Retinal Pigmentary Changes Research Articles

Pachychoroid spectrum disease.

Recent improvements in ophthalmic imaging have led to the identification of a thickened choroid or pachychoroid to be associated with a number of retinal diseases. The number of conditions linked to this phenotype has continued to widen with specific endophenotypes found within the pachychoroid spectrum. The spectrum includes choroidal features such as focal or diffuse choroidal thickening and thinning of the overlying inner choroid, and choroidal hyperpermeability as demonstrated by indocyanine green angiography. In addition, these diseases are associated with overlying retinal pigmentary changes and retinal pigment epithelial dysfunction and may also be associated with choroidal neovascularization. This article provides a comprehensive review of the literature looking at diseases currently described within the pachychoroid spectrum including central serous chorioretinopathy, pachychoroid pigment epitheliopathy, pachychoroid neovasculopathy, polypoidal choroidal vasculopathy/aneurysmal type 1 neovascularization, peripapillary pachychoroid disease and focal choroidal excavation. We particularly focus on clinical imaging, genetics and pathological findings in these conditions with the aim of updating evidence suggesting a common aetiology between diseases within the pachychoroid spectrum.

Clinical and Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy

Clinical and Genetic Findings in CTNNA1-Associated Macular Pattern Dystrophy

Compound heterozygous RPE65 mutations associated with an early onset autosomal recessive retinitis pigmentosa.

Retinitis pigmentosa (RP) is one of the most common form of inherited retinal dystrophies. Identification of disease-causing mutations is a prerequisite for applying targeted therapeutic approaches. The present study aimed to identify disease-associated mutations in a large Serbian family, in which two brothers have suffered from RP starting in the first decade of their lives. The index patient and 12 additional members of a four-generation family were analyzed. All participants underwent detailed ophthalmic examinations. Genomic DNA was isolated from family members to perform whole exome sequencing (WES) and Sanger sequencing of candidate genes. An early onset RP phenotype was presented in both ocular fundi of the index patient and his brother: arteriolar attenuation, as well as retinal pigmentary changes in peripheral fundus and waxy disc pallor. Both brothers showed foveal thinning. The index patient showed epiretinal membranes in both eyes and a parafoveal cystic lesion in his right eye, whereas the brother of the index patient showed choroid folds and vitreomacular adhesion in his left eye. We identified compound heterozygous mutations in the RPE65 gene (a novel c.1338+1G>A splice donor site mutation in addition to the frame-shifting mutation c.1207_1210dup (p.Glu404Alafs*4)) using an in-house WES pipeline. Evaluation of all previously described RPE65 mutations showed that the sequence variants identified in the present study located to rarely altered exons and likely effect a highly conserved region of the RPE65 protein. Gene augmentation therapies might be a promising treatment option for the patients described.

Incidence of Ocular Toxicity from Iron Chelating Agents at Siriraj Hospital

Objective: To determine the incidences of ocular toxicity and ocular findings, including structural and functional abnormalities, caused by iron chelating agents and detected by an electrophysiologic test at Siriraj Hospital.Methods: A retrospective chart review was conducted of patients receiving multiple blood transfusions and iron chelation therapy who had an eye examination at Siriraj Hospital between January 1995 and December 2017. Results: Ninety-seven charts were reviewed. The 88 patients included comprised 41 males and 47 females. Their ages ranged from 1 year 11 months to 47 years, with children predominant (mean: 8.13 years). Beta thalassemia HbE was the main diagnosis (87.5%). After receiving iron chelating agents, 3 patients had abnormal eye findings with suspected ocular toxicity. Two had retinal pigmentary changes, but only one of those two displayed a mildly decreased response in a scotopic electroretinogram. Although the third patient also showed a decreased electroretinogram response, there were no obvious retinal changes. All three received the iron chelating agents desferrioxamine, deferiprone, and/or deferasirox at different doses and for various durations.Conclusion: Although some pigmentary retinopathy and decreased electroretinogram responses were found, leading to ocular toxicity being suspected, there was a very low incidence of ocular toxicity from the chelating agents. In addition, the dosages of the agents causing ocular toxicity, and the duration of that toxicity, were inconclusive. Moreover, a gold standard for identifying ocular toxicity caused by chelating agents was not able to be established. Consequently, the risks and benefits of employing eye screening coupled with an invasive procedure like an electrophysiologic test will need to be weighed, especially with pediatric patients.

