ABSTRACT
Biallelic pathogenic variants in the PNPLA6 gene cause a broad spectrum of disorders leading to gait disturbance, visual impairment, anterior hypopituitarism and hair anomalies. PNPLA6 encodes neuropathy target esterase (NTE), yet the role of NTE dysfunction on affected tissues in the large spectrum of associated disease remains unclear. We present a systematic evidence-based review of a novel cohort of 23 new patients along with 95 reported individuals with PNPLA6 variants that implicate missense variants as a driver of disease pathogenesis. Measuring esterase activity of 46 disease-associated and 20 common variants observed across PNPLA6-associated clinical diagnoses unambiguously reclassified 36 variants as pathogenic and 10 variants as likely pathogenic, establishing a robust functional assay for classifying PNPLA6 variants of unknown significance. Estimating the overall NTE activity of affected individuals revealed a striking inverse relationship between NTE activity and the presence of retinopathy and endocrinopathy. This phenomenon was recaptured in vivo in an allelic mouse series, where a similar NTE threshold for retinopathy exists. Thus, PNPLA6 disorders, previously considered allelic, are a continuous spectrum of pleiotropic phenotypes defined by an NTE genotype:activity:phenotype relationship. This relationship, and the generation of a preclinical animal model, pave the way for therapeutic trials, using NTE as a biomarker.
Subject(s)
Phenotype , Animals , Female , Humans , Male , Mice , Acyltransferases , Carboxylic Ester Hydrolases/genetics , Mutation, Missense , Phospholipases/genetics , Retinal Diseases/geneticsABSTRACT
PURPOSE: In subretinal gene therapy for inherited retinal diseases (IRDs), blebs may not propagate predictably in the direction of the injection cannula. We evaluated factors that influenced bleb propagation among various IRDs. METHODS: Retrospective review of all subretinal gene therapy procedures performed by a single surgeon between September 2018 and March 2020 for various IRDs. Main outcome measures were directional bias of bleb propagation and intraoperative foveal detachment. RESULTS: Desired injection volumes and/or foveal treatment were successfully achieved in all 70 eyes of 46 patients with IRD regardless of IRD indication. Bullous foveal detachment was associated with retinotomy closer to the fovea, posterior bleb bias, and greater bleb volumes ( P < 0.01). Blebs biased anteriorly or posteriorly based on disease indication ( P = 0.04) and age ( P < 0.001). Retinotomy location ≤ 3.7 mm (approximately two disk diameters) from the fovea favored foveal detachment ( P < 0.001). Multiple retinotomies and blebs allowed greater surface area coverage in some eyes, but intersecting blebs did not propagate further. CONCLUSION: Bleb formation and propagation are predictable based on patient age, retinotomy location, disease indication, and how tangentially fluid is directed into the subretinal space.
Subject(s)
Retinal Detachment , Retinal Diseases , Humans , Retinal Detachment/surgery , Visual Acuity , Retina , Retinal Diseases/genetics , Retinal Diseases/surgery , Genetic TherapyABSTRACT
PURPOSE: To assess the long-term efficacy of intravitreal antivascular endothelial growth factor injections (IVI), alone or in combination with verteporfin photodynamic therapy (IVI/PDT), for management of choroidal neovascularization secondary to presumed ocular histoplasmosis syndrome (POHS). METHODS: Retrospective, comparative, interventional case series analyzing 82 eyes in 74 patients treated with either IVI or IVI/PDT for presumed ocular histoplasmosis syndrome choroidal neovascularization from January 2006 to January 2021. RESULTS: The average logarithm of the minimum angle of resolution VA in year 5 was 0.40 (20/50) and 0.52 (20/67) for IVI versus IVI/PDT groups, respectively ( P = 0.33), and in year 10 was 0.53 (20/58) and 0.64 (20/86), respectively ( P = 0.50). The average number of annual injections over the first 5 years of follow-up was 3.3 versus 1.7 for IVI versus IVI/PDT groups, respectively ( P < 0.001), and over 10 years was 3.3 versus 1.6, respectively ( P < 0.001). Treatment-free interval of 5 years was reached by 39% versus 60% in IVI versus IVI/PDT groups, respectively ( P = 0.95). CONCLUSION: Our study found both IVI and IVI/PDT to be effective in long-term management of presumed ocular histoplasmosis syndrome choroidal neovascularization, with a fewer number of annual injections and longer treatment-free interval in the combination group. However, given the limitations of a retrospective study, a prospective randomized study is necessary to determine whether the addition of PDT significantly decreases treatment burden.
