Site of Origin of the Ophthalmic Artery Influences the Risk for Retinal Versus Cerebral Embolic Events

Embolic events leading to retinal ischemia or cerebral ischemia share common risk factors; however, it has been well documented that the rate of concurrent cerebral infarction is higher in patients with a history of transient ischemic attack (TIA) than in those with monocular vision loss (MVL) due to retinal ischemia. Despite the fact that emboli to the ophthalmic artery (OA) and middle cerebral artery share the internal carotid artery (ICA) as a common origin or transit for emboli, the asymmetry in their final destination has not been fully explained. We hypothesize that the anatomic location of the OA takeoff from the ICA may contribute to the differential flow of small emboli to the retinal circulation vs the cerebral circulation.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Site of Origin of the Ophthalmic Artery Influences the Risk for Retinal Versus Cerebral Embolic Events Elizabeth J. Rossin, MD, PhD, Aubrey L. Gilbert, MD, PhD, Nicholas Koen, BS, Thabele M. Leslie-Mazwi, MD, Mary E. Cunnane, MD, Joseph F. Rizzo III, MD Downloaded from http://journals.lww.com/jneuro-ophthalmology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 05/04/2022 Background: Embolic events leading to retinal ischemia or cerebral ischemia share common risk factors; however, it has been well documented that the rate of concurrent cerebral infarction is higher in patients with a history of transient ischemic attack (TIA) than in those with monocular vision loss (MVL) due to retinal ischemia. Despite the fact that emboli to the ophthalmic artery (OA) and middle cerebral artery share the internal carotid artery (ICA) as a common origin or transit for emboli, the asymmetry in their final destination has not been fully explained. We hypothesize that the anatomic location of the OA takeoff from the ICA may contribute to the differential flow of small emboli to the retinal circulation vs the cerebral circulation. Methods: We report a retrospective, comparative, case– control study on 28 patients with retinal ischemia and 26 patients with TIA or cerebral infarction caused by embolic events. All subjects underwent either computed tomography angiography or MRA. The location of the ipsilateral OA origin off the ICA was then graded in a blinded fashion and compared between cohorts. Vascular risk factors were collected for all patients, including age, sex, hypertension, hyperlipidemia, arrhythmia, diabetes, coronary artery disease, and smoking. Results: We find that in patients with retinal ischemia of embolic etiology, the ipsilateral OA takeoff from the ICA is more proximal than in patients with cerebral infarcts or TIA Neuro-Ophthalmology Service (EJR, ALG, JFR), Harvard Medical School, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts; Vitreoretinal Surgery Service (EJR), Harvard Medical School, Department of Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts; Neuro-Ophthalmology (ALG), Kaiser Permanente, Oakland, Northern California; Department of Otolaryngology (NK), Massachusetts Eye and Ear, Boston, Massachusetts; The Warren Alpert Medical School (NK), Brown University, Providence, Rhode Island; Neurointerventional Service (TML-M), Massachusetts General Hospital, Boston, Massachusetts; and Department of Radiology (MEC), Harvard Medical School Department of Ophthalmology, Massachusetts Eye and Ear, Boston, Massachusetts. The authors report no conflicts of interest. E. J. Rossin, A. L. Gilbert, and N. Koen contributed equally. Address correspondence to Joseph F. Rizzo, MD, NeuroOphthalmology Suite, 9th Floor, 243 Charles Street, Boston, MA 02114; E-mail: [e-mail] 24 (P = 0.0002). We found no statistically significant differences in demographic, vascular, or systemic risk factors. Conclusions: We find that the mean anatomical location of the OA takeoff from the ICA is significantly more proximal in patients with MVL due to retinal ischemia compared with patients with TIA or cerebral ischemia. This finding contributes significantly to our understanding of a long observed but poorly understood phenomenon that patients with MVL are less likely to have concurrent cerebral ischemia than are patients with TIA. Journal of Neuro-Ophthalmology 2021;41:24–28 doi: 10.1097/WNO.0000000000000883 © 2020 by North American Neuro-Ophthalmology Society E mboli that arise from or pass through the internal carotid artery (ICA) can travel either into the ophthalmic circulation and cause ocular ischemia, or they can ascend more distally into the middle cerebral artery (MCA) and cause cerebral ischemia. The ultimate destination of emboli is likely influenced by numerous cardiovascular factors which are not yet fully understood. In either case, the consequences can be significant. Monocular vision loss (MVL) due to an embolus typically manifests either as transient monocular visual loss or as permanent vision loss due to obstruction of the ophthalmic artery (OA) or downstream branches including the central retinal artery, branch retinal arteries or, much more rarely, the cilioretinal artery. The clinical syndrome of each differs in predictable ways. Conversely, an embolus that bypasses the OA and travels into the cerebral circulation can cause a transient ischemic attack (TIA) with symptoms that resolve within 24 hours or a permanent deficit that can produce paralysis, aphasia, or blindness. Many such embolic events to the brain are silent (1,2). Although the general