Optical coherence tomography angiography findings in young β-thalassemia patients

Abstract

Purpose:

The purpose was to evaluate retinal vascular parameters by optical coherence tomography angiography in β-thalassemia major patients.

Methods:

Thirty-three patients with β-thalassemia major (study group) and 29 healthy children (control group) were enrolled in the study. All subjects underwent a complete ocular examination. The mean foveal avascular zone, non-flow area, foveal avascular zone perimeter, acircularity index of foveal avascular zone, foveal density, the superficial capillary plexus, and deep capillary plexus were scanned using 6 × 6 mm optical coherence tomography angiography scans centered on the macula. Superficial capillary plexus and deep capillary plexus were also scanned centered on the optic disk. We collected data on histories of patients, and hemoglobin and ferritin were also studied from both groups.

Results:

The mean age was 13.85 ± 4.69 years (range: 4–21 years) in β-thalassemia major group and 12.59 ± 3.66 years (range: 6–18 years) in the control group. The mean foveal avascular zone value was 0.265 ± 0.11 mm² in the study group and 0.296 ± 0.12 mm² in the control group. The mean non-flow area value was 0.468 ± 0.12 mm² in the study group and 0.479 ± 0.14 mm² in the control group (p > 0.05). Differences in the mean values for foveal density and acircularity index were statistically significant between the study group and control group (p < 0.05, p = 0.026, and p = 0.026, respectively). Superficial capillary plexus and deep capillary plexus were not a significant difference between the study and control groups in 6 × 6 mm scans on macula and 4.5 × 4.5 mm scans on optic disk area (p > 0.05). Acircularity index was negatively correlated (r = −0.292, p = 0.026), and foveal density was positively correlated with hemoglobin (r = 0.292, p = 0.026).

Conclusion:

By using optical coherence tomography angiography, we detected foveal microvascular changes in young β-thalassemia patients before significant ocular anomalies development.

Keywords

β-thalassemia major deep capillary plexus foveal density peripapillary retinal capillary density optical coherence tomography angiography superficial capillary plexus

Introduction

β-thalassemia syndromes include a group of hereditary blood disorders characterized by the development of anemia as a result of a combination of hemolysis, ineffective erythropoiesis, and iron overload due to defective β-globulin chain synthesis.¹ The World Health Organization reports that thalassemia is the most common chronic and genetic disease in 60 countries and affects about 10,000 people per year.² Intensive chronic anemia, growth retardation, bone disorders, hepatosplenomegaly, and congestive heart failure are the main clinical features of this disease. Some adverse ocular changes may occur in thalassemia patients due to iron burden or iron chelators secondary to blood transfusions. These ocular manifestations contain cataract, optic neuropathy, retinal pigment epithelial degeneration, retinal pigment epithelial mottling, retinal venous tortuosity, vitreoretinal hemorrhages, and iris pattern obliteration.³

Optical coherence tomography angiography (OCT-A) is a new non-invasive imaging modality that provides detailed visualization of the retinal vascular network without the use of intravenous contrast agents by sequential OCT scans of a given retinal area and obtaining and processing motion contrast of the erythrocytes within the vessel.⁴ OCT-A can display blood flow in various layers of the retina at high resolution and speed and can provide three-dimensional (3D) images of these vascular layers. This feature enables quantitative measurement of the areas of neovascular formations and the blood flow in these vessels.⁵ Recently, OCT-A has been used to detect vascular anomalies in childhood age groups such as sickle cell disease, retinopathy of prematurity, and diabetic retinopathy.^6–8 With known advantages, OCT-A may provide an exciting opportunity to advance the understanding of vascular changes occurring in ocular tissues in β-thalassemia major. However, as far as we know, a study using OCT-A in children with β-thalassemia is not available in literature. In the present study, we aimed to investigate retinal microvascular changes in young β-thalassemia patients by using OCT-A.

Methods

Study population and design

This study was carried out as a single-center and prospective study among 33 patients with β-thalassemia and 29 healthy children. The study was conducted in the Department of Pediatric Hematology and the Department of Ophthalmology of the University of Health Sciences Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey (a tertiary care hospital with a total of 1600 beds including 200 for pediatric patients). The study was approved by the local ethics committee (2011-KAEK-25 2019/04-24) and was carried out in accordance with the Declaration of Helsinki. Before inclusion in the study, written informed consent was obtained from all parents or legal tutors of the patients.