Post-traumatic bilateral blindness in a toddler

Abstract A unique case of vision loss in a two-year-old boy after sustaining a head injury as a pedestrian versus car was seen at our paediatric trauma unit. A CT brain was negative for fracture, intra-cranial haemorrhage and contusion. There were no neurological symptoms and no signs of abuse. Ophthalmological examination demonstrated retinal haemorrhages, cotton wool spots and Purtscher flecken that are pathognomonic for the diagnosis of Purtscher's retinopathy. This occlusive microvasculopathy, associated with cranial and chest trauma, may cause severe blindness. In literature, bilaterality was described in almost two thirds of cases. Regardless of management with or without medication, visual function improved in the majority of cases. In our case, despite treatment with high-dose intravenous methylprednisolone, the child's vision remained poor with bilateral optic atrophy and retinal pigmentary changes. Children with Purtscher's retinopathy should be examined for signs of non-accidental injury.

An Investigation into Retigabine (Ezogabine) Associated Dyspigmentation in Rat Eyes by MALDI Imaging Mass Spectrometry.

Retigabine (RTG) is an antiepileptic drug approved as an adjunctive treatment for refractory partial-onset seizures in adults. In April 2013, the Food and Drug Administration issued a warning that RTG could cause changes in retinal pigmentation and discoloration of skin, resulting in a blue appearance. As part of a larger preclinical effort to gain a mechanistic understanding as to the origins of retinal pigment changes associated with RTG, we conducted a long-term repeat dosing study in rats. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) was used to determine the distribution of RTG and its metabolites in the rat eye following 13 and 39 weeks of dosing. IMS revealed the presence of RTG, a previously characterized N-acetyl metabolite of RTG (NAMR), and several species structurally related through the dimerization of RTG and NAMR. These species were highly localized to the melanin-containing layers of the uveal tract of the rat eye including the choroid, ciliary body, and iris, suggesting that the formation of these dimers occurs from melanin bound RTG and NAMR. Furthermore, several of the RTG-related dimers have UV absorbance which give them a purple color in solution. We propose that the melanin binding of RTG and NAMR effectively concentrates the two compounds to enable mixed condensation reactions to occur when the binding provides the proper geometry in the redox environment of the uveal tissues. High lateral resolution images illustrate that the blood-retinal barrier effectively restricts retinal access to RTG-related compounds. The spatial information provided by MALDI IMS was critical in contextualizing the homogenate concentrations of key RTG-related compounds and helped provide a basis for the mechanism of dimer formation.

Unilateral pigmentary retinopathy: a retrospective case series.

To review the clinical characteristics and address the aetiology in a group of patients presenting with unilateral retinal pigmentary changes, best described as unilateral pigmentary retinopathy (UPR). The cohort of 42 patients was identified retrospectively from the Moorfields Eye Hospital electrophysiology database. All had undergone full-field [electroretinography (ERG)] and pattern electroretinography (PERG), with 13 additionally having multifocal ERG (mfERG). The clinical findings, fundus photographs and fundus autofluorescence (AF) images were reviewed. All index eyes showed ERG evidence of generalized photoreceptor dysfunction with most showing a similar degree of rod and cone involvement. However, although the fellow eyes all had a normal fundus examination, there were bilateral but asymmetrical ERG abnormalities in eight patients and a further four patients had PERG evidence of macular dysfunction in the fellow eye. A relevant medical history or the diagnosis of an ophthalmologic entity that might be related to the unilateral fundus changes was ascertained in 15 cases (~36%) including acute zonal occult outer retinopathy, trauma, systemic malignancy or autoimmune disease, retinal vasculitis, presumed pregnancy-related choroidal ischaemia and meningitis. Two patients had a family history of retinitis pigmentosa (RP; 4.8%). The underlying aetiology in most cases of UPR cannot accurately be identified, but an heritable cause is unlikely. Aspects of the history clearly suggest an acquired disorder in some patients. Twenty-five patients (60%) with nongenetic UPR did not adhere to the pattern of rod greater than cone dysfunction that occurs in RP (rod-cone dystrophy), and the pattern of rod>cone dysfunction seen in true RP is thus not a feature of most patients with UPR.

Ocular and systemic manifestations of beta-propeller protein-associated neurodegeneration

Beta-propeller protein-associated neurodegeneration (BPAN) is a rare genetic disorder characterized by neurodegeneration with brain iron accumulation (NBIA). We report an infant diagnosed with BPAN who was found to have high myopia and astigmatism, strabismus, and bilateral retinal pigmentary changes. While retinal pigmentary changes have been described in other disorders of NBIA, it has been only rarely reported in BPAN.