vasculopathic risk factors for embolic retinal and cerebral events are similar and the proximal vascular course toward the eye and brain is identical, the relative occurrence of each type of event Rossin et al: J Neuro-Ophthalmol 2021; 41: 24-28 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution (i.e., visual vs cerebral) is dissimilar. Roughly 20% of patients with acute retinal ischemia are found to have evidence of acute, concurrent cerebral infarctions on MRI, whereas patients who experience a hemispheric TIA have a risk that is roughly double (3–10). There are numerous systemic factors that increase the risk of retinal and cerebral embolization, including systemic hypertension, diabetes mellitus, hyperlipidemia, hyperviscosity, atherosclerotic vascular disease, cardiac factors (arrhythmia, valvular and septal abnormalities, and dyskinetic wall segments), and smoking, and none of these seems to explain the large differential risk of cerebral stroke between patients with retinal ischemia and those with TIAs. Shortly after the dawn of the age of angiographic investigation of ischemic brain strokes, it was noted that patients who experienced transient MVL only rarely experienced concomitant contralateral sensory or motor loss (11). Such cases of simultaneous occurrence of retinal and brain events were published as case reports. This discrepancy in relative risk was documented later in large studies that demonstrated the risk of ipsilateral hemispheric stroke to be substantially lower in patients who had experienced an attack of transient MVL than those with hemispheric TIA (3,4,6,9,10). Across these studies, there is evidence of an asymmetric risk for embolization into the ophthalmic vs more distal aspect of the ICA. There has been relatively little attention to the inherent vascular anatomy as a potential risk factor for differential embolization. Cadaveric studies have shown that the location of origin of the OA varies widely (12). In the 1990s, we conducted a preliminary study to explore anatomical factors that were potentially relevant in regard to the risk of retinal vs cerebral embolization (unpublished data). That study examined multiple sites of measurement of luminal width and of angulation of the ICA through the cavernous sinus as well as the angle of take-off of the OA by manual measurements of magnified sagittal radiographs obtained with the standard method of that era, which was invasive angiography. In 40 patients who had been diagnosed with MVL within a single neuro-ophthalmic practice and 40 control subjects, the only anatomical variable that proved to be statistically significant was the angle of origin of the OA and the probability of experiencing MVL vs a cerebral embolic event. This served as the motivation for our present study. Here, we used noninvasive imaging and digital analysis to assess the relationship between the origin of the OA and history of retinal or cerebral ischemia. No previous study has specifically addressed the anatomy of the ICA-OA region as a potential determinant of the risk of retinal vs cerebral embolization. METHODS The study was approved by institutional review boards at Massachusetts Eye and Ear and Massachusetts General Hospital. Rossin et al: J Neuro-Ophthalmol 2021; 41: 24-28 The hypothesis of the current study was that the angular origin of the OA off the ICA is a statistically significant risk factor that influences whether an embolus traveling up the ICA causes a retinal vs cerebral ischemic event. This hypothesis was tested by performing a retrospective, comparative, case–control study on 62 patients divided into 2 cohorts. The first cohort included adults who were diagnosed within our neuro-ophthalmology clinic with transient or permanent MVL due to either central or branch retinal artery occlusion with clinical evidence of an embolic etiology and no history or any suggestion of vasculitis, a different nonembolic etiology for ocular ischemia, or clinical or radiographic evidence of concurrent cerebral embolization. The comparative cohort included adults who were diagnosed with embolic MCA territory TIA or infarction by the neurology service at our adjoining Massachusetts General Hospital. Five patients who experienced simultaneous cerebral and retinal emboli were excluded, and 2 patients with TIA or cerebral infarction were excluded because there was complete occlusion of the ICA that precluded visualization of the origin of the OA. Twenty-eight patients with transient or permanent MVL and 26 patients with TIA or cerebral ischemia met our inclusion criteria. In addition to the radiological parameters, basic demographic data (age and sex) and vasculopathic risk factors (systemic hypertension, diabetes mellitus, smoking history, coronary artery disease, hyperlipidemia, and arrhythmia) were collected on all patients and statistically analyzed. Neuroimaging Analysis All subjects underwent either computed tomography angiography or MRA either at the Massachusetts Eye and Ear or the Massachusetts General Hospital. Reformatted images from these scans were made by using the thinnest slices available, typically #1 mm. Using a multiplanar reformatting program, oblique sagittal images were created parallel to the cavernous segment of the carotid artery to visualize the OA and its relationship to the convex curve of the ICA (Fig. 1A). Images that optimally demonstrated the origin of the OA were saved and placed randomly in a series among all other images. These images were then graded