -related retinitis pigmentosa (RP) by means of structural optical coherence tomography (OCT) and OCT-angiography (OCTA)., Methods: Observational, cross-sectional, multicenter study. All patients underwent best corrected visual acuity (BCVA) measurement, OCT (Spectralis HRA + OCT, Heidelberg Engineering) and OCTA (OCT DRI Topcon Triton, Topcon Corporation). We compared subfoveal choroidal thickness (SCT), choroidal vascularity index (CVI), presence of cystroid macular edema (CME), macular vessel density (VD) at the superficial and deep capillary plexa, as well as VD of the radial peripapillary capillary (RPC) network, between syndromic and non-syndromic patients with USH2A -associated retinopathy., Results: Thirty-four eyes from 18 patients (7 females) were included. Thirteen patients (72.2%) were affected by Usher syndrome type 2, whereas the remaining 5 subjects (27.8%) had non-syndromic retinitis pigmentosa (nsRP). Syndromic patients were younger than nsRP ( p  = 0.01) and had a worse visual acuity than those with the exclusively retinal phenotype. Patients with Usher syndrome type 2 had a higher prevalence of CME and a thicker choroid compared to nsRP, although these results were not statistically significant ( p  = 0.775 and p  = 0.122, respectively). Similarly, none of the other quantitative OCT and OCTA parameters was statistically different between the two groups., Conclusions: Despite their younger age, patients with Usher syndrome type 2 displayed similar choroidal and microvascular changes compared to those with nsRP., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Prof. Francesco Bandello is the Editor in Chief of EJO but he was not involved in the evaluation procedure of the present study. Francesco Bandello is consultant for Alcon (Fort Worth, Texas, USA), Alimera Sciences (Alpharetta, Georgia, USA), Allergan Inc (Irvine, California,USA), Farmila-Thea (Clermont-Ferrand, France), Bausch & Lomb (Rochester, New York, USA), Genentech (San Francisco, California, USA), Hoffmann-La-Roche (Basel, Switzerland), Novagali Pharma (Évry, France), Novartis (Basel, Switzerland), Bayer Shering-Pharma (Berlin, Germany), Sanofi-Aventis (Paris, France), Thrombogenics (Heverlee, Belgium), Zeiss (Dublin, USA), Pfizer (New York, USA), Sanofi-Aventis (Paris, France), Santen (Osaka, Japan), Sifi (Aci Sant’Antonio, Italy), Thrombogenics (Heverlee, Belgium), Zeiss (Dublin, USA). All other authors have no financial disclosure.

Introduction: Retinitis pigmentosa (RP), a heterogeneous inherited retinal disorder causing gradual vision loss, affects over 1 million people worldwide. Pathogenic variants in CNGA1 and CNGB1 genes, respectively, accounting for 1% and 4% of cases, impact the cyclic nucleotide-gated channel in rod photoreceptor cells. The aim of this study was to describe and compare genotypic and clinical characteristics of a cohort of patients with CNGA1- or CNGB1-related RP and to explore potential genotype-phenotype correlations., Methods: The following data from patients with CNGA1- or CNGB1-related RP, followed in five Italian inherited retinal degenerations services, were retrospectively collected: genetic variants in CNGA1 and CNGB1, best-corrected visual acuity (BCVA), ellipsoid zone (EZ) width, fundus photographs, and short-wavelength fundus autofluorescence (SW-AF) images. Comparisons and correlation analyses were performed by first dividing the cohort in two groups according to the gene responsible for the disease (CNGA1 and CNGB1 groups). In parallel, the whole cohort of RP patients was divided into two other groups, according to the expected impact of the variants at protein level (low and high group)., Results: In total, 29 patients were recruited, 11 with CNGA1- and 18 with CNGB1-related RP. In both CNGA1 and CNGB1, 5 novel variants in CNGA1 and 5 in CNGB1 were found. BCVA was comparable between CNGA1 and CNGB1 groups, as well as between low and high groups. CNGA1 group had a larger mean EZ width compared to CNGB1 group, albeit not statistically significant, while EZ width did not differ between low and high groups A statistically significant correlation between EZ width and BCVA as well as between EZ width and age were observed in the whole cohort of RP patients. Fundus photographs of all patients in the cohort showed classic RP pattern, and in SW-AF images an hyperautofluorescent ring was observed in 14/21 patients., Conclusion: Rod CNG channel-associated RP was demonstrated to be a slowly progressive disease in both CNGA1- and CNGB1-related forms, making it an ideal candidate for gene augmentation therapies., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Non-syndromic inherited retinal dystrophies (IRDs) such as retinitis pigmentosa or Leber congenital amaurosis generally manifest between early childhood and late adolescence, imposing profound long-term impacts as a result of vision impairment or blindness. IRDs are highly heterogeneous, with often overlapping symptoms among different IRDs, and achieving a definite diagnosis is challenging. This narrative review provides a clinical overview of the non-syndromic generalized photoreceptor dystrophies, particularly retinitis pigmentosa and Leber congenital amaurosis. The clinical investigations and genetic testing needed to establish a diagnosis are outlined, and current management approaches are discussed, focusing on the importance of the involvement of an interdisciplinary team from diagnosis and initial care to long-term follow-up and support., Results: The effective management of IRDs requires a multidisciplinary, and ideally interdisciplinary, team of experts knowledgeable about IRDs, with experienced professionals from fields as diverse as ophthalmology, neuropsychiatry, psychology, neurology, genetics, orthoptics, developmental therapy, typhlology, occupational therapy, otolaryngology, and orientation and mobility specialties. Accurate clinical diagnosis encompasses a range of objective and subjective assessments as a prerequisite for the genetic testing essential in establishing an accurate diagnosis necessary for the effective management of IRDs, particularly in the era of gene therapies. Improvements in genome sequencing techniques, such as next-generation sequencing, have greatly facilitated the complex process of determining IRD-causing gene variants and establishing a molecular diagnosis. Genetic counseling is essential to help the individual and their family understand the condition, the potential risk for offspring, and the implications of a diagnosis on visual prognosis and treatment options. Psychological support for patients and caregivers is important at all stages of diagnosis, care, and rehabilitation and is an essential part of the multidisciplinary approach to managing IRDs. Effective communication throughout is essential, and the patient and caregivers' needs and expectations must be acknowledged and discussed., Conclusion: As IRDs can present at an early age, clinicians need to be aware of the clinical signs suggesting visual impairment and follow up with multidisciplinary support for timely diagnoses to facilitate appropriate therapeutic or rehabilitation intervention to minimize vision loss., (© 2023. The Author(s).)

