Noninvasive Detection of Retinal Vascular Changes in Eyes with Non-arteritic Anterior Ischemic Optic Neuropathy

1. INTRODUCTION

Non-arteritic Anterior Ischemic Optic Neuropathy (NAION) is one of the most prevalent conditions affecting individuals over 50 years of age, leading to irreversible vision loss [1]. However, its pathogenesis, clinical features, and treatment options still remain controversial [2]. Several local risk factors for NAION have been identified, including insufficient blood supply to the optic nerve head and compromised watershed microcirculation [3, 4]. Numerous researchers [1, 5, 6] have suggested that “disc at risk” plays a role in the pathogenesis of NAION. Additionally, various systemic risk factors, such as metabolic syndrome (MetS), gender, and age, may also act as triggers [7-9].

The retinal vasculature offers a unique window to non-invasively and directly assess vascular segments in vivo, reflecting circulatory efficiency. Advancements in digital retinal photography and software have significantly enhanced our ability to measure the characteristics of retinal vessels with greater convenience [10, 11]. Integrative Vessel Analysis (IVAN), a novel software designed by the University of Wisconsin, allows for the measurement of retinal vessel caliber using fundus images [12]. Given that NAION is considered to stem from vascular insufficiency [13, 14], we hypothesized that vascular diameter is a risk factor for NAION. In this study, we used IVAN to measure retinal vessel caliber from fundus photographs to assess its relevance to the progression of NAION. Additionally, the correlation between retinal vascular parameters and NAION-related systemic factors was assessed.

2. MATERIALS AND METHODS

3. RESULTS

3.1. Quantification and Analysis of CRAE and CRVE among Groups

The baseline characteristics of the patients are summarized in Table 1. A total of 120 patients (81 women and 39 men) participated in our study, which divided them into three groups: the normal group (Normal), the hypertension group (Hyper), and the NAION group (NAION). Fig. (1) presents representative images for each group. No significant differences in age or gender were observed among the three groups at baseline.

We assessed the Central Retinal Artery Equivalent (CRAE) and Central Retinal Vein Equivalent (CRVE) in each group using the IVAN software, with representative images shown in Fig. (2). The overall measurements for CRAE and CRVE across all patients were 154.54 ± 21.53 μm and 252.22 ± 15.88 μm, respectively. In the normal group, CRAE and CRVE were 154.05 ± 11.72 μm and 237.60 ±13.98 μm, respectively. The hyper group showed CRAE and CRVE values of 150.05 ± 15.12 μm and 242.26 ± 14.53 μm, respectively. In contrast, the NAION group exhibited CRAE and CRVE values of 159.6 ± 17.07 μm and 277.17 ± 26.58 μm, respectively.

Table 1.

Characteristics	Total Participants (n=120)	Normal Participants (n=40)	Hypertension Participants (n=40)	NAION Participants (n=40)	p value
Age, year	58 ±9.98	53 ±10.04	56 ±8.01	58 ±11.4	0.0803
Gender, female%	81, 67.5%	29, 72.5%	26, 65%	26, 65%	0.7104
CRAE, μm	154.54 ±21.53	154.05 ±11.72	150.05 ±15.12	159.60 ±17.07	0.0173
CRVE, μm	252.22 ±15.88	237.60 ±13.98	242.26 ± 14.53	277.17 ±26.58	<0.0001

Abbreviations: CRAE: central retinal artery equivalent.
CRVE: central retinal vein equivalent.

Notably, a significant difference in CRAE was found among the three groups (p=0.017). Post hoc analyses indicated that the CRAE was significantly larger in the NAION group compared to the hyper group (p=0.013). However, no significant difference was found between the hyper and normal groups (p=0.451) (Fig. 3A).

Furthermore, a significant difference in CRVE was observed among the three groups (p < 0.0001). Post hoc comparisons revealed that CRVE was significantly larger in the NAION group compared to the hyper group (p <0.0001) and the normal group (p <0.0001). The NAION group consistently exhibited larger CRVE values than the other groups, while no significant difference was found between the hyper and normal groups (p=0.527) (Fig. 3B).

Table 2.

Systemic Factors	Normal (r, p value)	Hypertension (r, p value)	NAION (r, p value)
CRAE
Age, year	-0.140 (0.396)	-0.082 (0.616)	0.110 (0.499)
Gender	0.001 (0.994)	0.222 (0.118)	0.047 (0.770)
BMI	-0.10 (0.32)	0.03 (0.79)	-0.10 (0.04)
CRVE
Age, year	-0.110 (0.504)	-0.122 (0.454)	-0.196 (0.225)
Gender	-0.156 (0.343)	-0.215 (0.184)	-0.08 (0.622)
BMI	0.104 (0.29)	0.016 (0.95)	0.95 (0.01)

Abbreviations: CRAE: central retinal artery equivalent.
CRVE: central retinal vein equivalent.

