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Show Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Prevalence of Retinal Venous Malformations in Patients With Cerebral Cavernous or Arteriovenous Malformations Kyle S. Chan, BA, Melanie R. Daulton, MD, Vishruth D. Reddy, BA, Erin N. McComb, MD, Jeremy A. Lavine, MD, PhD Background: Cerebral vascular malformations (CVMs) may result in hemorrhage, seizure, neurologic dysfunction, and death. CVMs include capillary telangiectasias, venous malformations, cavernous malformations, and arteriovenous malformations. Cavernous and arteriovenous malformations carry the highest risk of complications. Retinal venous malformations (RVMs) have been proposed as an associated finding. Our objective was to determine the prevalence of RVMs in patients with high-risk CVMs. Methods: We retrospectively reviewed patients diagnosed with cerebral cavernous or arteriovenous malformations (high-risk CVMs) who were evaluated by the ophthalmology service at Northwestern University between 2017 and 2020. Patients were stratified into 3 cohorts based on level of certainty: dilated funduscopic examination (DFE), DFE with any form of ocular imaging, and DFE with complete imaging of the macula. We recorded ophthalmic examination abnormalities, ocular imaging findings, and major CVM complications. Results: We evaluated 156 patients with high-risk CVMs who had undergone DFE. Ocular imaging of any type was performed in 56 patients, of whom 46 had complete imaging of the macula. Zero RVMs were identified in any cohort (95% confidence interval: 0%–1.9% for the entire cohort, 0%–5.4% for any ocular imaging cohort, and 0%– 6.5% for the complete macular imaging cohort). Cerebral hemorrhage or seizure occurred in 15%–33% of patients. Associated visual field defects or cranial nerve palsies were found in 14%–20% of patients. Conclusions: Zero RVMs were identified in patients with high-risk CVMs. However, neuro-ophthalmic findings were common. Therefore, we recommend neuroimaging for patients with RVMs and neuro-ophthalmic signs or sympDepartments of Ophthalmology (KSC, MRD, VDR, JAL) and Radiology (ENM), Northwestern University Feinberg School of Medicine, Chicago, Illinois. Supported by an Illinois Society for the Prevention of Blindness research grant. K. S. Chan was supported by the Research to Prevent Blindness Medical Student Eye Research Fellowship. J. A. Lavine was supported by NIH grant K08 EY030923 and the Research to Prevent Blindness Sybil B. Harrington Career Development Award for Macular Degeneration. This study was supported by an Unrestricted Departmental Grant from Research to Prevent Blindness. The sponsor or funding organization had no role in the design or conduct of this research. J. A. Lavine is a consultant for Genentech for work unrelated to this study. All other authors report no conflicts of interest. K. S. Chan and M. R. Daulton contributed equally to this work. Address correspondence to Jeremy A. Lavine, MD, PhD, Departments of Ophthalmology and Rheumatology, Northwestern University Feinberg School of Medicine, 240 E Huron Avenue, McGaw M343, Chicago, IL 60611; E-mail: jeremy.lavine@northwestern.edu 226 toms. In asymptomatic patients with RVMs, a potential algorithm for neuroimaging is proposed. Journal of Neuro-Ophthalmology 2024;44:226–231 doi: 10.1097/WNO.0000000000001974 © 2023 by North American Neuro-Ophthalmology Society C erebral vascular malformations (CVMs) are areas of developmentally abnormal vasculature within the brain, which may result in complications later in life, including intracranial hemorrhage, seizure, neurologic dysfunction, or death.1 CVMs are categorized as arteriovenous malformations, cavernous malformations, developmental venous malformations, or capillary telangiectasias among others.1 Arteriovenous malformations and cavernous malformations have the greatest risk of intracranial hemorrhage, seizure, and neurologic deficit. In patients with arteriovenous malformations, there is an annual 2% risk of hemorrhage, and