Retinal Appearance Research Articles

THE GENETIC BASIS OF CLINICALLY SUSPECTED ACHROMATOPSIA IN THE UNITED ARAB EMIRATES.

Achromatopsia (ACHM) is a genetically heterogenous relatively stationary congenital autosomal recessive cone disorder characterized typically by photophobia, low vision, nystagmus, hyperopia, grossly normal retinal appearance, and absent photopic responses by full-field electroretinography. Incomplete forms occur as well. This study investigates the genetic basis of clinically suspected ACHM in the United Arab Emirates. Retrospective case series (January 2016-December 2023) of patients with (1) clinically suspected ACHM or (2) mutations in ACHM-associated genes ( CNGA3 , CNGB3 , GNAT2 , PDE6C , PDE6H , AT6 ). Twenty-two clinically suspected patients (19 probands) were identified. Biallelic disease genes and the number of probands were CNGA3 (9), CNGB3 (6), PDE6C (1), GNAT2 (1), RGS9BP (1), and CNNM4 (1). Some mutant alleles were recurrent across different families. Two probands had their diagnoses revised after genetic testing and phenotypic reassessment to RGS9BP -related bradyopsia and CNNM4 -related Jalili syndrome. Three additional cases (making 22 total probands) were identified from ACHM gene mutation review-one each related to PDE6C , to AT6 , and to CNGB3 in concert with CNGA3 (triallelic disease). All three presented with macular discoloration, an atypical finding for classic ACHM. CNGA3 was the single most frequent implicated gene. Bradyopsia and Jalili syndrome can resemble incomplete ACHM. Recurrent mutant alleles may represent founder effects. Macular discoloration on presentation can occur in PDE6C -related disease, AT6 -related disease, and triallelic CNGB3 / CNGA3 -related disease. The possibility for triallelic disease exists and requires genetic counseling beyond that of simple autosomal recessive inheritance.

Genotype-phenotype severity correlation in a multicentric portuguese cohort of ABCA4-associated retinopathy

PurposeTo investigate genotype-phenotype correlations in ABCA4-associated retinopathy and further validate a recently proposed genotype-phenotype correlation model. DesignMulticentric, cross-sectional cohort study. MethodsConsecutive patients with genetically confirmed ABCA4-associated retinopathy from three Portuguese centres were included. Patients were categorized into distinct phenotype groups according to the degree of hypoautofluorescence and retinal background appearance in ultra-widefield fundus autofluorescence (UW-FAF) imaging. Genotype classification was performed using two criteria: one according to the presence of the p.Gly1961Glu variant, a hypomorphic variant, at least one moderate variant, or two biallelic severe/PVS1 variants (genotype classification A, which corresponds to the newly described criteria); and another one based on the number of null variants identified (genotype classification B). Associations between clinical data and phenotype and genotype groups were analysed. ResultsA total of 50 patients were included. Significant correlations between age of onset, best-corrected visual acuity (BCVA), and both phenotype and genotype groups were found, with patients in more severe phenotype and genotype categories exhibiting earlier disease onset and poorer visual function (p < 0.001; p < 0.001; p < 0.001; p < 0.001, p < 0.001; and p = 0.004, respectively). Genotype classification A better predicted phenotype severity on UW-AF imaging, demonstrating milder genotypes in patients with less severe phenotypes and more severe genotypes in those with advanced disease (p < 0.001). A genotype-phenotype correlation matrix was constructed based on the classification of the two disease-causing variants and their corresponding phenotypic staging. ConclusionOur findings support the utility of the newly described genotype classification in evaluating ABCA4-associated retinopathy phenotype severity, with possible implications in future understanding of the disease genetics and assessment of individual prognosis for patients.

