Doppler ultrasound-based evaluation of hemodynamic changes in the ophthalmic artery and central retinal artery in patients with type 1 diabetes mellitus without retinopathy and with mild non-proliferative retinopathy

In view of the rising incidence of diabetes mellitus the search is on for new diagnostic methods to serve as markers of early diabetic changes. Diabetic retinopathy is the primary microvascular and neurodegenerative complication of diabetes. It is also the main ocular complication of diabetes and the most common reason behind vision loss among individuals between 20 and 74 years of age⁽¹⁾. Concurrently with the rise in the incidence of diabetes, there is a noticeable increase in the occurrence of chronic microvascular complications. After 20 years, diabetic retinopathy develops in nearly all patients with type 1 diabetes mellitus and in 60% of individuals with type 2 diabetes^(2,3). A key role is attributed to chronic hyperglycemia leading to microcirculation disorders. Other contributory factors include duration of the disease, comorbid hypertension, hyperlipidemia, smoking, and pregnancy. While the risk factors are well-documented, the exact pathogenesis of diabetic retinopathy is not fully understood, and the mechanisms causing vascular damage are multifaceted. The onset of the disease is influenced by a variety of aspects, including genetics, and metabolic and vascular conditions.

Evaluation of vascular flow in the retina and its supplying blood vessels by color Doppler ultrasound could serve as a valuable tool in expanding our understanding of the progression of diabetic retinopathy.

Doppler ultrasound imaging is a non-invasive diagnostic procedure used in ophthalmology to evaluate changes in blood flow in the orbital blood vessels.

The most commonly assessed vessels include the ophthalmic artery (OA), the central retinal artery (CRA), and the temporal posterior ciliary arteries (TPCA), while the main studied parameters comprise peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistance index (RI), which is a measure of peripheral vascular resistance. While it is possible to determine blood velocity in these vessels, direct measurement of their diameter poses a challenge because of their small size. Despite this limitation, velocity is regarded as a good indicator of blood flow^(4,5).

There are only scarce reports in the literature that specifically address blood flow in the orbital vessels in diabetic patients. Most measurements are carried out in small, heterogeneous patient groups, which diminishes the diagnostic value of results. In addition, discrepancies in the findings are frequently noted. Some sources have reported a decrease in PSV, EDV and RI in retrobulbar blood vessels in patients with diabetes, while other authors have presented opposing observations^{(6,7,8,9,10,11,12)}. The discrepancies in findings might be due to differences in patient selection criteria and heterogeneity of study groups in terms of diabetes type, patient age, duration of diabetes, control of metabolic parameters, stage of retinopathy, and treatment method.

The aims of the study were to assess the blood flow parameters in the orbital vessels in the OA and CRA in patients with type 1 diabetes mellitus without changes in the fundus and with mild nonproliferative retinopathy, to compare the parameters with a control group of healthy individuals, and to examine the correlations between the blood flow values in the orbital vessels and the duration and metabolic control of diabetes measured by the level of glycated hemoglobin (HbA_1c).

The study included a total of 161 participants, with 80 individuals aged 18–45 diagnosed with type 1 diabetes mellitus and 81 healthy individuals of a similar age range, serving as the control group. The study exclusion criteria included comorbidities, systemic diabetic complications, obesity, smoking, medications other than insulin, vision defects (up to ±3.0 diopters (D)), current or past eye conditions that may affect ocular vascular flow, ocular trauma, and history of ophthalmic surgery.

The participants gave their informed consent to take part in the study, which was approved by the Ethics Committee (decision No. KB/217/2016).

The study encompassed individuals aged 18–45 years who had been diagnosed with type 1 diabetes mellitus and treated for a period ranging from one to 25 years. The patients were divided into groups based on the presence or absence of diabetic fundus changes. Another classification was determined by the degree of diabetes control, as assessed by the level of HbA_1c: group HbA_1c 5.0–7.0%, group HbA_1c 7.1–13.0%. The third criterion was the duration of diabetes (evaluated in increments of five years).

All participants in the study underwent a general medical assessment and laboratory tests. The results, including renal function and lipid profile, fell within the normal range for all subjects. A full ophthalmic examination with pupil dilation and indirect ophthalmoscopy using a Volk +90D focusing lens in white and red-free light were performed. Color and red-free fundus images were taken using a Topcon TRC-NW7SF Mark II fundus camera at 30° and 45°. Optical coherence tomography (OCT) was performed along with fluorescein angiography (FA) in the participants who consented to the examination with a contrast agent. Diabetic alterations were assessed according to the ETDRS (Early Treatment Diabetic Retinopathy Study) scale. Depending on the findings of the fundus examination, diabetic patients were allocated to a group without retinopathy or with mild non-proliferative retinopathy.