Background: Congenital Stationary Night Blindness (CSNB) constitutes a group of non-progressive retinal disorders characterized by disturbances in scotopic vision and/or by a delay in adaptation to darkness, as well as by low visual acuity, myopia, nystagmus, and strabismus. Color vision and fundus appearance tend to be normal. To date, several CACNA1F gene variants have been linked to a CSNB phenotype but only few reports have focused on the optic nerve in this disease., Materials and Methods: Twelve patients underwent standard ophthalmological and genetic evaluation including spectral domain optical coherence tomography (SD-OCT), full-field electroretinography (ffERG), kinetic perimetry, fundus photography, magnetic resonance imaging (MRI), and next-generation sequencing (NGS). Bilateral thinning of the peripapillary nerve fiber layer (pRNFL) and the ganglion cell complex (GCC) supported involvement of the optic nerves. MRI, when available, was assessed for gross intracranial optic pathway abnormalities., Results: All patients were shown to carry pathogenic variants in the CACNA1F gene, and all showed signs of optic nerve involvement. All patients showed a certain degree of myopic refractive error. Low average pRNFL thickness was evident in all patients. In three of them, pRNFL thickness was evaluated longitudinally and was proven to be stable over time. MRI imaging was unremarkable in all cases., Conclusion: Our data support the hypothesis that CACNA1F could be related to early-onset or congenital optic nerve involvement without any signs of a progressive optic neuropathy. Even though additional data from larger cohorts and longer follow-up periods are needed to further support and confirm our findings, there is a clear significance to our findings in the preparation for future CACNA1F gene therapy trials.

