Broadening the ocular phenotypic spectrum of ultra-rare BRPF1 variants: report of two cases.

INTRODUCTION: BRPF1 gene on 3p26-p25 encodes a protein involved in epigenetic regulation, through interaction with histone H3 lysine acetyltransferases KAT6A and KAT6B of the MYST family. Heterozygous pathogenic variants in BRPF1 gene are associated with Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP), characterized by global developmental delay, intellectual disability, language delay, and dysmorphic facial features. The reported ocular involvement includes strabismus, amblyopia, and refraction errors. This report describes a novel ocular finding in patients affected by variants in the BRPF1 gene. METHODS: We performed exome sequencing and deep ocular phenotyping in two unrelated patients (P1, P2) with mild intellectual disability, ptosis, and typical facies. RESULTS: Interestingly, P1 had a Chiari Malformation type I and a subclinical optic neuropathy, which could not be explained by variations in other genes. Having detected a peculiar ocular phenotype in P1, we suggested optical coherence tomography (OCT) for P2; such an exam also detected bilateral subclinical optic neuropathy in this case. DISCUSSION: To date, only a few patients with BRPF1 variants have been described, and none were reported to have optic neuropathy. Since subclinical optic nerve alterations can go easily undetected, our experience highlights the importance of a more detailed ophthalmologic evaluation in patients with BRPF1 variant.

Childhood Chronic Idiopathic Uveitis in a Multicentre International Cohort.

IMPORTANCE: Idiopathic uveitis makes up around 50% of non-infectious uveitis but the clinical characteristics in children are poorly understood. OBJECTIVE: To report the demographic, clinical characteristics, and outcomes of children with idiopathic non-infectious uveitis (iNIU) in a multicentric retrospective study. RESULTS: There were 126 (61 female) children with iNIU. The median age at diagnosis was 9.3 years (3-16 years) . Uveitis was bilateral in 106 patients and anterior in 68.At onset,impaired visual acuity and blindness in the worse eye were reported, in 24.4% and 15.1% patients but at 3 years of follow-up, there was a significant improvement in visual acuity (mean 0.11 SD ±0.50 vs 0.42 SD ± 0.59 p < .001). CONCLUSIONS AND RELEVANCE: There is a high rate of visual impairment at presentation in children with idiopathic uveitis. The majority of patients have a significant improvement in vision, but 1 in 6 had impaired vision or blindness in their worse eye at 3 years.

This is a large retrospective study of children with chronic idiopathic uveitis,There is a high rate of visual impairment at presentation in children with idiopathic uveitis. Although visual acuity improves during follow-up, one in six still had impaired vision or blindness in their worse eye at 3 years.At 3 years, more than half of patients were on immunosuppression and one-third were on a biologic agent.

Efficacy of a Cationic Emulsion of Cyclosporine in Moderate Vernal Keratoconjunctivitis.

PURPOSE: The aim of this study was to demonstrate the efficacy of cyclosporine A 0.1% cationic emulsion (CsA CE) eye drops 4 times a day in pediatric patients affected by a moderate form of vernal keratoconjunctivitis (VKC). METHODS: This was a prospective study of pediatric patients, aged 5-16 years, with an active moderate form of VKC who were poor responders to topical antihistamines treatment and were treated 4 times a day with CsA CE. The clinical signs were graded for analysis as follows: hyperemia, tarsal papillae, and limbal papillae. RESULTS: Twenty-eight patients (22 males and 6 females) with a minimum follow-up period of 3 months were included in the analysis. Statistical analysis excluded tarsal papillae because of the very low baseline value. The clinical score of hyperemia and limbal papillae improved from the first evaluation and was maintained over the follow-up. No side effects were noted. CONCLUSION: CsA CE has been proposed as a treatment for severe forms of VKC. This study has shown that administration 4 times a day is also effective in the treatment of moderate forms of VKC in children.

The New Era of Therapeutic Strategies for the Treatment of Retinitis Pigmentosa: A Narrative Review of Pathomolecular Mechanisms for the Development of Cell-Based Therapies.