in a blinded fashion (by N.K. and A.L.G.), and each was reviewed for accuracy by a board-certified neuroradiologist (M.E.C.). The angular location of the ipsilateral OA origin off the carotid artery was assigned to one of 6 designated regions defined by 15° wedges along the curve of the carotid artery between 9 and 12 o’clock, with lower grade indicating a more proximal origin (Fig. 1B). Statistical Analysis Statistical comparisons were made between the patient groups using either the chi-squared or Fisher exact test for categorical variables (sex, systemic hypertension, diabetes mellitus, smoking history, coronary artery disease, 25 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Representative sagittal CTA image. A. The OA origin is highlighted. B. The region of interest was divided into six 15° wedges from 9 to 12 o’clock. C. Approximate mean grading for ophthalmic artery origin in monocular vision loss patients (open circle) and MCA stroke patients (closed circle) (image courtesy of A.Prof Frank Gaillard, Radiopaedia.org, rID: 36107). CTA, computed tomography angiography; MCA, middle cerebral artery; OA, ophthalmic artery. hyperlipidemia, and arrhythmia) and the 2-tailed Wilcoxon rank-sum test for continuous variables (age, OA origin score). Given that we tested 9 variables to compare between the 2 cohorts, we used a Bonferonni-corrected significance threshold cutoff of P , 0.0056. RESULTS There were no significant differences in age, sex, or any of the vasculopathic risk factors including systemic hypertension, diabetes mellitus, smoking history, coronary artery disease, hyperlipidemia, or arrhythmia between patients with MVL and those with MCA territory stroke (Table 1). With respect to the neurovascular anatomy, the mean angular location of origin of the ipsilateral OA was significantly more proximal for the MVL patients than for the MCA stroke patients (mean grading 3.07 vs 4.54, respectively, P = 0.0002) (Fig. 1C and Table 1), which met our threshold for significance. Although limited by sample size, we identified no significant difference in OA origin between patients who had experienced transient MVL (amaurosis fugax) and permanent MVL (branch retinal artery occlusion, central retinal artery occlusion) (P = 0.5836). CONCLUSIONS The motivation for this work was the observation reported by many that patients with acute retinal ischemia have a risk of acute, concurrent cerebral infarctions that is roughly half that of those with a hemispheric TIA (4,6,7,9,13). This study, using noninvasive techniques, reveals a statistically significant difference in the angular location of the origin of the OA along the convex curve of the anterior aspect of the ICA between our 2 study populations. Specifically, those patients who had experienced a monocular embolic visual event generally had a more proximal angular origin of the OA than patients who had experienced an embolic event to the brain. This result satisfies the hypothesis that motivated this study. The OA is the first major branch off the intradural ICA. Hayreh and others originally reported that in the majority of cases, the OA arose soon after the ICA exited the cavernous sinus by penetrating the dura; in 8% of cases, the OA arose from the ICA while still in the cavernous sinus or from the middle meningeal artery very rarely (12,14). In its typical course, the OA then takes 2 turns, the first being a retroflexive turn toward the orbit and the second being Table 1. Patient demographics, cardiovascular risk factors, and mean ophthalmic artery origin grading Parameter Age (mean, median) Female (%) Hypertension (%) Hyperlipidemia (%) Diabetes (%) Smoking history (%) Coronary artery disease (%) Arrhythmia (%) Ipsilateral ophthalmic artery origin grade (mean, median) Monocular Vision Loss Patients MCA Stroke Patients (n = 28) (n = 26) 66.3 (mean), 70 (median) 53.6 75.0 78.6 10.7 21.4 32.1 28.6 3.07 (mean), 3 (median) 67.5 (mean), 70 (median) 38.5 57.7 53.8 30.8 11.5 34.6 53.8 4.54 (mean), 5 (median) P* 0.70 0.40 0.29 0.10 0.09 0.54 1.00 0.11 0.0002 *Statistical comparisons were made between the patient groups using either the x2 or Fisher exact test for categorical variables or a 2-tailed Wilcoxon rank-sum test for continuous variables. Given that we tested 9 variables to compare between the 2 cohorts, we used a Bonferonni-corrected significance threshold cutoff of P , 0.0056. MCA, middle cerebral artery. 26 Rossin et al: J Neuro-Ophthalmol 2021; 41: 24-28 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution a displacement toward the inferior aspect of the optic nerve where it enters the optic canal (12,15). We were interested in the anatomy of the OA-ICA bifurcation because in vitro models of vessel bifurcations in flow networks modeled after cerebrovascular anatomy previously showed that the embolic trajectory at bifurcations was influenced by flow ratios and the size of the embolus and lumen (7,16,17). One study showed that for a set experimental system (4– 6 mm luminal size), smaller emboli (0.6 and 1.6 mm diameter, in keeping with human studies (18)) tended to travel as one would expect according to flow ratios at a bifurcation (i.e., in proportion to the amount of fluid going into each branch), whereas larger emboli that can fit into either vessel preferentially preferred the larger lumen, regardless of flow ratios or type (16). This finding was replicated in a silicone model of cerebral macrovasculature based on patient-specific anatomy (19). Based on these