Background: Orphan drugs are used for the diagnosis, prevention and treatment of rare diseases that, in the European Union, are defined as disorders affecting no more than 5 persons in 10,000. So far, a total of around 800 orphan medicinal products have been approved by the European Medicines Agency, however the utilization profile of orphan drugs has yet to be explored. This study aimed at assessing the utilization profile of orphan drugs authorized for marketing by the Italian Medicines Agency using population-based data. Methods: A total of 21 orphan drugs used in outpatient settings, approved in the European Union before or during the 2008-2018 period and involving 15 rare diseases, were included in the study. The monitored population included patients with one of the conditions surveilled by the population-based Tuscany Registry of Rare Diseases and diagnosed between 2000-2018. A multi-database approach was applied, by linking data from the registry with information collected in drug prescriptions databases. The prevalence and intensity of use were estimated for the selected orphan drugs and other non-orphan medications, used to treat the same rare disease and for which a change in the prevalence of use was hypothesized after authorization of the orphan drug. Results: For some diseases (acquired aplastic anemia, tuberous sclerosis complex, most metabolic diseases) a low prevalence of orphan drugs use was observed (range between 1.1-12.5%). Conversely, orphan drugs were frequently used in hemophilia B, Wilson disease and idiopathic pulmonary fibrosis (maximum of 78.3, 47.6 and 41.8%, respectively). For hemophilia B and Leber's hereditary optic neuropathy, there are currently no other medications used in clinical practice in addition to orphan drugs. Six orphan drugs were used for the treatment of pulmonary arterial hypertension, appearing the elective therapy for this disease, albeit with different utilization profiles (range of prevalence 1.7-55.6%). Conclusion: To the best of our knowledge, this is the first study investigating the utilization profile of orphan drugs prescribed in a defined geographical area, and providing relevant information to monitor over time potential changes in the prevalence of these medications as well as in the health care decision making., Competing Interests: RG reports a relationship with Tuscany Region that includes: funding grants. RG reports a relationship with Fondazione Cassa di Risparmio di Firenze that includes: funding grants. RG reports a relationship with Italian Ministry of Health that includes: funding grants. RG reports a relationship with Zogenix that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. RG reports a relationship with Biocodex that includes: speaking and lecture fees and travel reimbursement. PC reports a relationship with GSK SRL that includes: speaking and lecture fees. PC reports a relationship with AstraZeneca SpA that includes: speaking and lecture fees. GC reports a relationship with SOBI that includes: funding grants. GC reports a relationship with CSL Behring Spa that includes: funding grants. GC reports a relationship with Roche that includes: board membership, consulting or advisory, and speaking and lecture fees. GC reports a relationship with Bayer that includes: board membership and speaking and lecture fees. GC reports a relationship with CSL Berhing that includes: board membership and speaking and lecture fees. GC reports a relationship with Biomarin that includes: board membership and speaking and lecture fees. GC reports a relationship with Sanofi that includes: board membership and speaking and lecture fees. GC reports a relationship with Novo Nordisk that includes: board membership and speaking and lecture fees. GC reports a relationship with Takeda that includes: board membership and speaking and lecture fees. GC reports a relationship with Kedrion that includes: board membership and speaking and lecture fees. GC reports a relationship with LFB that includes: board membership and speaking and lecture fees. GC reports a relationship with Grifols that includes: board membership and speaking and lecture fees. GC reports a relationship with UniQure Inc. that includes: board membership and speaking and lecture fees. PP reports a relationship with GSK that includes: speaking and lecture fees. PP reports a relationship with LEOPharma that includes: speaking and lecture fees. FC reports a relationship with Pfizer that includes: consulting or advisory. FC reports a relationship with Alnylam that includes: consulting or advisory. FC reports a relationship with Akcea that includes: consulting or advisory. BS reports a relationship with Jazz that includes: speaking and lecture fees. BS reports a relationship with Pfizer that includes: board membership and speaking and lecture fees. BS reports a relationship with Novartis that includes: speaking and lecture fees. BS reports a relationship with Ariad that includes: speaking and lecture fees. BS reports a relationship with Amgen that includes: board membership and travel reimbursement. BS reports a relationship with Sanofi that includes: travel reimbursement. IO reports a relationship with Amicus that includes: consulting or advisory and funding grants. IO reports a relationship with Genzyme that includes: consulting or advisory and funding grants. IO reports a relationship with Menarini International that includes: funding grants. IO reports a relationship with BMS that includes: board membership, consulting or advisory, and funding grants. IO reports a relationship with Cytokinetics Inc. that includes: board membership, consulting or advisory, and funding grants. IO reports a relationship with Bayer that includes: funding grants and speaking and lecture fees. IO reports a relationship with Boston Scientific that includes: funding grants and speaking and lecture fees. IO reports a relationship with Tenaya that includes: consulting or advisory. SL reports a relationship with Takeda that includes: consulting or advisory, funding grants, and speaking and lecture fees. SL reports a relationship with Sanofi Genzyme that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. SL reports a relationship with SOBI that includes: funding grants, speaking and lecture fees, and travel reimbursement. SL reports a relationship with CLS-Behring that includes: funding grants and speaking and lecture fees. SL reports a relationship with NovoNordisk that includes: funding grants and speaking and lecture fees. SL reports a relationship with Roche that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. FP report a relationship with Biomarin International Limit that includes: board membership and speaking and lecture fees. FP report a relationship with Vitaflo that includes: travel reimbursement., (Copyright © 2022 Gorini, Santoro, Pierini, Mezzasalma, Baldacci, Bargagli, Boncristiano, Brunetto, Cameli, Cappelli, Castaman, Coco, Donati, Guerrini, Linari, Murro, Olivotto, Parronchi, Pochiero, Rossi, Scappini, Sodi, Vannucchi and Coi.)

Purpose: To report choroidal caverns in patients affected by recessive Stargardt disease (STGD1) and to investigate its clinical features., Methods: Retrospective analysis of STGD1 patients recruited at the Regional Reference Center for Hereditary Retinal Degenerations at the Eye Clinic in Florence from 2012 to 2017. Patients included in the study underwent a complete ophthalmic examination including best-corrected visual acuity, color fundus photography, fundus autofluorescence, optical coherence tomography (OCT) and OCT angiography., Results: Eighty-six patients (172 eyes) were included in the study. Twenty-three eyes (13.3%) of 21 patients presented choroidal caverns. The total number of detected choroidal caverns was 63. Choroidal caverns were only present in patients with stage III and IV STGD. Interestingly, patients with choroidal caverns presented larger macular atrophy (20.53 ± 16.9 mm2 vs. 18.11 ± 20.39 mm2), worse visual acuity (1.03 ± 0.29 vs. 0.83 ± 0.26), and a thinner choroidal thickness (245.9 ± 88.7 vs. 266.0 ± 110.5 µm)., Conclusions: Choroidal caverns are present only in the advanced stage of STGD1, and a possible degenerative origin of the finding has been hypothesized.

