Purpose
This article aims to review the impact of detecting and quantifying intraocular biomarkers (liquid biopsy) in both aqueous and vitreous humor in eyes of people affected by diabetes mellitus.
...Methods
This is a detailed review about aqueous and/or vitreous humor sampling in human diabetic eyes for proteomic and/or metabolomic analysis contributing to the understanding of the pathophysiology and treatment effects of diabetic retinopathy.
Results
Aqueous and vitreous humor molecular biomarkers proved to be directly correlated to each other and valuable to study retinal conditions. Moreover, proteomic and metabolomic analysis showed that the biomarkers of neuroinflammation, neurodegeneration, and vasculopathy are detectable in intraocular fluids and that their concentration changes in different stages of disease, and in response to treatment of all diabetic retinopathy aspects, mainly diabetic macular edema and proliferative retinopathy.
Conclusions
Liquid biopsy offers the possibility to improve our knowledge of intraocular eye disease induced by diabetes mellitus. The exact quantification of intraocular biomarkers contributes to the precision medicine approach even in the diabetic retinopathy scenario. The diffusion of this approach should be encouraged to have quantifiable information directly from the human model, which may be coupled with imaging data.
Purpose. To evaluate the changes in thickness of individual inner and outer macular and peripapillary retinal layers in diabetes. Methods. 124 subjects (124 eyes) were enrolled: 74 diabetics and 50 ...controls. Macular edema, proliferative diabetic retinopathy (DR), any intraocular treatment and refractive error >6 diopters were the main exclusion criteria. Full ophthalmic examination, stereoscopic fundus photography, and spectral domain-OCT were performed. After automatic retinal segmentation (layering) in 5 layers, the thickness of each layer was calculated, and values compared among groups. Results. Thirty patients had no DR, 44 patients had non proliferative DR. A significant increase of inner plexiform and nuclear layers was found in DR eyes versus controls (P<0.001). A significant decrease (P<0.01) of retinal nerve fiber layer (RNFL) and at specific sites of retinal ganglion cell layer (P=0.02) was documented in the macula. In the peripapillary area there were no differences between diabetics and controls. Conclusions. Decreased RNFL thickness and increased INL/OPL thickness in diabetics without DR or with initial DR suggest early alterations in the inner retina. On the contrary, the outer retina seems not to be affected at early stages of DM. Automatic intraretinal layering by SD-OCT may be a useful tool to diagnose and monitor early intraretinal changes in DR.
Pathophysiology of retinopathy of prematurity (ROP) still presents a gap. Lately blood tests parameters of premature infants have been measured at different times of ROP, attempting to detect ...correlations with ROP development and progression. So far, very early post-natal biomarkers, predictive of ROP outcome, have not been detected. Our purpose is to evaluate, in the earliest post birth blood sample, the correlation between routinely dosed blood parameters and ROP outcome. 563 preterm babies, screened according to ROP guidelines, were included and classified in conformity with ET-ROP study in "Group 1" (ROP needing treatment), "Group 2" (ROP spontaneously regressed) and "noROP" group (never developed ROP). The earliest (within an hour after delivery) blood test parameters routinely dosed in each preterm infant were collected. Platelet count was decreased in Group 1 versus noROP group (p = 0.0416) and in Group 2 versus noROP group (p = 0.1093). The difference of thrombocytopenic infants among groups was statistically significant (p = 0.0071). CRP was higher in noROP versus all ROPs (p = 0.0331). First post-natal blood sample revealed a significant thrombocytopenia in ROP needing treatment, suggesting a role of platelets in the pathophysiology and progression of ROP, possibly considering it as a predictive parameter of ROP evolution.
Purpose
To evaluate changes of specific retinal imaging biomarkers intraretinal hyper‐reflective retinal spots: HRS ; subfoveal neuroretinal detachment: SND; and increased foveal autofluorescence: ...IFAF after intravitreal steroid or anti‐vascular endothelial growth factor treatment in diabetic macular oedema (DME) as possible indicators of retinal inflammatory condition.
