Choroidal Structure and Function in Chronic Retinal Diseases

Introduction: The choroid plays an important role in maintaining retinal homeostasis. Changes in choroidal structure and a failure of choroidal autoregulation (the ability of a vascular bed to maintain blood flow despite changes in perfusion pressure) may have a great consequence in the pathogenesis of several chronic chorioretinal diseases including diabetic retinopathy (DR) and central serous chorioretinopathy (CSCR). Aim: The main aim of this thesis is to study the structure and function of the choroid and determine its role in the pathogenesis of DR and CSCR using enhanced depth imaging optical coherence tomography (EDI OCT) and laser Doppler flowmetry (LDF). Methods: A protocol for standardising the choroidal thickness (ChT) measurement using topographical appearances of the choroidal posterior boundary was developed and validated on EDI OCT images from healthy volunteers and patients with DR. Extensive experiments were performed in order to validate the hardware and software of the LDF device. Two controlled prospective studies were designed and performed; 1) Diabetic Retinopathy: Functional and Structural Study (DREFUS Study), and 2) Liverpool Central Serous Chorioretinopathy study (Liverpool CSCR Study). The DREFUS study involved diabetic patients with/without DR and healthy volunteers. DR patients were grouped using the presence or absence of clinically significant macular oedema (CSMO). The Liverpool CSCR study included patients presented with CSCR and healthy volunteers. For both of the studies the ChT was measured using a single horizontal EDI OCT scan while the choroidal blood flow (ChBFlow) parameters (choroidal blood volume [ChBVolume] and velocity [ChBVelocity]) were measured by using LDF. Isometric exercise was used to test choroidal autoregulation function. Mean arterial BP (MAP), ocular perfusion pressure (OPP) and change in choroidal vascular resistance were calculated to evaluate the choroidal autoregulation. In addition, best corrected visual acuity (BCVA), blood pressure (BP), colour fundus photography, fluorescein angiography (FA), and OCT were performed. Other tests including indocyanine green angiography (ICG), volumetric EDI OCT scans, microperimetry, intraocular pressure, and axial length were only performed by the CSCR study. Statistical analyses (correlation, t-test, ANOVA, ANCOVA, intraclass correlation coefficient [ICC], Fisher exact test, Mann-Whitney test) were performed as appropriate. Results: The standardised protocol for ChT measurement was produced. ICC for interobserver and intraobserver agreements on ChT measurements using of the protocol were 0.96 and 0.99 respectively for healthy eyes (n = 12) and 0.97 and 0.99 respectively for eyes with DR (n = 46). The mean subfoveal ChT (SfChT) was 304 µm (95% confidence interval (CI): 282 – 326) for patients with DR (N = 61). There were no significant differences in ChT between healthy eyes (N = 41; 351 µm (95% CI: 321 – 381)), diabetic eyes (N = 12; 299.9 µm (95% CI: 248.7 - 351.2) and eyes with DR (P >0.05). A statistically significant increase in ChBVelocity by 8% was observed following an increase of MAP by 18% in DR with CSMO. The mean SfChT of CSCR patients (N = 45) was 468.5 µm (95% CI: 437.1 – 499.9), approximately 30% thicker than in healthy eyes (N = 25; 361.4 µm (95% CI: 319.8 – 402.2) (P <0.05). Hypertension was identified as the main risk factor affecting ChT in CSCR, particularly during the active stage of CSCR (normotensive CSCR: SfChT = 431 µm (95% CI: 378 – 485) vs hypertensive CSCR: SfChT = 521 µm (95% CI: 468 – 574): P <0.05). An increase in OPP by 40% caused the ChT to increase significantly in CSCR patient (435.3 µm (95% CI: 378.2 - 492.4) at baseline vs 446.3 µm (95% CI: 393.4 - 499.2) at the end of exercise; P <0.05). An increase of OPP by 31% caused significant change in ChBVolume in CSCR patients compared to healthy eyes (P = 0.03). Changes in ChBVolume in CSCR patients were negatively correlated with changes in choroidal vascular resistance (r = -0.83, P <0.05). Conclusions: In patients with diabetes, no significant changes in the ChT were observed in any group of DR patients. ChBVelocity regulation was impaired in patients with severe DR. These findings suggest that functional changes of the choroid may occur well before the structural changes in patients with DR. In CSCR patients, increases in ChT and choroidal volume were observed in all CSCR phenotypes and also related with hypertension and the area of choroidal vascular hyperpermeability seen on ICG. The disruption of the regulation of choroidal structure and function was observed during isometric exercise in CSCR patients. These findings highlight the significance of choroidal regulation in the pathogenesis of DR and CSCR