Purpose: To investigate the course of inherited retinal degenerations (IRD) due to mutations in the RPE65 gene., Methods: This longitudinal multicentric retrospective chart-review study was designed to collect best corrected visual acuity (BCVA), Goldman visual field, optical coherence tomography (OCT), and electroretinography (ERG) measurements. The data, including imaging, were collected using an electronic clinical research form and were reviewed at a single center to improve consistency., Results: From an overall cohort of 60 Italian patients with RPE65-associated IRD, 43 patients (mean age, 27.8 ± 19.7 years) were included and showed a mean BCVA of 2.0 ± 1.0 logMAR. Time-to-event analysis revealed a median age of 33.8 years and 41.4 years to reach low vision and blindness based on BCVA, respectively. ERG (available for 34 patients) showed undetectable responses in most patients (26; 76.5%). OCT (available for 31 patients) revealed epiretinal membranes in five patients (16.1%). Central foveal thickness significantly decreased with age at a mean annual rate of -0.6%/y (P = 0.044). We identified 43 different variants in the RPE65 gene in the entire cohort. Nine variants were novel. Finally, to assess genotype-phenotype correlations, patients were stratified according to the number of RPE65 loss-of-function (LoF) alleles. Patients without LoF variants showed significantly (P < 0.05) better BCVA compared to patients with one or two LoF alleles., Conclusions: We described the natural course of RPE65-associated IRD in an Italian cohort showing for the first time a specific genotype-phenotype association. Our findings can contribute to a better management of RPE65-associated IRD patients.

Purpose: To report a case of choroideremia characterized by peripheral retinoschisis with vascular abnormalities and vitreous hemorrhage., Observations: A 58-year-old man affected by advanced-stage choroideremia was diagnosed with peripheral retinoschisis in both eyes. Vitreous hemorrhage was present in the right eye with a peculiar clot-like lesion at the periphery. At the 1-year follow-up, the vitreous hemorrhage had reabsorbed and the vascular clot-like lesion in the periphery had almost completely disappeared., Conclusion and Importance: We have reported fundoscopic and OCT features of peripheral-acquired retinoschisis with vascular abnormalities in a patient with choroideremia. OCT examination is extremely useful in clinical evaluation of the peripheral retinal alterations in these cases, where the absence of the retinal pigment epithelium and the choriocapillaris pose many diagnostic difficulties.

Purpose: To evaluate the correlation between Best Corrected Visual Acuity (BCVA) and the following parameters in Stargardt Disease (STGD): Central Retinal Thickness (CR-T), Central Outer Nuclear Layer Thickness (C-ONL-T), Areas of macular Photoreceptor loss (PHRa), and Retinal Pigment Epithelium (RPE) loss (RPEa)., Methods: A total of 64 eyes of 32 STGD patients were included in the study. All patients received a comprehensive ophthalmological examination, color fundus photographs, fundus auto-fluorescence imaging, and Optical Coherence Tomography (OCT). The CR-T and C-ONL-T were evaluated from standard SD-OCT scans. The PHRa and RPEa were calculated from enface OCT scans (sub RPE slab and photoreceptor slab). The collected OCT parameters were evaluated for possible association with BCVA., Results: The mean macular PHRa and RPEa was 16.16 ± 13.36 and 12.05 ± 12.57 mm 2 respectively. The mean CR-T measured 120.78 ± 41.49 μm while the mean C-ONL-T was assessed at 4.60 ± 13.73 μm. BCVA showed the highest correlation with the C-ONL-T ( r  = -0.72; p  < 0.001) while there was no correlation with the CR-T ( r  = -0.17; p  = 1.00)., Conclusions: Enface OCT permits a rapid and precise quantitative evaluation of the macular PHR and RPE atrophy area in STGD. Nonetheless, the OCT parameter that showed the highest correlation with visual acuity in STGD was the ONL thickness.