Subject(s)
Choroidal Neovascularization , Eye Infections, Fungal , Histoplasmosis , Photochemotherapy , Angiogenesis Inhibitors , Antibodies, Monoclonal, Humanized/therapeutic use , Choroidal Neovascularization/diagnosis , Choroidal Neovascularization/drug therapy , Choroidal Neovascularization/etiology , Endothelial Growth Factors , Eye Infections, Fungal/complications , Eye Infections, Fungal/drug therapy , Follow-Up Studies , Histoplasmosis/complications , Histoplasmosis/diagnosis , Histoplasmosis/drug therapy , Humans , Photosensitizing Agents/therapeutic use , Prospective Studies , Retrospective Studies , Treatment Outcome , Vascular Endothelial Growth Factor A , Visual AcuityABSTRACT
Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development.
Subject(s)
Glaucoma, Angle-Closure/genetics , Hyperopia/genetics , Membrane Proteins/genetics , Microphthalmos/genetics , Retinal Degeneration/genetics , Transcription Factors/genetics , Adult , Animals , Child , Child, Preschool , Exons , Family , Female , Frameshift Mutation/genetics , Genetic Variation/genetics , Glaucoma, Angle-Closure/metabolism , Humans , Hyperopia/metabolism , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Microphthalmos/metabolism , Middle Aged , Pedigree , RNA Splice Sites/genetics , Refractive Errors/genetics , Transcription Factors/metabolismABSTRACT
BACKGROUND: Usher syndrome (USH) is a neurosensory disorder characterised by deafness, variable vestibular areflexia and vision loss. The aim of the study was to identify the genetic defect in a Pakistani family (PKDF1051) segregating USH. METHODS: Genome-wide linkage analysis was performed by using an Illumina linkage array followed by Sanger and exome sequencing. Heterologous cells and mouse organ of Corti explant-based transfection assays were used for functional evaluations. Detailed clinical evaluations were performed to characterise the USH phenotype. RESULTS: Through homozygosity mapping, we genetically linked the USH phenotype segregating in family PKDF1051 to markers on chromosome 1p36.32-p36.22. The locus was designated USH1M. Using a combination of Sanger sequencing and exome sequencing, we identified a novel homozygous 18 base pair inframe deletion in ESPN. Variants of ESPN, encoding the actin-bundling protein espin, have been previously associated with deafness and vestibular areflexia in humans with no apparent visual deficits. Our functional studies in heterologous cells and in mouse organ of Corti explant cultures revealed that the six deleted residues in affected individuals of family PKDF1051 are essential for the actin bundling function of espin demonstrated by ultracentrifugation actin binding and bundling assays. Funduscopic examination of the affected individuals of family PKDF1051 revealed irregular retinal contour, temporal flecks and disc pallor in both eyes. ERG revealed diminished rod photoreceptor function among affected individuals. CONCLUSION: Our study uncovers an additional USH gene, assigns the USH1 phenotype to a variant of ESPN and provides a 12th molecular component to the USH proteome.
Subject(s)
Benign Paroxysmal Positional Vertigo/genetics , Deafness/genetics , Microfilament Proteins/genetics , Vision Disorders/genetics , Adult , Animals , Benign Paroxysmal Positional Vertigo/physiopathology , Deafness/physiopathology , Genetic Linkage/genetics , Genetic Predisposition to Disease , Genotype , Homozygote , Humans , Mice , Mutation , Pedigree , Phenotype , Retina/metabolism , Retina/physiopathology , Sequence Deletion/genetics , Vision Disorders/physiopathology , Exome Sequencing , Young AdultABSTRACT
PURPOSE: To investigate the effect of serial anterior chamber (AC) paracenteses in eyes with sustained elevations of intraocular pressure (IOP) in the setting of repeated intravitreal injections (IVI) of anti-vascular endothelial growth factor medications. METHODS: This is a retrospective records review of patients undergoing IVI of anti-vascular endothelial growth factor medication (bevacizumab, ranubizumab, or aflibercept), who demonstrated a sustained elevation of preinjection IOP and also received AC paracentesis immediately after IVI on at least three consecutive visits. Changes in preinjection IOP and cup-to-disk (C:D) ratio were compared before and after the initiation of IVI and before and after the introduction of AC paracenteses with each subsequent IVI. RESULTS: Twenty-three eyes of 17 patients receiving a median of 26 IVI experienced a rise in preinjection IOP from 16.3 mmHg to 21.1 mmHg (P = 0.004) and an increase in mean C:D ratio from 0.37 to 0.47 (P = 0.0002). After introduction of AC paracenteses (median of 12), mean IOP was returned to baseline 16.00 mmHg (P = 0.002), mean C:D ratio stabilized (0.50, P = 0.197), and maximum IOP decreased from 26.8 mmHg to 23.0 mmHg (P = 0.05). Nineteen (82.6%) eyes required an increase in topical glaucoma medications during the study period, and 13 (56.5%) still required additional therapies after initiation of AC paracenteses. Five eyes (38.5%) required laser or glaucoma drainage device procedures. CONCLUSION: Serial AC paracenteses reduced immediate postinjection IOP, and along with standard glaucoma care in most patients, reversed preinjection IOP elevation, and stabilized optic nerve changes associated with repeated intravitreal anti-vascular endothelial growth factor injections in a subset of patients with sustained elevation of preinjection IOP.