Examination protocol and study measurements

The participants with β-thalassemia were diagnosed using clinical, hematological, and electrophoretic studies. Hemoglobin (Hb; g/dL) and ferritin (ng/mL) levels and the data regarding the type and duration of chelating therapy were obtained. These patients were receiving regular blood transfusions approximately once a month, and deferiprone and deferasirox were used as chelating agents.

The control group consisted of healthy volunteers under the care of general pediatrics counseling for a routine eye examination.

All participants underwent a complete ophthalmologic examination including best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, Goldmann applanation tonometry, perimetry, and fundus examination. The patient and control group who participated in the study was first measured with their right eyes, but left eyes were found to be more comfortable to adapt to the device, and only the left eyes were included in the study.

OCT-A measurement

Refractive error measurements were performed with the same automatic refractor-keratometer device. XR Avanti Optical Coherence Tomography Angiography with AngioVue (RTVue XR AVANTI, Optovue, Fremont, CA, USA) was used to measure 6 × 6 mm macular images centered on foveola. 4.5 × 4.5 mm optical disk images of each patient were also obtained. All OCT-A measurements were made by the same doctor (M.E.C.) and made between the same hour interval (09:00–12:00). Three consecutive measurements were made in each eye of each patient. The ones with the best image quality were used to obtain data from the study (quality score > 7). The method used in obtaining OCT-A images is referred to as split-spectrum amplitude-decorrelation angiography (SSADA). This method is based on detailed imaging of the retinal vessel network by obtaining the motion contrast of erythrocytes within the vessel through successive OCT scans of a specific retinal area and processing them. With OCT-A’s face image, the detection of the facial capillary plexus, deep capillary plexus (DCP), and foveal avascular zone (FAZ) can be possible. Thanks to software in the OCT-A (software in our device, AngioVue), in the 6 × 6 mm measuring mode, in foveal centered three main areas; capillary plexus density can be detected in foveal, parafoveal, and perifoveal quadrants. The innermost ring refers to a foveal region of 1 mm, the middle ring refers to a parafoveal region of 3 mm, and the distal ring of 6 mm refers to a perifoveal region. In addition, these zones are separated with software to four main equal quadrants, nasal, temporal, superior, and inferior, and to equal two hemispheres, superior and inferior (Figure 1). Non-flow area (NFA) is measured from superior capillary plexus (SCP), and FAZ, FAZ perimeter, acircularity index (AI), and foveal density (FD) are automatically measured from all retinal layers (Figure 2).

Exclusion criteria

Ocular exclusion criteria for this study: prior history of significant ocular disease, a BCVA worse than 20/20, amblyopia, more than two diopters of cylindrical and/or four diopters of spherical refractive error, intraocular pressure readings greater than 21 mm Hg, glaucoma, history of uveitis, retinal disease, ocular trauma or tumor, poor image quality, and dense media opacities. Extraocular exclusion criteria for this study: associated systematic disorders that might affect the eyes (e.g. uncontrolled diabetes or hypertension).

Statistical analysis

All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS), version 21. Measurements taken from both eyes per subject were selected for the analyses. For each continuous variable, data normality was confirmed using the Kolmogorov–Smirnov test (p > 0.05). Pearson’s correlation was used to examine the relationships among the measured variables. For the comparison of the study group and the control group, an independent sample t test was performed for the normally distributed data. In comparison of categorical variables, a chi-square test was utilized. Values of p less than 0.05 were considered significant.

Results

The study involved 62 eyes of 62 patients. The study group included 33 β-thalassemia major patients, while the control group consisted of 29 healthy volunteers. The mean age was 13.85 ± 4.69 years (range: 4–21 years) in the β-thalassemia major group and 12.59 ± 3.66 years (range: 6–18 years) in the control group. There was no statistically significant difference between age and gender in both groups (p > 0.05). Average diagnosis times of β-thalassemia major patients in the study group were 13.09 ± 4.64 years. The demographics of the participants in the study and control group are summarized in Table 1.

Table 1.

Demographics and clinical characteristics of participants.