Purpose: To assess the choroidal structure using the Choroidal Vascularity Index (CVI) and analyse choroidal changes in choroideremia (CHM) carriers., Material and Methods: Female CHM carriers, genetically characterized, and a control group were recruited at the Eye Clinic of Careggi Teaching Hospital, Florence. The patients underwent a complete ophthalmic evaluation and retinal imaging. In particular, the Stromal Area (SA), Luminal Area (LA), Total Choroidal Area (TCA), CVI, and Subfoveal Choroidal Thickness (SFCT) were calculated for each eye using Optical Coherence Tomography (OCT) examinations., Results: Twelve eyes of 6 CHM carriers and 14 eyes of 7 age-matched controls were analysed. The mean SFCT was 270.9 ± 54.3μm in carriers and 281.4 ± 36.8μm in controls (p = 0.564); LA was 0.99 ± 0.25mm 2 and 1.01 ± 0.13mm 2 (p = 0.172); SA was 0.53 ± 0.09mm 2 and 0.59 ± 0.07mm 2 (p = 0.075), and TCA was 1.53 ± 0.34mm 2 and 1.69 ± 0.19mm 2 respectively (p = 0.146). Mean CVI measured 64.03 ± 3.98% in the CHM carriers and 65.25 ± 2.55% in the controls (p = 0.360)., Conclusions: The CVI and CVI-related parameters (SA, LA, and TCA) do not differ between CHM female carriers and controls. These findings reveal a preserved choroidal vasculature in eyes with RPE impairment and support the primary role of RPE in the pathogenesis of CHM disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mucciolo, Giorgio, Lippera, Passerini, Pelo, Cipollini, Sodi, Virgili, Giansanti and Murro.)

Background: To report a clinical case of a patient affected with choroideremia (CHM) who underwent macular surgery for a macular hole (MH) with Lamellar Hole-associated Epiretinal Proliferation (LHEP)., Case Presentation: We have described a 48-year-old male patient affected with CHM who developed MH with LHEP over a 7-year follow-up. The patient was referred to the Regional Center for Hereditary Retinal Degenerations of the Eye Clinic in Florence (Italy) in April 2012. The patient underwent vitrectomy and Inner Limiting Membrane (ILM) and LHEP peeling with fluid-air exchange. Ultra-structural examination of the excised epiretinal proliferation, carried out using electron microscopy, showed dense amorphous material, mainly composed of abundant clusters of fibrous collagens resembling compact fibrous long spacing collagen (FLSC), embedded in native vitreous collagen (NVC) and type IV collagen. No cells were detected in any of the specimens collected. At the 3rd-week postoperative follow-up the macular hole was closed., Conclusion: Macular hole with LHEP can be detected in CHM patients; in our patient the macular hole showed tractional and degenerative features, with good anatomical results after macular surgery., (© 2021. The Author(s).)

Purposes: To study the clinical and genetic background of a series of Italian patients affected by pattern dystrophy (PD). Methods: We reviewed patients with a clinical diagnosis of PD examined at the Eye Clinic in Florence from 2012 to 2019. We took into consideration patients with a standard ophthalmological examination, personal and familial ophthalmological history, fundus imaging, and molecular genetic analysis of genes PRPH2 and BEST1 . We labelled patients with BEST1 and PRPH2 mutations as m-PD group (mutated) whereas patients with no mutations in these 2 genes as nm-PD group (non-mutated). Results: Seventy-seven PD patients were assessed (average age 59.7 ± 14.2, range 31-88 years). Fifty patients were placed in the nm-PD group and 27 in the m-PD. Pathogenic BEST1 and PRPH2 mutations were detected in 7% and 22% of PD patients, respectively. In total, we reported 1 BEST1 and 8 PRPH2 novel mutations. Ten patients were characterized by drusen in the nm-PD group whereas in no patients in the m-PD group drusen were detected at the fundus. Conclusions: An important proportion of patients affected by PD showed BEST1 or PRPH2 mutations. Patients affected by drusen represent a different sub-phenotype. Genetic examination is recommended for a correct clinical management.

Purpose: To describe genetic analysis, treatment results, and complications of patients affected by retinal capillary hemangioblastoma (RCH) in von Hippel Lindau (VHL) syndrome., Methods: We collected 17 patients with VHL syndrome, who underwent a molecular test and an ophthalmic evaluation at the Eye Clinic of the University Hospital of Florence from January 2005 to February 2020. We focused on eyes showing RCHs examined using color fundus photographs, fluorescein angiography, and optical coherence tomography., Results: Eight eyes of six patients (6/17; 35%) showed RCHs at the fundoscopic examination. All RCHs were treated with laser therapy. Three eyes underwent episcleral surgery, one eye showing vitreous hemorrhage received three intravitreal (IV) anti-VEGF injections and three cryotherapy procedures, and one eye underwent vitrectomy. In patients with RCHs, five were characterized by a truncating mutation of the VHL protein, and one patient showed a missense mutation. We have reported two VHL mutations not reported in literature., Conclusions: Patients with multiple RCHs, who developed RCH secondary effects, showed truncating mutations of the VHL protein. We recommend early screening and close monitoring, especially if RCHs are detected at presentation, for every patient with VHL syndrome independently of the results of the molecular test for a missense or a truncating mutation in VHL ., (Copyright © 2021 Molecular Vision.)

