First in man study of intravitreal tripeptidyl peptidase 1 for CLN2 retinopathy.

BACKGROUND/OBJECTIVES: CLN2 Batten Disease is a fatal neurodegenerative condition of childhood associated with retinal dystrophy and blindness. Intracerebroventricular infusion of rhTPP1 greatly slows the rate of neurodegenerative decline but not retinopathy. Intravitreal rhTPP1 is known to slow retinal degeneration in a canine model of CLN2. We report a first-in-man controlled clinical trial of intravitreal rhTPP1 for CLN2 associated retinal dystrophy. SUBJECTS/METHODS: 8 children aged 5-9 with CLN2 Batten Disease were prospectively enroled. Severely affected patients were preferentially selected, provided that vision was better than no perception of light. Children underwent 8 weekly intravitreal injections of rhTPP1 (0.2 mg in 0.05 ml) into the right eye for 12-18 months. The left eye was untreated and acts as a paired control. The primary outcome was safety based on the clinical detection of complications. A secondary outcome was paracentral macular volume (PMV) measured by spectral domain OCT. Linear regression/paired t tests were used to compare rates of decline. RESULTS: No severe adverse reactions (uveitis, raised IOP, media opacity) occurred. The mean baseline PMV was 1.28 mm3(right), 1.27 mm3(left). 3 of the youngest patients exhibited bilateral progressive retinal thinning (p < 0.05), whereas retinal volume was stable in the remaining 5 patients. In the 3 patients undergoing retinal degeneration, the rate of PMV loss was slower in the treated vs. untreated eye (p = 0.000042, p = 0.0011, p = 0.00022). CONCLUSIONS: Intravitreal rhTPP1 appears to be a safe and effective treatment for CLN2 related retinopathy however commencement of treatment early in the course of disease is more likely to be efficacious.

Protocol for the treatment of cystoid macular edema secondary to retinitis pigmentosa and other inherited retinal dystrophies.

Inherited retinal dystrophies (IRD) are the leading cause of legal blindness in the working population. Cystic macular edema (CME) is one of the treatable causes of visual loss, affecting up to 50% of the patients. A bibliographic review has been carried out combining "inherited retinal dystrophy", "retinitis pigmentosa", "macular oedema" and a diagnostic-therapeutic protocol according to the levels of evidence and recommendations of the "US Agency for Healthcare Research and Quality". This protocol has been discussed in the monthly meetings of the XAREA DHR group with the participation of more than 25 ophthalmologists, creating a consensus document. The etiology of CME is multifactorial: dysfunction of the blood-retinal barrier, retinal pigment epithelium, and Müller cells, inflammation, and vitreous traction. OCT is the test of choice for the diagnosis and follow-up of CME associated with IRD. The drugs with the highest degree of scientific evidence are carbonic anhydrase inhibitors (IAC). Intravitreal corticosteroids, anti-VEGF, and vitrectomy with peeling of the internal limiting membrane do not have sufficient evidence. A treatment scheme is proposed for the CME in IRD in adults, another for pediatric patients and another for IRD and cataract surgery. Oral and topical IACs are effective in the treatment of CME secondary to IRD. Treatment with corticosteroids, anti-VEGF, and vitrectomy are second-line options. Randomized clinical trials are required to establish the therapeutic scale in these patients.

NOTCH2NLC mutation-positive neuronal intranuclear inclusion disease with retinal dystrophy: A case report and literature review.

