Discussion

Embolism originating from carotid or cardiac lesion is the most common cause of RAO while haemodynamically significant CAOD may also result in retinal ischaemia in fewer RAO cases.10 Both embolic and haemodynamic mechanisms can coincide in a RAO episode in special case.11 In a large cohort study, carotid Doppler/angiography showed ipsilateral ICA had >50% stenosis in 31% of non-arteritic CRAO and plaques in 71% of non-arteritic CRAO as the source of emboli.9 10 However, retinal embolus can be found under fundus photography in a few RAO eyes.12 13 Most causative emboli of RAO are not visible in the eye because the embolus may have migrated and disappeared or it is actually impacted in the proximal part, especially where CRA pierces the dura mater of the optic nerve sheath, the narrowest lumen of the artery.10 Asymptomatic emboli can be detected within the retinal artery in 0.4%–3.0% of adults and the elderly, and are associated with hypertension, smoking, vascular disease and increased stroke-related mortality.14–20 In the literature, the association of retinal emboli and increased risk of cerebrovascular disease has been well described.14–23

RAO is an emergent ocular vascular occlusive disorder that frequently results in profound loss of vision, and these patients are at risk of a cerebrovascular accident. In past decades, investigators had attempted to find out the association between RAO and CAOD, and what clinical features of RAO were related to haemodynamically significant CAOD. Merchut et al6 found the type of RAO, whether branch or central, was not predictive of severe CAOD and no clinical features of RAO were significantly associated with a flow-limiting carotid stenosis. Sharma et al7 noted haemodynamically significant CAOD in only 18.7% of patients with acute RAO. McCullough et al8 found that amaurosis fugax, Hollenhorst plaques and venous stasis retinopathy demonstrated moderate predictive value, whereas RAO and all other ocular findings demonstrated no predictive value in identifying CAOD. They all concluded that ocular symptoms and findings including retinal embolus and type of RAO are poor predictors of haemodynamically significant CAOD.6–10

In recent years, with the development and application of high-resolution carotid imaging studies including carotid arteriography, Duplex ultrasonography, CTA and MRA, more timely clinical information and evidences can be collected and surveyed to facilitate the understanding of relationships between RAO and CAOD. During review of our cases, we found a very special subgroup, RAO eyes with multiple retinal emboli, is strikingly correlated with ipsilateral CAOD. In this subgroup, 11 RAO eyes (91.7%) had ipsilateral carotid plaques with high-grade stenosis; among them, 5 were total carotid occlusion. In nine cases (81.8%), significant haemodynamic changes as decreased carotid/cerebral blood perfusion were found (table 1). Compensatory flows from the contralateral ICA or the vertebral arteries contribute to the redistribution of intracranial circulation via the circle of Willi in most cases (figure 3).

RAO eyes with presence of multiple emboli and severe CAOD is not a new disease entity. Sporadic cases have been reported since 1970s,24 but little is discussed about the pathogenesis of multiple emboli in the condition of totally occluded and severely stenotic carotid arteries on the same side. The pathogenesis of RAO with multiple emboli and ipsilateral CAOD may be more complicated than we previously learnt. Embolism is the most common cause of RAO; carotid plaques or cardiac lesions are usually the source of embolism, and there are three main types of embolic findings in RAO that include cholesterol, calcium and platelet-fibrin emboli.9 10 In our case series, an embolus was seen impacted on the optic disc in six eyes, while numerous microemboli were present in the peripheral retinal arteries, at the bifurcation or the terminal in all RAO eyes (figures 1A and 2A). These microemboli may result from different pathogenesis and pathways. A classic way of multiple emboli formation is that blood flow through a stenotic vessel or diseased valve may cause turbulence with part of an unstable plaque dislodged from the vessel wall; and it may possibly act like a comet with a major nuclei associated with many minor meteoric dust flaked off in the same time. However, this mechanism is possible only for part of our cases whose carotid arteries were stenotic, but not for those cases with totally occluded arteries.

In addition to the mechanism of direct embolism from carotid or cardiac lesions, indirect embolism from collaterals during haemodynamic changes of severe CAOD also plays an important role. There are two collateral pathways: from the intracranial or the external collaterals (figure 5). First, during haemodynamic changes of severe carotid stenosis, the compensatory flows from contralateral ICA perfused via the circle of Willis may have flow in abnormal direction and thus raise some dust or cell debris forming microemboli in the vessel. Most probable site for emboli formation during haemodynamic changes, we suspect, is the ipsilateral distal ICA where they collapse with reduced perfusion immediately at the onset of proximal ICA occlusion and later become re-opened by the compensatory flows from intracranial communicating vessels downwards and then feeding the ophthalmic territories (figure 5A). Since most of our cases showed no neurological deficit, these microemboli are benign in the cerebral territories but may be visible in the eye and result in retinal infarctions with visual symptoms. This mechanism is possible for cases who has compensated intracranial circulations with antegrade ophthalmic flow as observed by orbital CDI in most of our reported cases.