Retinitis pigmentosa, defined more properly as cone-rod dystrophy, is a paradigm of inherited diffuse retinal dystrophies, one of the rare diseases with the highest prevalence in the worldwide population and one of the main causes of low vision in the pediatric and elderly age groups. Advancements in and the understanding of molecular biology and gene-editing technologies have raised interest in laying the foundation for new therapeutic strategies for rare diseases. As a consequence, new possibilities for clinicians and patients are arising due to the feasibility of treating such a devastating disorder, reducing its complications. The scope of this review focuses on the pathomolecular mechanisms underlying RP better to understand the prospects of its treatment using innovative approaches.

A multidisciplinary approach to inherited retinal dystrophies from diagnosis to initial care: a narrative review with inputs from clinical practice.

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.

Challenges and management of childhood noninfectious chronic uveitis.

INTRODUCTION: Childhood uveitis is a sight-threatening condition, because if not properly recognized and treated can lead to several ocular complications and blindness. It represents a real challenge not only from an etiologic/diagnostic point of view, but also for management and therapy. AREAS COVERED: In this review we will discuss the main etiologies, the diagnostic approach, risk factors associated to childhood noninfectious uveitis (cNIU), and the difficulties in eye examination in childhood. Moreover, we will discuss the treatment of cNIU in terms of therapeutic choice, timing of initiation, and withdrawal. EXPERT OPINION: Identification of specific diagnosis is mandatory to prevent severe complications, thus a thorough differential diagnosis is essential. Pediatric eye examination may be extremely challenging due to the scarce collaboration, but novel techniques and biomarkers will help in identifying low grade of inflammation, eventually modifying long-term outcomes. Once identified the appropriate diagnosis, recognition of children who may benefit of a systemic treatment is crucial. What, When, and how long are the key questions to address in this field. Current evidence and future results of ongoing clinical trials will help in driving treatment. A proper ocular screening, not only in the context of systemic disease, should be discussed by experts.

Long-term effects of early/late-onset visual deprivation on macular and retinal nerve fibers layer structure: A pilot study.

BACKGROUND/AIMS: Tomographic analysis of macular and peripapillary retinal nerve fibers layer (RNFL) thickness in patients with history of congenital (CC) and developmental cataract (DC). METHODS: Analysis of macular and RNFL thickness using a spectral-domain optical coherence tomography was performed. Retinal layers thickness was measured using the internal segmentation software. Measurements of affected (unilateral and bilateral), contralateral eyes and control eyes were compared. RESULTS: Patients with history of CC or DC (n = 13 and 11 respectively) and 35 healthy control subjects were enrolled. Thicker inner and outer nuclear layers (INL, ONL) and thicker ONL were found when CC and DC group when compared to controls respectively. Bilateral CC showed the most relevant differences. Slight thickening of CC inner retinal layers were found when compared to DC. Increased superonasal RNFL thickness was found in CC group when compared to DC and controls. Thickening of RNFL of contralateral unaffected eyes of unilateral CC were found when compared to controls. CONCLUSION: Significant macular and RNFL thickness changes between CC, DC patients and controls that partially involve also contralateral unaffected eyes of unilateral congenital cataract were found. CC and DC groups show significant differences only in inner retinal layers thickness. Our data suggest that early visual deprivation may influence retinal arrangements occurring during development involving predominantly the outer nuclear layer and para/perifoveal inner retinal layers, and confirm that early treatment of CC allow to achieve better long-term visual outcome. Moreover functional and structural data support the hypothesis that unilateral amblyopia is not exclusively an unilateral issue.

Acute Rejection Following COVID-19 Vaccination in Penetrating Keratoplasty in a Young Male - A Case Report and Review of Literature.