rupture carries a 23% risk of disability and a 29% risk of death.2 In patients with cavernous malformations, the 5-year risk of intracranial hemorrhage is 16%, and the annual risk of seizure is 2%.3 Management of these high-risk CVMs ranges from observation to aggressive surgical intervention depending on location and individual risk, whereas low-risk CVMs are typically observed. The brain and retinal vasculature share common developmental and signaling pathways.4 These explain the vascular abnormalities found in both the brain and retina in von Hippel–Lindau and Wyburn-Mason syndrome. Retinal venous malformations (RVMs) are large, abnormal veins of the macula with a vascular distribution crossing the horizontal raphe and were previously not believed to be associated with cerebral pathology. RVMs are usually asymptomatic, incidental findings that were originally termed congenital retinal macrovessels and presumed to be predominantly veins with rare instances of arterial involvement.5 However, a recent multicenter retrospective study by Pichi et al5 proposed a nomenclature change from congenital retinal macrovessel to RVM because all macrovessels were veins in patients who underwent fluorescein angiography. Their study also supported a possible association between RVMs and CVMs.5 In a multicenter retrospective chart review of 49 patients with RVMs, Pichi et al5 found CVMs in 12 of 49 (24%) total patients and 12 of 27 (44%) patients who underwent cerebral MRI. Their findings Chan et al: J Neuro-Ophthalmol 2024; 44: 226-231 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution led to a recommendation for neuroimaging for all patients with RVMs. Notably, in Pichi et al.’s study, the neuroimaging was performed not because of the RVM, but for neurological indications such as headache. Therefore, their conclusions may be confounded by symptom presentation and lack of generalizability to asymptomatic patients with RVMs. If the pathophysiologic development of RVMs and CVMs is related, one may hypothesize that RVMs would be identifiable in a population of patients with CVMs. To better understand the association between RVMs and CVMs, we performed a retrospective study examining the prevalence of RVMs and other ophthalmic findings in a population of patients with high-risk CVMs. We focused on highrisk lesions, given the importance of early detection to prevent morbidity and mortality. METHODS We performed a retrospective chart review of 610 patients with a known diagnosis of cerebral arteriovenous malformation or cavernous malformation between January 1, 2017, and December 31, 2020. This study was approved by the Institutional Review Board of Northwestern University (Chicago, IL) and was conducted in accordance with the tenets of the Declaration of Helsinki and regulations of the Health Insurance Portability and Accountability Act. Inclusion criteria were both a neuroradiology-confirmed diagnosis of cerebral cavernous or arteriovenous malformation and a dilated funduscopic examination (DFE) with the Northwestern Ophthalmology service. We collected demographic information, ocular and systemic diagnoses, and ophthalmic examination findings. Race and ethnicity were recorded from documentation in the electronic medical record for the purposes of understanding the demographic composition of the patient cohort. Other was defined as not American Indian or Alaskan Native, Asian, Black, Declined, Hispanic or Latino, Native Hawaiian or Pacific Islander, or Caucasian. Fundus imaging, when available, was reviewed independently by an ophthalmologist (M.R.D.), and the presence or absence of an RVM was documented. Images that could not be definitively interpreted were reviewed by a vitreoretinal specialist (J.A.L.). MRIs were reviewed by a board-certified neuroradiologist. Patients were documented to have multifocal cavernous or arteriovenous malformations if lesions were identified in 2 or more locations of the brain. Results were analyzed using descriptive statistics. Patients were stratified into 3 