INTRODUCTION: Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that produces a broad spectrum of clinical conditions such as dementia, upper motor neuron involvement, extrapyramidal symptoms, and neuropathy. Some studies have reported ophthalmological conditions associated with the disease; however, the details of these conditions remain unclear. PATIENT CONCERNS: We report a 63-year-old Japanese female with cognitive decline, blurred vision, photophobia, and color blindness at 52 years of age who was diagnosed with cone dystrophy. She also had anxiety, insomnia, depression, delusions, hallucinations, a wide-based gait with short steps, and urinary incontinence. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Magnetic resonance imaging revealed diffuse cerebral white matter changes and subcortical hyperintensity on diffusion-weighted imaging. Skin biopsy showed p62-positive intranuclear inclusions in sweat glands. NOTCH2NLC gene analysis revealed abnormal GGC expansion; therefore, NIID was diagnosed. CONCLUSION: NOTCH2NLC mutation-positive NIID may be associated with retinal dystrophy. Brain magnetic resonance imaging and skin biopsy are helpful diagnostic clues, and gene analysis is crucial for accurate diagnosis and appropriate management.

Is RPGR-related retinal dystrophy associated with systemic disease? A case series.

BACKGROUND: Ciliopathies responsible for retinitis pigmentosa can also cause systemic manifestations. RPGR is a ciliary gene and pathogenic variants in RPGR cause a retinal ciliopathy, the commonest cause of X-linked recessive retinitis pigmentosa. The RPGR protein interacts with numerous other ciliary proteins present in the transition zone of both motile and sensory cilia, and may play an important role in regulating ciliary protein transport. There has been a growing, putative association of RPGR variants with systemic ciliopathies: mainly sino-respiratory infections and primary ciliary dyskinesia. MATERIALS AND METHODS: Retrospective case series of patients with RPGR-RP presenting to Oxford Eye Hospital with systemic disease. RESULTS: We report three children with RPGR-related rod-cone dystrophy, all of whom have mutations in the N-terminus of RPGR. Two cases co-presented with confirmed diagnoses of primary ciliary dyskinesia and one case with multiple sino-respiratory symptoms strongly suggestive of primary ciliary dyskinesia. These and all previously reported RPGR co-pathologies relate to ciliopathies and have no other systemic associations. CONCLUSIONS: The link between RPGR variants and a systemic ciliopathy remains plausible, but currently unproven.

Childhood blindness incidence and aetiologies trends in Israel 2014-2020: what should we focus on?

OBJECTIVES: Analyse trends in incidence and aetiologies of childhood blindness (CHB) in Israel during 2014-2020, with comparison to the previous decade. METHODS: Descriptive, retrospective population-based trend study using Poisson regression. Data retrieved from the Israeli National Registry of the Blind included demographics, registration-years, and aetiologies. Primary and secondary outcomes were incidence of new certified blindness cases and its comparison with the previous decade, respectively. RESULTS: In total, 4.19 new CHB certificates per 100,000 were issued in Israel during 2014-2020, with a slight non-significant increase (p = 0.31). Males and younger children had higher incidence rates (p = 0.0008 and p = 0.0002, respectively). Leading causes were optic nerve anomalies (ONA), retinal dystrophies (RDYS), other retinal disorders (ORD) and cerebral visual impairment (CVI) (16.9%, 15.1%, 12.4% and 10.5%, respectively). Compared with the previous decade: ONA rates remained unchanged (p = 0.13) as did some other main aetiologies (i.e., albinism, CVI and nystagmus), while rates of RDYS and ORD increased (by 21.9%, p = 0.001 and 9.9% p = 0.02, respectively). Rates of retinopathy of prematurity (ROP), glaucoma, cataract and amblyopia remained very low (weighted average of 0.15, 0.14, 0.09 and 0.03 per 100,000, respectively). CONCLUSIONS: The incidence of CHB certifications in Israel remained stable with a slight increase, stemming chiefly from RDYS resurgence and an increase in ORD. Main causes remained ONA and RDYS. The most common avoidable cause, ROP, remained scarce, maintaining the reduction seen in the earlier decade, as did cataract, glaucoma, and amblyopia. This may support future nationwide prevention policies to decrease the incidence of RDYS and ORD.

Cystoid macular oedema without leakage in fluorescein angiography: a literature review.