Subject(s)
Anterior Chamber/surgery , Bevacizumab/adverse effects , Intraocular Pressure/physiology , Ocular Hypertension/surgery , Paracentesis/methods , Ranibizumab/adverse effects , Wet Macular Degeneration/drug therapy , Aged , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Bevacizumab/administration & dosage , Female , Humans , Intraocular Pressure/drug effects , Intravitreal Injections , Male , Ocular Hypertension/chemically induced , Ocular Hypertension/physiopathology , Ranibizumab/administration & dosage , Retrospective Studies , Tonometry, Ocular , Treatment Outcome , Vascular Endothelial Growth Factor A/antagonists & inhibitorsABSTRACT
PURPOSE: There is no established therapy for exudative-hemorrhagic complications in primary retinal arteriolar macroaneurysm (RAM). METHODS: Retrospective multicenter interventional study of anti-vascular endothelial growth factor in symptomatic RAMs. Central macular thickness in µm and best-corrected visual acuity in logMar were correlated with the RAM size and distance to the macula. Statistical analyses were performed using paired comparisons and Pearson correlation. RESULTS: Thirty-two eyes (32 patients) were treated with a mean of 2.7 injections over a mean follow-up of 16.6 months. Initial best-corrected visual acuity correlated with the RAM size and distance to the macula (P = 0.02). Central macular thickness decreased by 131,180, and 211 µm at 1, 2, and 3 months after the first injection (P < 0.001). Best-corrected visual acuity improved by 0.47 and 0.38 Early Treatment Diabetic Retinopathy Study lines at 2 and 3 months (P = 0.005). Anti-vascular endothelial growth factor response correlated with the RAM size (P = 0.04) and the distance to the macula (P = 0.009). CONCLUSION: Symptomatic RAMs can be treated successfully with anti-vascular endothelial growth factor injections, leading to a decrease in macular edema.
Subject(s)
Bevacizumab/administration & dosage , Macula Lutea/pathology , Ranibizumab/administration & dosage , Receptors, Vascular Endothelial Growth Factor/administration & dosage , Recombinant Fusion Proteins/administration & dosage , Retinal Arterial Macroaneurysm/drug therapy , Visual Acuity , Angiogenesis Inhibitors/administration & dosage , Drug Therapy, Combination , Exudates and Transudates , Fluorescein Angiography , Follow-Up Studies , Fundus Oculi , Humans , Intravitreal Injections , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Retinal Arterial Macroaneurysm/diagnosis , Retrospective Studies , Tomography, Optical Coherence , Treatment OutcomeABSTRACT
PURPOSE: To report the clinical outcome after intravitreal dexamethasone implant in patients with retinitis pigmentosa and cystoid macular edema. METHODS: Multicenter retrospective case series of eyes with retinitis pigmentosa and cystoid macular edema that underwent intravitreal dexamethasone implant. Primary outcome measures were best-corrected visual acuity in LogMAR and central macular thickness. Statistical analyses used two-tailed comparison with Wilcoxon signed-rank test. RESULTS: There were a total of 45 eyes from 34 patients with a mean age of 32.7 years (range 16-57) and mean follow-up of 15.5 ± 13.0 months. At Month 3 after the first injection, mean initial best-corrected visual acuity improved from 0.61 ± 0.38 (20/81) to 0.37 ± 0.16 (20/47) (P = 0.012), whereas mean central macular thickness (µm) decreased from 506 ± 288 µm to 311.7 ± 71.6 µm (P < 0.001) and mean intraocular pressure increased from 15.7 ± 2.3 mmHg to 19.8 ± 11.0 mmHg (P = 0.01). Fourteen eyes had multiple injections (1-7 reinjections) at a mean interval of 6 months. Treatment effect was durable with multiple injections, but with seven eyes developing visually significant cataracts. CONCLUSION: Best-corrected visual acuity improved up to 4 months in around half of the eyes. Eyes that benefited the most were pseudophakic, steroid nonresponsive, with large initial central macular thickness, and profuse fluorescein dye leakage.