groups based on level of evidence: DFE, DFE with any form of ocular imaging, and DFE with complete macular imaging. Complete macular imaging was defined as either a color fundus photograph or optical coherence tomography with near-infrared reflectance image that showed the full macula. We calculated 95% CIs using the Hanley formula (3/N).6 Chan et al: J Neuro-Ophthalmol 2024; 44: 226-231 RESULTS We performed a retrospective chart review of patients with cavernous or arteriovenous malformations to determine the prevalence of RVMs in patients with high-risk CVMs. We identified 610 patients with a diagnosis of high-risk CVM. One hundred fifty-six of 610 (25.6%) patients had a documented DFE with the Northwestern Ophthalmology service. We parsed our 156 patients into 3 groups based on our level of certainty. Patients with a DFE alone (N = 156) had the lowest level of evidence. Fundus imaging, including fundus photography or optical coherence tomography with near-infrared reflectance for review of the retinal vasculature, was available for 56 of 156 patients (35.9%). A moderate level of evidence was defined as a DFE and any imaging of the macula (N = 56). Complete macular imaging, defined as a full view of the macula, with DFE (N = 46) had the highest level of evidence for the presence or absence of an RVM (Table 1). Each evidence tier was well matched in terms of demographics and comorbid conditions (Table 1). The average age when initial cerebral imaging was performed at our institution was 54 years for all groups, higher than the mean ages of diagnosis for cavernous malformations (40 years)7 and arteriovenous malformations (31 years)8 reported in previous literature. Each group was approximately 60% female and identified as Caucasian in 67% of patients. Comorbid conditions included hypertension (47%–52%), hyperlipidemia (35%–41%), malignancy (14%–21%), diabetes (14%–16%), and venous thromboembolism (4%– 10%). We found a 0% prevalence of RVMs in patients with high-risk CVMs in all groups (Table 2). The 95% CI for the prevalence of RVMs in patients with high-risk CVMs was 0%–6.5% in the highest evidence tier, 0%–5.4% in the moderate evidence tier, and 0%–1.9% in the lowest evidence tier.6 The most common retinal pathology in the cohort was epiretinal membrane or macular hole in 9% of patients with funduscopic examination, and this prevalence was expectedly higher (23%–26%) in patients with macular imaging (Table 2). Diabetic retinopathy was found in 5%–11% of patients, which was consistent with the 15% prevalence of diabetes in our patient population (Table 1). Finally, hypertensive retinopathy or retinal vein occlusions were identified in 1%–3% of patients with funduscopic examination and in 2%–9% of patients with macular imaging (Table 2), which was consistent with the high rates of hypertension and hyperlipidemia in our patient population. We identified multifocal high-risk CVMs in nearly 18% of patients (Table 3). Because the retinal vasculature shares common development pathways with the cerebral vasculature, these data suggest that multiple lesions are possible in patients with high-risk CVMs, and we would expect this to include the retinal vasculature. 227 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographics and clinical information for patients with a diagnosis of arteriovenous or cavernous malformation previously evaluated by an ophthalmologist with dilated fundus examination Age at time of initial brain imaging (year ±SD) Gender (%) Male Female Race and ethnicity (%) American Indian or Alaskan Native Asian Black Declined Hispanic or Latino Native Hawaiian or Pacific Islander Other Caucasian Systemic diagnoses (%) Hypertension Hyperlipidemia Malignancy Diabetes Venous thromboembolism Eye Examinations (N = 156) Any Fundus Imaging (N = 56) Complete Macula Imaging (N = 46) 54.3 ± 17.3 54.6 ± 15.7 53.9 ± 15.8 66 (42.0) 90 (58.0) 23 (41.1) 33 (58.9) 17 (37.0) 29 (63.0) 1 (0.6) 10 (6.4) 14 (9.0) 4 (2.6) 15 (9.6) 2 (1.3) 5 (3.2) 105 (67.3) 0 (0) 3 (5.4) 5 (8.9) 1 (1.8) 6 (10.7) 