Inherited retinal diseases (IRDs) are a heterogeneous group of conditions that include retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EO[S]RD), which differ in severity and age of onset. IRDs are caused by mutations in >250 genes. Variants in the RPE65 gene account for 0.6-6% of RP and 3-16% of LCA/EORD cases. Voretigene neparvovec is a gene therapy approved for the treatment of patients with an autosomal recessive retinal dystrophy due to confirmed biallelic RPE65 variants ( RPE65 -IRDs). Therefore, the accurate molecular diagnosis of RPE65 -IRDs is crucial to identify 'actionable' genotypes-i.e., genotypes that may benefit from the treatment-and is an integral part of patient management. To date, hundreds of RPE65 variants have been identified, some of which are classified as pathogenic or likely pathogenic, while the significance of others is yet to be established. In this review, we provide an overview of the genetic diagnostic workup needed to select patients that could be eligible for voretigene neparvovec treatment. Careful clinical characterization of patients by multidisciplinary teams of experts, combined with the availability of next-generation sequencing approaches, can accelerate patients' access to available therapeutic options.

Purpose: The purpose of this study was to perform a detailed longitudinal phenotyping and genetic characterization of 32 Italian patients with a nonsyndromic retinal dystrophy and mutations in the CEP290 gene., Methods: We reviewed the clinical history and examinations of 32 patients with a nonsyndromic retinal dystrophy due to mutations in the CEP290 gene, followed up (mean follow-up: 5.9 years) at 3 Italian centers. The clinical examinations included: best corrected visual acuity (BCVA), optical coherence tomography (OCT), and full-field electroretinogram (ERG)., Results: Patients (mean age = 19.0 ± 3.4 years) had a mean BCVA of 1.73 ± 0.20 logMAR. Longitudinal analysis of BCVA showed a nonsignificant decline. Central retinal thickness (CRT) declined significantly with age at an exponential rate of 1.0%/year (P = 0.001). At disease onset, most patients (19/32; 49.4%) had nystagmus. The absence of nystagmus was significantly associated with better BCVA and more preserved CRT (P < 0.05). ERG showed undetectable responses in most patients (64.0%), whereas reduced scotopic and photopic responses were observed in four patients (16.0%) who had no nystagmus. We identified 35 different variants, among which 12 were novel. Our genotype-phenotype correlation analysis shows a significantly worse BCVA in patients harboring a loss-of-function mutation and the deep-intronic variant c.2991+1655A>G., Conclusions: Our study highlights a mild phenotype of the disease, characterized by absence of nystagmus, good visual acuity, considerably preserved retinal morphology, and recordable ERG, confirming the wide spectrum of CEP290-related retinal dystrophies. Finally, in our cohort, the deep intronic variant c.2991+1655A>G was associated with a more severe phenotype.

Background: Pseudoxanthoma elasticum (PXE) is a rare ectopic calcification genetic disease mainly caused by ABCC6 rare sequence variants. The clinical phenotype is characterized by typical dermatological, ophthalmological and cardiovascular manifestations, whose frequency and severity are differently reported in the literature., Methods: A retrospective study was performed on 377 PXE patients of Italian origin, clinically evaluated according to the Phenodex Index, who underwent ABCC6 biomolecular analyses. Moreover, 53 PXE patients were further characterized by in-depth ophthalmological examinations., Results: A total of 117 different ABCC6 rare sequence variants were detected as being spread through the whole gene. The severity of the clinical phenotype was dependent on age, but it was not influenced by gender or by the type of sequence variants. In-depth ophthalmological examinations focused on the incidences of coquille d'oeuf , comet lesions, pattern dystrophy-like lesions, optic disk drusen and posterior-pole atrophy. Conclusion : Given the large number of patients analyzed, we were able to better evaluate the occurrence of less frequent alterations (e.g., stroke, myocardial infarction, nephrolithiasis). A more detailed description of ophthalmological abnormalities allowed us to stratify patients and better evaluate disease progression, thus suggesting a further update of the PXE score system.

Purpose: To evaluate choroidal features in young patients affected by choroideremia (CHM)., Methods: Young CHM patients and control subjects were recruited at the Eye Clinic in Florence. High-resolution choroidal imaging was obtained using swept-source optical coherence tomography with long optical coherence tomography scans (12 × 9 mm optical coherence tomography scans). We considered the subfoveal choroidal area within 9 mm of the optic disk in the horizontal plane and the subfoveal choroidal area within a 3-mm diameter centered over the fovea. The subfoveal choroidal thickness, total choroidal area, luminal area, stromal area, and choroidal vascularity index were assessed using the "ImageJ" software in both groups., Results: Eight patients (16 eyes; mean age, 19.3 ± 5.2 years) and seven control subjects (14 eyes; mean age, 19.0 ± 5.0 years) were included in this study. Best-corrected visual acuity was 20/20 in both eyes of seven CHM patients and in all control subjects and 20/25 in both eyes in one CHM patient. Mean subfoveal choroidal thickness did not differ between CHM patients and control subjects. Luminal area9mm, stromal area9mm, and total choroidal area9mm were reduced in patients compared with the control group. Luminal area3mm, stromal area3mm, and total choroidal area3mm did not differ between patients and control subjects. Choroidal vascularity index9mm and choroidal vascularity index3mm were not different between patients and control subjects., Conclusion: There are no differences in the choroidal vascularity index between young CHM patients and control subjects; this result suggests a simultaneous, proportional impairment of both the stromal and vascular components of the choroid in the early stages of the disease.