Subject(s)
Dexamethasone/administration & dosage , Macula Lutea/pathology , Macular Edema/drug therapy , Retinitis Pigmentosa/complications , Visual Acuity , Adolescent , Adult , Dose-Response Relationship, Drug , Drug Implants , Female , Follow-Up Studies , Glucocorticoids/administration & dosage , Humans , Intravitreal Injections , Macula Lutea/drug effects , Macular Edema/diagnosis , Macular Edema/etiology , Male , Middle Aged , Retinitis Pigmentosa/diagnosis , Retinitis Pigmentosa/drug therapy , Retrospective Studies , Time Factors , Tomography, Optical Coherence , Treatment Outcome , Young AdultABSTRACT
PURPOSE: To describe a novel macular phenotype that is associated with normal visual function. DESIGN: Retrospective, observational case series. PARTICIPANTS: Thirty-six affected individuals from 23 unrelated families. METHODS: This was a retrospective study of patients who had a characteristic macular phenotype. Subjects underwent a full ocular examination, electrophysiologic studies, spectral-domain optical coherence tomography (OCT), and fundus autofluorescence imaging. Genomic analyses were performed using haplotype sharing analysis and whole-exome sequencing. MAIN OUTCOME MEASURES: Visual acuity, retinal features, electroretinography, and whole-exome sequencing. RESULTS: Twenty-six of 36 subjects were female. The median age of subjects at presentation was 15 years (range, 5-59 years). The majority of subjects were asymptomatic and presented after a routine eye examination (22/36 subjects) or after screening because of a positive family history (13/36 subjects) or by another ophthalmologist (1/36 subjects). Of the 3 symptomatic subjects, 2 had reduced visual acuity secondary to nonorganic visual loss and bilateral ametropic amblyopia with strabismus. Visual acuity was 0.18 logarithm of the minimum angle of resolution (logMAR) or better in 30 of 33 subjects. Color vision was normal in all subjects tested, except for the subject with nonorganic visual loss. All subjects had bilateral symmetric multiple yellow dots at the macula. In the majority of subjects, these were evenly distributed throughout the fovea, but in 9 subjects they were concentrated in the nasal parafoveal area. The dots were hyperautofluorescent on fundus autofluorescence imaging. The OCT imaging was generally normal, but in 6 subjects subtle irregularities at the inner segment ellipsoid band were seen. Electrophysiologic studies identified normal macular function in 17 of 19 subjects and normal full-field retinal function in all subjects. Whole-exome analysis across 3 unrelated families found no pathogenic variants in known macular dystrophy genes. Haplotype sharing analysis in 1 family excluded linkage with the North Carolina macular dystrophy (MCDR1) locus. CONCLUSIONS: A new retinal phenotype is described, which is characterized by bilateral multiple early-onset yellow dots at the macula. Visual function is normal, and the condition is nonprogressive. In familial cases, the phenotype seems to be inherited in an autosomal dominant manner, but a causative gene is yet to be ascertained.