The Spectrum of Structural and Functional Abnormalities in Female Carriers of Pathogenic Variants in the RPGR Gene.

The purpose of this study was to investigate the phenotype and long-term clinical course of female carriers of RPGR mutations. This was a retrospective cohort study of 125 heterozygous RPGR mutation carriers from 49 families. Eighty-three heterozygotes were from retinitis pigmentosa (RP) pedigrees, 37 were from cone-/cone-rod dystrophy (COD/CORD) pedigrees, and 5 heterozygotes were from pedigrees with mixed RP/CORD or unknown diagnosis. Mutations were located in exon 1-14 and in ORF15 in 42 of 125 (34%) and 83 of 125 (66%) subjects, respectively. The mean age at the first examination was 34.4 years (range, 2.1 to 86.0 years). The median follow-up time in heterozygotes with longitudinal data (n = 62) was 12.2 years (range, 1.1 to 52.2 years). Retinal pigmentary changes were present in 73 (58%) individuals. Visual symptoms were reported in 51 (40%) cases. Subjects with both symptoms and pigmentary fundus changes were older than the other heterozygotes (P = 0.01) and had thinner foveal outer retinas (P = 0.006). Complete expression of the RP or CORD phenotype was observed in 29 (23%) heterozygotes, although usually in milder forms than in affected male relatives. Best-corrected visual acuity (BCVA) was <20/40 and <20/400 in at least one eye in 45 of 116 (39%) and 11 of 116 (9%) heterozygotes, respectively. Myopia was observed in 74 of 101 (73%) subjects and was associated with lower BCVA (P = 0.006). Increasing age was associated with lower BCVA (P = 0.002) and decreasing visual field size (P = 0.012; I4e isopter). RPGR mutations lead to a phenotypic spectrum in female carriers, with myopia as a significantly aggravating factor. Complete disease expression is observed in some individuals, who may benefit from future (gene) therapeutic options.

Clinical and genetic study of a new mutation in the choroidoremia gene

PurposeTo describe retinal findings as well as spectral domain OCT and fundus autofluorescence in a new genetic mutation in a choroidoremia family.MethodsAn 11 year old boy was diagnosed with choroidoremia by his fundus changes. In his mother′s family there was another cousin with the same symptoms and his grandfather and great grandfather had an impaired vision. The family was studied.ResultsThe boy has a reduced visual acuity of 20/40 in both eyes with ‐6D, reduced sensibility in his perimetry, and important retinal pigment changes in his fundus. SD‐OCT findings include changes in the external hyperreflective layers and hypofluorescence and hyperfluorescence changes in his fundus autofluorescence. His mother showed a normal OCT with hypofluorescence changes. His cousin, who was 13 years old, showed similar changes with a 20/20 vision and no myopic defect. The boys were hemizygous for a novel mutation c.1083_1084dupT of the CHM gene. The mutation was confirmed in heterozygosity in both carriers. The sister was not affected.ConclusionsClinical diagnosis and molecular analysis showed the new mutation leading to loss of function of the REP‐1 protein. Autofluorescence changes were presented in both patients and carriers. Myopia could increases the visual loss and pigment changes in choroidoremia.

Pigmentary retinopathy, rod–cone dysfunction and sensorineural deafness associated with a rare mitochondrial tRNALys (m.8340G>A) gene variant

Background/AimThe rare mitochondrial DNA (mtDNA) variant m.8340G>A has been previously reported in the literature in a single, sporadic case of mitochondrial myopathy. In this report, we aim to investigate the...

Retinal pigmentary changes in chronic uveitis mimicking retinitis pigmentosa.

To present retinal pigmentary changes mimicking retinitis pigmentosa (RP) as a finding of advanced uveitis. We retrospectively reviewed charts of patients without a family history of inherited retinal degenerations who presented with retinal pigment changes and signs of past or present intraocular inflammation. Comprehensive eye examination including best-corrected visual acuity, slit-lamp examination and dilated fundus examination was performed on all patients in addition to color fundus photography, optical coherence tomography, fluorescein angiography (FA), and full-field electroretinogram testing. We identified five patients with ages ranging from 33 to 66years, who presented with RP-like retinal pigmentary changes which were eventually attributed to longstanding uveitis. The changes were bilateral in three cases and unilateral in two cases. Four of five cases presented with active inflammation, and the remaining case showed evidence of active intraocular inflammation during follow-up. This study highlights the overlapping features of advanced uveitis and RP including the extensive pigmentary changes. Careful review of possible past uveitis history, detailed examination of signs of past or present inflammation and ancillary testing, with FA often being most helpful, are required for the correct diagnosis. This is important, because intervention can prevent further damage if the cause of the pigmentary changes is destructive inflammation.