Doppler ultrasound examinations of blood flow in the orbital vessels were carried out using a Siemens Acuson X300 ultrasound system equipped with a VF10-5 linear transducer. Blood flow was assessed in the OA and CRA. During the examination, the patients were positioned lying on their back with closed eyelids. A linear probe with ultrasound gel was used, with no pressure applied to the eyeball. By capturing an image of the eye in B-scan presentation, the optic nerve was identified, serving as a reference point for the retrobulbar vessels. The visualization of the ophthalmic and central retinal arteries was routinely achieved with the eye positioned in a straight-ahead gaze. The OA was typically identified nasal to the optic nerve, following its path towards the medial part of the optic nerve. The CRA was visualized along with the homonymous vein in the lumen of the optic nerve, with measurements conducted prior to its passage through the lamina cribrosa. Adopting an appropriate scan depth, a narrow sampling gate (1.5 mm) was set in the vessel lumen, with an angle correction of 0–30°. In this set-up, a flow velocity spectrum was recorded for the OA (Fig. 1) and CRA (Fig. 2).

Fig. 1.

Fig. 2.

The following blood flow parameters were analyzed:

peak systolic velocity (PSV, m/s), i.e. maximum velocity of blood flow during the systolic phase of the cardiac cycle (heart contraction);

The assessment of blood flow parameters in the orbital vessels was carried out in a cohort of young patients with type 1 diabetes mellitus, without comorbidities, who had not yet developed diabetic changes in the fundus or exhibited early signs of mild non-proliferative diabetic retinopathy. By selecting this group of patients, it was possible to eliminate potential factors contributing to changes in the characteristics of blood flow in the orbital vessels in patients with type 1 diabetes mellitus, and to determine whether alterations in blood flow parameters in the CRA and OA could be seen in this group of patients despite the absence of changes or early changes in the fundus of the eye.

The study involved patients with a diagnosis of type 1 diabetes mellitus who exhibited changes in blood flow parameters compared to the control group, specifically a statistically significant reduction in PSV and EDV in the central retinal artery along with an increase in RI in relation to the control group.

A correlation was found between the blood flow parameters and the progression of changes in the eye fundus in this group. Alterations in blood flow parameters were evident already in individuals without diabetic changes in the fundus. However, the presence of retinopathy further decreased the blood flow velocity (specifically PSV and EDV) in the central retinal artery compared to the group of patients where no retinal changes were observed. The findings obtained in the study point to the early onset of hemodynamic alterations in the CRA, preceding the emergence of clinical abnormalities in the fundus.

Depending on the level of glycated hemoglobin (HbA_1c) which serves as an indicator of diabetes control, changes in blood flow values in the OA and CRA were noted. In the group of patients with uncontrolled diabetes, significant reductions in PSV were observed both in the OA and CRA.

The duration of diabetes was found to have an impact on changes in blood flow parameters in the CRA, manifesting as a decrease in PSV, in patients who had diabetes for more than 20 years. In this group, a significant difference was observed between the individuals with stable glycemia compared to those with elevated levels of HbA_1c.

The ophthalmic artery was characterized by variability of blood flow parameters depending on the level of diabetes control, manifested as a significant reduction in PSV in the group with poorly controlled glycemia.

Chronic hyperglycemia disturbs the body’s autoregulatory mechanisms, contributing to the onset of diabetic retinopathy by altering the diameter of blood vessels, reducing the perfusion pressure, and inducing changes in peripheral resistance^(13,14). The authors’ research suggests that changes in blood flow within the orbital vessels occur in patients without and with retinopathy. Major abnormalities in blood flow parameters, specifically a significant decrease in the measured values of PSV and EDV, are noted in the central retinal artery. The deviations correlate with the severity of fundus lesions, metabolic control of diabetes, and duration of the condition. In the OA, variability in blood flow parameters was shown, depending on diabetes control, with a decrease in PSV observed in patients with elevated levels of HbA_1c. Hemodynamic changes observed in the central retinal artery among the study participants with type 1 diabetes mellitus without evident fundus lesions and with mild non-proliferative retinopathy might, therefore, reflect early vascular changes. The central retinal artery seems to hold particular significance as a vessel for evaluating these initial alterations. As a branch of the ophthalmic artery, the central retinal artery is anatomically terminal, and studies have found significant changes in blood flow parameters in this vessel.

Blood flow in the vessels is contingent upon both perfusion pressure and vascular resistance. These two parameters, in turn, are influenced by a range of hyperglycemia-sensitive local factors encompassing blood vessel structure and diameter, obstacles in the flow path, neurogenic and angiogenic factors, and blood rheology^(15,16).

The outcomes derived from this study, including diminished PSV and EDV levels in the CRA compared to the healthy group, might suggest that ischemia and inadequate perfusion precede the onset of clinical signs of retinopathy, and increased RI in the CRA may be linked to elevated peripheral vascular resistance.

A review of publications addressing the application of Doppler ultrasound for evaluating blood flow in the orbital vessels in diabetic patients reveals discrepancies in study findings. They may be due to the absence of standardized eligibility criteria across the study groups, including variations in age ranges^(7,8,9,17) and type of diabetes (most publications focus on correlations with type 2 diabetes or combined diabetes types)^(18,19). The groups under comparison also exhibited variations in the duration of the disease and the advancement of fundus lesions. The most commonly described hemodynamic parameters of the orbital vessels include PSV, EDV, and RI. A number of authors have reported a decrease in orbital blood flow velocity in diabetic patients, while others have observed an increase in blood flow. Vascular resistance index demonstrates variability across authors as well.^(6,12,13,20).

