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State-of-the-Art Retinal Screening

Retinal Microvasculature, Microcirculation and Microstructure

A recently released paper, entitled “Age-related alterations in the retinal microvasculature, microcirculation and microstructure”, is unique in assessing state of the art clinical modalities for retinal analysis and reporting on naturally occurring changes due to aging.  It gives fascinating insight into both functional and structural changes, offering important considerations for the clinical interpretation of such data that might be made within a screening scenario.  This is important as in concert, such modalities can offer a comprehensive and fully-automated assessment of retinal health.  The potential efficacy for screening is, therefore, considerable, but overall utility requires first an understanding of normative ranges that will facilitate individual assessments.  This is an important and necessary first step in this direction, and all the more interesting given the recent advancement in each of these modalities and their readiness for more widespread clinical adoption.

Modalities

The modalities investigated were:

  • Microvasculature – OCT Angiography (OCTA) was performed using the Angioplex OCTA device (Carl Zeiss Meditec, Dublin, CA, USA).  Retinal vessel network (RVN) images were processed using custom software developed at Bascom Palmer Eye Institute (BPEI) to create binary vessel maps and then define the foveal avascular zone (FAZ).  Further quantitative analysis used the fractal analysis toolbox (TruSoft Benoit Pro 2.0, TruSoft International, Inc., St. Petersburg, FL, USA), the box counting method was used to calculate the fractal dimension (Dbox) in the annulus, which represents vessel density in each zone.
  • Microcirculation – The retinal blood flow velocity (BFV) was measured using a Retinal Function Imager (RFI).  The RFI (RFI-3000, Optical Imaging, Rehovot, Israel) uses a standard fundus camera, a stroboscopic flash lamp system, and an advanced digital camera to non-invasively image blood cells moving through capillaries.
  • Microstructure – Custom ultra-high resolution optical coherence tomography (UHR-OCT) [Tan 2016] was used to capture structural OCT images using a 512 × 128 macular cube protocol centered on the fovea.  Automatic retinal segmentation software (Orion, Voxeleron LLC, Pleasanton, CA, USA) was used to segment six intraretinal layers and process the thickness maps of the intraretinal layers with hemispheric and the Early Treatment Diabetic Retinopathy Study (ETDRS) partitions.

Findings

The analysis is both detailed and comprehensive, facilitating a better understanding of changes that are normally occurring with age; as opposed to abnormally occurring due to disease.  Four population age groups were studied – G1 (<35 years), G2 (35-49 years), G3 (50-64 years) and G4 (>64 years) – and it was found that a natural process of aging results in decreases in:

  • Retinal vessel density,
  • Inner retinal layer thicknesses and
  • Venular blood flow velocity.

Beneath the general conclusion are several interesting findings that we will summarize followed by bullet points with our brief comments.  Being the first to study these advanced modalities, these are interesting insights, paving the way for wider clinical adoption and comprehensive screening techniques.

“We found that thinning of the RNFL (retinal nerve fiber layer) and GCIPL (ganglion cell, inner plexiform layer) coexisted with the decreased density of the retinal micro-vessels and altered microcirculation during normal aging.”

  • This finding offers unique insight into how different retinal components might impact each other with aging.  The order in which this occurs is unknown although the authors do speculate that the thinning of the macular RNFL may happen before alterations in the neuro-vascular-hemodynamic system are measurable.  An earlier study by Sohn et al. also saw structural changes using OCT before microvascular changes were evident in this case in diabetes mellitus [Sohn 2016].

“In the present study, up to 6 intraretinal layers were delineated and measured with good repeatability using our custom-made ultra high resolution OCT and the Orion automatic segmentation software.”

  • If structural changes do indeed precede functional changes, the screening would perhaps be best served using standard OCT and advanced analysis software such as that used in this study.  This is also the lowest cost option as OCTA and RFI devices are more expensive.  There is also sufficient clinical data to retrospectively analyse to derive very precise normative limits that may be used in a device independent way given Orion’s support of all major OCT devices.

“In contrast to the thinning of the inner layers of the retina, there was aging-related thickening found in the sublayers of the outer retina, including the OPL (outer plexiform layer) and PR (photoreceptor complex) layer in this study.”

  • Very importantly, measures of total retinal thickness will mask subtle changes indicative of either disease or normal aging.  This is reported in this study, where thickening in the outer retina is observed, which, coincident with thinning in the inner retina, can mask changes if the segmentation software only reports on total thickness (i.e., it will be constant).  We’ve seen this too in disease processes, both in multiple sclerosis and non-arteritic ischaemic optic neuropathy, in [Behbehani 2017] and [Keller 2015], respectively.

“As the inner retinal layers thin across aging, retinal vessels in the inner layers alter as well. However, recent studies of retinal vasculature using OCTA reported controversial results. There is no consensus on whether aging plays a role in the changes of the inner retinal vasculature.”

  • We postulate very simply here that quantitative analysis in OCTA is in part to blame here.  Firstly, there are no standard metrics that are derived from this modality.  Secondly, each device uses a different method of generating the motion decorrelation signal used to create the angiography images.  Thirdly, no quantification methods are even available for clinical use.  And lastly, the underlying definitions of the different vascular plexuses are widely inaccurate.  In expert hands, however, careful conclusions can be drawn, and here we see that the results: “clearly showed that age was a factor related to the decreased micro-vessel density in the DVP (deep vascular plexus) and SVP (superficial vascular plexus)”.

Closing Remarks

As a closing remark, it should be reiterated how relevant this study is to laying the groundwork for a better understanding of the retinal changes in structure, vascular density and venular flow change with age.  As previously mentioned, the implications for comprehensive screening are profound, as this work broadens our understanding of the relationship between these retinal components and how and when they change.

References

[Keller 2015] – Changes in macular layers in the early course of non-arteritic ischaemic optic neuropathy.  Keller J, Oakley JD, Russakoff DB, Andorrà-Inglés M, Villoslada P and Sánchez-Dalmau BF.  Graefes Arch Clin Exp Ophthalmol. 2016 Mar;254(3):561-7.

[Behbehani 2017] – Optical coherence tomography segmentation analysis in relapsing remitting versus progressive multiple sclerosis.  Raed Behbehani, Abdullah Abu Al-Hassan, Ali Al-Salahat, Devarajan Sriraman, Jonathan Oakley and Raed Alroughani.  PLoS One. 2017 Feb 13;12(2):e0172120.

[Sohn 2016] – Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus.  Sohn EH, van Dijk HW, Jiao C et al.  Proc Natl Acad Sci U S A. 2016 May 10;113(19):E2655-64.

[Tan 2016] – The measurement repeatability using different partition methods of intraretinal tomographic thickness maps in healthy human subjects.  Tan J, Yang Y, Jiang H, et al.  Clin Ophthalmol. 2016; 10: 2403–2415.

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