Methods
Retrospective analysis of images and clinical charts of 49 eyes (49 patients) with DME treated with intravitreal dexamethasone (dexamethasone, 23 eyes) or intravitreal ranibizumab (ranibizumab, 26 eyes). All patients had fundus colour photograph, spectral domain optical coherence tomography (SD OCT) and fundus autofluorescence (FAF), best‐corrected visual acuity (BCVA) and microperimetry recorded before and 1 month after the end of treatment. Central macular thickness (CMT), number of HRS and presence of SND were evaluated by SD OCT. Fundus autofluorescence images were evaluated for area of (IFAF). Retinal sensitivity within 4° and 12° from fovea was quantified by microperimetry. Changes in morphologic and functional parameters were assessed, and correlation was performed by Pearson's correlation.
Results
Best‐corrected visual acuity and CMT improved in all patients, (p < 0.05, for both groups). Mean number of HRS decreased after both treatments (p < 0.0001). Subfoveal neuroretinal detachment resolved in 85.7% dexamethasone‐treated eyes (p = 0.014) and in 50% ranibizumab‐treated eyes (p = 0.025). Mean IFAF area decreased in both groups, (p < 0.0001, for both). A significantly higher decrease in CMT was observed in dexamethasone‐ versus ranibizumab‐treated eyes, (p = 0.032). In dexamethasone group, higher number of HRS at baseline and larger IFAF were correlated with higher increase in retinal sensitivity; eyes with SND at baseline had major decrease in CMT versus those without SND, (p = 0.003).
Conclusion
Higher number of HRS, larger area of IFAF and presence of SND may indicate a prevalent inflammatory condition in DME with specific response to targeted treatment.
To investigate macular and peripapillary choroidal thickness (CT) in diabetic patients with and without diabetic retinopathy (DR).
One hundred and fifty subjects were enrolled: 102 diabetic patients ...(102 eyes) and 48 normals, as controls. Exclusion criteria were previously treated DR, refractive error higher than ± 3 diopters, and treated or untreated glaucoma. All patients underwent full ophthalmic examination, stereoscopic color fundus photography, and spectral domain optical coherence tomography (RS-3000; Nidek). Spectral domain optical coherence tomography examination consisted of linear scans, 6 mm in length, centered onto the fovea, and circle scan positioned around the optic disk (3.46 mm in diameter). Choroidal thickness was measured manually at the fovea and at 1, 2, and 3 mm distance along all scans in the macula. Peripapillary CT was measured at eight points along the circle scan. All measurements were performed independently by 2 masked graders.
Mean age was not significantly different between patients with diabetes and controls. In the macular area, CT was significantly lower in the nasal quadrant versus all other quadrants (P < 0.0001), in both groups. In the peripapillary area, CT was significantly lower in the inferior quadrant versus all other quadrants (P < 0.05), in both groups. Mean macular and peripapillary CT progressively and significantly decreased with increasing level of DR (nonproliferative and proliferative DR vs. controls, P < 0.05). No significant CT difference was found between controls and diabetic eyes without detectable DR. Diabetic macular edema did not influence CT. Interobserver coefficient of repeatability was 28.8 (95% confidence interval, 24.8-32.8) for foveal measurements and 13.0 (95% confidence interval, 11.2-14.8) for peripapillary measurements. Pearson correlation coefficient was 0.99, and P <0.0001 for all measurements.
Choroidal thickness is reduced in diabetic eyes and parallels appearance and evolution of DR. Spectral domain optical coherence tomography clearly confirms in vivo previously reported histopathologic observations. The role of choroid in the pathophysiology of DR needs to be adequately investigated.
