Radiation effects on retinal layers revealed by OCT, OCT-A, and perimetry as a function of dose and time from treatment.

Optical coherence tomography (OCT) has become a key method for diagnosing and staging radiation retinopathy, based mainly on the presence of fluid in the central macula. A robust retinal layer segmentation method is required for identification of the specific layers involved in radiation-induced pathology in individual eyes over time, in order to determine damage driven by radiation injury to the microvessels and to the inner retinal neurons. Here, we utilized OCT, OCT-angiography, visual field testing, and patient-specific dosimetry models to analyze abnormal retinal layer thickening and thinning relative to microvessel density, visual function, radiation dose, and time from radiotherapy in a cross-sectional cohort of uveal melanoma patients treated with 125I-plaque brachytherapy. Within the first 24 months of radiotherapy, we show differential thickening and thinning of the two inner retinal layers, suggestive of microvessel leakage and neurodegeneration, mostly favoring thickening. Four out of 13 eyes showed decreased inner retinal capillary density associated with a corresponding normal inner retinal thickness, indicating early microvascular pathology. Two eyes showed the opposite: significant inner retinal layer thinning and normal capillary density, indicating early neuronal damage preceding a decrease in capillary density. At later time points, inner retinal thinning becomes the dominant pathology and correlates significantly with decreased vascularity, vision loss, and dose to the optic nerve. Stable multiple retinal layer segmentation provided by 3D graph-based methods aids in assessing the microvascular and neuronal response to radiation, information needed to target therapeutics for radiation retinopathy and vision loss.

Reduced blood flow by laser speckle flowgraphy after 125I-plaque brachytherapy for uveal melanoma.

BACKGROUND: To determine whether reductions in retinal and choroidal blood flow measured by laser speckle flowgraphy are detected after 125I-plaque brachytherapy for uveal melanoma. METHODS: In a cross-sectional study, retinal and choroidal blood flow were measured using laser speckle flowgraphy in 25 patients after treatment with 125I-plaque brachytherapy for uveal melanoma. Flow was analyzed in the peripapillary region by mean blur rate as well as in the entire image area with a novel superpixel-based method. Relationships between measures were determined by Spearman correlation. RESULTS: Significant decreases in laser speckle blood flow were observed in both the retinal and choroidal vascular beds of irradiated, but not fellow, eyes. Overall, 24 of 25 patients had decreased blood flow compared to their fellow eye, including 5 of the 6 patients imaged within the first 6 months following brachytherapy. A significant negative correlation between blood flow and time from therapy was present. CONCLUSIONS: Decreases in retinal and choroidal blood flow by laser speckle flowgraphy were detected within the first 6 months following brachytherapy. Reduced retinal and choroidal blood flow may be an early indicator of microangiographic response to radiation therapy.

Temporal Relationship Between Visual Field, Retinal and Microvascular Pathology Following 125I-Plaque Brachytherapy for Uveal Melanoma.

Purpose: To define the temporal relationship of vascular versus neuronal abnormalities in radiation retinopathy. Methods: Twenty-five patients with uveal melanoma treated with brachytherapy and sixteen controls were tested. Functional outcome measures included visual acuity and threshold perimetry (HVF 10-2), while structural outcomes included retinal thickness by OCT and vascular measures by OCT angiography and digital fundus photography. The degree of structural abnormality was determined by intereye asymmetry compared with normal subject asymmetry. Diagnostic sensitivity and specificity of each measure were determined using receiver operating characteristic curves. The relationships between the outcome measures were quantified by Spearman correlation. The effect of time from brachytherapy on visual function, retinal layer thickness, and capillary density was also determined. Results: Within the first 2 years of brachytherapy, outcome measures revealed visual field loss and microvascular abnormalities in 38% and 31% of subjects, respectively. After 2 years, they became more prevalent, increasing to 67% and 67%, respectively, as did retinal thinning (50%). Visual field loss, loss of capillary density, and inner retinal thickness were highly correlated with one another. Diagnostic sensitivity and specificity were highest for abnormalities in digital fundus photography, visual field loss within the central 10°, and decrease in vessel density. Conclusions: Using quantitative approaches, radiation microvasculopathy and visual field defects were detected earlier than loss of inner retinal structure after brachytherapy. Strong correlations eventually developed between vascular pathology, change in retinal thickness, neuronal dysfunction, and radiation dose. Radiation-induced ischemia seems to be a primary early manifestation of radiation retinopathy preceding visual loss.

The Effect of Acetazolamide and Weight Loss on Intraocular Pressure in Idiopathic Intracranial Hypertension Patients.

PURPOSE: Acetazolamide (ACZ) lowers intraocular pressure (IOP), acutely in normal eyes and both acutely and chronically in eyes with glaucoma, and cerebrospinal fluid pressure (CSFp), chronically in patients with idiopathic intracranial hypertension (IIH). We hypothesize chronic daily ACZ would significantly reduce IOP and contribute to a translaminar pressure gradient change reflected by alteration in the CSFp-IOP difference and the deformation of the neural canal in patients with IIH and no glaucoma. PATIENTS AND METHODS: Before randomization to ACZ or placebo treatment for 6 months, 165 participants in the IIH Treatment Trial had evaluations that included Goldmann applanation, CSFp measurement, and optical coherence tomography determination of the neural canal deformation. These measures were repeated at the 6-month outcome. RESULTS: The IOP was not significantly decreased from baseline at 1, 3, or 6 months in eyes in both treatment groups. At month 6, the amount of ACZ or weight modification did not correlate with any IOP change. The 6-month mean change in neural canal deformation was 0.96 and -0.04 (P=0.001) and in CSFp was -128 and -38 mm H2O (P=0.001), but CSFp-IOP difference change was not significant, in the ACZ and placebo groups, respectively. CONCLUSIONS: ACZ does not reduce the IOP in eyes without glaucoma but does decrease the pathologic elevated CSFp, providing evidence that normal systems can compensate for chronic medication effects. The CSFp-IOP is not a direct marker of translaminar pressure gradient and the ACZ normalization of the neural canal deformation appears due to CSFp reduction alone.