Purpose: To compare the efficacy between fixed and variable treatment regimens of subthreshold yellow micropulse laser for the treatment of diabetic macular edema., Methods: This is a retrospective, comparative, 12-month study of 39 eyes: 24 eyes received fixed treatment regimen of subthreshold micropulse laser treatment and 15 eyes underwent variable treatment regimen of subthreshold micropulse laser, all eyes were followed up for 12 months. Subthreshold micropulse laser was performed with the following parameters: 100 μm spot size on slit lamp, 5% duty cycle of 0.2 s, and 250 mW power. To choose the power of the variable treatment regimen of subthreshold micropulse laser group, continuous laser power was titrated to a barely visible burn and then switched to MicroPulse mode, multiplying the test burn power by 4 and using a 5% duty cycle of 0.2 s. Main outcomes included changes in central macular thickness and best-corrected visual acuity., Results: At baseline, the mean LogMAR best-corrected visual acuity was 0.297 ± 0.431 in the variable treatment regimen of subthreshold micropulse laser group and 0.228 ± 0.341 in the fixed treatment regimen of subthreshold micropulse laser group. At the end of follow-up, the mean LogMAR best-corrected visual acuity was 0.289 ± 0.473 (p = 0.785) and 0.245 ± 0.376 (p = 0.480) in the variable and fixed treatment regimens of subthreshold micropulse laser groups, respectively. Similarly, central macular thickness decreased in both groups after treatment; at baseline, the mean central macular thickness was 371.06 ± 37.8 in the variable treatment regimen of subthreshold micropulse laser group and improved to 325.60 ± 110.0 μm (p = 0.025) at the end of the follow-ups, while it was 342.30 ± 35.4 in the fixed treatment regimen of subthreshold micropulse laser group and improved to 308.51 ± 67.5 (p = 0.037)., Conclusion: Both treatment regimens are effective for the treatment of mild center-involving diabetic macular edema: fixed treatment appears more suitable minimizing treatment time and reducing the possible errors due to wrong titration in the switch from continuous to micropulse mode.

Purpose: To describe the retinal findings of patients affected by pseudoxanthoma elasticum (PXE) using a multimodal imaging approach including flood-illumination adaptive optics ophthalmoscopy (AO)., Design: Retrospective case series., Materials and Methods: Patients affected by PXE were retrospectively studied. Clinical data, color, infrared and autofluorescence fundus imaging, optical coherence tomographic scans, and AO examinations were collected. Furthermore, the photoreceptor count was assessed. PXE diagnosis was confirmed by a positive skin biopsy and/or genetic testing., Results: Twenty-one eyes of 18 patients (11 females and 7 males) were included in the study. In 3 patients, both eyes were studied. The mean age at examination was 37.7 ± 16.4 years (range 14-66) and the mean best-corrected visual acuity (BCVA) was 0.1 ± 0.2 logMAR (range 0-1). We identified 3 types of angioid streaks (AS) using AO: "crack," "band," and "hypopigmented." The first 2 were very similar and they differed in size; the third type showed specific clinical features. Comet lesions appeared as hyper-reflective round lesions on AO imaging. In all eyes, the cone mosaic appeared reduced inside the streaks compared to the neighboring areas (13,532.8 ± 1,366.5 cones/mm 2 vs 16,817.1 ± 1,263.0 cones/mm 2 respectively)., Conclusion: Using AO imaging in PXE-related retinopathy, we were able to observe the presence of the photoreceptors within the angioid streaks, differentiate 3 types of angioid streaks, based on size and reflective features, and identify the very small crystalline bodies not identifiable using other retinal imaging techniques., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To describe clinical and genetic features in a series of Italian patients with sector retinitis pigmentosa (sector RP)., Methods: Fifteen patients with sector RP were selected from the database of Hereditary Retinal Degenerations Referring Center of Careggi Hospital (Florence, Italy). Eleven patients from five independent pedigrees underwent genetic analysis with next-generation sequencing (NGS) confirmed with Sanger sequencing. The diagnosis of sector RP was based on the detection of topographically limited retinal abnormalities consistent with corresponding sectorial visual field defects. Best-corrected visual acuity (BCVA), fundus color pictures as well as fundus autofluorescence (FAF), spectral domain-optical coherence tomography (SD-OCT), full-field electroretinography (ERG), and 30-2 Humphrey visual field (VF) data were retrospectively collected and analyzed., Results: For the 30 eyes, the mean BCVA was 0.05 ± 0.13 logMAR, and the mean refractive error was -0.52 ± 1.89 D. The inferior retina was the most affected sector (86.7%), and the VF defect corresponded to the affected sector. FAF showed a demarcation line of increased autofluorescence between the healthy and affected retina, corresponding on SD-OCT to an interruption of the ellipsoid zone (EZ) band in the diseased retina. Dark-adapted ERG amplitudes were decreased in comparison to normative values. In five unrelated families, the sector RP phenotype was associated with sequence variants in the RHO gene. The same mutation c.568G>A p.(Asp190Asn) was found in nine patients of four families., Conclusions: Typical sector RP is a mild form of RP characterized by preserved visual acuity with limited retinal involvement and, generally, a more favorable prognosis than other forms of RP., (Copyright © 2021 Molecular Vision.)