The pathophysiology of diabetic macular edema (DME) is multifactorial and partly still unknown. An increasing body of evidence suggests that neurodegeneration and retinal glial cells activation occur ...even before the earliest clinical manifestation of diabetic retinal vasculopathy. Nowadays, new non-invasive techniques are available to assess and characterize DME, not only in a quantitative perspective, but also making it possible to understand and quantify the pathogenic processes sustaining fluid accumulation. Optical coherence tomography (OCT) allows documenting not only parameters such as macular volume, central and sectorial retinal thickness, fluid localization, and integrity of retinal layers, but also new still poorly investigated reflectivity aspects. Hyperreflective intraretinal spots (HRS) have been detected on OCT scans through the retinal layers, with a presumptive migration pattern towards the external layers during the occurrence of diabetic retinopathy and DME. These HRS have been hypothesised to represent an in-vivo marker of microglial activation. Autofluorescence of the fundus (FAF) also offers a non-invasive imaging technique of DME. The area of increased FAF correlates with the presence of intraretinal fluid and probably retinal glial activation. Microperimetry allows the measurement of retinal sensitivity by testing specific selected retinal areas. Some studies have shown that increased macular FAF in DME correlates better with visual function assessed with microperimetry than with visual acuity, showing that new imaging and functional techniques may help to elucidate DME pathogenesis and to target therapeutical strategies.
Metamorphopsia is a common symptom in different macular disorders. Micropsia and macropsia are special types of metamorphopsia. Recent theories suggest that both retinal and cortical mechanisms are ...involved in the development and changes of metamorphopsia. Different functional tests have been proposed for the evaluation of metamorphopsia: from the Amsler grid to the hand-held mobile devices for home monitoring. This review addresses some new insights into the pathophysiology of metamorphopsia and different available tests for the evaluation of this symptom in most common macular disorders. The importance of quantification of metamorphopsia in macular diseases is confirmed by the most recent therapeutic approaches.
To identify early biomarkers of retinal Müller cell activation in diabetic eyes with or without clinically detectable signs of diabetic retinopathy (DR).
This study was a cross-sectional comparative ...case series. The aqueous humor (AH) of 34 eyes was collected in 12 healthy controls, 11 diabetic patients without DR, and 11 diabetic patients with nonproliferative DR. Full ophthalmic examination and spectral-domain optical coherence tomography were performed in all eyes. Glial fibrillary acidic protein (GFAP), aquaporin 1 (AQP1), and aquaporin 4 (AQP4) were quantified in AH samples as biomarkers of Müller cell activity by ELISA. Statistical analysis was performed with ANOVA followed by Tukey-Kramer post hoc test.
There was no significant difference in the age among the three groups. Mean concentration of GFAP, AQP1, and AQP4 significantly increased in diabetic eyes versus controls (P < 0.05, for each comparison). Glial fibrillary acidic protein and AQP1 showed an approximate 2-fold increase, whereas AQP4 showed an approximate 25-fold increase in diabetics with DR versus controls. In diabetics without DR, AQP4 showed an approximate 6-fold increase versus controls.
Glial fibrillary acidic protein, AQP1, and AQP4-biomarkers of Müller cell activity-are significantly increased in human eyes with diabetes, confirming that Müller cells are precociously affected by diabetes mellitus.
The high prevalence of cardiovascular disease particularly in the elderly population is associated with retinal vascular disease. Retinal vein occlusions represent severe disturbances of the ...hypoxia-sensitive neurosensory retina. Acute and excessive leakage leads to the diagnostic hallmarks of retinal hemorrhage and edema with substantial retinal thickening. Advanced diagnostic tools such as OCT angiography allow to evaluate retinal ischemia and identify the risk for late complications and will soon reach clinical routine besides fluorescein angiography. Accordingly, the duration of non-perfusion is a crucial prognostic factor requiring timely therapeutic intervention. With immediate inhibition of vascular leakage, anti-VEGF substances excel as treatment of choice. Multiple clinical trials with optimal potential for functional benefit or a lesser regenerative spectrum have evaluated aflibercept, ranibizumab, and bevacizumab. As retinal vein occlusion is a chronic disease, long-term monitoring should be individualized to combine maintenance with practicability. While steroids may be considered in patients with systemic cardiovascular risk, surgery remains advisable only for very few patients. Destructive laser treatment is an option if reliable monitoring is not feasible. Ophthalmologists are also advised to perform a basic systemic workup to recognize systemic concomitants. The current edition of the EURETINA guidelines highlights the state-of-the-art recommendations based on the literature and expert opinions in retinal vein occlusion.
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