An Unusually Late Presentation of Recurrent Cardiac Syncope in Kearns Sayre Syndrome

Background: Kearns Sayre Syndrome (KSS) is a rare mitochondrial disorder with systemic involvement characterised by skeletal, smooth and cardiac muscle dysfunction; pigmentary retinal changes; neurological and endocrine dysfunction. KSS arise from a large-scale deletion of mitochondrial DNA which typically occurs as a sporadic event. Recurrent cardiac syncope is one way of the initial presentation of this syndrome due to involvement of cardiac conduction system. Case presentation: A 51-year-old male, previously well apart from having stable angina for which he was on aspirin and statin, presented to medical casualty with recurrent syncopal episodes with loss of consciousness lasting 3 minutes to 5 minutes and spontaneous recovery after each event. On ocular examination he was found to be have poor vision (best corrected visual acuity in both eyes was 6/60), bilateral posterior subcapsular cataract and both eyes fundus revealed features of retinitis pigmentosa with cystoid macular oedema. A 12 lead electrocardiography (ECG) on admission showed evidence of atrial flutter with variable heart block leading to significant pauses and the patient underwent permanent pacemaker insertion as he was severely symptomatic. Patient was referred to visual rehabilitation. Conclusion: Mitochondrial myopathy is an important differential diagnosis which needs to be considered in a patient presenting with recurrent cardiac syncope in the context of multisystem involvement.

PEMBROLIZUMAB ADMINISTRATION ASSOCIATED WITH POSTERIOR UVEITIS

To describe the development of uveitis and retinal vasculitis in association with pembrolizumab treatment for metastatic uveal melanoma. A case report and a brief review of the literature are presented. Information collected and reported include the patient's clinical course, physical examination findings, fluorescein angiogram images, retinal photographs, and her response to treatment. A 54-year-old woman was diagnosed with a large choroidal malignant melanoma and had the affected eye enucleated. Pathology confirmed a mixed cell choroidal melanoma, and gene expression profiling was Class 2. Seventeen months after enucleation, the patient was diagnosed with metastatic uveal melanoma to the liver. Disease progression was observed during ipilimumab treatment. Pembrolizumab treatment was initiated, and after four infusions, she presented to clinic complaining of floaters and blurred vision. Examination revealed a nongranulomatous panuveitis characterized by perivascular retinal pigment epithelium pigmentary changes, retinal venous sheathing, 1+ anterior chamber and vitreous cellular reaction, 2+ vitreous haze, and optic disk edema. A dexamethasone sustained-release implant was administered and the uveitis regressed. A relapse in symptoms occurred but quickly subsided with a repeat injection. Pembrolizumab may induce a uveitic reaction. There is mounting evidence that patients using prembrolizumab should be educated and monitored for signs of uveitis.

Unilateral Sectoral Retinitis Pigmentosa in a Patient of Iranian Origin

Abstract Introduction: Sectoral retinitis pigmentosa (RP) is a rare clinical condition. Case Presentation:We present a 60-year-old femalewith a history ofmild night blindness and decreased vision in the left eye for about 15 years. Conclusions: Fundus examination revealed retinal pigmentary changes in the inferotemporal sector and reduced arterial caliber. In addition, fundus autofluorescence, fluorescein angiography,multifocal electroretinogramscans and electro-oculogramconfirmed these clinical findings. To the best of our knowledge, the present study is the first to describe sectorial RP in the inferotemporal sector of Iranian origin.

Acquired retinal pigmentary degeneration in a child with 13q deletion syndrome

Orbeli syndrome, or 13q deletion syndrome, is a rare condition caused by a distal deletion in the long arm of chromosome 13. The syndrome is characterized by severe physical malformations and developmental delays and has been associated with numerous ocular manifestations. We report the case of a 10-year-old boy with 13q deletion syndrome, who was evaluated for impaired vision and found to have bilateral retinal pigmentary changes resembling those seen in retinitis pigmentosa. There has only been one other case of retinal pigment variation in association with 13q deletion syndrome; however, this represents the first case of bilateral symmetric retinal pigmentary changes with corresponding rod and cone dysfunction on electroretinography.

