Aims

The core research of EQUATΘR is to combine quantitative analysis with modern ocular imaging technologies to provide reliable measures of the activity of the disease and any cumulative damage. We are applying the principles of the techniques to all the major signs of inflammation within the eye.

A clear example of the value of this technique is in the measurement of vitreous haze. Vitreous haze (cloudiness of the central gel of the eye) is a valuable sign of inflammation, but the clinical score (the NEI Vitreous Haze Score)¹ has a number of major problems. This limits its usefulness and reliability in both clinical practice and as an outcome measure for clinical trials.²

References

1. Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardizationof vitreal inflammatory activity in intermediate and posterior uveitis. Ophthalmology 1985;92(4):467-71.
2. Hornbeak DM, Payal A, Pistilli M, et al . Interobserver agreement in clinical grading of vitreous haze using alternative grading scales. Ophthalmology. 2014 Aug;121(8):1643-8. doi: 10.1016/j.ophtha.2014.02.018. Epub 2014 Mar 31. PubMed PMID: 24697913.

 

Optimising Image Acquisition

2018

Our latest study tests the limits of reliability by assessing a number of operator-dependent image acquisition parameters. We assessed the effects of different retinal positioning within the acquisition frame, image averaging (ART level), gain and focus on test-retest reliability in healthy individuals.

We showed that our technique had good reliability in normal subjects under a range of ‘real world’ conditions, such as when the operator changes the image averaging value. We also successfully identified those parameters which degraded the reliability of our measure: severe inaccurate focusing and abnormal downward displacement of the image.

References

1. Montesano G, Way CM, Ometto G, et al. Optimizing OCT acquisition parameters for assessments of vitreous haze for application in uveitis. Sci Rep 2018;8:1648.
   http://www.nature.com/articles/s41598-018-20092-y

 

 

Using OCT-derived Vitreous Haze to Detect Treatment Response

2017

In 2017, we published our retrospective analysis of patients with uveitis receiving Sub-Tenon’s Triamcinolone for cystoid macular oedema. Even in a relatively small sample of 22 patients, a significant decrease in VIT/RPE-relative intensity was found post-treatment, and this was associated with a reduction in central macular thickness and improvement in visual acuity.

Why It Matters

The results from this study provides evidence that VIT/RPE-relative intensity can be used as a sensitive marker of disease activity and treatment response in uveitis. Furthermore, the sensitivity of this small study to detect a change at a highly statistically significant level (p=0.00003), shows how the acceptance of OCT-derived objective indices could transform our approach to effectiveness trials in uveitis.

References

1. Sreekantam S, Macdonald T, Keane PA, et al. Quantitative analysis of vitreous inflammation using optical coherence tomography in patients receiving sub-Tenon’s triamcinolone acetonide for uveitic cystoid macular oedema. Br J Ophthalmol 2017;101:175–179.
   http://dx.doi.org/10.1136/bjophthalmol-2015-308008

 

 

Further Validation on a Different OCT Platform (Cirrus HD-OCT)

2016

We applied the same concept using a different spectral domain OCT device (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, California, USA) in a tertiary referral uveitis clinic in Barcelona, Spain.

This study included 105 patients with varying degrees of vitreous haze. Using the same custom software (OCTOR), OCT images of each eye was analysed to give an “absolute” measurement of vitreous signal intensity and retinal pigment epithelium intensity, from which the VIT/RPE-Relative Intensity score is derived.

We found VIT/RPE-relative intensity to correlate positively with vitreous haze score (r = 0.535, P < .001) and this correlation remained significant after adjusting for factors governing media clarity, such as AC cells, AC flare, and phakic status (R²-adjusted = 0.424, P < .001).

Why It Matters

Data from this cohort support the findings of the previous proof-of-concept study. We show that the technique is reproducible with a different spectral-domain OCT device and in a different cohort of uveitis patients. Importantly, the data also give evidence that the method may be valid regardless of phakic status or previous pars plana vitrectomy.

References

1. Zarranz-Ventura J, Keane P, Sim D, Llorens V, Tufail A, Sadda S et al. Evaluation of Objective Vitritis Grading Method Using Optical Coherence Tomography: Influence of Phakic Status and Previous Vitrectomy. American Journal of Ophthalmology. 2016;161:172-180.e4.
   https://doi.org/10.1016/j.ajo.2015.10.009

 

 

Automating the Analysis

2015

We developed an automated custom software (VITAN – VITreous ANanlysis) to automatically segment and analyse OCT images and derive the VIT/RPE-relative intensity. As with our original studies, the VIT/RPE-relative intensity correlated with clinical vitreous haze. Automating the process reduced the image analysis time from 5 minutes (semi-automated) to less than 2 seconds (VITAN).

References

1. Keane PA, Balasakas K, Sim DA, Aman K, Denniston AK, Aslam T for the EQUATOR study group. Automated analysis of vitreous inflammation using SD-OCT. TVST. 2015
   http://tvst.arvojournals.org/article.aspx?doi=10.1167/tvst.4.5.4

 

 

First Use of OCT to Measure Vitreous Haze – A Case Example

2014

In our proof-of-concept study we presented data from 60 patients comprising groups with uveitis with varying degrees of vitreous haze, uveitis with no vitreous haze, and non-uveitic patients.³ Among other parameters, the presence and severity of vitreous haze was classified according to the NEI Vitreous Haze Score. SD-OCT images (Spectralis, Heidelberg) were taken on a standard macula-focussed setting, and analyzed using custom software (OCTOR). This software provided an “absolute” measurement of vitreous signal intensity, which was then compared to that of the retinal pigment epithelium (RPE), generating an optical density ratio with arbitrary units (“VIT/RPE-Relative Intensity”).

In this study we found that the VIT/RPE-Relative Intensity was significantly higher in uveitic eyes with known vitreous haze (0.150) than in uveitic eyes without haze or in healthy controls (0.0767, p=0.0001). Importantly VIT/RPE-Relative intensity positively correlated with clinical vitreous haze scores (r=0.566, p=0.0001). Other ocular characteristics of inflammation also correlated with VIT/RPE-Relative Intensity including AC cells (r=0.613, p=0.0001) and AC flare (r=0.385, p=0.003). Importantly in the context of developing a tool that is objective and reliable, measurement of VIT/RPE-Relative Intensity showed a good degree of inter-grader reproducibility (95% limits of agreement: -0.019 to 0.016).

 

Why It Matters

This study was the first to demonstrate proof-of-concept that OCT-derived measurements of vitreous signal intensity may be useful as an outcome measure in patients with uveitis. This is an exciting advance since these measures may serve as an objective, quantitative disease activity endpoint, with the potential to improve the “signal:noise” ratio of clinical trials in this area. This would enable smaller studies for the same level of statistical power, with cost and feasibility benefits. The implications for clinical practice may be similarly profound.

Since this initial study we are continuing to build on this work through the establishment of the EQUATΘR consortium. EQUATΘR is an exciting partnership which brings together leading UK, European and US centres with expertise in both ocular imaging and trial endpoint design, with new applications to the complex field of uveitis. Although most uveitis specialists primarily use the OCT for detecting and measuring macular oedema, we believe that in the next few years its applications will rapidly diversify enabling us to have similar precise objective quantification of a number of key indicators of disease activity in uveitis.

References

1. Keane PA, Karampelas M, Sim DA et al. Objective Measurement of Vitreous Inflammation Using Optical Coherence Tomography. Ophthalmology. 2014 May15. pii: S0161-6420(14)00230-9. doi: 10.1016/j.ophtha.2014.03.006. [Epub ahead of print] PubMed PMID: 24835759.