Diabetic retinopathy neovascularization -
A range of angiogenic growth factors VEGF, bFGF, and IGF-1 , integrins, and derangements of extracellular matrix ECM components such as collagen type IV are associated with pathologic neovascularization in PDR, any or all of which could potentially affect tbdn-1 expression.
and is known to contain a range of ECM components, such as collagen type IV, heparan sulfate proteoglycans, laminin, and entactin. Despite the likely caveats associated with interpreting the regulation of endothelial behavior in reconstitution experiments in vitro and during PDR in vivo, our results indicate a correlation between suppression of tbdn-1 expression and retinal capillary formation occurring in choroid-retina capillary outgrowth in vitro and during neovascularization of PDR in vivo.
We are currently in the process of identifying the ECM components that may regulate tbdn-1 expression. Of particular interest, the expression of tbdn-1 in normal adult retinal blood vessels parallels the expression of pigment epithelium derived factor PEDF in adult retina, a recently described novel antiangiogenic serpin family member produced by the normal retinal pigment epithelium.
Decreases in the expression levels of PEDF have been observed during oxygen-induced retinal neovascularization in mice and rats, 30 31 and systemic administration of PEDF to mice with ischemia-induced retinopathy prevents retinal neovascularization in this model.
We also do not know at this time whether tbdn-1 can be regulated either directly or indirectly by PEDF. Although animal models of retinal neovascularization have been studied, little information is available about the intracellular mechanisms in retinal vascular cells that are associated with neovascularization during PDR in human specimens.
Polymorphisms of the aldose reductase gene, which may alter aldose reductase mRNA levels within cells, are thought to predispose patients with diabetes to retinopathy through possible disturbances in the polyol pathway and subsequent vascular damage.
Our finding of high levels of tbdn-1 expression in adult ocular blood vessel endothelial cells during homeostasis and the loss of this expression of tbdn-1 during retinal capillary outgrowth occurring in PDR sheds light on the intracellular processes that are disregulated during neovascularization associated with PDR.
The re-expression of tbdn-1 in diseased vessels in PDR may be necessary to restore homeostasis and stop neovascularization.
Tbdn-1 is associated with an acetyltransferase activity and contains protein—protein interaction and DNA binding-like motifs.
Submitted for publication January 17, ; revised July 17, ; accepted August 6, Commercial relationships policy: N. The publication costs of this article were defrayed in part by page charge payment. Corresponding author: Robert L. rlgendron chmcc.
F igure 1. View Original Download Slide. Tbdn-1 was specifically detected by anti-tbdn-1 Ab antibody in mouse and human vascular endothelial cells and in rhesus macaque choroid-retina endothelial cells.
Arrow : kDa tbdn-1 band, which resolves as a doublet in the IEM cells. F igure 2. Tbdn-1 protein and endothelial marker expression in sections of normal adult human eye. A Limbic vessel tbdn-1 expression red stain; arrows : tbdn-1—positive endothelial cells in a limbic blood vessel.
C , E Retinal endothelial tbdn-1 expression in longitudinal- and transverse-sectioned blood vessels in normal adult eye red stain; arrows: tbdn-1—positive endothelial cells in retinal blood vessels. B , D Retinal endothelial von Willebrand factor expression in longitudinal- and transverse-sectioned blood vessels in normal adult eye red stain, arrows : von Willebrand factor—positive endothelial cells in retinal blood vessels.
Adjacent sections stained with equal concentrations of preimmune IgY control antibody showed no staining F. G A low-power and labeled view of a methyl green—stained section of the retinal areas shown in A — F is provided for orientation purposes.
Sections were developed using alkaline phosphatase and fast red substrate; methyl green counterstain. lmb, limbic region of cornea; nr, neural retina; vb, vitreous body; cbrc, cell bodies of rods and cones; opl, outer plexiform layer; ibpcl, integrating bipolar cell layer; ipl, inner plexiform layer; gcl, ganglion cell layer.
