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BACKGROUND: Cerebral malaria (CM) continues to present a major health challenge, particularly in sub-Saharan Africa. CM is associated with a characteristic malarial retinopathy (MR) with diagnostic and prognostic significance. Advances in retinal imaging have allowed researchers to better characterize the changes seen in MR and to make inferences about the pathophysiology of the disease. The study aimed to explore the role of retinal imaging in diagnosis and prognostication in CM; establish insights into pathophysiology of CM from retinal imaging; establish future research directions. METHODS: The literature was systematically reviewed using the African Index Medicus, MEDLINE, Scopus and Web of Science databases. A total of 35 full texts were included in the final analysis. The descriptive nature of the included studies and heterogeneity precluded meta-analysis. RESULTS: Available research clearly shows retinal imaging is useful both as a clinical tool for the assessment of CM and as a scientific instrument to aid the understanding of the condition. Modalities which can be performed at the bedside, such as fundus photography and optical coherence tomography, are best positioned to take advantage of artificial intelligence-assisted image analysis, unlocking the clinical potential of retinal imaging for real-time diagnosis in low-resource environments where extensively trained clinicians may be few in number, and for guiding adjunctive therapies as they develop. CONCLUSIONS: Further research into retinal imaging technologies in CM is justified. In particular, co-ordinated interdisciplinary work shows promise in unpicking the pathophysiology of a complex disease.
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Malária Cerebral , Doenças Retinianas , Humanos , Inteligência Artificial , Retina/diagnóstico por imagem , Doenças Retinianas/diagnóstico por imagem , Tomografia de Coerência Óptica/métodosRESUMO
PURPOSE: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). DESIGN: Multicenter, observational study. PARTICIPANTS: A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). METHODS: Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. MAIN OUTCOME MEASURES: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). RESULTS: The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. CONCLUSIONS: We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.
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Albinismo Ocular , Albinismo Oculocutâneo , Albinismo , Defeitos da Visão Cromática , Albinismo Ocular/diagnóstico , Albinismo Ocular/genética , Albinismo Oculocutâneo/diagnóstico , Albinismo Oculocutâneo/genética , Defeitos da Visão Cromática/diagnóstico , Defeitos da Visão Cromática/genética , Proteínas do Citoesqueleto , Fóvea Central/anormalidades , Humanos , Proteínas de Membrana , Transtornos da Visão/diagnósticoRESUMO
Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.
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Fibrose/patologia , Músculos Oculomotores/patologia , Oftalmoplegia/patologia , Nervo Óptico/patologia , Retina/patologia , Adulto , Nervos Cranianos/patologia , Feminino , Fibrose/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Oftalmoplegia/genética , Disco Óptico/patologia , Fenótipo , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica/métodos , Adulto JovemRESUMO
Purpose: This is the first systematic comparison of visual field (VF) deficits in people with albinism (PwA) and idiopathic infantile nystagmus (PwIIN) using static perimetry. We also compare best-corrected visual acuity (BCVA) and optical coherence tomography measures of the fovea, parafovea, and circumpapillary retinal nerve fiber layer in PwA. Methods: VF testing was performed on 62 PwA and 36 PwIIN using a Humphrey Field Analyzer (SITA FAST 24-2). Mean detection thresholds for each eye were calculated, along with quadrants and central measures. Retinal layers were manually segmented in the macular region. Results: Mean detection thresholds were significantly lower than normative values for PwA (-3.10 ± 1.67 dB, P << 0.0001) and PwIIN (-1.70 ± 1.54 dB, P < 0.0001). Mean detection thresholds were significantly lower in PwA compared to PwIIN (P < 0.0001) and significantly worse for left compared to right eyes in PwA (P = 0.0002) but not in PwIIN (P = 0.37). In PwA, the superior nasal VF was significantly worse than other quadrants (P < 0.05). PwIIN appeared to show a mild relative arcuate scotoma. In PwA, central detection thresholds were correlated with foveal changes in the inner and outer retina. VF was strongly correlated to BCVA in both groups. Conclusions: Clear peripheral and central VF deficits exist in PwA and PwIIN, and static VF results need to be interpreted with caution clinically. Since PwA exhibit considerably lower detection thresholds compared to PwIIN, VF defects are unlikely to be due to nystagmus in PwA. In addition to horizontal VF asymmetry, PwA exhibit both vertical and interocular asymmetries, which needs further exploration.