experiments, it has been hypothesized that the difference in stroke risk between MVL and TIA might be related to the size of an embolus, where a small embolus has a higher chance of going to the OA than does a larger one and a larger embolus can more easily go to the cerebral vasculature. Because the proximal lumen of the OA is only 0.7– 1.4 mm in diameter, larger emboli are simply not able to pursue this vascular path forward (15). The role of embolus size remains in speculation, however, and it still does not explain the differential in risk for those who incur transient MVL and TIA from smaller emboli. Of note, our findings are relevant only for emboli smaller than the size of the OA (w1 mm). Still, other factors are likely to contribute. Benavante et al speculated that better collateral circulation in patients with MVL may explain their lower risk of hemispheric stroke, and in a review of patients with transient MVL vs TIA, patients with transient MVL more often demonstrated collateral circulation (6,20). Others have found that plaque distribution and orientation as well as sheer hotspots play a role in the destination of an embolus (21). Lessier et al found that patients with centeral retinal artery occlusion were more likely to have plaques in the distal portions of the ICA—specifically the cavernous and clinoid portions— than the cardiac valves, the aortic arch, or proximal ICA (22,23). Notably, the degree of carotid artery stenosis has not been found to explain the difference; in fact, Benavante et al found that patients with MVL had a higher degree of ipsilateral carotid artery stenosis than those with a hemispheric TIA (6). The earlier studies mentioned provide a useful conceptual framework, but the rheological factors that govern the predilections of flow patterns of embolic are likely complex, with multiple plausible but poorly understood variables. Although flow ratios, luminal size, and caliber of an embolus are almost surely relevant factors, our study reveals that the architecture of vessels also is a relevant factor. To the best of our knowledge, this is the first study Rossin et al: J Neuro-Ophthalmol 2021; 41: 24-28 to report a differential risk of embolic events to the eye vs brain based on the location of the origin of the OA. Interestingly, there are other locations in the body where emboli follow the course of a diverging artery and may be governed by similar anatomical rules. Lee et al (24) found that posterior inferior cerebellar artery (PICA) territory infarction was independently associated with the angle at which the PICA takes off from the vertebral artery. Robinson et al found an increased risk of pulmonary embolism (PE) in patients with deep vein thrombosis if the distance between the right common iliac artery (RCIA) and the closest vertebral body was greater (25). Analogous to our consideration about the size of emboli, it is suspected that there is a correlation between the lumen size and whether an embolus can cause a symptomatic PE, but these authors report an independent risk factor involving anatomical placement of the RCIA (25,26). The renal arteries, which emerge from the aorta at 65–70° angles, very rarely are conduits to emboli causing renal infarction, but the relationship between the takeoff anatomy and renal infarction has not been studied (27). The limitations of this study include the relatively small sample size (28 patients with MVL and 26 patients with TIA or MCA stroke) and the specific focus on the location of take-off of the OA without also addressing other factors discussed previously that might influence the trajectory of emboli, including relative luminal diameters, spectrum of differential flow rates, type or size of emboli (which is often not knowable), and viscosity of blood. Our study did indicate, however, that the general profile of systemic vascular risk factors was not different between the 2 groups. Nonetheless, our use of noninvasive methods will facilitate comparative studies by others and exploration of the some of the parameters that we acknowledge we did not study. The findings reported here do not indicate that there should be a change in medical practice. Both retinal ischemia and TIA alike demand a cardiovascular workup for stroke. However, we feel that our findings may prompt future noninvasive studies of similar anatomical factors to better understand embolic trajectory. With further validation, it may be possible to understand who is at higher risk of future cerebral embolic events based in part on their vascular anatomy. In summary, we report a retrospective, comparative, case–control study that reveals that one specific detail of neurovascular anatomy—the angular origin of the OA from the ICA—contributes to the trajectory taken by ascending emboli such that a more proximal origin of the OA predisposes to ocular (over cerebral) ischemia. Further evaluation with a larger cohort of patients is needed to validate this finding and to explore other anatomical and physiological factors, especially those that might be modifiable or that might exacerbate or mitigate this risk of permanent loss of function. 27 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Author contributions: Hypothesis generation and project oversight: J. F. Rizzo and A. L. Gilbert. Data generation and analysis: A. L. Gilbert, E. J. Rossin, N. Koen, T. M. Leslie-Mazwi, and M. E. Cunnane. Manuscript writing and figure generation: E. J. Rossin, A. L. 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