Scale bar, 50μ m. F igure 3. Double staining for tbdn-1 and ASMA in a retinal vessel of a normal human eye section. Shown is a representative view of a normal human retinal blood vessel double stained for tbdn-1 dark brown peroxidase stain and ASMA bright red alkaline phosphatase stain.
The tbdn-1 and ASMA stains did not colocalize in these retinal blood vessels in normal human eye sections. Black arrows : locations of tbdn-1 expression brown staining in endothelial cells; white arrows : locations of ASMA expression bright red staining in pericyte and perivascular contractile cells.
F igure 4. B , arrows Similar capillary sprouts as indicated by arrows in A ; cl indicates main body of the colony. Staining of sections was developed using alkaline phosphatase and fast red substrate.
Methyl green counterstain in B reveals the capillary sprouts shown by arrows in the capillary colony before processing, in A , and after processing, in B. F igure 5. Tbdn-1 protein expression was suppressed in specimens of eyes from patients with PDR.
A Retinal endothelial tbdn-1 expression arrows : retinal blood vessels stained red in normal adult eye. C — E Tbdn-1 staining in blood vessels in preretinal membranes in sections of eyes from three separate representative patients with PDR.
F Tbdn-1 staining in blood vessel fronds cut longitudinally in a neural retinal area in a section of eye from a fourth and separate representative patient.
C , F , insets von Willebrand factor staining of abnormal blood vessels arrows in sections from the same PDR specimens and adjacent to those stained for tbdn Blood vessels in the diseased retinal tissue showed either very low levels of tbdn-1 expression or no detectable tbdn-1 expression, compared with normal specimens, whereas the same abnormal blood vessels expressed von Willebrand factor see also the Results section for quantitative analysis of tbdn-1 expression levels in these sections.
B Tbdn-1 staining arrow , red of limbic blood vessels in the anterior part of the same section as that shown in D to exemplify normal tbdn-1 expression in unaffected areas of PDR-affected eyes. All sections were also incubated with equal concentrations of preimmune IgY and showed no staining see example in Fig.
Low-power views of a normal retina G and a diabetic retina with a preretinal membrane H , both stained for tbdn-1 are provided for orientation purposes. Sections were developed using alkaline phosphatase and fast red substrate with methyl green counterstain.
lmb, limbic region of cornea; nr, neural retina; vb, vitreous body; c, choriocapillaris; preretinal membrane. Scale bar, 50 μm. The authors thank Candace Kao for expert technical assistance and Dale L.
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Publication languages were restricted. Most included studies were observational and non-comparative. Risk of bias regarding case representativeness. OCT-based retinal imaging technologies are advancing rapidly and the trend is to be noninvasive and wide-field.
OCT has proven invaluable in diagnosing, staging and management of proliferative diabetic disease with daily application in clinical and surgical practices.
Diabetes mellitus affected an estimate of million people worldwide in and this number is projected to rise to million by and million by [ 1 ]. Diabetic retinopathy DR is its leading microvascular complication and a major cause of blindness [ 2 , 3 ].
Vision-threatening DR is due to diabetic macular edema DME or proliferative DR PDR [ 2 , 3 ]. A pooled meta-analysis estimated a global prevalence of 7.
The high impact and global burden of PDR urge the need to continue researching on diagnostic and treatment modalities.
The hallmark of PDR is the presence of retinal NVE or disc NVD neovascularization [ 4 , 5 ] and color fundus photography CFP and fluorescein angiography FA have been the most relevant imaging techniques used in the last decades [ 6 , 7 , 8 , 9 ].
In recent years, there have been significant developments in noninvasive imaging technologies [ 10 , 11 , 12 ]. Optical coherence tomography OCT was first introduced in ophthalmology in , becoming standard of care for macular disease in [ 13 ].