Prognostication in Stargardt Disease Using Fundus Autofluorescence: Improving Patient Care

To explore fundus autofluorescence (FAF) imaging as an alternative to electroretinography as a noninvasive, quick, and readily interpretable method to predict disease progression in Stargardt disease (STGD). Retrospective case series of patients who attended Moorfields Eye Hospital (London, United Kingdom). Patients with STGD who met the following criteria were included: (1) biallelic disease-causing variants in ABCA4, (2) electroretinography testing performed in house with an unequivocal electroretinography group classification, and (3) ultrawidefield (UWF) FAF imaging performed up to 2 years before or after the electroretinography. Patients were divided into 3 electroretinography groups based on retinal function and 3 FAF groups according to the extent of hypoautofluorescence and retinal background appearance. Fundus autofluorescence images of 30° and 55° were reviewed subsequently. Electroretinography and FAF concordance and its association with baseline visual acuity (VA) and genetics. Two hundred thirty-four patients were included in the cohort. One hundred seventy patients (73%) were in electroretinography and FAF groups of the same severity, 33 (14%) were in a milder FAF than electroretinography group, and 31 (13%) were in a more severe FAF than electroretinography group. Children < 10 years of age (n= 23) showed the lowest electroretinography and FAF concordance at 57% (9 of the 10 with discordant electroretinography and FAF showed milder FAF than electroretinography), and adults with adult onset showed the highest (80%). In 97% and 98% of patients, 30° and 55° FAF imaging, respectively, matched with the group defined by UWF FAF. We demonstrated that FAF imaging is an effective method to determine the extent of retinal involvement and thereby inform prognostication by comparing FAF with the current gold standard of electroretinography. In 80% of patients in our large molecularly proven cohort, we were able to predict if the disease was confined to the macula or also affected the peripheral retina. Children assessed at a young age, with at least 1 null variant, early disease onset, poor initial VA, or a combination thereof may have wider retinal involvement than predicted by FAF alone, may progress to a more severe FAF phenotype over time, or both. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Retinal Phenotyping of a Murine Model of Lafora Disease.

Lafora disease (LD) is a progressive neurologic disorder caused by biallelic pathogenic variants in EPM2A or EPM2B, leading to tissue accumulation of polyglucosan aggregates termed Lafora bodies (LBs). This study aimed to characterize the retinal phenotype in Epm2a-/- mice by examining knockout (KO; Epm2a-/-) and control (WT) littermates at two time points (10 and 14 months, respectively). In vivo exams included electroretinogram (ERG) testing, optical coherence tomography (OCT) and retinal photography. Ex vivo retinal testing included Periodic acid Schiff Diastase (PASD) staining, followed by imaging to assess and quantify LB deposition. There was no significant difference in any dark-adapted or light-adapted ERG parameters between KO and WT mice. The total retinal thickness was comparable between the groups and the retinal appearance was normal in both groups. On PASD staining, LBs were observed in KO mice within the inner and outer plexiform layers and in the inner nuclear layer. The average number of LBs within the inner plexiform layer in KO mice were 1743 ± 533 and 2615 ± 915 per mm2, at 10 and 14 months, respectively. This is the first study to characterize the retinal phenotype in an Epm2a-/- mouse model, demonstrating significant LB deposition in the bipolar cell nuclear layer and its synapses. This finding may be used to monitor the efficacy of experimental treatments in mouse models.

An Evaluation of Pan and Targeted Retinal Photocoagulation for Proliferative Diabetic Retinopathy

This study evaluates the efficacy of pan retinal and targeted retinal photocoagulation (PRP and TRP) for the treatment of proliferative diabetic retinopathy (PDR). A retrospective review of medical records was conducted of patients with PDR who had undergone PRP or TRP as primary treatment at a tertiary care center. Outcome measures included visual acuity, intraocular pressure, and retinal appearance. Results showed that PRP and TRP were both effective in reducing intraocular pressure and improving visual acuity, with no significant difference between the two. However, PRP was associated with a higher rate of retinal detachment and greater risk of recurrence of PDR. Based on the results, PRP and TRP are both effective treatments for PDR, but PRP may be associated with increased risk of complications.

Genotypic and phenotypic characterisation of RP2- and RPGR- associated X-linked inherited retinal dystrophy, including female manifestations.