Subject(s)
Eye Proteins/genetics , Macula Lutea/pathology , Macular Degeneration/diagnosis , Mutation , Visual Acuity , Adolescent , Adult , Child , Child, Preschool , DNA Mutational Analysis , Electroretinography , Exome , Eye Proteins/metabolism , Female , Fluorescein Angiography , Follow-Up Studies , Fundus Oculi , Humans , Macular Degeneration/metabolism , Macular Degeneration/physiopathology , Male , Middle Aged , Pedigree , Phenotype , Retrospective Studies , Tomography, Optical Coherence , Young AdultABSTRACT
PURPOSE: To determine the feasibility and safety of bilateral simultaneous vitreoretinal surgery in pediatric patients. DESIGN: International, multicenter, interventional, retrospective case series. PARTICIPANTS: Patients 17 years of age or younger from 24 centers worldwide who underwent immediate sequential bilateral vitreoretinal surgery (ISBVS)-defined as vitrectomy, scleral buckle, or lensectomy using the vitreous cutter-performed in both eyes sequentially during the same anesthesia session. METHODS: Clinical history, surgical details and indications, time under anesthesia, and intraoperative and postoperative ophthalmic and systemic adverse events were reviewed. MAIN OUTCOME MEASURES: Ocular and systemic adverse events. RESULTS: A total of 344 surgeries from 172 ISBVS procedures in 167 patients were included in the study. The mean age of the cohort was 1.3±2.6 years. Nonexclusive indications for ISBVS were rapidly progressive disease (74.6%), systemic morbidity placing the child at high anesthesia risk (76.0%), and residence remote from surgery location (30.2%). The most common diagnoses were retinopathy of prematurity (ROP; 72.7% [P < 0.01]; stage 3, 4.8%; stage 4A, 44.4%; stage 4B, 22.4%; stage 5, 26.4%), familial exudative vitreoretinopathy (7.0%), abusive head trauma (4.1%), persistent fetal vasculature (3.5%), congenital cataract (1.7%), posterior capsular opacification (1.7%), rhegmatogenous retinal detachment (1.7%), congenital X-linked retinoschisis (1.2%), Norrie disease (2.3%), and viral retinitis (1.2%). Mean surgical time was 143±59 minutes for both eyes. Higher ROP stage correlated with longer surgical time (P = 0.02). There were no reported intraoperative ocular complications. During the immediate postoperative period, 2 eyes from different patients demonstrated unilateral vitreous hemorrhage (0.6%). No cases of endophthalmitis, choroidal hemorrhage, or hypotony occurred. Mean total anesthesia time was 203±87 minutes. There were no cases of anesthesia-related death, malignant hyperthermia, anaphylaxis, or cardiac event. There was 1 case of reintubation (0.6%) and 1 case of prolonged oxygen desaturation (0.6%). Mean follow-up after surgery was 103 weeks, and anatomic success and globe salvage rates were 89.8% and 98.0%, respectively. CONCLUSIONS: This study found ISBVS to be a feasible and safe treatment paradigm for pediatric patients with bilateral vitreoretinal pathologic features when repeated general anesthesia is undesirable or impractical.
Subject(s)
Cataract Extraction , Scleral Buckling/methods , Vitrectomy/methods , Vitreoretinal Surgery , Adolescent , Anesthesia/methods , Cataract/complications , Child , Child, Preschool , Feasibility Studies , Female , Humans , Infant , Internationality , Male , Operative Time , Persistent Hyperplastic Primary Vitreous/complications , Persistent Hyperplastic Primary Vitreous/surgery , Retinal Diseases/complications , Retinal Diseases/congenital , Retinal Diseases/surgery , Retinopathy of Prematurity/complications , Retinopathy of Prematurity/surgery , Retinoschisis/complications , Retinoschisis/surgery , Retrospective Studies , Vitreoretinopathy, Proliferative/complications , Vitreoretinopathy, Proliferative/surgeryABSTRACT
BACKGROUND: Oliver-McFarlane syndrome is characterised by trichomegaly, congenital hypopituitarism and retinal degeneration with choroidal atrophy. Laurence-Moon syndrome presents similarly, though with progressive spinocerebellar ataxia and spastic paraplegia and without trichomegaly. Both recessively inherited disorders have no known genetic cause. METHODS: Whole-exome sequencing was performed to identify the genetic causes of these disorders. Mutations were functionally validated in zebrafish pnpla6 morphants. Embryonic expression was evaluated via in situ hybridisation in human embryonic sections. Human neurohistopathology was performed to characterise cerebellar degeneration. Enzymatic activities were measured in patient-derived fibroblast cell lines. RESULTS: Eight mutations in six families with Oliver-McFarlane or Laurence-Moon syndrome were identified in the PNPLA6 gene, which encodes neuropathy target esterase (NTE). PNPLA6 expression was found in the developing human eye, pituitary and brain. In zebrafish, the pnpla6 curly-tailed morphant phenotype was fully rescued by wild-type human PNPLA6 mRNA and not by mutation-harbouring mRNAs. NTE enzymatic activity was significantly reduced in fibroblast cells derived from individuals with Oliver-McFarlane syndrome. Intriguingly, adult brain histology from a patient with highly overlapping features of Oliver-McFarlane and Laurence-Moon syndromes revealed extensive cerebellar degeneration and atrophy. CONCLUSIONS: Previously, PNPLA6 mutations have been associated with spastic paraplegia type 39, Gordon-Holmes syndrome and Boucher-Neuhäuser syndromes. Discovery of these additional PNPLA6-opathies further elucidates a spectrum of neurodevelopmental and neurodegenerative disorders associated with NTE impairment and suggests a unifying mechanism with diagnostic and prognostic importance.