Cystoid macular oedema (CMO), which is defined as a macular thickening and cystic changes due to accumulation of fluid, could be asymptomatic and only diagnosed using paraclinical techniques. Fluorescein angiography (FA) and optical coherence tomography (OCT) are useful in detecting CMO in clinical practice. Non-leaking CMO, also known as angiographically silent CMO, is referred to as cases of CMO without leakage in fluorescein angiography. This type of CMO has been reported in some retinal dystrophies, in cases of maculopathy as a side effect of certain drugs, and also in some systemic disorders. The exact mechanism and treatment options for this type of CMO are still not clear. This literature review aims to discuss different causes of non-leaking CMO, proposed mechanisms, and management options. Three sections including drugs, retinal dystrophies, and systemic disorders are discussed in this review.

Idiopathic intracranial hypertension in a child with Bardet-Biedl syndrome.

BACKGROUND: Bardet-Biedl syndrome (BBS) is known to be associated with hydrocephalus, but not with idiopathic intracranial hypertension (IIH). Case presentation: We describe such a case and propose the pathogenesis. We also discuss the challenges of diagnosis, treatment, and monitoring outcomes in this population that is already at high risk of vision loss from retinal dystrophy. CONCLUSION: IIH can result from a combination of risk factors in conjunction with the underlying dysfunctional cilia in BBS patients. Monitoring disease progression is difficult, and as such IIH may be underdiagnosed or missed. Management must be adjusted to account for BBS patients' impaired metabolic and renal physiology. It is important that clinicians be aware of these challenges in this vulnerable population, and regular monitoring should be done to avoid preventable vision loss.

Amyotrophic lateral sclerosis associated with a pathological expansion in the ATXN7 gene.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant hereditary neurodegenerative disease caused by the expansion of a CAG-repeat in the ataxin-7 (ATXN7) gene, usually characterized by progressive cerebellar ataxia and retinal dystrophy. We report the case of a 45-year-old woman presenting with a rapid-onset amyotrophic lateral sclerosis (ALS) phenotype associated with a 39-CAG-repeat expansion in ATXN7. This patient had neither ataxia nor retinal dystrophy, but she had an oculomotor cerebellar syndrome and a family history suggestive of SCA7. In SCA7, shorter expansions may be associated with less severe and incomplete clinical phenotypes, which could explain the patient's phenotype. Unknown genetic and environmental factors may also influence the patient's phenotype. We suggest that a pathological expansion in ATXN7 should be considered in cases of ALS-like phenotype, particularly when associated with oculomotor abnormalities or a family history of ataxia or blindness.

Long-term follow-up of a case of choroidal neovascularization secondary to reticular pigmentary retinal dystrophy / Seguimento de longo-prazo de um caso de neovascularização de coroide secundária à distrofia reticular pigmentar da retina

ABSTRACT Reticular pigmentary retinal dystrophy, also known as Sjögren's reticular dystrophy, is a rare condition characterized by macular lesions with a reticular pattern, which are best seen on fluorescein angiogram. Choroidal neovascularization secondary to this type of dystrophy is even less common. This report describes a case of reticular pigmentary retinal dystrophy with vision loss due to neovascular membrane, which responded well to treatment with anti-vascular endothelial growth factor.

RESUMO A distrofia reticular pigmentar da retina, também conhecida como distrofia reticular de Sjögren, é uma doença rara, caracterizada por lesões maculares com um padrão reticular, que são mais bem visualizadas na angiografia com fluoresceína. A neovascularização de coroide secundária a este tipo de distrofia é ainda menos comum. Este relato descreve um caso de distrofia reticular pigmentar da retina, com perda de visão devido à membrana neovascular, que respondeu bem ao tratamento com fator de crescimento endotelial antivascular.