PURPOSE: To report a case of a boy with acute keratoplasty rejection manifesting 12 days after receiving BNT162b2 messenger RNA (mRNA) vaccine for COVID-19. STUDY DESIGN: A case report. RESULTS: A 15-year-old boy with a history of penetrating keratoplasty due to acanthamoeba keratitis developed corneal decompensation 12 days after BNT162b2 messenger RNA vaccine for COVID-19 disease. One-week treatment with topical Dexamethasone 2% eye drops resulted in a complete resolution of corneal edema. CONCLUSIONS: This case suggests that BNT162b2 messenger RNA (mRNA) vaccine can be associated with acute keratoplasty rejection in children, which responds completely to topical steroids. Ophthalmologists should be aware of this risk of cornea decompensation after COVID-19 vaccine in children who received a cornea transplant.

Optic nerve involvement in CACNA1F-related disease: observations from a multicentric case series.

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.

Efficacy and safety of intraoperative use of tropicamide 0.02%/phenylephrine0.31%/lidocaine1% intracameral combination during pediatric cataract surgery.

BACKGROUND: To demonstrate the safety and efficacy of the intracameral use of tropicamide 0.02%/phenylephrine 0.31%/lidocaine 1% in pediatric cataract surgery, a combination widely used in adult patients but still off-label in children. METHODS: Design: two-center, prospective, observational study. SETTING: San Giuseppe Hospital, Milan and Meyer Children's Hospital, Florence. STUDY POPULATION: children from 0 to 4 years of age undergoing cataract surgery with or without intraocular IOL implantation, in the absence of clinically significant systemic conditions, history of ocular surgery, concurrent ocular medication, hypersensitivity to any of the substances and post-traumatic cataracts. During the surgery, patients received the combination drug after the primary access to the anterior chamber. Efficacy was evaluated by achieving an adequate mydriasis in order to perform capsulorhexis, while safety was assessed by recording vital signs (heart rate, blood pressure, respiratory rate, temperature) pre- and post-administration of the substance. RESULTS: This study included 53 surgical procedures of 36 patients: 41 eyes were left aphakic, while 12 eyes received primary IOL implantation. The pupil size was adequate to safely perform capsulorhexis in 52 procedures of 53. The difference in pupil enlargement was significant (6.0 ± 1.14 mm, P = < 0.001). There were no notable changes in vital parameters. CONCLUSIONS: The administration of intracameral tropicamide 0.02%/phenylephrine 0.31%/lidocaine 1% in pediatric cataract surgery is effective for obtaining an adequate mydriasis without any vital parameters changes throughout the procedure.

Microperimetry assessment in foveal hypoplasia: functional results in a series of pediatric patients.

OBJECTIVE: To study the relationships of functional and morphologic retinal parameters in a series of pediatric patients with varying degrees of foveal hypoplasia (FH). DESIGN: Monocentric observational retrospective study. PARTICIPANTS: Among 21 pediatric patients, 16 met inclusion criteria, having FH confirmed with spectral-domain optical coherence tomography (SD-OCT) scan METHODS: Data were analyzed retrospectively. Patients able to undergo macular microperimetry (MP) and SD-OCT examinations were included in the analysis. MP and SD-OCT outcomes were compared with FH grading and best-corrected visual acuity (BCVA) using Pearson's correlation. RESULTS: Thirty-one eyes from 16 patients (mean age 12.4 years) with different degrees of FH were analyzed. Two patients had grade 1, 7 had grade 2, 5 had grade 3, and 2 had grade 4 FH. Clinical nystagmus was present in 8 patients. The correlation between BCVA and SD-OCT data (-0.31) was lower than that found between BCVA and nystagmus (0.64), that for fixation index P1 (-0.60), as well as that for macular sensitivity (-0.63). CONCLUSIONS: Although limited by the small sample, our study confirms the feasibility of automated MP evaluation in pediatric patients with FH. The added value of this work is the provision of data on relationships between anatomic and functional macular measurements acquired with SD-OCT, MP, and BCVA in eyes with various degrees of FH. Larger prospective studies are necessary to confirm these results.

Active control of dielectric singularities in indium-tin-oxides hyperbolic metamaterials.