4. DISCUSSION

NAION is a multifactorial ocular disease. The primary mechanism underlying NAION is believed to be acute hypoperfusion of the optic nerve due to compromised posterior ciliary artery branches. Specifically, transient or permanent reduction in blood flow through the short posterior ciliary arteries, which supply the optic nerve head (ONH), may trigger optic disc edema. This can lead to compartment syndrome in the non-expansible area between the ONH surface and the lamina cribrosa, particularly in structurally predisposed, crowded optic discs. Secondary inflammation may further exacerbate damage to optic nerve axons and glial tissue, ultimately leading to retinal ganglion cell death through apoptosis [17, 18]. Since the exact pathophysiology of NAION remains unclear, examining retinal vascular morphology may provide valuable insights into the disease's pathological processes from a fresh perspective.

Currently, several methods are used to measure retinal vascular caliber from fundus images [19-21]. The IVAN method provides a noninvasive approach to assess retinal vessel changes, often serving as a marker for systemic factors, such as age and hypertension [22]. In this study, the retinal vessel calibers in the NAION group were significantly larger than those in the other groups, suggesting that the vessels in NAION patients were markedly dilated, which may be linked to the ischemic state observed in these patients [23]. The two most widely accepted explanations for NAION include the presence of a small, crowded optic disc and associated systemic comorbidities [24]. Previous studies have reported that NAION patients have a higher prevalence of small or absent optic cups, which may lead to optic nerve fiber crowding and limited space within the optic disc [25, 26]. Ischemia triggers vessel dilation as a compensatory response, allowing tissues to receive adequate oxygen.

In comparing CRAE, we found a significant increase in the NAION group compared to the normal group. We hypothesize that this arterial enlargement is due to the hypoxic conditions in the retinal environment in NAION. Under hypoxic stress, vasodilation occurs to improve blood perfusion to affected tissues [27], driven by the activation of KATP channels and a reduction in ATP in vascular smooth muscle cells, resulting in dilation [28]. Additionally, CRVE measurements revealed that the NAION group exhibited the largest retinal venous dimensions, which is consistent with previous findings on NAION. This abnormality may hinder central retinal venous return, elevate retinal venous pressure, and contribute to venous dilation [29]. In normal clinical assessments, the arteriolar-to-venular ratio (AVR) is typically around 2:3. Our findings showed that the AVR in the NAION group was the lowest among the three groups, indicating that venous dilation was more pronounced in NAION patients compared to the other groups. This result aligns with previous studies [30].

Age, gender, and BMI have been extensively discussed as risk factors for NAION in numerous studies. It has been well established that older individuals tend to have narrower vascular calibers across various studies and populations [31-33], an inverse correlation that aligns with our findings. Previous research demonstrated that a higher BMI was associated with narrower retinal arteriolar caliber in six-year-old children [34], while a recent meta-analysis also showed that smaller retinal arteriolar caliber correlated with increasing age and higher BMI [35]. These results are consistent with those of our study, where we observed that CRAE was narrower in patients with higher BMI while CRVE was wider. However, Xiao et al. reported no significant correlation between retinal caliber and BMI [36].

Diabetes mellitus (DM) is widely recognized as a major risk factor for vascular diseases, significantly influencing retinal vessel calibers [37]. Li et al. found that mothers with gestational diabetes mellitus (GDM) exhibited narrower retinal vessels, reduced fractal dimensions, and larger branching angles, suggesting that hyperglycemia may contribute to small-vessel abnormalities [38]. The vasoconstrictive effect observed in DM patients is likely due to the hyperglycemic state [39]. However, we did not include DM status in our study for several reasons. First, DM can affect vessel caliber measurements, and we aimed to focus on NAION without introducing additional confounding factors. Second, incorporating three conditions (NAION, hypertension, and DM) might complicate the analysis by affecting NAION incidence. Several studies have identified a strong association between hypertension and the development of NAION, particularly in individuals under 50 years of age. Therefore, we included patients with hypertension in this study to facilitate direct comparisons between the hypertension and normal groups, as well as between the NAION and normal groups.

Our findings may have significant clinical implications for NAION. First, this study provides insights into the assessment of vascular caliber in NAION patients, suggesting that CRAE and CRVE measurements could serve as valuable markers for the disease. Second, these data could offer therapeutic value in managing NAION patients. However, our study has some limitations. It was limited to Chinese patients, so including other ethnic groups would be essential to improve the generalizability of the findings. Additionally, our sample size of 120 patients was relatively small, and future studies should aim to include larger cohorts.

CONCLUSION

Our result suggested the assessment of the CRAE and CRVE may serve as valuable markers for identifying NAION patients, highlighting the importance of paying closer attention to subclinical vascular abnormalities. Additionally, IVAN is recommended as a reliable method for measuring vascular caliber in patients with NAION and for monitoring the occurrence of NAION in the contralateral eye.

REFERENCES