Real-world experience of using stereotactic radiotherapy combined with anti-vascular endothelial growth factor to treat neovascular AMD

IntroductionAdjunctive treatment or longer-acting drugs are required to treat nAMD to help ease burdens for patients and hospital clinics alike. Stereotactic therapy is one such option, providing a reduction in the number of injections over time.ObjectiveTo determine the clinical outcomes in a cohort of patients with nAMD receiving a combination therapy of stereotactic radiotherapy (SRT) with intravitreal anti-VEGF injections (IVI).MethodA retrospective analysis of 74 patients with nAMD, who had received IVI and SRT (16 Gray maximum dose to the macula) at a large tertiary university eye hospital, between March 2018 and September 2019 was performed. The number of IVIs, visual acuity (VA), and central retinal thickness (CRT) were evaluated at 12, 24, and 36 months after patients received SRT and compared to the same time interval prior to SRT.ResultsFollow-up data at 12, 24, and 36 months following and prior to SRT was available for 74, 48, and 22 patients respectively. Overall there was a significant reduction in the number of injections post-SRT. Twelve months following SRT, the median number of IVI was reduced by 1 (p &lt; 0.05). The reduction in the median number of IVI was significantly reduced by 3 and 6 injections at 24- and 36-month follow-up respectively (p &lt; 0.05). The CRT was significantly reduced post-SRT compared to the baseline values at all time periods. There was no statistically significant difference in VA at 12-month follow-up compared to baseline. The VA, however, significantly decreased at 24- and 36-month follow-up (p &lt; 0.05).ConclusionA therapy combining SRT with IVI has shown an overall reduction in the number of injections required in nAMD patients at 12, 24, and 36 months following SRT compared to IVI treatment alone. These real-world outcomes are comparable to other studies while also confirming the maintenance of the reduced frequency of required IVI for patients with nAMD

Standardization of choroidal thickness measurements using enhanced depth imaging optical coherence tomography

AIM: To describe and evaluate a standardized protocol for measuring the choroidal thickness (ChT) using enhanced depth imaging optical coherence tomography (EDI OCT). METHODS: Single 9 mm EDI OCT line scans across the fovea were used for this study. The protocol used in this study classified the EDI OCT images into four groups based on the appearance of the choroidal-scleral interface and suprachoroidal space. Two evaluation iterations of experiments were performed:first, the protocol was validated in a pilot study of 12 healthy eyes. Afterwards, the applicability of the protocol was tested in 82 eyes of patients with diabetes. Inter-observer and intra-observer agreements on image classifications were performed using Cohen’s kappa coefficient (k). Intraclass correlation coefficient (ICC) and Bland-Altman’s methodology were used for the measurement of the ChT. RESULTS: There was a moderate (k=0.42) and perfect (k=1) inter- and intra-observer agreements on image classifications from healthy eyes images and substantial (k=0.66) and almost perfect (k=0.86) agreements from diabetic eyes images. The proposed protocol showed excellent inter- and intra-observer agreements for the ChT measurements on both, healthy eyes and diabetic eyes (ICC>0.90 in all image categories). The Bland-Altman plot showed a relatively large ChT measurement agreement in the scans that contained less visible choroidal outer boundary. CONCLUSIONS: A protocol to standardize ChT measurements in EDI OCT images has been developed; the results obtained using this protocol show that the technique is accurate and reliable for routine clinical practice and research

Standardization of choroidal thickness measurements using enhanced depth imaging optical coherence tomography

To describe and evaluate a standardized protocol for measuring the choroidal thickness (ChT) using enhanced depth imaging optical coherence tomography (EDI OCT)