1 (1.8) 3 (5.4) 37 (66.1) 0 (0) 3 (6.5) 2 (4.3) 1 (2.2) 6 (13.0) 1 (2.2) 2 (4.3) 31 (67.4) 73 (46.8) 64 (41.0) 33 (21.2) 25 (16.0) 15 (9.6) 27 (48.2) 20 (35.7) 8 (14.3) 8 (14.3) 3 (5.4) 24 (52.2) 16 (34.8) 8 (17.4) 7 (15.2) 2 (4.3) In our cohort of patients with high-risk CVMs, major complications were common. In 26%–33% of our patients, the CVM was complicated by hemorrhage, and 15%–20% of patients had experienced seizures (Table 3). This frequency is comparable with previously reported complication rates for high-risk CVMs.9,10 Importantly, neuro-ophthalmic abnormalities were commonly detected in our high-risk cohort. The most common neuro-ophthalmic finding was visual field defect in 15%– 17% of patients (Table 4), of which 57%–65% were attributable to the CVM. The second most common finding was cranial nerve palsy in 14%–20% of patients (Table 4), of which 44%–52% were attributable to the CVM. Other less common neuro-ophthalmic abnormalities resulting from complications of high-risk CVMs included Horner syndrome, vertical gaze abnormalities, internuclear ophthalmo- plegia, optic nerve atrophy, papilledema, nystagmus, and ptosis (Table 4). DISCUSSION We report the ophthalmic findings of 156 patients with a diagnosis of cavernous or arteriovenous malformations. In 46 patients with the highest level of evidence, the prevalence of RVMs was 0% (95% CI: 0%–6.5%). In 56 patients with a moderate level of evidence, the prevalence of RVMs was 0% (95% CI: 0%–5.4%). In 156 patients with only DFE, the prevalence of RVMs was 0% (95% CI: 0%–1.9%). However, neuroophthalmic findings, such as visual field defects and cranial nerve palsies, were found in 14%–20% of patients. TABLE 2. Retinal pathologies in the patient cohort Retinal venous malformation (95% CI) Epiretinal membrane/macular hole (%) Diabetic retinopathy (%) Hypertensive retinopathy (%) Retinal venous occlusion (%) Retinal arterial occlusion (%) Retinal detachment/tear (%) Macular degeneration (%) 228 Eye Examinations (N = 156) Any Fundus Imaging (N = 56) Complete Macula Imaging (N = 46) 0 (0–1.9) 14 (9.0) 7 (4.5) 2 (1.3) 4 (2.6) 1 (0.6) 2 (1.3) 2 (1.3) 0 (0–5.4) 13 (23.2) 5 (8.9) 1 (1.8) 4 (7.1) 1 (1.8) 1 (1.8) 1 (1.8) 0 (0–6.5) 12 (26.1) 5 (10.9) 1 (2.2) 4 (8.7) 1 (2.2) 1 (2.2) 1 (2.2) Chan et al: J Neuro-Ophthalmol 2024; 44: 226-231 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Characteristics and major complications of arteriovenous and cavernous malformations Eye Examinations (N = 156) Any Fundus Imaging (N = 56) Complete Macula Imaging (N = 46) Focality (%) Unifocal Multifocal Major complications (%) Hemorrhage Seizure 128 (82.1) 28 (17.9) 46 (82.1) 10 (17.9) 38 (82.6) 8 (17.4) 51 (32.7) 28 (17.9) 15 (26.8) 11 (19.6) 12 (26.1) 7 (15.2) Our findings weaken the association between RVMs and CVMs reported by Pichi et al,5 which found that patients with RVMs had a 24% (12 of 49) prevalence of CVMs. There may be several explanations for this difference. The previous study reviewed MRIs that were obtained for indications besides RVM (such as headache), meaning that symptom presentation may be a confounder for the presence of CVMs. It is also unclear to us how patients from the 7 retinal clinics, as well as the clinics themselves, were selected in the previous study. There is a risk of selection, ascertainment, and/or confirmation bias, given patients and institutions may have been included in the study because researchers recalled a unique association between RVM and CVM firsthand in the clinical setting. Several findings in our study support a lack of association between RVM and CVM. First, if there is truly a shared pathophysiological origin between RVM and CVM, we would expect to detect RVMs in patients with CVMs. This is demonstrated by phakomatoses, which show a high association between retinal and cerebral findings. For example, in von Hippel–Lindau syndrome, 68% of patients develop retinal hemangioblastomas.11 Similarly in Wyburn-Mason syndrome, at least 43% of patients with retinal arteriovenous malformations show