Parameters	Study group (n = 33)	Control group (n = 29)	p value
Age in years*	13.85 ± 4.65	12.59 ± 3.66	0.247
Female/male	14/19	16/13	0.316
The duration of β-thalassemia major, years*	13.09 ± 4.64	N/A	–
Hemoglobin (g/dL)*	9.1 ± 0.52	12.8 ± 0.64	<0.001^**
Ferritin (nmol/L)*	1838 ± 1122	67.2 ± 22.7	<0.001^**

The values are presented as mean ± standard deviation.

indicates a statistical significance (p <0.05).

The mean values of the non-flow and FAZ assessment tool parameters in the β-thalassemia major and control groups are shown in Table 2. The mean FD and AI were statistically significant between the β-thalassemia major group and the control group (p < 0.05, p = 0.026, and p = 0.026, respectively). There were no statistically significant differences between the groups for the NFA in the SCP and FAZ area in the whole retina (p > 0.05).

Table 2.

Comparison of the Non-flow and Foveal avascular zone assessment tool parameters in both groups.

	Study group (n = 33)	Control group (n = 29)	p value
Non-flow area (mm²) (SCP)	0.468 ± 0.12	0.479 ± 0.14	0.740
FAZ area (mm²) (whole retina)	0.265 ± 0.11	0.296 ± 0.12	0.323
FAZ perimeter (mm)	1.96 ± 0.43	2.05 ± 0.44	0.462
AI	1.10 ± 0.02	1.08 ± 0.02	0.026^*
FD (%)	55.75 ± 3.47	57.85 ± 3.51	0.026^*

SCP: superficial capillary plexus; FAZ: foveal avascular zone; AI: acircularity index; FD: foveal density.

indicates a statistical significance (p <0.05).

The data of OCT-A device deep and surface capillary plexus densities in different quadrants in foveal, perifoveal, and parafoveal regions are summarized in Table 3. No statistically significant difference was found between the two groups in terms of SCP densities (p > 0.05). Although there was a statistically significant difference in DCP densities only in the perifoveal nasal quadrant (p < 0.05), these differences in the other quadrants were not statistically significant (p > 0.05, for all). Similarly, no significant difference was found between capillary plexus densities in the optic disk region in both groups (p > 0.05, for all).

Table 3.

Comparison of the vessel density assessment tool parameters in different sections.

	Study group*	Control group*	p value
Vessel density, SCP flow (%)
Whole retina	51.68 ± 2.01	51.90 ± 2.08	0.674
Superior-hemi	51.65 ± 1.97	51.97 ± 2.15	0.562
Inferior-hemi	51.70 ± 2.19	51.84 ± 2.24	0.808
Fovea	22.90 ± 6.11	21.67 ± 6.65	0.461
Parafovea	54.05 ± 2.61	54.40 ± 3.76	0.676
Superior-hemi	54.02 ± 2.76	54.38 ± 3.99	0.684
Inferior-hemi	54.09 ± 2.93	54.38 ± 3.69	0.743
Temporal	54.36 ± 2.11	54.29 ± 4.19	0.938
Superior	54.22 ± 3.43	54.62 ± 4.64	0.703
Nasal	53.20 ± 2.90	53.27 ± 3.44	0.932
Inferior	54.46 ± 3.53	55.35 ± 3.85	0.357
Perifovea	52.24 ± 2.24	52.42 ± 2.22	0.757
Superior-hemi	52.28 ± 2.19	52.58 ± 2.30	0.614
Inferior-hemi	52.04 ± 2.29	52.24 ± 2.45	0.747
Temporal	49.24 ± 2.46	49.35 ± 2.52	0.875
Superior	52.03 ± 2.50	52.33 ± 2.68	0.661
Nasal	55.35 ± 2.01	56.03 ± 2.71	0.283
Inferior	51.73 ± 2.75	51.95 ± 2.64	0.756
Vessel density, DCP flow (%)
Whole retina	53.44 ± 5.80	55.54 ± 5.58	0.169
Superior-hemi	53.96 ± 5.81	55.78 ± 5.70	0.236
Inferior-hemi	52.90 ± 5.98	55.30 ± 5.68	0.127
Fovea	39.55 ± 7.95	38.98 ± 8.54	0.794
Parafovea	56.91 ± 4.81	58.62 ± 4.56	0.173
Superior-hemi	57.25 ± 4.37	58.93 ± 4.92	0.173
Inferior-hemi	56.57 ± 5.62	58.32 ± 4.46	0.203
Temporal	58.19 ± 4.50	59.38 ± 4.77	0.333
Superior	56.67 ± 4.60	58.44 ± 5.27	0.178
Nasal	57.08 ± 4.99	58.95 ± 4.56	0.147
Inferior	55.74 ± 6.30	57.75 ± 5.06	0.193
Perifovea	54.90 ± 5.94	57.09 ± 5.89	0.166
Superior-hemi	55.52 ± 5.96	57.48 ± 5.89	0.218
Inferior-hemi	54.25 ± 6.13	56.70 ± 6.20	0.139
Temporal	57.13 ± 5.40	59.01 ± 4.46	0.163
Superior	55.33 ± 6.74	56.65 ± 6.73	0.459
Nasal	53.48 ± 6.10	56.94 ± 6.74	0.047^**
Inferior	53.52 ± 6.68	55.73 ± 7.21	0.232
RPC density, optic disk
Whole	50.48 ± 2.25	50.16 ± 2.09	0.579
Inside disk	53.01 ± 3.50	54.46 ± 3.73	0.133
Peripapillary	51.48 ± 2.83	51.03 ± 2.59	0.533
Superior-hemi	51.85 ± 3.11	51.02 ± 2.83	0.295
Inferior-hemi	51.04 ± 3.09	51.03 ± 2.88	0.988

