RESUMEN
PURPOSE: To report on the indications, outcomes, and complications of endoscopic vitrectomy in a large cohort of pediatric vitreoretinal patients. METHODS: This is a retrospective interventional case series consisting of 244 eyes of 211 patients aged 18 years or younger undergoing a total of 326 endoscopic vitrectomies from 2008 to 2017. A 23-gauge vitrectomy was performed with use of a 19-gauge endoscope. RESULTS: Two hundred and eleven patients with a mean age of 7.5 years (range: 0-18 years) and median follow-up since last surgery of 28 months (range: 3 months-8.7 years) were included. The most common indication for endoscopic vitrectomy was retinal detachment (234/326; 72%) with proliferative vitreoretinopathy (162/234; 69%). Other diagnoses included trauma (25%), retinopathy of prematurity (15%), and glaucoma (9%). Twenty-five percent of surgeries (80/326) were performed on eyes with significant corneal opacities. Retinal reattachment was achieved in 67% of eyes with retinal detachment (119/178). Visual acuity improved in 26% of retinal detachment eyes versus 53% of nonretinal detachment eyes (P = 0.005). Surgical complications included band keratopathy (15%), hypotony (8%), cataract (7%), and elevated intraocular pressure (3%). CONCLUSION: In this large series of pediatric endoscopic vitreoretinal surgeries, anatomic outcomes and complication rates were comparable with previous studies.
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Endoscopía/métodos , Retina/anatomía & histología , Agudeza Visual/fisiología , Vitrectomía/métodos , Cirugía Vitreorretiniana , Adolescente , Niño , Preescolar , Lesiones Oculares/cirugía , Femenino , Glaucoma/cirugía , Humanos , Lactante , Recién Nacido , Masculino , Desprendimiento de Retina/cirugía , Retinopatía de la Prematuridad/cirugía , Estudios Retrospectivos , Vitreorretinopatía Proliferativa/cirugíaRESUMEN
PURPOSE: We sought to evaluate discrepancy rates between outside interpretations, radiology trainee preliminary reports, and subspecialist attending final interpretations for pediatric second opinion consultations on plain film and computed tomography imaging and to evaluate the impact of a process improvement for second opinion consultations. METHODS: Of a total of 572 requests for second opinion consultations during 1-year preintervention period, we utilized RADPEER to score concurrence of 158 requests which occurred overnight and included outside radiologist interpretations and resident preliminary reports. In consultation with clinician committees, we developed new guidelines for requesting second opinion consultations. We evaluated the impact on the number of consultations for the 1-year period following implementation of this process improvement. RESULTS: There was concurrence between the outside interpretation and pediatric subspecialist second opinion in 146 of 158 cases (92%). There was concurrence between the radiology resident and pediatric subspecialist second opinion in 145 of 158 cases (92%). During the 1-year period following our process improvement implementation, the total number of second opinion consultations decreased to 185 (from 572, a decrease of 68%) and the number of overnight requests for resident preliminary reports decreased to 11 (from 158, a decrease of 93%). CONCLUSIONS: There was a high degree of concurrence between interpretations provided by outside radiologists, overnight radiology residents, and attending pediatric radiologists at our institution. Analyzing institutional-specific discrepancy rates is a valuable first step in partnering with clinicians to develop appropriate guidelines for second opinion consultations.
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Pediatría/métodos , Radiología/métodos , Derivación y Consulta , Humanos , Internado y Residencia , Variaciones Dependientes del Observador , RadiólogosAsunto(s)
Lesiones Oculares/etiología , Armas de Fuego , Juego e Implementos de Juego/lesiones , Niño , Femenino , Humanos , Los Angeles , Masculino , Adulto JovenRESUMEN
Importance: Next-generation sequencing can detect variants of uncertain significance (VUSs), for some of which gene therapy would not be advantageous. Therefore, the pathogenicity of compound heterozygous or homozygous variants should be confirmed before bilateral vitrectomy and administration of voretigene neparvovec-rzyl. Objective: To describe an in vitro mutagenesis assay for assessing the pathogenicity of variants in the RPE65 gene. Design, Setting, and Participants: This case series was conducted at 2 tertiary referral centers. Clinical history, imaging, and electrophysiologic testing results were reviewed from September 5, 2008, to December 31, 2019. Participants were 4 pediatric patients with Leber congenital amaurosis who were evaluated for or met the inclusion criteria for phase 1 to 3 clinical trials or were referred for voretigene neparvovec-rzyl treatment. Main Outcomes and Measures: A functional assay was used to confirm the pathogenicity of novel RPE65 VUSs in 4 patients with Leber congenital amaurosis. Results: Four patients with Leber congenital amaurosis had VUSs in RPE65. Patients 1 and 2 were siblings with the homozygous VUS c.311G>T p.(G104V). Patient 3 was a compound heterozygote with 1 known pathogenic allele, c.1202_1203insCTGG p.(Glu404AlafsTer4), and 1 VUS, c.311G>T p.(G104V), which segregated to separate alleles. Patient 4 was also a compound heterozygote with 1 pathogenic variant, c.11 + 5G>A, and 1 variant in trans, c.1399C>T p.(P467S). In vitro mutagenesis revealed that the G104V and P467S RPE65 proteins were catalytically inactive (0% isomerase activity). Patients 1 and 2 were excluded from participation in a phase 1 trial owing to high Adeno-associated virus 2 capsid-neutralizing antibodies. Patients 3 (G104V) and 4 (P467S) underwent successful surgical gene therapy with voretigene neparvovec-rzyl, and their response to lower white light intensity and visual field increased in fewer than 30 days after gene therapy intervention. Conclusions and Relevance: Findings from this study suggest that, in patients with missense mutations in RPE65, functional assays of protein function can be performed to assess the pathogenicity of variants in both compound heterozygous and homozygous cases. Given the potential risks of gene therapy operations, in vitro RPE65 activity testing should be considered to avoid the possibility of treating a false genotype.