In DR, it has been primarily used in DME assessment [ 9 ] and in its usefulness in PDR was first reported [ 14 ]. OCT allows the evaluation of diabetic neovascularization in the earliest stages and to recognize associated vitreoretinal interface changes [ 14 , 15 , 16 , 17 , 18 ], but information about vessel structure and blood flow cannot not be obtained [ 19 , 20 ], limiting its application in evaluating disease progression and treatment response [ 18 , 21 ].
In , commercial OCT angiography OCTA was introduced [ 13 ] and in the last years there has been a significant number of publications demonstrating proliferative diabetic changes [ 22 , 23 , 24 , 25 , 26 , 27 , 28 ], some even using widefield WF imaging [ 29 , 30 , 31 , 32 ].
OCT-based retinal imaging technologies are advancing rapidly and the trend is to be noninvasive and widefield. Therefore, it is important to revise noninvasive PDR imaging for future application in daily clinical and surgical practices.
We performed an electronic database search on PubMed and EMBASE, last run on December 19th, and adopted PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using a PRISMA checklist Additional file 1. All designs and publication types were accepted, except for case-reports, conference proceedings and letters.
Studies based on time-domain OCT were also excluded, considering its lower resolution and higher artifact profile. No restrictions existed on age, diabetes type, metabolic status or follow-up.
A detailed search strategy is provided in Additional file 2. All papers were screened through title and abstract by two independent reviewers, proceeding to full-text assessment when eligible. Article selection was based on three criteria: theme within scope of review; assessment of outcomes of interest; and appropriate methodological quality.
The latter was assessed through the Newcastle—Ottawa Scale for observational studies [ 36 ]; this tool was modified to assess non-comparative studies as well, removing all topics on comparability. Data extraction was performed in duplicate by study authors, guaranteeing double verification as a way to minimize reporting errors.
The Newcastle—Ottawa Scale for observational studies was used for purposes of risk of bias assessment, performed by 2 authors on the individual study level.
This tool was modified to assess non-comparative studies as well, removing all items on group comparability. Reviews were assessed considering the quality of their included studies.
Disagreements concerning inclusion or methodological appropriateness were solved by consensus or a third author. Our search identified studies; after duplicates removed, studies were screened for inclusion through title and abstract, with proceeding to full text-assessment, and 60 included in this qualitative systematic review Fig.
A of included studies is provided in Additional file 3. healthy controls —5; secondary analysis of previously published prospective trials—1.
Overall, included studies were classified as having a moderate-to-good methodological quality. On the other side, a more significant risk of bias was assessed regarding the representativeness of cases, as only a minority of studies reported a systematic or consecutive inclusion of cases.
Tomographic evaluation of NVDs using structural spectral-domain OCT SD-OCT was first reported in by Cho et al. Muqit et al.
More advanced NVDs consisted on thick tissue protruding from the disc that grew axially along the PH and extended into the peri-papillary ILM surface Fig.
Absence of posterior vitreous detachment PVD on the disc was more frequent among active NVDs. These originated outside the physiological cupping and grew along the PH which served as scaffold. Occasionally, there was breaching of the PH and growth into the vitreous cavity [ 15 , 17 , 18 , 48 ].
After laser treatment, NVDs were seen to regress with involution of the vitreous projections, and larger NVDs were described as free-floating in the vitreous due to tractional avulsion [ 15 ].
Examples of NVD on structural SD-OCT. a , b NVDs asterisk as hyperreflective tissue sitting on the disc with an attached posterior hyaloid.
c , d NVD protruding from the disc into the vitreous with posterior hyaloid breaching, in c note the detached hyaloid.
e , f Depict advanced NVDs with thick fibrovascular tissue asterisk protruding from the disc and growth along the posterior hyaloid, which serves as scaffold, into the peri-papillary area and macular traction.
More recently, OCTA identified the vascular structure of NVDs by the presence of blood flow signal in the en-face OCT angiogram, which corresponded in the OCT B-scan to structures with positive flow signal above the optic disc or peripapillary retinal surface Fig.