Peripapillary Retinal Pigment Epithelium Layer Shape Changes From Acetazolamide Treatment in the Idiopathic Intracranial Hypertension Treatment Trial.

Purpose: Recent studies indicate that the amount of deformation of the peripapillary retinal pigment epithelium and Bruch's membrane (pRPE/BM) toward or away from the vitreous may reflect acute changes in cerebrospinal fluid pressure. The study purpose is to determine if changes in optic-nerve-head (ONH) shape reflect a treatment effect (acetazolamide/placebo + weight management) using the optical coherence tomography (OCT) substudy of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT) at baseline, 3, and 6 months. Methods: The pRPE/BM shape deformation was quantified and compared with ONH volume, peripapillary retinal nerve fiber layer (pRNFL), and total retinal (pTR) thicknesses in the acetazolamide group (39 subjects) and placebo group (31 subjects) at baseline, 3, and 6 months. Results: Mean changes of the pRPE/BM shape measure were significant and in the positive direction (away from the vitreous) for the acetazolamide group (P < 0.01), but not for the placebo group. The three OCT measures reflecting the reduction of optic disc swelling were significant in both treatment groups but greater in the acetazolamide group (P < 0.01). Conclusions: Change in the pRPE/BM shape away from the vitreous reflects the effect of acetazolamide + weight management in reducing the pressure differential between the intraocular and retrobulbar arachnoid space. Weight management alone was also associated with a decrease in optic nerve volume/edema but without a significant change in the pRPE/BM shape, implying an alternative mechanism for improvement in papilledema and axoplasmic flow, independent of a reduction in the pressure differential. (ClinicalTrials.gov number, NCT01003639.).

The Effect of Treatment of Idiopathic Intracranial Hypertension on Prevalence of Retinal and Choroidal Folds.

PURPOSE: We described 3 types of folds in the retina and a crease in the outer retina associated with papilledema owing to idiopathic intracranial hypertension (IIH) at presentation. We report the change in folds relative to treatment of IIH over the 6 months. METHODS: In this substudy of a randomized clinical trial, study eyes of subjects assigned to acetazolamide (ACZ, n = 44) or placebo (PLB, n = 43) had spectral-domain optical coherence tomography (SDOCT) images of the optic disc and macula regions at baseline and at 3 and 6 months. Images were evaluated for peripapillary wrinkles (PPW), retinal folds (RF), choroidal folds (CF), and creases using transaxial and en face views. The optic nerve head (ONH) shape, retinal nerve fiber layer (RNFL) thickness, ONH volume, and papilledema grade were measured. Outcome was determination of the presence or absence of PPW, RF, CF, and creases. RESULTS: At presentation, except for an increase of PPW in ACZ eyes (64% vs 28%), both treatment groups were matched for all OCT features. At 6 months, ACZ-treated, but not PLB-treated, eyes had fewer folds of all types (P < .01), with a 57% reduction in frequency of RF. Creases did not resolve. Resolution of RF, but not of PPW and CF, was associated with significant reduction in RNFL thickness, ONH volume, and papilledema grade. CONCLUSIONS: The various types of retinal folds associated with papilledema reflect biodynamic processes and show an ACZ treatment effect. Persistence of these folds despite marked improvement in ONH swelling suggests permanent changes in the affected retinal tissues.

Causes and Prognosis of Visual Acuity Loss at the Time of Initial Presentation in Idiopathic Intracranial Hypertension.

PURPOSE: To determine the etiology and prognosis of visual acuity loss in idiopathic intracranial hypertension (IIH) at presentation and to provide objective measures to predict visual outcome. METHODS: A retrospective review of 660 patients with IIH (2009-2013) identified 31 patients (4.7%) with 48 eyes having best-corrected visual acuity (BCVA) of 20/25 or worse on initial presentation. Fundus photography, optical coherence tomography (OCT) of the optic disc and macula, and perimetry were used to determine the causes and prognosis of vision loss. Segmentation of the macula OCT was performed using the Iowa Reference Algorithm to determine the retinal ganglion cell-inner plexiform layer complex (GCL-IPL) thickness. RESULTS: Outer retinal changes alone caused decreased BCVA at initial presentation in 22 eyes (46%): subretinal fluid in 16, chorioretinal folds in 5, and peripapillary choroidal neovascularization in 1. The vision loss was reversible except for some eyes with chorioretinal folds. Optic neuropathy alone caused decreased BCVA in 10 eyes (21%) and coexisting outer retinal changes and optic neuropathy caused decreased BCVA in 16 eyes (33%). A GCL-IPL thickness less than or equal to 70 µm at initial presentation or progressive thinning of greater than or equal to 10 µm within 2 to 3 weeks compared with baseline correlated with poor visual outcome. CONCLUSIONS: Visual acuity loss in IIH can be caused by both outer retinal changes and optic neuropathy. Vision loss from outer retinal changes is mostly reversible. The outcome of patients with coexisting outer retinal changes and optic neuropathy or optic neuropathy alone depends on the degree of optic neuropathy, which can be predicted by the GCL-IPL thickness.