Subject(s)
Blepharoptosis/enzymology , Blepharoptosis/genetics , Carboxylic Ester Hydrolases/genetics , Dwarfism/enzymology , Dwarfism/genetics , Genetic Predisposition to Disease , Hypertrichosis/enzymology , Hypertrichosis/genetics , Intellectual Disability/enzymology , Intellectual Disability/genetics , Laurence-Moon Syndrome/enzymology , Laurence-Moon Syndrome/genetics , Retinitis Pigmentosa/enzymology , Retinitis Pigmentosa/genetics , Alleles , Amino Acid Sequence , Animals , Carboxylic Ester Hydrolases/chemistry , Central Nervous System/pathology , Developmental Disabilities/enzymology , Developmental Disabilities/genetics , Embryonic Development/genetics , Gene Expression Regulation, Developmental , Humans , Molecular Sequence Data , Mutation/genetics , Phenotype , Phospholipases/chemistry , Phospholipases/genetics , Protein Structure, Tertiary , Retina/pathology , Zebrafish/embryologyABSTRACT
PURPOSE: To report outcomes of patients who have undergone combined Trabectome and pars plana vitrectomy. METHODS: Institutional Review Board-approved retrospective chart review of patients seen at the Cincinnati Eye Institute before January 2014 undergoing combined Trabectome and pars plana vitrectomy for uncontrolled glaucoma and visually significant retina pathology. Charts were reviewed to identify changes in intraocular pressure, visual acuity, and change in glaucoma medication requirement up to 1 year after surgery. RESULTS: Four patients met the inclusion criteria with 12-month follow-up, and two of the patients were male. All patients underwent 25-gauge pars plana vitrectomy and Trabectome surgery. Mean preoperative LogMAR visual acuity was 0.39 (20/49) and 12-month LogMAR visual acuity was 0.21 (20/32) (P = 0.06). Mean preoperative intraocular pressure was 17 mmHg and mean preoperative glaucoma medication requirement was 2.5 topical medications. Twelve-month mean intraocular pressure was 12.8 mmHg (P = 0.07), and mean topical glaucoma medication requirement was 2.3 medications (P = 0.39). All patients were off steroids and anti-inflammatories at the final visit. One patient developed a hyphema requiring anterior chamber washout at 1 week. No other complications occurred. CONCLUSION: The results suggest that combined Trabectome and pars plana vitrectomy seems effective in the management of glaucoma in patients with visually significant retina pathology.