With the promise of gene replacement therapy, eligible males and females with X-linked inherited retinal dystrophy (XL-IRD) should be identified. Retrospective observational cohort study to establish the phenotypic and genotypic spectrum of XL-IRD within New Zealand (NZ). Thirty-two probands, including 9 females, with molecularly proven XL-IRD due to RP2 or RPGR mutations, and 72 family members, of which 43 were affected, were identified from the NZ IRD Database. Comprehensive ophthalmic phenotyping, familial cosegregation, genotyping, and bioinformatics were undertaken. Main outcome measures were: RP2 and RPGR pathogenic variant spectrum, phenotype in males and females (symptoms, age of onset, visual acuity, refraction, electrophysiology, autofluorescence, retinal appearance), and genotype-phenotype correlation. For 32 families, 26 unique pathogenic variants were identified; in RP2 (n=6, 21.9% of all families), RPGR exons 1-14 (n=10, 43.75%), and RPGR-ORF15 (n=10, 34.3%). Three RP2 and 8 RPGR exons 1-14 variants are novel, rare, and cosegregate. Thirty-one% of carrier females were significantly affected, with 18.5% of families initially classified as autosomal dominant. Of 5 Polynesian families, 80% had novel disease-causing variants. One Māori family showed keratoconus segregating with an ORF15 variant. Significant disease was present in 31% of genetically proven female carriers, often leading to an erroneous presumption of the inheritance pattern. Pathogenic variants in 44% of the families were in exon 1-14 of RPGR, more frequent than usually described, which may inform the gene testing algorithm. Proving cosegregation in families for novel variants and identifying affected females and males translates to optimised clinical care and potential for gene therapy.

Retinal honeycomb appearance and its role in patients with X-linked retinoschisis

BackgroundTo investigate the clinical characteristics of retinal honeycomb appearance in a large cohort of patients with X-linked retinoschisis (XLRS) and to determine whether it is associated with complications like retinal detachment (RD) and vitreous hemorrhage (VH).MethodsA retrospective observational case series. A chart review of medical records, wide-field fundus imaging, and optical coherence tomography (OCT) was performed on 78 patients (153 eyes) diagnosed with XLRS at Beijing Tongren eye center between Dec 2017 and Feb 2022. The chi-square test or Fisher exact test was performed on the 2 × 2 cross-tabulations of honeycomb appearance and other peripheral retinal findings and complications.ResultsThirty-eight patients (48.7%), and 60 eyes (39.2%) had a honeycomb appearance of different areas on the fundus. The supratemporal quadrant was the most commonly affected (45 eyes, 75.0%), followed by the infratemporal (23 eyes, 38.3%), the infranasal (10 eyes,16.7%), and supranasal (9 eyes,15.0%). The appearance was significantly associated with peripheral retinoschisis, inner retinal layer break, outer retinal layer break, RD, and rhegmatogenous retinal detachment (RRD) (p < 0.01, p = 0.032, p < 0.01, p = 0.008, p < 0.01, respectively). All the eyes complicated with RRD had the appearance. None of the eyes without the appearance had RRD.ConclusionsThe data suggest that the honeycomb appearance is not uncommon in patients with XLRS and is more likely to be accompanied by an RRD, and inner and outer layer breaks, thus should be treated with caution and close observation.

Macular dystrophies associated with Stargardt-like phenotypes.

Stargardt-like phenotype has been described as associated with pathogenic variants besides the ABCA4 gene. This study aimed to describe four cases with retinal appearance of Stargardt disease phenotypes and unexpected molecular findings. This report reviewed medical records of four patients with macular dystrophy and clinical features of Stargardt disease. Ophthalmic examination, fundus imaging, and next-generation sequencing were performed to evaluate pathogenic variants related to the phenotypes. Patients presented macular atrophy and pigmentary changes suggesting Stargardt disease. The phenotypes of the two patients were associated with autosomal dominant inheritance pattern genes (RIMS1 and CRX) and in the other two patients were associated with recessive dominant inheritance pattern genes (CRB1 and RDH12) with variants predicted to be pathogenic. Macular dystrophies may have phenotypic similarities to Stargardt-like phenotype associated with other genes besides the classic ones.