There are only scarce reports in the literature describing hemodynamic changes in the orbital vessels in young patients with type 1 diabetes mellitus who have not yet developed diabetic changes in the fundus or the abnormalities are still in the early stages. The presence of statistically significant blood flow disruptions in the CRA in patients with type 1 diabetes mellitus without fundus changes and with early signs of retinopathy, as demonstrated in our study, appears to be an important observation, aligned with a limited number of existing reports in the literature and findings from other studies employing alternative measurement techniques for the CRA⁽²¹⁾ or based on animal models⁽²²⁾, suggesting that reductions in CRA flow precede ocular fundus changes.

Our study findings align with the results of the metaanalysis of 13 studies conducted by Meng et al.⁽¹⁹⁾ in patients without retinopathy and with diabetic retinopathy who had their blood parameters assessed by color Doppler. Just two out of the 13 publications reviewed focused specifically on individuals with type 1 diabetes mellitus. The remaining studies either involved patients with type 2 diabetes or comprised a mixed group, reflecting the scarcity of literature discussing hemodynamic alterations in type 1 diabetes mellitus. Referring to studies involving patients with type 2 diabetes mellitus might result in an inaccurate assessment of hemodynamic changes. Typically, these patients represent a different age group and often present with systemic complications, including vascular abnormalities. Consequently, this particular group, as well as patients with type 1 diabetes mellitus and advanced fundus changes, were excluded from the discussion. In the available literature, some researchers studying patients with type 1 diabetes have reported findings consistent with those observed by the authors of this paper, including an elevation in RI in the OA and CRA, indicating a probable rise in peripheral vascular resistance. Additionally, a significant decline in PSV and EDV in the CRA has been reported, potentially suggesting ischemia and compromised blood perfusion even before the onset of clinical features indicative of diabetic retinopathy. Kawagishi et al.⁽⁶⁾ assessed the blood flow parameters in the central retinal artery in patients diagnosed with type 1 diabetes mellitus without retinopathy, and compared the measurements with those in the control group. Similar to the authors of this paper, the researchers obtained significantly lower PSV and EDV values in the CRA and increased RI in the CRA, which indicates that hemodynamic changes in the retinal vessels emerge before the onset of clinical symptoms of diabetic retinopathy. Varying results were obtained for the CRA and OA by Ovali et al.⁽²⁰⁾ in young patients diagnosed with type 1 diabetes mellitus but without retinopathy. The study group was characterized by a wide age range (2–20 years). The researchers observed elevated EDV in the OA compared to the control group and reduced RI values in the OA in diabetic patients over five years of age. In cases where diabetes was accompanied by microalbuminuria, there was an observed increase in RI in the CRA. Modrzejewska et al.⁽²³⁾ evaluated the retrobulbar arterial flow characteristics in a cohort of young individuals with type 1 diabetes mellitus but without fundus lesions and in a control group, examining the relationship between these arterial blood flow parameters and serum lipid levels. The study revealed a reduction in PSV in the CRA compared to the control group, and a decrease in RI. A similar relationship was observed in the OA and TPCA. Disturbances in the lipid profile were associated with fluctuations in vascular resistance, primarily in the OA. The authors concluded that reduced values of RI in the CRA and TPCA, and of PI in the TPCA might be linked to the early-onset dilation of retinal arterioles and precapillary vessels resulting from vascular dysregulation. Research conducted by the authors revealed a decrease in blood flow parameters (a significant reduction in PSV in the OA) only in patients with poorly controlled diabetes, with HbA_1c >7. A decrease was also noted in EDV (close to the level of significance). Similar associations were reported by Ozates et al.⁽²⁴⁾. The authors found reduced PSV and EDV values and elevated PI in the OA in patients with type 1 diabetes mellitus without signs of diabetic retinopathy in the fundus, with recently diagnosed type 1 diabetes. The observed decreased blood velocity and increased PI values may be attributed to vascular changes and elevated vascular resistance.

In summary, the findings of the reported study may indicate that alterations in blood flow parameters in the central retinal artery reflect vascular dysfunction preceding the onset of visible signs of retinopathy. Thus, they might serve as sensitive markers of hemodynamic disorders in patients with type 1 diabetes mellitus without fundus changes, and they are more prominent in patients presenting with signs of retinopathy. Uncontrolled diabetes, measured by the level of HbA_1c, further decreases vascular flow velocity both in the CRA and OA. The duration of diabetes and the level of glycemic control, which are widely recognized as the most critical risk factors for the development of microangiopathy, were also mirrored in the hemodynamic changes in the orbital vessels found in the study. However, what appears to be particularly important is the fact that changes in blood flow parameters occurred in the early stages of diabetes, even before the onset of retinopathy, which highlights the value of the adopted research methodology and substantiates the need for further studies in this area.