SCP: superficial capillary plexus; DCP: deep capillary plexus; RPC: radial peripapillary capillary.

The values are presented as mean ± standard deviation.

indicates a statistical significance (p <0.05).

Correlations between age, Hb, ferritin levels, disease duration, chelation uptake time, chelation type, and ocular changes were investigated. Only Hb levels were found to be correlated with ocular changes. AI was negatively correlated (r = −0.292, p = 0.026), and FD was positively correlated with Hb (r = 0.292, p = 0.026).

Discussion

In the current study, we compared the density of vascular plexus in different regions in different layers of the retina with OCT-A device in β-thalassemia major patients and healthy volunteers. We, therefore, considered early detection of retinal changes in the course of the disease in β-thalassemia major patients without any symptoms and associated complications with OCT-A, a non-invasive method. To our knowledge, our study is the first to evaluate retinal microvascular changes in children with β-thalassemia by using OCT-A.

Anemia causes chronic tissue hypoxia due to the level of severity.⁹ Mean Hb levels of β-thalassemia major patients were 3.7 ± 0.12 low compared to the control group (p < 0.001). Besides, AI was negatively correlated (r = −0.292, p = 0.026), and FD was positively correlated with Hb (r = 0.292, p = 0.026). The secondary iron burden to recurrent transfusions and ineffective erythropoiesis in patients with β-thalassemia is the main life-threatening problem.¹⁰ Although iron is important for normal metabolic processes, iron overload causes an increase in oxidative stress with excessive free radical formation.¹¹ Taneja et al.³ examined the relationship between serum ferritin levels and ophthalmic findings in their study and found out that ocular changes increase as a result of increased serum ferritin levels. In our study, although there was a high difference within ferritin levels between β-thalassemia major patients and control group, ocular changes detected did not correlate with ferritin.

Chelating agents are a commonly used form of treatment coping with chronic iron overload. In our study, chelators were used in all our patients. Although anti-neurodegenerative and neuroprotective effects of brain chelators have been observed in animal experiments, some ocular side effects such as cataract, retrobulbar optic neuritis, pigmentary retinopathy, and vitelliform maculopathy have been reported.^12,13 Simon et al.¹⁴ reported a significant ocular toxicity of desferrioxamine and recommended that patients taking desferrioxamine have regular eye examinations. Viola et al.¹⁵ reported retinal pathologies resulting in progressive retinal pigment epithelium and vision loss in patients receiving long-term desferrioxamine. In our study, we found no correlation between chelator uptake time and ocular changes.

Although the exact cause of optic nerve involvement in β-thalassemia is not known, the use of iron-overload, iron-mediated oxidative stress, and chronic chelator contribute to the pathogenesis of ocular involvement. As a result, various ocular manifestations can be seen in β-thalassemia patients including color vision anomalies, night blindness, cataract, visual field defects, decreased visual acuity, and optic neuropathy.¹ We did not find any eye findings to be detected yet in our study patients.