Subject(s)
Glaucoma, Open-Angle/surgery , Retinal Diseases/surgery , Trabeculectomy/methods , Vitrectomy/methods , Aged , Aged, 80 and over , Female , Follow-Up Studies , Glaucoma, Open-Angle/physiopathology , Humans , Intraocular Pressure/physiology , Lens Implantation, Intraocular , Male , Microsurgery , Middle Aged , Phacoemulsification , Prognosis , Retinal Diseases/physiopathology , Retrospective Studies , Tonometry, Ocular , Trabecular Meshwork/surgery , Visual Acuity/physiologySubject(s)
Anticoagulants/adverse effects , Pentosan Sulfuric Polyester/adverse effects , Vitelliform Macular Dystrophy/chemically induced , Aged , Cystitis, Interstitial/drug therapy , Female , Humans , Photoreceptor Cells, Vertebrate/drug effects , Photoreceptor Cells, Vertebrate/pathology , Tomography, Optical Coherence , Vitelliform Macular Dystrophy/diagnostic imagingABSTRACT
PURPOSE: To report the outcomes of combined cataract surgery with toric intraocular lens (IOL) implantation when performed in conjunction with transconjunctival sutureless pars plana vitrectomy. DESIGN: Retrospective interventional case series. PARTICIPANTS: Consecutive series of 55 eyes of 51 patients from April 2007 to December of 2010. METHODS: All eyes underwent combined simultaneous small incision cataract surgery, toric IOL implantation, and transconjunctival sutureless vitrectomy surgery. MAIN OUTCOME MEASURES: Postoperative visual acuity, postoperative astigmatism, and rotational stability of the IOL. RESULTS: Preoperative best-corrected visual acuity was 0.32 ± 0.15 logMar (Snellen 20/43) and improved to 0.16 ± 0.10 (Snellen 20/29) postoperatively uncorrected (P < 0.01) and to 0.08 ± 0.11 best-corrected (Snellen 20/24) (P < 0.01). Preoperative astigmatism was 1.75 ± 1.0 diopters (D) (range, 0-4.75 D) and improved to 0.5 ± 0.50 D (range, 0-2.5 D) postoperatively (P < 0.01). Final measured postoperative IOL axis deviation from target axis was 4 ± 6° (range, 0-32). Final IOL axis was within 5° of target in 47 (85%) eyes, within 10 degrees of target in 51 (93%) eyes, and was within 15° of target in 52 (95%) eyes. CONCLUSION: Toric lens position and axis remained stable after implantation during combined cataract surgery and transconjunctival sutureless vitrectomy.
Subject(s)
Lens Implantation, Intraocular , Lenses, Intraocular , Phacoemulsification/methods , Pseudophakia/physiopathology , Visual Acuity/physiology , Vitrectomy , Aged , Aged, 80 and over , Astigmatism/physiopathology , Conjunctiva/surgery , Female , Humans , Male , Middle Aged , Postoperative Complications , Prosthesis Failure , Retinal Diseases/surgeryABSTRACT
PURPOSE: To describe multimodal imaging and electrophysiologic characteristics of an unusual subset of patients with genetically confirmed autosomal recessive Stargardt disease (STGD1) who exhibited a central form of cone dysfunction resembling occult macular dystrophy that preceded the development of lipofuscin flecks, atrophy of retinal pigment epithelium (RPE), or full-field electroretinography abnormalities. METHODS: Retrospective, observational descriptive case series. RESULTS: Five patients with compound heterozygous ABCA4 mutations presented with bilateral visual acuity reduction, normal-appearing fundi, and blocked choroidal fluorescence on fluorescein angiography. One sibling each of two probands with identical genotypes was also included for analysis. Full-field electroretinography testing was normal in all patients, but multifocal electroretinography demonstrated centripetally depressed amplitudes exceeding areas of fundus autofluorescence, infrared imaging, and spectral domain optical coherence tomography abnormalities. Spectral domain optical coherence tomography initially revealed disruption of the inner segment ellipsoid band accompanying an ovoid hypofluorescent foveolar lesion. Progression to later stages was accompanied by the loss of the foveal photoreceptor outer segments, creating foveal cavitation with preservation of the RPE. Fundus autofluorescence and infrared imaging demonstrated corresponding bull's eye lesions. Over time, the foveal potential space on spectral domain optical coherence tomography collapsed, and three patients developed RPE atrophy and visible lipofuscin flecks. The flecks were detectable by fundus autofluorescence and infrared imaging earlier than by biomicroscopy. From these findings, a staging system for this subset of Stargardt disease presenting with central cone dysfunction was developed and presented herein. CONCLUSION: Autosomal recessive Stargardt disease may present as a central cone dysfunction syndrome before the development of lipofuscin flecks, atrophy of RPE, or full-field electroretinography abnormalities. If emerging therapies for Stargardt disease succeed, early recognition and treatment of patients with preserved foveal photoreceptor and RPE cell bodies may yield a more favorable visual prognosis.