Distrofia macular en patrón unilateral y enfermedad sistémica asociada / Unilateral pattern of macular dystrophy and associated systemic pathology

Las distrofias en patrón de la retina son un grupo heterogéneo de maculopatías, en general, bilaterales y simétricas, que curiosamente se pueden asociar a diferentes enfermedades sistémicas. En este artículo se describe el caso de una paciente con distrofia en patrón unilateral que presentó asociada enfermedad de McArdle y fibrosis pulmonar idiopática

Retinal pattern dystrophies are a heterogeneous group of generally bilateral and symmetrical maculopathies that, curiously, can be associated with different systemic diseases. This article describes a patient with unilateral pattern dystrophies, as well as associated McArdle disease and idiopathic pulmonary fibrosis

A diagnostic approach to syndromic retinal dystrophies with intellectual disability.

Inherited retinal dystrophies are a group of monogenic disorders that, as a whole, contribute significantly to the burden of ocular disease in both pediatric and adult patients. In their syndromic forms, retinal dystrophies can be observed in association with intellectual disability, frequently alongside other systemic manifestations. There are now over 80 genes implicated in syndromic retinal dystrophies with intellectual disability. Identifying and accurately characterizing these disorders allows the clinician to narrow the differential diagnosis, evaluate for relevant associated features, arrive at a timely and accurate diagnosis, and address both sight-threatening ocular manifestations and morbidity-causing systemic manifestations. The co-occurrence of retinal dystrophy and intellectual disability in an individual can be challenging to investigate, diagnose, and counsel given the considerable phenotypic and genotypic heterogeneity that exists within this broad group of disorders. We performed a review of the current literature and propose an algorithm to facilitate the evaluation, and clinical and mechanistic classification, of these individuals.

CRB1-related retinopathy overlapping the ocular phenotype of S-adenosylhomocysteine hydrolase deficiency.

BACKGROUND: S-adenosylhomocysteine hydrolase deficiency due to pathologic variants in AHCY gene is a rare neurometabolic disease for which no eye phenotype has been documented. Pathologic variants in CRB1 gene are known to cause a wide spectrum of autosomal recessive retinal diseases with Leber's congenital amaurosis as a most common. The aim of this study is to report co-inheritance of neurometabolic disease and eye disease in a pedigree. MATERIALS AND METHODS: Comprehensive eye examination was performed in available family members together with color vision test, visual fields, fundus images, OCT, electroretinogram and visual evoked potentials. Genetic testing included whole-exome sequencing (WES), retinal dystrophy gene panel and segregation analysis. RESULTS: Two children from a family not known to be consanguineous were affected with neurometabolic disease and one of them presented with reduced vision due to maculopathy. The mother had symptoms of retinal degeneration of unspecified cause. Clinical WES revealed homozygous missense pathologic variants in AHCY gene c.148G>A, p.(Ala50Thr) as a cause of S-adenosylhomocysteine hydrolase deficiency. Retinal dystrophy gene panel sequencing revealed two heterozygous missense pathologic variants in CRB1 gene c.1831T>C, p.(Ser611Pro) and c.3955T>C, p.(Phe1319Leu) in the proband and her mother. These variants segregated with disease phenotype in family members. CONCLUSIONS: Establishing an ocular genetic diagnosis may be challenging with the co-existence of a rare systemic genetic disease with previously unknown eye involvement. Extensive phenotyping and genotyping of available family members showed that the proband and her mother shared a CRB1-related retinopathy at different stages while the brother did not.

Anti-VEGF and Retinal Dystrophies.

The therapeutic approach based on anti-vascular endothelial growth factor (anti-VEGF) molecules can be used to treat two important complications of retinal dystrophies: choroidal neovascularization and macular edema. The macular involvement in retinal dystrophies can lead to further visual deterioration in patients at a young age and already affected by functional limitations. The study reports the effect of anti-VEGF treatment in several subforms of retinal dystrophies, critically discussing advantages and limitations.

Retinal dystrophy associated with a Kizuna (KIZ) mutation and a predominantly macular phenotype.