They originated from the retinal vein, artery or choroid and arose from bending vessels inside or near the optic disc rim, mostly in the upper temporal sector [ 21 , 25 ]. Alteration in NVD blood flow in OCTA did not necessarily translate into structural regression [ 23 ].
Examples of NVD using OCTA. a Swept-Source OCTA showing a small early NVD in the en-face angiogram dashed line, top , which corresponded in the OCT B-scan to a structure above the disc with positive flow signal dashed line, bottom , indicating active disease. b SD-OCTA demonstrating an active NVD with irregular new vessels on the en-face image dashed line, top and flow signal in red on the OCT B-scan dashed line, bottom.
c Example of an NVD with pruning and little branching on the en-face image dashed line, top , with fibrotic tissue and minimum flow signal on the co-registered B-scan dashed line, bottom. Ishibazawa et al. Pruning and regression in EVP with reduction in NVD flow area was documented after panretinal photocoagulation PRP [ 28 ].
Various studies found that OCTA and WF-OCT were able to define all NVDs [ 20 , 39 , 46 , 47 ], with a superior visualization when compared to FA [ 20 ]. B-scan OCT had an Elbendary et al. In structural OCT, NVEs presented as homogenous hyperreflective loops breaching the ILM and protruding into the vitreous with posterior retinal shadowing Fig.
These complexes arose from the outer plexiform layer and extended through the inner retinal layers, penetrated the ILM and attached to the PH [ 15 ].
As seen in NVDs, PH served as scaffold for NVE development and in most cases is attached or partially detached and tethered to neovascular tissue [ 16 , 17 , 18 ].
Using SD-OCT, NVEs have been proposed to develop in 3 stages: I—disruption of ILM; II—horizontal growth along ILM and III—multiple breach of PH and linear growth [ 16 ]. According to their morphology they have been classified by Vaz-Pereira et al.
NVEs were also classified according to location in 1 above the ILM and 2 below the ILM types [ 56 ] based on their intraretinal component [ 15 , 67 , 68 ]; nonetheless most use the histopathology definition of NVE, where a breach of the ILM is a requisite [ 4 , 16 , 69 , 70 ].
Examples of the morphology of NVE on structural SD-OCT. a , b Flat NVE confined to the posterior hyaloid. c , d Forward configuration into the vitreous, in d note the hyperreflective dots in the vitreous arrowhead corresponding to localized vitreous hemorrhage.
e Flat lesion growing along the posterior hyaloid with forward extensions and vitreous invasion. With OCTA, by combining the en-face angiograms with B-scans, NVEs appeared as irregular masses of vessels with positive flow signal above the ILM, distinguishing them from microaneurysms and IRMA Fig.
A study using WF-OCTA evaluated the distribution of NVCs and found NVEs more prevalent superotemporally [ 32 ]. Magnification of top b and bottom c annotated area in a shows small neovascular complexes on the en-face angiogram breaching the ILM and with positive flow signal in the structural B-scan within dashed lines , in accordance with active NVEs.
Note than in d , left annotated area, the microvascular abnormality depicted in the en-face angiogram does not breach the ILM in the co-registered B-scan and the flow signal is only intraretinal, in accordance with IRMA.
Pan et al. The presence of vitreous hyperreflective dots in SD-OCT was more significant in active PDR, while the presence of epiretinal membrane, inner retinal tissue contracture, vitreous invasion and vitreous protrusion was more associated with quiescent disease [ 18 ].
Using OCTA, EVP was more frequent in treatment-naïve NVCs—thus EVP should be considered an active sign of neovascularization [ 28 ]. When comparing imaging modalities, structural OCT and B-scan OCTA had the best detection rate for new-onset NVCs, but B-scan OCTA was superior for follow-up, due to the persistence of the NVC tissue on OCT [ 27 ].