Dielectric singularities (DSs) constitute one of the most exotic features occurring in the effective permittivity of artificial multilayers called hyperbolic metamaterials (HMMs). Associated to DSs, a rich phenomenology arises that justifies the ever-increasing interest profuse by the photonic community in achieving an active control of their properties. As an example, the possibility to "canalize" light down to the nanoscale as well as the capability of HMMs to interact with quantum emitters, placed in their proximity, enhancing their emission rate (Purcell effect), are worth mentioning. HMMs, however, suffer of an intrinsic lack of tunability of its DSs. Several architectures have been proposed to overcome this limit and, among them, the use of graphene outstands. Graphene-based HMMs recently shown outstanding canalization capabilities achieving λ/1660 light collimation. Despite the exceptional performances promised by these structures, stacking graphene/oxide multilayers is still an experimental challenge, especially envisioning electrical gating of all the graphene layers. In this paper, we propose a valid alternative in which indium-tin-oxide (ITO) is used as an electrically tunable metal. Here we have numerically designed and analyzed an ITO/SiO2 based HMM with a tunable canalization wavelength within the range between 1.57 and 2.74 µm. The structure feature light confinement of λ/8.8 (resolution of about 178 nm), self-focusing of the light down to 0.26 µm and Purcell factor of approximately 700. The proposed HMM nanoarchitecture could be potentially used in many applications, such as ultra-fast signal processing, high harmonic generation, lab-on-a-chip nanodevices, bulk plasmonic waveguides in integrated photonic circuits and laser diode collimators.

Effect of the Combination of Gold Nanoparticles and Polyelectrolyte Layers on SERS Measurements.

In this study, polyelectrolyte (PE) layers are deposited on substrates made by glass covered with an array of gold nanoparticles (GNPs). In particular, the samples studied have 0 PE layers (GGPE0), 3 PE layers (GGPE3), 11 PE layers (GGPE11), and 21 PE layers (GGPE21). All samples have been studied by micro-Raman spectroscopy. An acetic acid solution (10% v/v) has been used as a standard solution in order to investigate the SERS effect induced by different numbers of PE layers in each sample. The Surface Enhancement Raman Spectroscopy (SERS) effect correlating to the number of PE layers deposited on the samples has been shown. This effect is explained in terms of an increase in the interaction between the photon of the laser source and the plasmonic band of the GNPs due to a change of the permittivity of the surrounding medium around the GNPs. The trends of the ratios of the intensities of the Raman bands of the acetic acid solution (acetic acid and water molecules) on the band at 1098 cm-1 ascribed to the substrates increase, and the number of PE layers increases.

Optical Coherence Tomography Significance in Managing Early Onset of Optic Pathway Gliomas in Children Younger than 5 Years of Age-A Retrospective Study.

We aimed to investigate the significance of optical coherence tomography (SD-OCT) in managing pediatric optic pathway gliomas (OPGs) in children younger than 5 years of age. A retrospective monocentric study was conducted. SD-OCT scans were obtained using the handheld iVue system to assess peripapillary retinal nerve fibre layer (pRNFL) thickness at three time points: baseline (OCT1), end of treatment (OCT2), and at last follow-up (OCT3). We compared the median value of pRNFL (and interquartile range-IQR) at different follow-up times and in different sub-groups (stable disease-SD, partial response-PR, and progression disease-PD). Thirteen children younger than 5 years of age were included. The Median follow-up time was 3.9 years (IQR 1.2). Six patients showed a pRNFL change of more than 10% during follow-up. Seven patients showed PD during follow-up. Median pRNFL at baseline was 81.5 µm (IQR 31.5); median pRNFL at the end of treatment was 73 µm (IQR 33); median pRNFL at last follow-up was 72 µm (IQR 38.5). The mean pRNFL at baseline was significantly lower than the mean normative values. Only subjects with PD showed pRNFL change close to statistical significance. This study confirms the role of SD-OCT in managing OPGs for therapeutic decisions and strategy planning of visual rehabilitation.

Expanding the Spectrum of Oculocutaneous Albinism: Does Isolated Foveal Hypoplasia Really Exist?