Introduction: Mutations in Kizuna (KIZ), a gene involved in ciliary function, have been previously associated with rod-cone dystrophy with relative macular sparing and a number of other systemic abnormalities.Purpose: We present a patient with a phenotype dominated by retinal dystrophy and macular cysts as a result of a homozygous nonsense mutation in KIZ.Methods: A 32-year-old female of Ashkenazi Jewish ancestry presented with progressive central vision loss and peripheral visual field loss following decades of night-blindness. She was noted to have a bull's-eye pattern of macular hyper-autofluorescence, intraretinal cystoid macular changes and outer retinal atrophy in both eyes. Visual fields were constricted to <10 degrees centrally with inferior preserved islands of vision. Genetic testing revealed a homozygous KIZ c.226 C > T (p.Arg76*) nonsense mutation. The patient was treated with topical dorzolamide and showed significant improvement in the degree of macular cysts.Conclusion: Mutations in KIZ can present with a predominantly macular phenotype and develop cystoid macular changes responsive to carbonic anhydrase inhibitor treatment. Because of the importance of KIZ in cilia function, it is critical to look for associated systemic manifestations to ensure best patient care.

Danon disease presenting with early onset of hypertrophic cardiomyopathy and peripheral pigmentary retinal dystrophy in a female with a de novo novel mosaic mutation in the LAMP2 gene.

Purpose: To describe the phenotype and genotype in a young woman with Danon disease. Methods: The patient underwent an ophthalmic examination including best corrected visual acuity (BCVA), fundus photography and fundus autofluorescence (FAF), full-field electroretinography (full-field ERG), multifocal ERG, optical coherence tomography (OCT) and SAP-Humphrey 30-2 at the ages of 20 and 25. Electrooculography, fluorescein angiography (FA), indocyanine angiography and OCT angiography were performed only once. Genetic testing using a Next-Generation Sequencing panel and immunohistochemical analysis of LAMP2 protein expression were performed in the patient's explanted heart, and the patient's cardiologic and ophthalmologic records were retrospectively reviewed. Results: A de novo, novel, mosaic mutation, c.135dupA; p.(Trp46Metfs*10) was identified in exon 2 of the LAMP2 gene. Immunohistochemical investigation of the myocardium in the explanted heart revealed pronounced deficiency of LAMP2 protein in cardiomyocytes. The color photographs, FAF images and FA revealed more extensive peripheral pigmentary retinal dystrophy (PPRD) at the 5-year follow-up examination. No changes were observed in BCVA, OCT, SAP-Humphrey 30-2 or multifocal ERG findings at follow-up. Full-field ERG showed an asymmetric interocular reduction in ERG response at follow-up: the b-wave amplitude of the rod response had decreased by 29% in the right eye, but by only 6 % in the left eye. The a-wave amplitude of single-flash response had decreased by 9 % in the left eye, while it had increased by 3% in the right eye. Conclusions: Although PPRD progressed slowly, it was an important clue in the diagnosis of the life-threatening condition of Danon disease.

Los cambios estructurales de la retina, ¿nuevos biomarcadores de los trastornos mentales? Una revisión sistemática y síntesis temática de la literatura / Could structural changes in the retinal layers be a new biomarker of mental disorders? A systematic review and thematic synthesis