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Albinismo , Doenças Genéticas Ligadas ao Cromossomo X , Nistagmo Congênito , Humanos , Campos Visuais , Escotoma/diagnóstico , Escotoma/etiologia , RetinaRESUMO
Purpose: Our primary aim was to compare adult full-field ERG (ffERG) responses in albinism, idiopathic infantile nystagmus (IIN), and controls. A secondary aim was to investigate the effect of within-subject changes in nystagmus eye movements on ffERG responses. Methods: Dilated Ganzfeld flash ffERG responses were recorded using DTL electrodes under conditions of dark (standard and dim flash) and light adaptation in 68 participants with albinism, 43 with IIN, and 24 controls. For the primary aim, the effect of group and age on ffERG responses was investigated. For the secondary aim, null region characteristics were determined using eye movements recorded prior to ffERG recordings. ffERG responses were recorded near and away from the null regions of 18 participants also measuring the success rate of recordings. Results: For the primary aim, age-adjusted photopic a- and b-wave amplitudes were consistently smaller in IIN compared with controls (P < 0.0001), with responses in both groups decreasing with age. In contrast, photopic a-wave amplitudes increased with age in albinism (P = 0.0035). For the secondary aim, more intense nystagmus significantly reduced the success rate of measurable responses. Within-subject changes in nystagmus intensity generated small, borderline significant differences in photopic b-wave peak times and a-and b-wave amplitudes under scotopic conditions with standard flash. Conclusions: Age-adjusted photopic ffERG responses are significantly reduced in IIN adding to the growing body of evidence of retinal abnormalities in IIN. Differences between photopic responses in albinism and controls depend on age. Success at obtaining ffERG responses could be improved by recording responses at the null region.
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Albinismo , Doenças Genéticas Ligadas ao Cromossomo X , Nistagmo Congênito , Nistagmo Patológico , Adulto , Humanos , Nistagmo Patológico/diagnóstico , Movimentos OcularesRESUMO
INTRODUCTION: Postoperative delirium in older people may result from the interaction between intrinsic brain vulnerability (e.g. neurodegeneration) and precipitating factors (e.g. surgery induced cytokines). Intrinsic brain vulnerability may be overt (e.g. Alzheimer's disease) or preclinical. In cognitively intact older people presenting for surgery, identification of preclinical neurodegeneration using bedside tools could aid postoperative delirium risk stratification. Thinning of the circumpapillary retinal nerve fibre layer thickness is associated with neurodegenerative disorders e.g. Alzheimer's disease. We propose that thinning of the retinal nerve fibre layer may be present some older people with postoperative delirium due to preclinical neurodegeneration, albeit to a lesser extent than in overt dementia. OBJECTIVES: The primary objective: Feasibility of acquiring usable retinal images with the hand-held optical coherence device, at the bedside of older, hip fracture surgery patients. Secondary objective: Comparison of the circumpapillary retinal nerve fibre layer thickness between people who did/did not have postoperative delirium. Proportion of exclusions due to retinal pathology. METHOD: Feasibility study involving 30, cognitively intact, older people recovering from hip fracture surgery. Retinal images were obtained using the hand-held optical coherence tomography device at the participants' bedside. Imaging was deferred in participants who had postoperative delirium. RESULTS: Retinal images that could be assessed for circumpapillary retinal nerve fibre layer thickness were obtained in 26 participants (22 no postoperative delirium, 4 postoperative delirium). The mean circumpapillary retinal nerve fibre layer thickness was lower in the participants who had postoperative delirium compared to those who did not experience postoperative delirium (Mean (95% CI) of 76.50 (62.60-90.40) vs 89.19 (85.41-92.97) respectively). CONCLUSION: Retinal imaging at the patient's bedside, using hand-held OCT is feasible. Our data suggests that the circumpapillary retinal nerve fibre layer may be thinner in older people who experience postoperative delirium compared to those who do not. Further studies are required.