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Figure 5

Schematic diagrams of the collateral pathways for haemodynamically significant carotid artery occlusion disease. (A) In the status of unilateral carotid occlusion, compensatory flows perfuse from contralateral ICA may have flow in abnormal direction in the circle of Willis. Most probable site for emboli formation is the ipsilateral distal ICA (star) where they collapse at the onset of proximal ICA occlusion and later become re-opened by the compensatory flows. The ophthalmic flow is antegrade in the orbit. (B) In the status of bilateral carotid occlusion with poor function of Willisian collaterals, compensatory flows from the vertebral arteries are not sufficient to the eye. The source of blood supply is then from branches of the ECA. The ophthalmic flow becomes retrograde in the orbit. ACA, anterior cerebral artery; ECA, external carotid artery; ICA, internal carotid artery; MCA, middle cerebral artery; MMA, middle meningeal artery; PCA, posterior cerebral artery; OA, ophthalmic artery; VA, vertebral artery.

The second pathway of emboli is from the compensated flow originated from ECA/ophthalmic anastomosis in poor function of Willisian collaterals (figure 5B). CTA of case 2 demonstrated bilateral carotid occlusion with intracranial compensatory flow only from the vertebral circulation (figure 3B). It may be fair for the brain but not sufficient to the eye and will lead to the recruitment of external collaterals with reversed ophthalmic flow noted by orbital CDI (figure 4). The major source of blood supply to the ophthalmic artery is then from branches of the ECA.10 The enlargement of an anastomosis and flow direction changes of the compensatory circulation may facilitate debris scaling off the vessel wall and become emboli in the fundus. Reversed ophthalmic flow is also noted in ocular ischaemic syndrome secondary to chronic CAOD. But retinal whitening and emboli are seldom found in such cases.

The circle of Willis is the major collateral pathway that can rapidly compensate for decreased cerebral perfusion pressure. External collaterals through the ophthalmic artery is recruited when compensatory flow via the circle of Willis is inadequate for the brain or to the eye.25 Thus, during attack of severe CAOD, haemodynamic changes will response with compensatory flows to redistribute the intracranial circulations in order to restore enough blood perfusion for the brain to prevent neurological deficits and stroke. All the haemodynamic changes in collaterals, including dilatation of collateral vessels, flow direction changes in communicating vessels, reopening of collapsed carotid artery and enlargement of an anastomosis, could contribute to the formation of emboli (figure 5). We believe that indirect emboli from collaterals could be the answer for pathogenesis of multiple emboli in cases of CAOD with haemodynamic changes. Thus, the presentation of RAO with multiple emboli is highly correlated with haemodynamically significant CAOD as a sign marking that compensatory flows for redistribution has already re-established.

Multiple emboli were rarely found in all RAO eyes, only 5.7% of our survey. Multiple emboli may also form during invasive carotid procedures. Sequelae of carotid arteriography and endarterectomy, such as RAO or CVA may have occurred during or after the procedure.26 27 Retinal emboli can be asymptomatic and happen more often than we would expect. Hayreh mentioned that ‘during carotid endarterectomy, in which showers of multiple, moving emboli kept appearing and disappearing without any permanent residual embolus seen later on in the retinal arteries, or visual loss’.10 With distal embolic protection device to occlude ICA temporarily during carotid angioplasty and stenting to prevent embolic stroke, ipsilateral RAO and retinal embolisation could still occur.28–30 The passage of debris through the collaterals poses a significant risk as flushing debris through the orbital branch of ECA to ophthalmic artery may lead to retinal embolisation (figure 5B).29 Transient blindness in patients with a fully occluded ipsilateral ICA also unequivocally indicates the collateral pathway to be a mechanism for retinal embolisation. The retina provides a unique observatory for the study of emboli, which may occur either directly or indirectly via collaterals to the ophthalmic artery.28

The finding of a retinal embolus is considered a grim prognostic sign for survival of RAO cases as they are of higher risk of CVA.14–23 With experiences of the presenting cases in this report, we recognised the fact that, although most patients are fully ambulatory without neurological deficits, cases of RAO with multiple emboli are in a critical condition as amaurosis fugax and transient ischaemic attacks (TIAs) and are at increasing risk of neurological morbidity and mortality. It is an important warning that, prior to the attack of neurological deficit signs of CVA, there already exist haemodynamically significant CAOD with circulatory redistribution. It could be an inevitable result of severe CAOD. However, this subgroup is small in number and is often missed clinically or obscured in large cohort study. Thorough carotid/cerebral evaluations and adequate treatment should be arranged and performed earlier as possible to prevent the occurrence of impending cerebrovascular accident.

In conclusion, RAOs with multiple emboli are highly associated with severe CAOD. Either from the carotid or cardiac lesions directly or via the collaterals indirectly could be the pathway of embolism. Multiple emboli may represent existence of haemodynamic changes as a result of severe CAOD that compensatory flow to redistribute the intracranial circulation has established and perfuse again to the eye with emboli. The presentation of RAO with multiple emboli is emerging as an alarm of an incoming stroke more definitely, a critical sign as amaurosis fugax and TIA, alerting physicians to start actions to manage these patients with thorough evaluations and treatments to prevent further deterioration.