The use of OCT to detect signs of intracranial hypertension in patients with sagittal suture synostosis: Reference values and correlations

PurposeTo obtain pediatric normative reference values and determine whether optical coherence tomography (OCT) corresponds better with clinical signs of intracranial hypertension (ICH) compared to the traditional screening method fundoscopy in a large cohort of one type of single suture craniosynostosis.MethodsControl subjects without optic nerve diseases and isolated sagittal synostosis patients aged 3–10 years who underwent fundoscopy and OCT were included in this prospective cohort study. Normative reference values were obtained through bootstrap analysis. Main outcome was the association between peripapillary total retinal thickness (TRT) and total retinal volume (TRV) and appearance on fundoscopy. Signs and symptoms suggestive of ICH, including skull growth arrest, fingerprinting, and headache, were scored.ResultsSixty-four healthy controls and 93 isolated sagittal synostosis patients were included. Normative cut-off values for mean TRT are < 256 μm and > 504 μm and for mean TRV < 0.21 mm3 and > 0.39 mm3. TRT was increased in 16 (17%) and TRV in 15 (16%) of 93 patients, compared to only 4 patients with papilledema on fundoscopy (4%). Both parameters were associated with papilledema on fundoscopy (OR = 16.7, p = 0.02, and OR = 18.2, p = 0.01). Skull growth arrest was significantly associated with abnormal OCT parameters (OR = 13.65, p < 0.01).ConclusionsThe established cut-off points can be applied to screen for ICH in pediatrics. The present study detected abnormalities with OCT more frequent than with fundoscopy, which were associated with skull growth arrest. Therefore, a combination of OCT, fundoscopy, and skull growth arrest can improve clinical decision-making in craniosynostosis.

PATHOMORPHOLOGICAL CHANGES IN THE RETINAL LAYERS AT THE END OF THE SEVENTH DAY OF EXPERIMENTAL OPIOID EXPOSURE

The aim of the work was to clarify the fundamental issues regarding the dynamics of early changes in the retinal layers under experimental exposure of opioids. Research was done on 15 adult 4-months-old mature male mongrel rats, having 100.0-160.0 g weight. Opioid eff ects were modelled by daily intramuscular injections of nalbuphine 1 time per day in one period of time (10-11 am) for 7 days. The initial dose of nalbuphine was 0.212 mg ̸kg. Histological slides were prepared according to generally accepted methods using the dyes, as hematoxylin, eosin and azan according to the Heidenhain method.All animals were kept in the vivarium and the work was carried out according to the European Convention for t he Protection of Vertebrate Animals used for experimental and other scientifi c purposes [Strasbourg, 1985]. During the experimental opioid administration after one week of research the changes in the structure of the retinal layers were established. In the early stages of low-dose opioid analgesia administration, the fi rst pathomorphological changes were de tected during the fi rst week, in the form of initial manifestations of vacuole dystrophy of the pigmental epithelium, signs of microcystic degeneration of the outer retinal and neurofi brous layers with the vacuole dystrophy of retinal ganglion cells appearance.

Abnormal Appearance of the Area Centralis in Labrador Retrievers With an ABCA4 Loss-of-function Mutation.

PurposeTo study retinal appearance and morphology in Labrador retrievers (LRs) heterozygous and homozygous for an ABCA4 loss-of-function mutation.MethodsOphthalmic examination, including ophthalmoscopy and simple testing of vision, was performed in five ABCA4wt/wt, four ABCA4wt/InsC, and six ABCA4InsC/InsC LRs. Retinas were also examined with confocal scanning laser ophthalmoscopy (cSLO) and optical coherence tomography (OCT). Infrared and fundus autofluorescence (FAF) images were studied, and outer nuclear layer (ONL) and neuroretinal thickness were measured in the central and peripheral area centralis.ResultsClinical signs in young ABCA4InsC/InsC LRs were subtle, whereas ophthalmoscopic findings and signs of visual impairment were obvious in old ABCA4InsC/InsC LRs. Retinal appearance and vision testing was unremarkable in heterozygous LRs regardless of age. The cSLO/OCT showed abnormal morphology including ONL thinning, abnormal outer retinal layer segmentation, and focal loss of retinal pigment epithelium in the fovea equivalent in juvenile ABCA4InsC/InsC LRs. The abnormal appearance extended into the area centralis and visual streak in middle-aged ABCA4InsC/InsC and then spread more peripherally. A mild phenotype was seen on cSLO/OCT and FAF in middle-aged to old ABCA4wt/InsC LRs.ConclusionsAbnormal appearance and morphology in the fovea equivalent are present in juvenile ABCA4InsC/InsC. In the older affected LRs, the visual streak and then the peripheral retina also develop an abnormal appearance. Vision deteriorates slowly, but some vision is retained throughout life. Older heterozygotes may show a mild retinal phenotype but no obvious visual impairment. The ABCA4InsC/InsC LR is a potential model for ABCA4-mediated retinopathies/juvenile-onset Stargardt disease in a species with human-sized eyes.Translational RelevanceThe ABCA4InsC mutation causes juvenile-onset abnormal appearance of the fovea equivalent in affected dogs that slowly spreads in the retina, while only a mild phenotype is seen in older carriers. This is the first non-primate, large-animal model for ABCA4-related/STGD1 retinopathies in a species with a fovea equivalent.