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Delírio , Estudos de Viabilidade , Fraturas do Quadril , Complicações Pós-Operatórias , Retina , Tomografia de Coerência Óptica , Humanos , Tomografia de Coerência Óptica/métodos , Masculino , Feminino , Idoso , Fraturas do Quadril/cirurgia , Fraturas do Quadril/diagnóstico por imagem , Idoso de 80 Anos ou mais , Retina/diagnóstico por imagem , Retina/cirurgia , Retina/patologia , Delírio/etiologia , Delírio/diagnóstico por imagem , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Fibras Nervosas/patologiaRESUMO
MEETING PRESENTATION: Presented at the 2016 Association for Research in Vision and Ophthalmology meeting and at the 2015 British Isles Paediatric, Ophthalmology and Strabismus Association meeting. PURPOSE: To investigate the time course of foveal development after birth in infants with albinism. DESIGN: Prospective, comparative cohort optical coherence tomography study. METHODS: Thirty-six children with albinism were recruited. All participants were between 0 and 6 years of age and were seen at Leicester Royal Infirmary. A total of 181 mixed cross-sectional and longitudinal optical coherence tomography examinations were obtained, which were analyzed for differences in retinal development in comparison to 297 cross-sectional control examinations. RESULTS: Normal retinal development involves migration of the inner retinal layers (IRLs) away from the fovea, migration of the cone photoreceptors into the fovea, and elongation of the outer retinal layers (ORLs) over time. In contrast to controls where IRL migration from the fovea was almost completed at birth, a significant degree of IRL migration was taking place after birth in albinism, before arresting prematurely at 40 months postmenstrual age (PMA). This resulted in a significantly thicker central macular thickness in albinism (Δ = 83.8 ± 6.1, P < .0001 at 69 months PMA). There was evidence of ongoing foveal ORL elongation in albinism, although reduced in amplitude compared with control subjects after 21 months PMA (Δ = -17.3 ± 4.3, P < .0001). CONCLUSIONS: We have demonstrated evidence of ongoing retinal development in young children with albinism, albeit at a reduced rate and magnitude compared with control subjects. The presence of a period of retinal plasticity in early childhood raises the possibility that treatment modalities, which aim to improve retinal development, could potentially optimize visual function in albinism.
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Albinismo , Fóvea Central , Recém-Nascido , Criança , Pré-Escolar , Lactente , Humanos , Estudos Prospectivos , Estudos Transversais , Tomografia de Coerência Óptica/métodosRESUMO
Cerebral malaria (CM) remains a significant global health challenge with high morbidity and mortality. Malarial retinopathy has been shown to be diagnostically and prognostically significant in the assessment of CM. The major mechanism of death in paediatric CM is brain swelling. Long term morbidity is typically characterised by neurological and neurodevelopmental sequelae. Optical coherence tomography can be used to quantify papilloedema and macular ischaemia, identified as hyperreflectivity. Here we describe a protocol to test the hypotheses that quantification of optic nerve head swelling using optical coherence tomography can identify severe brain swelling in CM, and that quantification of hyperreflectivity in the macula predicts neurodevelopmental outcomes post-recovery. Additionally, our protocol includes the development of a novel, low-cost, handheld optical coherence tomography machine and artificial intelligence tools to assist in image analysis.
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Purpose: Infantile nystagmus syndrome (INS) causes altered visual development and can be associated with abnormal retinal structure, to which vascular development of the retina is closely related. Abnormal retinal vasculature has previously been noted in albinism but not idiopathic infantile nystagmus. We compared the number and diameter of retinal vessels in participants with albinism (PWA) and idiopathic infantile nystagmus (PWIIN) with controls. Methods: Fundus photography data from 24 PWA, 10 PWIIN, and 34 controls was analyzed using Automated Retinal Image Analyzer (ARIA) software on a field of analysis centered on the optic disc, the annulus of which extended between 4.2 mm and 8.4 mm in diameter. Results: Compared with controls, the mean number of arterial branches was reduced by 24% in PWA (15.5 vs. 20.3, P < 0.001), and venous branches were reduced in both PWA (29%; 12.9 vs. 18.2, P < 0.001) and PWIIN (17%; 15.1 vs. 18.2, P = 0.024). PWA demonstrated 7% thinner "primary" (before branching) arteries (mean diameter: 75.39 µm vs. 80.88 µm, P = 0.043), and 13% thicker (after branching) "secondary" veins (66.72 µm vs. 59.01 µm in controls, P = 0.009). Conclusions: PWA and PWIIN demonstrated reduced retinal vessel counts and arterial diameters compared with controls. These changes in the superficial retinal vascular network may be secondary to underdevelopment of the neuronal network, which guides vascular development and is also known to be disrupted in INS.