OCT-A technology is an important advance in ophthalmology and offers the opportunity to non-invasively visualize different retinal capillary layers without the need for fluorescein sodium contrast agent injection.¹⁶ OCT-A allows clinicians to see for the first time the precise 3D microarchitecture of vessels such as the perifoveal superficial and deep capillary network, which they have previously only been able to see through histological examination. However, OCT-A is unable to show leaks, and it still has poorly understood artifacts, especially in deep plexus.^17,18 Since the availability of OCT-A, there have been several studies that have reported the changes of retinal microvasculature in some childhood diseases.^6–8

The FAZ is a good indicator of the capillary drop out, especially affected by retinal microvascular change.¹⁹ FAZ expansion is associated with decreased visual acuity.²⁰ Niestrata-Ortiz et al.⁸ have also detected FAZ expansion in children without diabetic retinopathy in their study. In some studies performed in premature children, they found contraction in the FAZ area, indicating that this may be related to the vascular remodeling process in the foveal center.^21,22 In another publication, they found an increase in the FAZ field in myopic children compared to the control group.²³

In studies conducted with changes in FAZ perimetry, AI, and FD, it has been shown that there may be differences in the early stages of the disease even in the preclinical stages.²⁴ In their study in diabetic children, it is shown that FAZ perimeter, AI, and FD change without retinopathy findings. Similarly, Lynch et al.²⁵ performed a study in children with sickle cell anemia, in whom FAZ perimeter and AI showed a significant increase compared to the control group.

Capillary density is one of the other indicators of capillary drop out except FAZ parameters. Quantitative values can be obtained by capillary density measurement. By this, non-invasive detection of microvascular changes may be possible. These changes are indicative of signs of retinal ischemia. They reported that in literature, especially in type 1 patients, deep and surface capillary plexus density decreased and this may be the early signs of the disease.^26,27

Strengths and limitations

The strengths of the study include the prospective nature of patients’ recruitment, and to our knowledge, our study is the first to evaluate retinal microvascular changes in children with β-thalassemia by using OCT-A. However, this study has several limitations. The number of patients was low due to poor patient cooperation in the pediatric group during OCT-A screening. Information on macular anatomy in children is very limited. Children undergoing OCT-A have not reported normal values. Therefore, literature that can compare our study is quite limited. Another limitation of our publication is that the measurements of 6 × 6 mm area cannot be taken with the OCT-A device and the peripheral retina cannot be evaluated. Since the device cannot detect at low current speeds, it can display these areas as capillary non-perfused areas. Finally, there is a need to investigate whether OCT-A would make a suitable screening technique for β-thalassemia in children.

In conclusion, we detected changes in capillary density in the foveal region without any clinical findings in patients with β-thalassemia major. Although there is no enlargement in the FAZ area of our patients, the observed FD changes emphasize the importance of OCT-A, which is a non-invasive method, especially to show early eye effects of the disease. This finding should be supported by studies with large number of cases and studies which can evaluate peripheral retina.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Muhammet Furkan Korkmaz

Mehmet Erol Can

References

Uzun

Karaca

Yildiz Yerlikaya

, et al. Retinal nerve fiber layer thickness in children with beta-thalassemia major. Saudi J Ophthalmol 2017; 31(4): 224–228.

Aksoy

Aslan

Aslankurt

, et al. Retinal fiber layer thickness in children with thalessemia major and iron deficiency anemia. Semin Ophthalmol 2014; 29(1): 22–26.

Taneja

Malik

Sharma

, et al. Multiple transfused thalassemia major: ocular manifestations in a hospital-based population. Indian J Ophthalmol 2010; 58(2): 125–130.

Wylegala

Teper

Dobrowolski

, et al. Optical coherence angiography: a review. Medicine 2016; 95(41): e4907.

de Carlo

Romano

Waheed

, et al. A review of optical coherence tomography angiography (OCTA). Int J Retina Vitreous 2015; 1: 5.

Roemer

Bergin

Kaeser

, et al. Assessment of macular vasculature of children with sickle cell disease compared to that of healthy controls using optical coherence tomography angiography. Retina 2018; 39: 2384–2391.