Case report of benign familial fleck retina

Benign familial fleck Retina is a rare inherited retinal disease first reported by Sabel Aish and Dajani in 1980. It is an autosomal recessive condition associated with a distinctive retinal appearance with no apparent visual or electrophysiological deficits. Fundus photography, autofluorescence and enhanced depth optical coherence tomography B-scan imaging modalities aid in the diagnosis. We present a case report of a 19-year-old female diagnosed with benign familial fleck retina which belongs to a heterogeneous group of flecked retina syndromes, and should be considered in patients with yellowish-white retinal lesions sparing the macula.

Characterizations of Hamster Retina as a Model for Studies of Retinal Cholesterol Homeostasis.

Simple SummaryThis work represents a comprehensive evaluation of hamster retina by state-of-the-art methodologies and provides evidence that hamsters may represent a better model for studies of retinal cholesterol maintenance than mice. The latter is an important finding, as disturbances in retinal cholesterol homeostasis are linked to age-related macular degeneration and diabetic retinopathy, which are blinding diseases.Cholesterol homeostasis in the retina, a sensory organ in the back of the eye, has been studied in mice but not hamsters, despite the latter being more similar to humans than mice with respect to their whole-body cholesterol maintenance. The goal of this study was to begin to assess hamster retina and conduct initial interspecies comparisons. First, young (3-month old) and mature (6-month old) Syrian (golden) hamsters were compared with 3- and 6-month old mice for ocular biometrics and retinal appearance on optical coherence tomography and fluorescein angiography. Of the 30 evaluated hamsters, seven had retinal structural abnormalities and all had increased permeability of retinal blood vessels. However, hamsters did not carry the mutations causing retinal degenerations 1 and 8, had normal blood glucose levels, and only slightly elevated hemoglobin A1c content. Cholesterol and six other sterols were quantified in hamster retina and compared with sterol profiles in mouse and human retina. These comparisons suggested that cholesterol turnover is much higher in younger than mature hamster retina, and that mature hamster and human retinas share similarities in the ratios of cholesterol metabolites to cholesterol. This study supports further investigations of cholesterol maintenance in hamster retina.

Ensemble Learning Approach to Retinal Thickness Assessment in Optical Coherence Tomography

Manual assessment of the retinal thickness in optical coherence tomography images is a time-consuming task, prone to error and inter-observer variability. The wide variability of the retinal appearance makes the automation of retinal image processing a challenging problem to tackle. The difficulty is even more accentuated in practice when the retinal tissue exhibits large structural changes due to disruptive pathology. In this work, we propose an ensemble-learning-based method for the automated segmentation of retinal boundaries in optical coherence tomography images that is robust to retinal abnormalities. The segmentation accuracy of the proposed algorithm was evaluated on two publicly available datasets that included cases of severe retinal edema. Moreover, the performance of the proposed method was compared to two existing methods, widely referenced in the relevant literature. The proposed algorithm outperformed reference methods at segmenting the retinal boundaries in both normal and pathological images. Furthermore, a thorough reliability analysis showed a strong agreement between the retinal thickness measurements derived from the segmentation obtained with the proposed method and corresponding manual measurements computed with the manual annotations.

Benign Familial Fleck Retina

Familial fleck retina is a rare inherited retinal disease. Sabel Aish &amp; Dajani (1980) first reported ocular findings in seven of 10 siblings in one Arab family. It is an autosomal-recessive condition associated with a distinctive retinal appearance and no apparent visual or electrophysiological deficits . Affected individuals are asymptomatic with a large number of yellow−white flecks of variable size and shape in the midperipheral to far peripheral retina, but did not have any ocular complaints such as loss of visual acuity (VA), impaired visual fields and dark adaptation disturbances. Fluorescein angiograms documented an irregular and spotty hyperfluorescence throughout the retina (sparing the macula). This report discusses a case of 22 year old female of both eye Benign familial fleck retina.