Subject(s)
Macular Degeneration/congenital , Macular Degeneration/diagnosis , Retinal Cone Photoreceptor Cells/pathology , Retinal Pigment Epithelium/pathology , ATP-Binding Cassette Transporters/genetics , Adolescent , Adult , Atrophy , Child , Electroretinography , Female , Fluorescein Angiography , Genes, Recessive , Humans , Macular Degeneration/genetics , Male , Multimodal Imaging , Mutation , Retrospective Studies , Stargardt Disease , Tomography, Optical Coherence , Visual Acuity/physiologySubject(s)
Intraocular Pressure , Paracentesis , Anterior Chamber , Endothelial Growth Factors , Humans , Tonometry, OcularABSTRACT
PURPOSE: Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a rare genetic (CAPN5) autoimmune condition typically diagnosed in adulthood and characterized by a triad of inflammation, retinal degeneration, and neovascularization. We report novel multimodal imaging findings in children and young adults with ADNIV, and early treatment response to short-duration local and systemic corticosteroids. DESIGN: Retrospective consecutive case series. PARTICIPANTS: Ten patients aged <25 years with ADNIV and available multimodal imaging. METHODS: The medical records of patients aged <25 years with a diagnosis of ADNIV with ultrawidefield fluorescein angiography (UWFFA) and OCT data were reviewed. MAIN OUTCOME MEASURES: Ultrawidefield fluorescein angiography and OCT findings at baseline and after local corticosteroids. RESULTS: Median age at presentation was 14 years (range, 9-24 years). OCT on presentation demonstrated cystoid macular edema in 8 of 20 eyes and symptomatic vitreoretinal interface disease in 2 of 20 eyes. Initial UWFFA demonstrated retinal vascular leakage (20/20 eyes, 100%), peripheral nonperfusion (13/20 eyes, 65%), and retinal neovascularization (6/20 eyes, 30%). Retinal vascular leakage improved with local corticosteroids, and neovascularization regressed with anti-VEGF therapy. CONCLUSIONS: Ultrawidefield fluorescein angiography findings of prefibrotic ADNIV reported in adults were also present in children and young adults. Early testing for a pathogenic CAPN5 variant in at-risk children and regularly scheduled screening for uveitis and retinal vasculitis with UWFFA and OCT may prompt earlier intervention. Short-duration local steroids are effective at treating retinal vascular leakage and macular edema but are not durable, suggesting a potential role for steroid-sparing immunosuppressive therapy. Early treatment may alter the natural history of disease. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
ABSTRACT
PURPOSE: Classify the appearance and quantify the growth rate of chorioretinal atrophy in patients who received voretigene neparvovec-rzyl (VN) for RPE65-mediated retinal degeneration. DESIGN: Multicenter retrospective analysis. SUBJECTS: Patients who underwent subretinal VN injection at 5 institutions and demonstrated posterior-pole chorioretinal atrophy. METHODS: Ultrawidefield scanning laser ophthalmoscopy or color fundus photos were assessed before and after subretinal VN. Atrophy was defined as regions with ≥ 2 of the following: (1) partial or complete retinal pigment epithelial depigmentation; (2) round shape; (3) sharp margins; and (4) increased visibility of choroidal vessels. Atrophy was qualitatively classified into different subtypes. All atrophy was manually segmented. Linear mixed-effects models with random slopes and intercepts were fit using atrophy area and square root of atrophy area. MAIN OUTCOME MEASURES: Number of eyes with each atrophy pattern, and slopes of linear mixed-effects models. RESULTS: Twenty-seven eyes from 14 patients across 5 centers developed chorioretinal atrophy after subretinal VN. A mean of 5.8 ± 2.7 images per eye obtained over 2.2 ± 0.8 years were reviewed, and atrophy was categorized into touchdown (14 eyes), nummular (15 eyes), and perifoveal (12 eyes) subtypes. Fifteen eyes demonstrated > 1 type of atrophy. Thirteen of 14 patients demonstrated bilateral atrophy. The slopes of the mixed-effects models of atrophy area and square root of atrophy area (estimate ± standard error) were 1.7 ± 1.3 mm2/year and 0.6 ± 0.2 mm/year for touchdown atrophy, 5.5 ± 1.3 mm2/year and 1.2 ± 0.2 mm/year for nummular atrophy, and 16.7 ± 1.8 mm2/year and 2.3 ± 0.2 mm/year for perifoveal atrophy. The slopes for each type of atrophy were significantly different in the square root of atrophy model, which best fit the data (P < 0.05). CONCLUSIONS: Chorioretinal atrophy after subretinal VN for RPE65-mediated retinal degeneration developed according to a touchdown, nummular, and/or perifoveal pattern. Perifoveal atrophy grew the most rapidly, while touchdown atrophy grew the least rapidly. Understanding the causes of these findings, which are present in a minority of patients, merits further investigation. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.