This study investigated a number of features of retinal emboli in RAO. With regard to the content of the emboli, platelet-fibrin and cholesterol were most frequently observed. In terms of location, emboli were most frequently observed in the optic disc or peripheral retinal artery in all groups. Differences in emboli content may arise from differences in the primary source of the emboli. In support of this idea, Hollenhorst
14 reported that cholesterol emboli are generated from ulcerated proximal atherosclerotic lesions, platelet-fibrin emboli originate from arterial atheromatous plaques in the absence of substantial luminal encroachment, and calcific emboli, which are comparatively rare, are generated by calcific aortic stenosis or calcific valvular heart disease.
24,25 In this study, both of the more common types of emboli were thought to originate from the carotid artery. This observation is consistent with previous reports, and it is widely known that the most common embolic source in RAO is the carotid artery.
1,26–29 However, the underlying diseases differ between races, and such differences may result in racial differences in the contents of retinal emboli, and may also have influenced the relatively low retinal emboli detection rates in this study of RAO patients.
1,3,30 As time from symptom onset to initial diagnosis is an important factor with regard to detection rates, the relatively low detection rate of 37.5% in the current study when compared with the detection rate of 71% in CRAO and 66% in BRAO reported by Hayreh et al.
1 can be explained on this basis. Additionally, the content of emboli may affect emboli movement, supporting the hypothesis that platelet-fibrin emboli, which show high movement rates, early movement times, and frequent spontaneous degradation, cause amaurosis fugax.
20
The movement of emboli is less affected by location when compared with other factors. Movement rates are similar when emboli are located in the optic disc or peripheral retinal artery. Thus, the embolic content is a more important factor than location in determining emboli movement. Emboli movement is known to have a significant effect on vascular reperfusion.
11 In the current study, we observed that the vascular perfusion state returned to normal at an early stage in most cases with emboli movement. On the other hand, we observed vascular reperfusion, albeit in most cases delayed or limited, occurring over time when emboli maintained their position. Interestingly, there were no cases of no reperfusion in the no movement group.
Several hypotheses can be proposed for the mechanism of recovery of vascular flow on FA even in the presence of a blood vessel impacted by an embolus. We propose two mechanisms to explain vascular reperfusion in the emboli movement group (i.e., complete degradation and peripheral migration). There are also at least three possible mechanisms to explain vascular reperfusion in the no emboli movement group (i.e., partial dislodgement, angiophagy, and development of a collateral circulation). First, spontaneous partial dislodgement of emboli may occur via the hydrostatic pressure of a continuously applied blood flow or by the endogenous fibrinolytic system. This pattern of emboli is similar to that mentioned in a previous report on embolus characterization, which included fragments of cholesterol or thrombi origin partially filling the arterial lumen on optical coherence tomography.
31 Another possibility is that this is not true reperfusion, but filling by retrograde flow from the adjacent normally filling retina in the late phase of FA, giving the appearance that reperfusion has occurred. This mechanism applies to platelet-fibrin emboli and cholesterol emboli.
11 However, calcific emboli are thought to have almost no effect on endogenous fibrinolysis. Lam et al.
32 have suggested the possibility of recovery of perfusion in vessels blocked by calcific emboli via the mechanism of extravasation of the embolus, or “angiophagy”. This refers to engulfment by the endothelium and translocation through the microvascular walls of blood vessels from 2 to 7 days after occurrence of abnormal emboli. This has been suggested as an alternative mechanism for the clearance of emboli.
32–34 However, some view this as inhibiting early washout. The FA results from the no movement group in this study showed recovery of flow even in the presence of emboli at a position with an initial lack of flow (i.e., late incomplete perfusion, which may support the above hypothesis). However, FP is limited in that it is two-dimensional. More supporting data comparing temporal changes in ultra-thin sections of spectral domain optical coherence tomographic images around blood vessels where emboli are located is required to verify extravasation of retinal emboli. Lastly, although rarely the case, the development of a collateral circulation from the adjacent normally perfused retina may function as a possible mechanism of vascular reperfusion. As shown in
Figure 6, when reperfusion fails, the development of a collateral circulation may promote retinal vascular flow as an alternative delayed mechanism. In cases with CRAO, we could not find a collateral circulation. It might be induced by relatively high complete reperfusion rates or racial differences in association with differences in the underlying disease or small case numbers.
In summary, there are three types of retinal emboli (i.e., platelet-fibrin, cholesterol, and calcific emboli). Platelet-fibrin emboli migrate frequently, as do cholesterol emboli but less often than platelet-fibrin emboli, while calcific emboli, which are rough in texture, become impacted, and usually do not migrate. Emboli movement is caused by complete degradation or peripheral migration, and may lead to early or late complete vascular reperfusion. On the other hand, in cases where emboli maintain their location, delayed complete or incomplete reperfusion may occur by partial dislodgement, angiophagy, or a collateral circulation mechanism (
Fig. 7).
Our study had some limitations. First, the time from symptom onset to the first FP and FA examination varied from 1 hour to 14 days in the patients evaluated, which may have affected the FP and FA findings at baseline. Specifically, a longer duration between symptom onset and the initial visit may influence emboli movement and detection rate at the initial visit. Second, the use of wide-field FP and FA along with standard FP and FA in BRAO patients may have caused differences in the rates of detection of emboli in the periphery of the retina. Further, we included only a small number of CRAO patients, because detection of emboli in CRAO was limited and occlusion points in most cases are presumed to be invisible proximal to the lamina cribrosa. Lastly, intra-arterial thrombolysis was performed in 23 patients (23/54, 44%) after initial examination. Although the initial data are not related to intra-arterial thrombolysis, other follow-up data such as the fate of the emboli might have been affected by the procedure. However, despite its limitations, our study is significant in that it identified features of emboli together with vascular perfusion states in a relatively large number of RAO patients, and these parameters have rarely been investigated in previous studies. In this study, we observed that the pattern of movement of emboli differed according to the embolic contents, which might be contributed to underlying disease or risk factors and have an effect on vascular reperfusion. Clinically, this information might be helpful for predicting movement of emboli and vascular reperfusion at the initial diagnostic stage. Our study showed that no emboli movement is associated with late incomplete reperfusion and this could affect the chronic ischemia of the retina and eyeball. We believe that regular fundus FA and anterior segment inspection in eyes with incomplete reperfusion might be necessary to detect the complications related to chronic ischemia, although further research is needed in a larger cohort of patients before concluding a relationship between vascular reperfusion status and ocular complications. Furthermore, we need to evaluate cautiously the effects of emboli characteristics on the outcome of intra-arterial thrombolysis. A comparative analysis of several types of RAO, including idiopathic RAO without visible emboli and iatrogenic filler–induced RAO is needed in the future.
In addition, our findings can be applied to embolic infarction of the brain, where visualization of emboli is not possible. Thus, our study results might help to increase our understanding and elucidate the reperfusion mechanisms in cerebrovascular occlusion and stroke in general.
35–37
In conclusion, this study has identified characteristics of emboli in RAO patients that affect their movement. Emboli movement may also affect vascular reperfusion. Further research in a larger cohort is needed before conclusions can be made with regard to ocular complications.