Granulicatella adiacens endophthalmitis after phacoemulsification cataract surgery.

Two cases of acute postoperative Granulicatella adiacens endophthalmitis following uneventful phacoemulsification surgery are reported. The cases had intracameral cefuroxime as antibiotic prophylaxis, visual acuity (VA) was perception of light and hand movements, respectively, and there was severe anterior chamber inflammation and dense vitritis with no fundal view. Vitreous biopsy identified G adiacens using genome sequencing. Intraoperative findings included extensive retinal hemorrhages, abscesses, occluded retinal vessels, and retinal necrosis. Because of the ischemic retinal appearance, pan-retinal photocoagulation endolaser was performed. Postoperatively both cases developed rhegmatogenous retinal detachment (RRD) anterior to the laser marks and were successfully treated. VA improved to 6/18 and 6/60, respectively. Hyperreflective dots and Henle fiber layer hemorrhage are reported for the first time, to the authors' knowledge, in association with endophthalmitis. The successful outcome suggested that intraoperative pan-retinal photocoagulation could be considered in such ischemic cases to prevent rubeosis and to reduce the risk for postoperative RRD or limit its extent if it recurs.

Classification of dry age‐related macular degeneration and diabetic macular oedema from optical coherence tomography images using dictionary learning

Age-related Macular Degeneration (AMD) and Diabetic Macular Edema (DME) are the major causes of vision loss in developed countries. Alteration of retinal layer structure and appearance of exudates are the most significant signs of these diseases. In this paper, with the aim of automatic classification of DME, AMD, and normal subjects using Optical Coherence Tomography (OCT) images, a dictionary-learning based classification is proposed. The two important issues intended in this approach are avoiding retinal layer segmentation and attempting to mimic the authors' understanding based on normal and abnormal region identifications, considering that the signs of diseases appear in a small fraction of B-Scans. The histogram of oriented gradients feature descriptor was utilized to characterize the distribution of local intensity gradients and edge directions. To capture the structure of extracted features, different dictionary learning-based classifiers are employed. The dataset consists of 45 subjects: 15 patients with AMD, 15 patients with DME, and 15 normal subjects. The proposed classifier leads to an accuracy of 95.13, 100.00, and 100.00% for DME, AMD, and normal OCT images, respectively, only by considering 4% of all B-Scans of a volume, which outperforms the state-of-the-art methods.

Inadequate laser coagulation is an important cause of treatment failure in Type 1 retinopathy of prematurity.

To examine the cause of treatment failures in Type 1 retinopathy of prematurity (ROP). The medical charts of all infants with disease persistence after laser treatment at Uppsala University Hospital, Sweden, during a 10-year period (2009-2019) were reviewed. RetCam photography and angiography were used to document the retinal appearance before and after retreatment. Ten infants (18 eyes), of whom nine were referred from other hospitals, had persistence of Type 1 ROP in zone I or zone II despite previous laser treatment. Their mean gestational age was 24weeks and their mean birth weight was 618g. Seven eyes were diagnosed as stage 3 plus, eight eyes as stage 4A and three eyes as stage 4B. In eight infants (14 eyes), inadequate laser coagulation was suspected to be the cause for persistence of type 1 disease. Two infants (four eyes) were appreciated to have persistence of plus disease because of presence of zone I disease. For persistence of Type 1 ROP, five infants (seven eyes) were treated with vitrectomy, two infants (three eyes) with laser photocoagulation and anti-vascular endothelial growth factor (VEGF), two infants (four eyes) with anti-VEGF alone and finally two infants (four eyes) with laser photocoagulation alone. The anatomical outcome was good in 14 eyes and poor in four eyes (three infants). Inadequate laser coagulation is an important cause of treatment failure of ROP Type 1. Another cause is laser coagulation in zone I. To minimize remaining visual disability, some kind of centralization of the ROP treatment is suggested.