Also, WF and ultra-WF UWF OCTA demonstrated increased value in NVC imaging. Compared to UWF FA, SS-OCTA was more sensitive in detecting microvascular changes indicating possible disease progression [ 27 , 31 ] with some authors suggesting WF-OCTA as the single preferred imaging strategy for PDR detection and monitoring [ 29 , 31 , 44 , 52 ].
Nineteen studies mentioned IRMA characteristics [ 14 , 16 , 19 , 21 , 22 , 24 , 25 , 26 , 30 , 31 , 38 , 39 , 40 , 41 , 54 , 56 , 59 , 65 , 72 ]. These hyperreflective structures were intraretinal, frequently extending across more than one layer [ 40 ] and without ILM breach [ 14 , 16 , 21 , 24 , 25 , 26 , 30 , 31 , 38 , 39 , 40 , 41 , 59 , 65 ].
However, focal areas of outpouching of the ILM [ 9 , 14 , 16 , 40 ] were sometimes observed—even in these cases, the ILM and the PH were intact.
Lee et al. Similarly, the OCTA flow overlay depicted mild-moderate intraretinal flow possibly outpouching and distorting ILM contour, without breaching through the ILM or PH Fig. These outpouching IRMA seemed to have relative increased vascularity on flow overlay, when compared to nonoutpouching IRMA and surrounding normal vasculature [ 59 ].
The ability to breach through the ILM to differentiate into NVE seemed to be exclusive to sea-fan-like IRMA [ 25 ]. IRMA were consistently identified adjacent to NPAs [ 21 , 22 , 25 , 26 , 30 , 38 , 39 , 40 , 59 ].
Of the definite IRMA detected with this technology, only half were imaged in CFP ETDRS protocol ; conversely, all IRMA detected on CFP were imaged with SS-OCTA, portraying a higher sensitivity for IRMA detection with OCT [ 30 ]. In angiographic studies, vessel wall staining was noted [ 22 ], but prominent fluorescein leakage was mostly excluded—distinguishing IRMA from NVE [ 14 , 19 , 40 , 56 ].
A low agreement was reported between fluorescein leakage on FA and OCT discrimination of NVE vs. NPAs represent capillary occlusion and are regarded as ischemic areas [ 11 , 23 , 38 , 40 ].
Using OCTA, NPAs were identified as areas of absent signal because of low capillary perfusion or dropout Fig. NPAs could be quantified [ 29 , 30 , 60 ] and PDR patients were found to have a significant lower capillary density compared to non-PDR patients and increased and irregular FAZ [ 45 , 60 ].
Also, IRMAs and NVCs were more frequently associated with NPAs [ 23 , 24 , 25 , 30 , 38 , 39 , 40 , 41 , 42 , 58 , 65 , 66 , 73 ]. Vitreoschisis corresponds to splitting of the posterior vitreous cortex and is a consequence of anomalous PVD, where a strong vitreomacular adhesion splits the posterior vitreous, leaving an outer layer attached to the retina while the remaining vitreous collapses anteriorly [ 17 , 37 , 50 ].
It is represented in OCT as multilayered hyperreflective bands of the posterior vitreous cortex, separated by an optically clear hyporeflective space [ 17 , 37 , 50 , 74 ]. Vitreoschisis can complicate PDR by causing additional traction on NVCs, which may contribute to bleeding and complicate vitreoretinal surgery [ 37 , 74 ].
Considering its high-resolution and ability for microstructural delineation of tractional NVCs, OCT has proven invaluable in identifying the cleavage plan in retinal surgery when used preoperatively and intraoperatively, resulting in safer surgeries [ 12 , 15 , 17 , 19 , 27 , 35 , 37 ].
OCT is an established noninvasive technology mandatory in the management of DR. Although widely used to evaluate DME, recent studies have demonstrated its utility in assessing PDR. The first reports on diabetic NVCs were based on histopathology [ 4 , 16 , 68 , 70 ], but OCT has shed significant light on NVC development, growth and response to treatment.