Recientemente se ha planteado que las alteraciones de las capas de la retina podrían ser un biomarcador de determinados trastornos mentales, al derivar esta de la misma capa embrionaria que el cerebro y estar conectada con este a través del nervio óptico. El objeto del presente artículo es ofrecer una revisión sistemática de la literatura y una síntesis temática sobre el estado actual de las alteraciones de las capas de la retina identificadas mediante tomografía de coherencia óptica en los pacientes con esquizofrenia, trastorno bipolar y depresión mayor. Para ello se realizó una búsqueda sistemática de la literatura, la lectura crítica de los artículos seleccionados y la síntesis temática de los resultados. Los pacientes con esquizofrenia son los que presentan más alteraciones, seguidos de los pacientes con trastorno bipolar, siendo muy escasos los hallazgos en la depresión. La capa de fibras nerviosas de la retina es la capa retiniana con más alteraciones en la esquizofrenia y en el trastorno bipolar, mientras que ningún estudio en depresión mayor encontró alteraciones en ella. De los parámetros clínicos, la duración de la enfermedad correlaciona significativa e inversamente con el grosor de las distintas capas en todos los trastornos. A la hora de interpretar estos datos es necesario tener en cuenta las limitaciones y diferencias de los estudios, especialmente el tiempo medio de evolución de los trastornos. Dado que este era muy diferente entre los 3 trastornos (más del doble en el caso de la esquizofrenia respecto a la depresión mayor), las diferencias en los resultados encontrados podrían deberse más al efecto del tiempo de evolución que al trastorno en sí. En conclusión, los hallazgos de la tomografía de coherencia óptica son esperanzadores, ya que podrían proporcionar biomarcadores de la neurodegeneración y/o neuroprogresión tanto de la esquizofrenia como del trastorno bipolar

It has recently been suggested that alterations of the layers of the retina could be a biomarker of specific mental disorders since they originate in the same embryonic layer as the brain and both are interconnected through the optic nerve. The purpose of this article is to offer a systematic review of the literature and a thematic synthesis on the current state of the alterations of the retina layers identified by optical coherence tomography in patients with schizophrenia, bipolar disorder and major depression. For this purpose, we performed a bibliographic search, a systematic review of the studies and a thematic synthesis of the reported findings. Patients with schizophrenia have more abnormal findings followed by patients with bipolar disorder, with very few findings in depression. The nerve fiber layer is the retinal layer with more abnormal findings both in schizophrenia and in bipolar disorder, while no study in major depression found alterations in it. Of the clinical parameters, the duration of the illness correlates significantly and inversely with the thickness of the different layers in all disorders. When interpreting these data, it is necessary to take into account the limitations and differences of the studies, especially the mean length of the disorders. Given that this was very different among the 3 disorders (more than doubled in the case of schizophrenia respect to major depression), the differences in the results found could be due more to the effect of the length of illness than to the disorder itself. In summary, optical coherence tomography findings are promising, since they could provide biomarkers of neurodegeneration and/or neuroprogression of both schizophrenia and bipolar disorder

Anti-VEGF treatment for choroidal neovascularization complicating pattern dystrophy-like deposit associated with pseudoxanthoma elasticum.

PURPOSE: To evaluate the efficacy of intravitreal anti-VEGF injections in choroidal neovascularization (CNV) related to pattern dystrophy-like deposit in pseudoxanthoma elasticum (PXE). METHODS: One-year prospective, interventional study. Nine eyes were recruited in the ophthalmology departments of San Raffaele University and University of Barcelona. Each patient underwent best corrected visual acuity (BCVA) measurement on ETDRS chart, slit-lamp biomicroscopy, fluorescein angiography (FA), indocyanine green angiography (ICGA), and optical coherence tomography (OCT). The protocol included a first anti-VEGF injection, followed by monthly evaluations with re-treatments based on new funduscopic hemorrhages, fluid on OCT or leakage on FA and/or ICGA. Primary outcome measures were the mean BCVA changes. Secondary outcomes included central macular thickness (CMT) variations and the number of injections needed. RESULTS: At month 12, mean BCVA significantly improved from 20/45 to 20/35 Snellen equivalent, with 3 eyes gaining at least 3 ETDRS lines. Mean CMT decreased from 297 ± 22 to 262 ± 13 µm, after 5.5 ± 4.0 injections. No leakage was observed at the end of follow-up. CONCLUSIONS: Intravitreal anti-VEGF injections represent an effective treatment for CNV related to pattern dystrophy-like deposit in PXE, with an improvement of BCVA and CMT. Mean injection number is in line with other studies performed in CNV secondary to angioid streaks.