cerebral involvement.12 However, our rate of 0% is in contrast to other diseases with shared pathophysiology between cerebral and retinal vasculature. In addition, given the common origin between retinal and cerebral vasculature, one might expect a higher probability of retinal involvement in patients with multifocal CVMs if there is a shared developmental process. In our study, 18% of patients with high-risk CVMs had multifocal cerebral lesions, and no RVMs were identified. However, we recognize the retinal vascular volume makes TABLE 4. Neuro-ophthalmic examination abnormalities in the patient cohort Visual field defect (%) Associated with CVM Cranial nerve palsy (%) Associated with CVM Horner syndrome (%) Associated with CVM Vertical gaze abnormality/skew deviation (%) Associated with CVM Internuclear ophthalmoplegia (%) Associated with CVM Optic nerve atrophy (%) Associated with CVM Papilledema (%) Associated with CVM Nystagmus (%) Associated with CVM Convergence insufficiency (%) Associated with CVM Ptosis (%) Associated with CVM One-and-a-half syndrome (%) Associated with CVM Eye Examinations (N = 156) Any Fundus Imaging (N = 56) Complete Macular Imaging (N = 46) 23 (14.7) 15 (65.2) 21 (13.5) 11 (52.4) 2 (1.3) 1 (50.0) 5 (3.2) 3 (60.0) 1 (0.6) 1 (100.0) 9 (5.8) 3 (33.3) 2 (1.3) 2 (100.0) 4 (2.6) 4 (100.0) 6 (3.8) 2 (33.3) 5 (3.2) 2 (40.0) 1 (0.6) 1 (100.0) 10 (17.9) 6 (60.0) 9 (16.1) 4 (44.4) 0 (0) 0 (0) 1 (1.8) 0 (0) 0 (0) 0 (0) 6 (10.7) 2 (33.3) 1 (1.8) 1 (100.0) 0 (0) 0 (0) 1 (1.8) 1 (100.0) 3 (5.4) 1 (33.3) 0 (0) 0 (0) 7 (15.2) 4 (57.1) 9 (19.6) 4 (44.4) 0 (0) 0 (0) 1 (2.2) 0 (0) 0 (0) 0 (0) 3 (6.5) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2.2) 1 (100.0) 2 (4.3) 0 (0) 0 (0) 0 (0) CVM, cerebral vascular malformation. Chan et al: J Neuro-Ophthalmol 2024; 44: 226-231 229 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution up only a minimal portion of cerebral vascular volume (retinal blood flow is an estimated 0.046 mL/min, whereas cerebral blood flow is an estimated 633.5 mL/min in an average-sized human brain).13,14 Therefore, the probability of multifocal vascular abnormalities involving the small proportion of retinal vasculature may be low and could explain the lack of RVMs seen in patients with multifocal lesions. Nonetheless, our results again suggest a lack of association between RVM and CVM and consequently distinct developmental processes for the 2 pathologies. In support of this distinction, cavernous and arteriovenous malformations show abnormal vascular and endothelial cell pathology.15 Arteriovenous malformations consist of dilated vessels, which often cannot be classified as an artery or vein, with irregular thickening, intimal hyperplasia, and hyalinization on pathology.15,16 It is postulated that abnormal involvement of vascular endothelial growth factor and angiopoietin receptors promote angiogenesis and result in arteriovenous malformation development.16,17 Cavernous malformations consist of enlarged sinusoidal vessels comprising thin vessel walls lacking smooth muscle or elastic tissue on pathology, with the congenital form arising because of genetic mutations affecting endothelial cell function as a potential etiology.15,18 In both cases, abnormal vascular pathology can lead to hemorrhage and related complications. Although the pathology of RVM remains poorly understood, RVMs are typically asymptomatic, incidental findings, which rarely lead to complications. Therefore, RVMs may simply be mispatterned vascular development and a distinct pathology from cavernous and arteriovenous malformations. Importantly, we identified a high prevalence of neuroophthalmic examination abnormalities in patients with high-risk CVMs. Although this finding is expected, given the risk of neurologic complications from CVMs, it highlights the importance of a detailed neuro-ophthalmic examination when evaluating RVM patients. Based on our findings of a high rate of neuro-ophthalmic findings and a low rate of RVMs in high-risk CVM patients, we propose the following