Oculocutaneous albinism is an autosomal recessive disorder characterized by the presence of typical ocular features, such as foveal hypoplasia, iris translucency, hypopigmented fundus oculi and reduced pigmentation of skin and hair. Albino patients can show significant clinical variability; some individuals can present with only mild depigmentation and subtle ocular changes. Here, we provide a retrospective review of the standardized clinical charts of patients firstly addressed for evaluation of foveal hypoplasia and slightly subnormal visual acuity, whose diagnosis of albinism was achieved only after extensive phenotypic and genotypic characterization. Our report corroborates the pathogenicity of the two common TYR polymorphisms p.(Arg402Gln) and p.(Ser192Tyr) when both are located in trans with a pathogenic TYR variant and aims to expand the phenotypic spectrum of albinism in order to increase the detection rate of the albino phenotype. Our data also suggest that isolated foveal hypoplasia should be considered a clinical sign instead of a definitive diagnosis of an isolated clinical entity, and we recommend deep phenotypic and molecular characterization in such patients to achieve a proper diagnosis.

Treatment of Inherited Retinal Dystrophies with Somatic Cell Therapy Medicinal Product: A Review.

Inherited retinal dystrophies and retinal degenerations related to more common diseases (i.e., age-related macular dystrophy) are a major issue and one of the main causes of low vision in pediatric and elderly age groups. Advancement and understanding in molecular biology and the possibilities raised by gene-editing techniques opened a new era for clinicians and patients due to feasible possibilities of treating disabling diseases and the reduction in their complications burden. The scope of this review is to focus on the state-of-the-art in somatic cell therapy medicinal products as the basis of new insights and possibilities to use this approach to treat rare eye diseases.

Impact of screen exposure on pediatric vernal Keratoconjunctivitis: a survey during the COVID-19 pandemic in Italy.

BACKGROUND: The SARS-CoV-2 outbreak pushed the Italian government to start a strict lockdown, replacing school attendance with long-distance learning. This caused reduced exposure to sunlight but increased exposure to screens. Vernal keratoconjunctivitis (VKC) is a chronic inflammatory ocular condition in which exposure to light plays a cardinal role. We conducted an online survey to evaluate the impact of screen exposure on children with VKC during the COVID-19 lockdown. METHODS: We performed a survey-based observational study, asking patients followed at the Allergology clinics of Meyer Children's University Hospital in Florence and of Policlinico Umberto I in Rome to provide grading on 6 subjective ocular clinical manifestations presented during the lockdown and to give an estimate of their hours/day of screen exposure. RESULTS: Mean scores of signs and symptoms increased homogeneously when studying patients exposed to longer screen time. When comparing scores collected in 2019 to those in 2020, there was not a significant reduction in clinical manifestations, although the situation differed between the two centers due to geographical differences in sunlight exposure. CONCLUSION: During the lockdown, there was a reduction in sunlight exposure but conversely an increase in the time spent in front of screens that correlated with the worsening of VKC signs and symptoms in direct proportion to the hours/day of screen exposure. Our results also showed a statistically significant difference in the relative impact of long-distance learning on VKC clinical manifestations in the different Italian regions.

Low Cost and Easy Validation Anticounterfeiting Plasmonic Tags Based on Thin Films of Metal and Dielectric.

Multilevel anticounterfeiting Physical Unclonable Function (PUF) tags based on thin film of silver (Ag), Zinc Oxide (ZnO) and PolyVinylPyrrolidone (PVP), are experimentally demonstrated and validated. We exploit the low adhesion of silver to glass and consequent degradation during ZnO deposition to induce morphological randomness. Several photographs of the tag surfaces have been collected with different illumination conditions and using two smartphones of diverse brand. The photos were analyzed using an image recognition algorithm revealing low common minutiae for different tags. Moreover, the optical response reveals peculiar spectra due to labels of plasmonic nature. The proposed systems can be easily fabricated on large areas and represent a cost-effective solution for practical protection of objects.