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Terapia Genética , Vectores Genéticos , Amaurosis Congénita de Leber/genética , Amaurosis Congénita de Leber/terapia , Mutagénesis/genética , Mutación Missense/genética , Parvovirinae/genética , cis-trans-Isomerasas/genética , Adolescente , Niño , Análisis Mutacional de ADN , Dependovirus , Electroforesis en Gel de Poliacrilamida , Femenino , Genotipo , Humanos , Immunoblotting , Amaurosis Congénita de Leber/fisiopatología , Masculino , Hermanos , Tomografía de Coherencia Óptica , Agudeza Visual/fisiologíaRESUMEN
Endoscopic vitrectomy is a useful and unique adjunct to microincision vitreoretinal surgery. The optical properties of endoscopy allow for some clinically advantageous approaches that are not possible with regular microscope viewing systems, namely, the ability to both bypass optically signficant anterior segment opacities and directly visualize dificult-to-access retroirideal, retrolental, and anterior retinal structures in their natural anatomical configuration. The surgical benefits include improved surgical access to the pars plana, pars plicata, ciliary sulcus, ciliary body, and peripheral lens, along with unique access to anterior traction in complex pediatric anterior detachments, particularly in retinopathy of prematurity. This review will focus on the development and surgical utility of intraocular endoscopy, provide an update on its current uses in the era of microincision vitreoretinal surgery, and highligh its role in pediatric vitreoretinal diseases.
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Endoscopía/métodos , Enfermedades de la Retina/cirugía , Cirugía Vitreorretiniana/métodos , Niño , HumanosRESUMEN
Neuronal arborization is regulated by cell-autonomous and nonautonomous mechanisms including endosomal signaling via BDNF/TrkB. The endosomal Naâº/H⺠exchanger 6 (NHE6) is mutated in a new autism-related disorder. NHE6 functions to permit proton leak from endosomes, yet the mechanisms causing disease are unknown. We demonstrate that loss of NHE6 results in overacidification of the endosomal compartment and attenuated TrkB signaling. Mouse brains with disrupted NHE6 display reduced axonal and dendritic branching, synapse number, and circuit strength. Site-directed mutagenesis shows that the proton leak function of NHE6 is required for neuronal arborization. We find that TrkB receptor colocalizes to NHE6-associated endosomes. TrkB protein and phosphorylation are reduced in NHE6 mutant neurons in response to BDNF signaling. Finally, exogenous BDNF rescues defects in neuronal arborization. We propose that NHE6 mutation leads to circuit defects that are in part due to impoverished neuronal arborization that may be treatable by enhanced TrkB signaling.
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Endosomas/metabolismo , Red Nerviosa/metabolismo , Neuronas/metabolismo , Receptor trkB/genética , Transducción de Señal , Intercambiadores de Sodio-Hidrógeno/genética , Animales , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Células Cultivadas , Dendritas/fisiología , Endosomas/genética , Ratones , Ratones Noqueados , Neurogénesis/genética , Neurogénesis/fisiología , Receptor trkB/metabolismo , Transducción de Señal/fisiología , Intercambiadores de Sodio-Hidrógeno/metabolismoRESUMEN
In this review, we outline critical molecular processes that have been implicated by discovery of genetic mutations in autism. These mechanisms need to be mapped onto the neurodevelopment step(s) gone awry that may be associated with cause in autism. Molecular mechanisms include: (i) regulation of gene expression; (ii) pre-mRNA splicing; (iii) protein localization, translation, and turnover; (iv) synaptic transmission; (v) cell signaling; (vi) the functions of cytoskeletal and scaffolding proteins; and (vii) the function of neuronal cell adhesion molecules. While the molecular mechanisms appear broad, they may converge on only one of a few steps during neurodevelopment that perturbs the structure, function, and/or plasticity of neuronal circuitry. While there are many genetic mutations involved, novel treatments may need to target only one of few developmental mechanisms.