algorithm for patients diagnosed with an RVM (Fig. 1). If a patient with an RVM has any neurologic symptoms or abnormalities on their neuro-ophthalmic examination, neuroimaging is indicated to rule out CVM. In patients without neurologic or neuro-ophthalmic signs or symptoms, age is an important determinant in clinical decision-making because high-risk CVMs have a cumulative risk over time. In patients aged 40 years or younger (1 SD below the mean age of imaging in our cohort), we recommend neuroimaging because it will provide the greatest benefit-to-cost ratio for these younger patients with RVMs, given their remaining life expectancy. In addition, the mean age of diagnosis is 31–40 years of age for high-risk CVMs.7,8 In patients aged 70 years and older (1 SD above the mean) with RVMs, we do not recommend neuroimaging because there is a high likelihood that a high-risk CVM would already have been identified. In patients aged 40–70 years with RVMs, we recommend the ophthalmologist participate in shared decision-making with patients. We recommend MRI brain with and without contrast because cavernous malformations are often not seen on computed tomography. A susceptibility-weighted imaging (SWI) sequence should be added for optimal cavernous malformation detection.19 The MRI brain can show flow voids when arteriovenous malformations are present, but MR angiogram is more sensitive for detection.20 Since cavernous malformations can develop over time, we recommend initial screening MRI brain with and without contrast with SWI sequence and MR angiogram, and if negative, repeat imaging if new neurologic symptoms develop, as recommended for familial cerebral cavernous malformation syndrome.19 It is important to note that our study had limitations as well. Most importantly, our cohort size was limited to 156 patients with high-risk CVMs who had received a DFE and 46 patients with complete macular imaging. FIG. 1. Clinical decision-making algorithm for patients with asymptomatic retinal venous malformation. 230 Chan et al: J Neuro-Ophthalmol 2024; 44: 226-231 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Therefore, our study may be underpowered to detect a very low prevalence of RVMs in patients with high-risk CVMs. However, given the sample sizes of our cohorts, we estimate with a 95% CI, the prevalence to be between 0%–1.9% and 0%–6.5%, depending on the level of evidence.6 Our study may also be limited by its retrospective design, relying on data recorded in the electronic medical record. Because RVMs have long been considered to be benign, incidental findings, it is possible that some were simply not documented. However, in all macular imaging available for our own review, there were no RVMs identified. Finally, our study investigated only cases of highrisk CVMs, so our findings are not applicable to other CVM subtypes including purely venous malformations. However, this variable was specifically chosen because of the importance of detecting high-risk lesions. Overall, we believe this study was generalizable, given the diverse nature of our patient cohort. Future next steps include expanding this study to a multicenter setting and studying patients with other CVM subtypes. Conclusions We did not detect any RVMs in patients with high-risk CVMs. Current recommendations include neuroimaging for all patients with RVMs. Alternatively, we propose MRI brain with and without contrast, including SWI sequence, and MR angiogram to detect high-risk CVMs in young patients with RVMs. STATEMENT OF AUTHORSHIP Conception and design: M. Daulton, E. McComb, J. Lavine; Acquisition of data: K. Chan, M. Daulton, V. Reddy, E. McComb; Analysis and interpretation of data: K. Chan, M. Daulton, V. Reddy. Drafting the manuscript: K. Chan, M. Daulton, J. Lavine; Revising the manuscript for intellectual content: K. Chan, M. Daulton, V. Reddy, E. McComb, J. Lavine. Final approval of the completed manuscript: K. Chan, M. Daulton, V. Reddy, E. McComb, J. Lavine. 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