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Albinismo , Nistagmo Congênito , Nistagmo Patológico , Disco Óptico , Doenças Genéticas Ligadas ao Cromossomo X , Humanos , Disco Óptico/irrigação sanguínea , Vasos RetinianosRESUMO
Purpose: This prospective study investigates longitudinal changes in retinal structure in patients with achromatopsia (ACHM) using optical coherence tomography (OCT). Methods: Seventeen patients (five adults, 12 children) with genetically confirmed CNGA3- or CNGB3-associated ACHM underwent ocular examination and OCT over a follow-up period of between 2 and 9.33 years (mean = 5.7 years). Foveal tomograms were qualitatively graded and were segmented for quantitative analysis: central macular thickness (CMt), outer nuclear layer thickness (ONLt), and size of the foveal hyporeflective zone (vertical HRZ thickness: HRZt and horizontal HRZ width: HRZw) were measured. Data were analyzed using linear mixed regression models. Both age and visit were included into the models, to explore the possibility that the rate of disease progression depends on patient age. Results: Fifteen of 17 patients (88%) showed longitudinal changes in retinal structure over the follow-up period. The most common patterns of progression was development of ellipsoid zone (EZ) disruption and HRZ. There was a significant increase in HRZt (P = 0.01) and HRZw (P = 0.001) between visits and no significant change in CMt and ONLt. Retinal parameters showed no difference in changes by genetic mutation (CNGA3 (n = 11), CNGB3 (n = 6)). Conclusions: This study demonstrates clear longitudinal changes in foveal structure mainly in children, but also in adults with ACHM, over a long follow-up period. The longitudinal foveal changes suggest that treatment at an earlier age should be favored.
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Defeitos da Visão Cromática , Adulto , Criança , Defeitos da Visão Cromática/diagnóstico por imagem , Defeitos da Visão Cromática/genética , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Humanos , Estudos Prospectivos , Tomografia de Coerência Óptica/métodos , Acuidade VisualRESUMO
BACKGROUND: Congenital cranial dysinnervation disorders (CCDDs) are a group of diseases with high clinical and genetic heterogeneity. Clinical examinations combined with Magnetic resonance imaging (MRI) and whole exome sequencing (WES) were performed to reveal the phenotypic and genotypic characteristics in a cohort of Chinese CCDDs patients. RESULTS: A total of 122 CCDDs patients from 96 families were enrolled. All patients showed restrictive eye movements, and 46 patients from 46 families (47.9%, 46/96) were accompanied by multiple congenital malformations. Multi-positional high-resolution MRI was performed in 94 patients from 88 families, of which, all patients had hypoplasia of the cranial nerves except HGPPS patients and 15 patients from 15 families (17.0%,15/88) were accompanied by other craniocerebral malformations. WES was performed in 122 CCDDs patients. Ten pathogenic variants were detected in KIF21A, TUBB3, and CHN1 genes in 43 families. Three variants were unreported, including KIF21A (c.1064T > C, p.F355S), TUBB3 (c.232T > A, p.S78T) and CHN1 (c.650A > G, p.H217R). Of the 43 probands harboring pathogenic variants, 42 were diagnosed with Congenital Fibrosis of Extraocular Muscles (CFEOM) and one was Duane Retraction Syndrome (DRS). No definite pathogenic variants in known candidate genes of CCDDs were found in sporadic DRS, Möbius Syndrome (MBS) and Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) patients. The CFEOM patients harboring R380C, E410K and R262H variants in TUBB3 gene and F355S variant in KIF21A gene exhibited syndromic phenotypes. CONCLUSIONS: This study broadened the phenotypic and genotypic spectrums of CCDDs, and it was the largest clinical and genetic investigation for CCDDs patients from China. KIF21A and TUBB3 were the common pathogenic genes in Chinese CFEOM. MRI coupled with WES can provide a supportive diagnosis in patients with clinically suspected CCDDs.