Electroretinogram assessment of children with sensorineural hearing loss: implications for screening.

The guidelines of the National Deaf Children's Society recommend that children with sensorineural hearing loss (SNHL) be routinely screened for ophthalmological problems and suggest electroretinography (ERG) to exclude Usher syndrome. The present study reports the nature and prevalence of abnormal ERG findings in a cohort of children with SNHL undergoing ERG with the aim of identifying risk factors for the diagnosis of Usher syndrome. The medical records of children (<18 years of age) with SNHL referred for ERG at Moorfields Eye Hospital, London, between January 2009 and December 2011 were retrospectively reviewed. Patients were included if they had been referred with SNHL by an audiological medicine consultant and the primary indication for electrodiagnostic testing was possible Usher syndrome. A total of 84 cases met inclusion criteria of which 13 (15%) had ERG findings showing rod-cone dysfunction consistent with a diagnosis of Usher syndrome. Two patients with retinal pigmentary changes had normal ERGs and were diagnosed with rubella retinopathy based on the clinical findings. Risk factor analysis showed that age of ≥8 years at the time of ERG, sex, and bilateral hearing loss were not predictive of a diagnosis of Usher syndrome. However, the presence of or referral for cochlear implants, having relevant symptoms and/or clinical signs consistent with a retinal dystrophy, and profound hearing loss were all highly predictive. ERG is a useful diagnostic tool in children with SNHL and should be performed in children with SNHL who have cochlear implants and/or have signs or symptoms of retinal dystrophy. A focused approach could have potential cost-saving benefit.

The “eye of the tiger” sign

An 8-year-old boy presented with recurrent falls while walking and abnormal twisting postures of all four limbs for last 2 yr. He also had cognitive decline and decrease in speech output. His elder brother died of similar illness at the age of 11 yr. Examination revealed generalized dystonia, spasticity and dysarthria. Fundus examination showed bilateral retinal pigmentary changes and optic atrophy (Fig. 1). Magnetic resonance imaging of brain revealed hypo-intense globus pallidi with central hyperintensity, i.e. “eye of the tiger” sign on T2-weighted images (Fig. 2). These findings were consistent with the diagnosis of pantothenate kinase associated neurodegeneration (PKAN). Genetic testing could not be performed because of financial constraints. PKAN, formerly called Hallervorden-Spatz disease is a form of neurodegenerationwith brain iron accumulation, inherited in an autosomal recessive manner [1]. PKAN is characterized by progressive dystonia, rigidity, dysarthria, intellectual deterioration and pigmentary retinopathy starts before 10 yr of age. The “eye of the tiger” sign describes the central region of hyperintensity surrounded by a rim of hypointensity on coronal or transverse T2-weighted images of the globus pallidus. The hypointensity on T2-weighted image is because of

Ophthalmological Findings of Turkish Children With Muscular Dystrophies.

To present the results of ophthalmological examinations in children with muscular dystrophies and highlight the importance of their ophthalmological evaluation. Retrospective analysis of the ophthalmological examination records in 74 children with a type of muscular dystrophy, examined between January 2011 and January 2015, was performed. The most common type of muscular dystrophy observed in our patients was Duchenne muscular dystrophy (67.5%), followed by Becker muscular dystrophy (9.4%), myotonic dystrophy (8%), limb-girdle muscular dystrophy (6.7%), merosin-negative muscular dystrophy (4%), and Ullrich muscular dystrophy (4%). Ten cases of Duchenne muscular dystrophy had both macular and retinal pigmentary changes (20%) and 9 had abnormal electroretinographies with decreased photopic and scotopic responses. Ptosis was the most common finding (83.3%). No abnormalities of light reflexes, pupil size, or saccadic and smooth pursuit movements were seen among cases with myotonic dystrophy. Ophthalmological problems are commonly seen in children with muscular dystrophies. Simple ophthalmological screening and early intervention can improve their communication skills by way of increasing their visual talents.

Retinal degeneration in autoimmune polyglandular syndrome type 1: a case series

BackgroundAutoimmune polyglandular syndrome type 1 (APS1) is a rare autosomal recessive disorder due to mutations in the AIRE gene.AimTo report the ocular features and characterise the retinal phenotype in molecularly...