Association of Clinical and Genetic Heterogeneity With BEST1 Sequence Variations

Detailed phenotypic information on the spectrum of fundus abnormalities and clinical variability of all phenotypes associated with sequence variations in BEST1 is limited. To report a detailed phenotypic and genetic analysis of a patient cohort with sequence variations in BEST1. This retrospective case series took place at the Oxford Eye Hospital in Oxford, UK. Thirty-six patients from a single center with disease-causing sequence variations in BEST1 from 25 different families were analyzed. Data were collected from November 2017 to June 2018, and analysis began April 2018. Results of ocular phenotyping and genetic testing using targeted next-generation sequencing to identify BEST1 sequence variations. Thirty-six patients from 25 families with disease-causing sequence variations in BEST1 were included. Of 36 patients, 20 (55.6%) were female. Three distinct clinical phenotypes were identified: autosomal recessive bestrophinopathy (ARB), best vitelliform macular dystrophy (BVMD), and adult-onset vitelliform macular dystrophy. The ARB phenotype group comprised 18 patients from 9 families with age in years at symptom onset ranging from less than 10 to 40s. All patients showed a common phenotype of fundus autofluorescence abnormalities, and spectral-domain optical coherence tomography features were similar in all patients with schitic and cystoid changes. A phenotype of a beaten metallic retinal appearance extending from the mid periphery to the far periphery was identified in 8 patients. Four patients from 1 family with ARB were previously reported to have autosomal recessive retinitis pigmentosa but were reclassified as having ARB as part of this study. The BVMD phenotype group comprised 16 patients from 14 families with age at symptom onset ranging from less than 10 to 70s. Fundus features were localized to the macula and consistent with the stage of BVMD. In the adult-onset vitelliform macular dystrophy phenotype group, the age in years at symptom onset varied from 50s to 70s in 2 patients from 2 families. Fundus features included small vitelliform lesions. Where available, electro-oculogram results demonstrated a reduced or absent light rise in all patients with ARB and BVMD. Genetic testing identified 22 variants in BEST1. These findings support the notion that ARB, BVMD, and adult-onset vitelliform macular dystrophy are clinically distinct and recognizable phenotypes and suggest that the association of autosomal recessive retinitis pigmentosa with sequence variations in BEST1 should be rereviewed.

Topical Trabodenoson Is Neuroprotective in a Rodent Model of Anterior Ischemic Optic Neuropathy (rNAION).

PurposeNonarteritic anterior ischemic optic neuropathy (NAION) is the leading cause of sudden optic nerve–related vision loss currently without effective treatment. We evaluated the neuroprotective potential of ocular (topical) delivery of trabodenoson, a selective A1 receptor mimetic, in a rodent model of NAION (rNAION).MethodsDaily topical delivery of 3% trabodenoson or vehicle administered in both eyes 3 days prior to rNAION induction and for 21 days post induction. Retinal appearance and optic nerve head (ONH) edema was evaluated using spectral-domain optical coherence tomography (SD-OCT). Retinal function was evaluated before and after induction by ganzfeld electroretinography (ERG). Brn3a(+) retinal ganglion cells (RGCs) were quantified by stereology. Axonal ultrastructure was evaluated by electron microscopy.ResultsTrabodenoson-treated eyes had significantly reduced optic nerve (ON) edema compared with vehicle-treated eyes (ANOVA, P < 0.05). Electrophysiologically, there was a nonsignificant trend toward b-wave and oscillatory potential (OP) preservation in the trabodenoson-treated eyes. RGC counts were higher in trabodenoson-treated eyes compared to vehicle (74% versus 47% of the contralateral eye; two-tailed t-test; P = 0.01), as were ON axons. No overt morphologic differences in cell inflammation were observed between vehicle- and trabodenoson-treated ONHs, but trabodenoson-treated ONHs revealed increased expression of astrocyte-related neuroprotective responses.ConclusionsTrabodenoson preserves RGCs in the rodent NAION model. While previous clinical trials focused on trabodenoson's ocular antihypertensive effect, our data suggest trabodenoson's primary target may be both the retina and ONH. Selective adenosine A1 agonists may prove an appropriate neuroprotective adjunctive for ischemia-related ON diseases such as NAION and glaucoma.Translational RelevanceRGC and ON neuroprotection in ischemic neuropathies may be achievable by topical administration of A1 adenosine agonists rather than by simply relying on intraocular pressure reduction.