Chen

SN.

Foveal microvascular anomalies on optical coherence tomography angiography and the correlation with foveal thickness and visual acuity in retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 2019; 257(1): 23–30.

Niestrata-Ortiz

Fichna

Stankiewicz

, et al. Enlargement of the foveal avascular zone detected by optical coherence tomography angiography in diabetic children without diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2019; 257(4): 689–697.

Haase

VH.

Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev 2013; 27(1): 41–53.

10.

Cao

Galanello

Beta-thalassemia. Genet Med 2010; 12(2): 61–76.

11.

Kassab-Chekir

Laradi

Ferchichi

, et al. Oxidant, antioxidant status and metabolic data in patients with beta-thalassemia. Clin Chim Acta 2003; 338(1–2): 79–86.

12.

Gumienna-Kontecka

Pyrkosz-Bulska

Szebesczyk

, et al. Iron chelating strategies in systemic metal overload, neurodegeneration and cancer. Curr Med Chem 2014; 21(33): 3741–3767.

13.

van der Kooij

Groenendaal

Kavelaars

, et al. Combination of deferoxamine and erythropoietin: therapy for hypoxia-ischemia-induced brain injury in the neonatal rat. Neurosci Lett 2009; 451(2): 109–113.

14.

Simon

Athanasiov

Jain

, et al. Desferrioxamine-related ocular toxicity: a case report. Indian J Ophthalmol 2012; 60(4): 315–317.

15.

Viola

Barteselli

Dell’arti

, et al. Abnormal fundus autofluorescence results of patients in long-term treatment with deferoxamine. Ophthalmology 2012; 119(8): 1693–1700.

16.

Ting

DSW

Tan

GSW

Agrawal

, et al. Optical coherence tomographic angiography in type 2 diabetes and diabetic retinopathy. JAMA Ophthalmol 2017; 135(4): 306–312.

17.

Bradley

Sim

Keane

, et al. The evaluation of diabetic macular ischemia using optical coherence tomography angiography. Invest Ophthalmol Vis Sci 2016; 57(2): 626–631.

18.

Hwang

Gao

Liu

, et al. Automated quantification of capillary nonperfusion using optical coherence tomography angiography in diabetic retinopathy. JAMA Ophthalmol 2016; 134(4): 367–373.

19.

Tam

Dhamdhere

Tiruveedhula

, et al. Subclinical capillary changes in non-proliferative diabetic retinopathy. Optom Vis Sci 2012; 89(5): E692–E703.

20.

Arend

Wolf

Harris

, et al. The relationship of macular microcirculation to visual acuity in diabetic patients. Arch Ophthalmol 1995; 113(5): 610–614.

21.

Takagi

Maruko

Yamaguchi

, et al. Foveal abnormalities determined by optical coherence tomography angiography in children with history of retinopathy of prematurity. Eye 2019; 33(12): 1890–1896.

22.

Miki

Yamada

Nakamura

The size of the foveal avascular zone is associated with foveal thickness and structure in premature children. J Ophthalmol 2019; 2019: 8340729.

23.

Golebiewska

Biala-Gosek

Czeszyk

, et al. Optical coherence tomography angiography of superficial retinal vessel density and foveal avascular zone in myopic children. PLoS ONE 2019; 14(7): e0219785.

24.

Inanc

Tekin

Kiziltoprak

, et al. Changes in retinal microcirculation precede the clinical onset of diabetic retinopathy in children with type 1 diabetes mellitus. Am J Ophthalmol 2019; 207: 37–44.

25.

Lynch

Scott

Linz

, et al. Foveal avascular zone morphology and parafoveal capillary perfusion in sickle cell retinopathy. Br J Ophthalmol. Epub ahead of print 23 July 2019. DOI: 10.1136/bjophthalmol-2019-314567.

26.

Simonett

Scarinci

Picconi

, et al. Early microvascular retinal changes in optical coherence tomography angiography in patients with type 1 diabetes mellitus. Acta Ophthalmol 2017; 95(8): e751–e755.

27.

Carnevali

Sacconi

Corbelli

, et al. Optical coherence tomography angiography analysis of retinal vascular plexuses and choriocapillaris in patients with type 1 diabetes without diabetic retinopathy. Acta Diabetol 2017; 54(7): 695–702.