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Transtornos Congênitos de Denervação Craniana , Síndrome da Retração Ocular , Síndrome de Möbius , Oftalmoplegia , Humanos , População do Leste Asiático , Síndrome da Retração Ocular/diagnóstico , Síndrome da Retração Ocular/genética , Síndrome de Möbius/diagnóstico , FibroseRESUMO
We aimed to investigate structural retinal changes in malarial retinopathy (MR) using hand-held optical coherence tomography (HH-OCT) to assess its diagnostic potential. Children with MR (n = 43) underwent ophthalmoscopy, fluorescein angiography and HH-OCT during admission, 1-month (n = 31) and 1-year (n = 8) post-discharge. Controls were comatose patients without malaria (n = 6) and age/sex-matched healthy children (n = 43). OCT changes and retinal layer thicknesses were compared. On HH-OCT, hyper-reflective areas (HRAs) were seen in the inner retina of 81% of MR patients, corresponding to ischaemic retinal whitening on fundus photography. Cotton wool spots were present in 37% and abnormal hyper-reflective dots, co-localized to capillary plexus, in 93%. Hyper-reflective vessel walls were present in 84%, and intra-retinal cysts in 9%. Vascular changes and cysts resolved within 48 h. HRAs developed into retinal thinning at 1 month (p = 0.027) which was more pronounced after 1 year (p = 0.009). Ischaemic retinal whitening is located within inner retinal layers, distinguishing it from cotton wool spots. Vascular hyper-reflectivity may represent the sequestration of parasitized erythrocytes in vessels, a key CM feature. The mechanisms of post-ischemic retinal atrophy and cerebral atrophy with cognitive impairment may be similar in CM survivors. HH-OCT has the potential for monitoring patients, treatment response and predicting neurological deficits.
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Malária Cerebral/diagnóstico , Malária Cerebral/patologia , Retina/patologia , Doenças Retinianas/diagnóstico , Doenças Retinianas/patologia , Tomografia de Coerência Óptica/métodos , Assistência ao Convalescente , Criança , Pré-Escolar , Técnicas de Diagnóstico Oftalmológico , Feminino , Angiofluoresceinografia , Humanos , Lactente , Malária Falciparum/diagnóstico , Malária Falciparum/patologia , Masculino , Oftalmoscopia , Vasos Retinianos/patologiaRESUMO
Purpose: To investigate feasibility and reliability of 3-dimensional full circumpapillary retinal nerve fiber layer (cpRNFL) analysis in children, with and without glaucoma, without the use of sedation and to recommend a protocol for hand-held optical coherence tomography use. Methods: A cohort of pediatric glaucoma patients and normal children were imaged with hand-held optical coherence tomography to assess the feasibility of obtaining full cpRNFL. Two consecutive scans were acquired in a smaller sample to investigate test-retest repeatability and interassessor reproducibility. The cpRNFL thickness was assessed in four quadrants, at several visual angles from the optic nerve center. Results: Scanning was attempted in both eyes of 90 children with pediatric glaucoma and 180 controls to investigate feasibility (mean age, 6.98 ± 4.42 years). Scanning was not possible in 68 eyes of glaucoma children mainly owing to nystagmus, unclear optical media, or high refractive errors. Where three-dimensional imaging was possible, success at obtaining full cpRNFL was 67% in children with glaucoma and 89% for controls. Seventeen children with pediatric glaucoma and 34 controls contributed to reliability analysis (mean age, 6.3 ± 3.63 years). For repeatability intraclass correlation coefficients across quadrants ranged from 0.63 to 0.82 at 4° and improved to 0.88 to 0.94 at 6°. Intraclass correlation coefficients for reproducibility were also highest at 6° (>0.97 across all quadrants). Conclusions: We demonstrate that acquisition and measurement of cpRNFL thickness values using 3-dimensional hand-held optical coherence tomography volumes in awake children is both feasible and reliable and is optimal at 6° from optic nerve center. Translational Relevance: Our recommended protocol provides guidance on how pediatric optic nerve pathologies are managed by clinicians.