OCT provides images in real time and in vivo—as an optical biopsy [ 13 ]. Structural OCT can identify NVCs, IRMAs and associated vitreoretinal changes [ 14 , 15 , 16 , 17 , 18 , 37 ], but is limited by not recognizing blood flow.
NVDs can be observed as tissue sitting or protruding from the disc. Regarding NVEs, it is important to distinguish them from IRMAs as the presence of neovascularization is the hallmark of PDR and indicates more severe disease, with implications in treatment and prognosis [ 4 , 5 ]. IRMAs may be precursors of NVE, but are a definite risk factor for PDR [ 16 , 24 , 68 ].
The status of the posterior vitreous is also significant in PDR evaluation as the presence of PVD is believed to be protective for the development of PDR [ 16 , 17 , 18 , 77 ]. Moreover, it is known that diabetic vitreopathy is responsible for a strong adhesion between the vitreous and retinal vessels, resulting in an incomplete anomalous PVD and vitreoschisis, with the PH acting as scaffold for newly growing NVCs [ 17 , 37 , 78 ].
The study of the vitreoretinal interface is also valuable when preparing for surgical management. Incomplete PVD with or without retinal traction or vitreoschisis may increase the risk of intraoperative bleeding, for which the retinal surgeon must plan in advance [ 14 , 15 , 17 , 35 , 37 , 78 ].
To date, few studies have addressed the use of intra-operative OCT and it will be interesting to see in the next few years if tomography will claim its place in the operating room [ 33 , 34 , 35 ].
OCTA brought a major advance as it clearly demonstrates microvascular changes by showing the vascular structure in the en-face image and the flow signal in the co-registered B-scans.
These features are important to differentiate NVEs from IRMAs, to establish and quantify the presence of both NVD and NVEs, monitor treatment response and noninvasively evaluate other findings such as NPAs [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 47 , 48 , 49 , 51 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 71 ].
When compared to biomicroscopy and CFP, OCT and OCTA were more reliable in identifying and distinguishing IRMA and NVCs [ 27 ].
In this context, UWF and WF-OCTA may be of particular interest, as a structural and functional wide view of the retina is provided non-invasively [ 29 , 30 , 31 , 32 , 44 , 52 , 61 , 71 ].
The safety of these complementary tests allows a more frequent imaging follow-up, probably achieving a tighter control of the retinal vascular status.
Having considered the advantages of tomography studies and despite its recognizable worth, we should keep in mind OCTA is an expensive technology, still unavailable in many ophthalmology practices, especially in its widefield and ultra-widefield variants, and the en-face image must be evaluated with the corresponding structural B-scan.
As so, making the most out of available standard OCT techniques is still necessary. This last limitation could set barriers to the widespread application of our findings; however, considering the inclusion of a vast array of papers published on the topic, we believe we covered all existing literature on the tomographic findings of PDR.
As knowledge and experience increase, OCTA and WF-OCTA have been proving their added benefit not only in NVC detection, but also in further characterizing NPAs and microvascular abnormalities—stratifying the odds for DR progression towards high-risk stages.
As so, these imaging modalities will definitely establish their value in the clinical setting. This review intended to be one of the steps in this process by sharing and summarizing information for tomography users.
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Ophthalmology and Visual Sciences. Jesse Vislisel and Thomas Retinopthy, MS, MD. Diabetic retinopathy falls High protein diet for kids two neovacularization classes: Clean caffeine alternative and proliferative. The word "proliferative" High protein diet for kids to whether or not there is neovascularization abnormal blood vessel growth in the retinaEarly disease without neovascularization is called nonproliferative diabetic retinopathy NPDR. As the disease progresses, it may evolve into proliferative diabetic retinopathy PDRwhich is defined by the presence of neovascularization and has a greater potential for serious visual consequences.
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