Purpose: We aimed to develop indicators based on electronic administrative data to compare treatment intensity at a hospital level in Tuscany, Italy., Methods: Data from 3 university hospitals (UHs), 11 local hospitals (LHs) and 2 private hospitals were analysed. Patients newly treated with an intravitreal injection were followed up for 365 days. Indicator #1 concerned hospitals with >80% of injections linked to a drug and patients with all injections linked to a drug. Indicator #2 included patients who received ⩾3 injections during the first 90 days, regardless of injection-drug linkage., Results: Indicator #1 was computed on four hospitals and included 3210 patients (48.3%). The average number of injections was 3.24 in the largest UH1. Compared to the latter, indicator #1 was significantly lower in UH2 and UH3 (-0.47 and -0.58, respectively; p   <  0.001). Indicator #2 was computed on all hospitals and included 2789 patients (41.9%). UH1 delivered about 4.33 injections. Compared to the latter, LH4 delivered +0.62 injections ( p   <  0.001) and nine other hospitals delivered between -0.22 and -0.94 injections ( p   <  0.05)., Conclusion: The two indicators proved to have the potential for supporting clinicians and policy makers in promoting the appropriate treatment intensity with intravitreal anti-vascular endothelial growth factor drugs.

Purpose: To evaluate the effect of photodynamic therapy and/or intravitreal injections on choroidal neovascularization in treatment-naïve patients affected by Best Macular Dystrophy using OCT-A., Materials and Methods: BMD patients with CNV treated using PDT and/or IV were included in the study. All patients underwent a complete ophthalmological examination, OCT and 3 × 3 mm OCT-A. The OCT-A images were analyzed using an open-source software (ImageJ) to assess the CNV membrane area (CNV-MA), the CNV vessel area (CNV-VA), and vessel density (VD) at the follow-ups (3 months after PDT and 1 month after IV)., Results: Five eyes of four patients with CNV were included. All eyes received PDT as first-line therapy; 4 eyes underwent more than 1 treatment session: three eyes received 1 IV, whereas one eye had one further PDT. After PDT, the CNV-MA, CNV-VA, and VD quantitative parameters were obtained for four out of five eyes: in three eyes of two patients CNV-MA, CNV-VA, and VD first decreased and then gradually increased during follow-up, whereas in one eye of one patient CNV-MA, CNV-VA, and VD slightly increased. After IV the CNV-MA, CNV-VA, and VD had significantly decreased at the 1-month follow-up in three eyes of three patients., Conclusion: OCT-A is an important tool for the diagnosis of both naïve and fibrotic CNV in BMD patients; it is a non-invasive method for the qualitative and quantitative analysis of neovascular lesions during follow-up. Our results have shown a cyclic remodeling of treated CNV in BMD patients using both PDT and IV.

Purpose: To evaluate circulating endothelial and circulating progenitor cells as biomarkers in age-related macular degeneration patients (both exudative and atrophic forms) in order to establish the possible clinical implication of their assessment., Methods: We have enrolled 44 age-related macular degeneration patients: 22 patients with a recently diagnosed exudative (neovascular) form (Group A) and 22 patients with an atrophic (dry) form (Group B). The control group consisted of 22 age and sex-matched healthy subjects (Group C). The number of circulating endothelial progenitor cells (CD34+/KDR+, CD133+/KDR+, and CD34+/KDR+/CD133+), circulating progenitor cells (CD34+, CD133+, and CD34+/CD133+), and circulating endothelial cells were determined in the peripheral venous blood samples by flow cytometry. Neovascular age-related macular degeneration patients were evaluated at baseline and 4 weeks after a loading phase of three consequent intravitreal injections of ranibizumab., Results: Comparing age-related macular degeneration patients with the control group, endothelial progenitor cell and circulating progenitor cell levels were not significantly different, while age-related macular degeneration patients showed significantly higher levels of circulating endothelial cells ( p = 0.001). Anti-vascular endothelial growth factor treatment with intravitreal ranibizumab was associated with a significant reduction of endothelial progenitor cell levels, with no significant influence on circulating progenitor cells and circulating endothelial cells., Conclusion: We reported higher levels of circulating endothelial cells in age-related macular degeneration patients in comparison with the control group, thereby supporting the hypothesis of an involvement of endothelial dysregulation in the age-related macular degeneration and a reduction of the endothelial progenitor cell level in neovascular age-related macular degeneration patients after three intravitreal injections of ranibizumab.