The Clinical Significance of Small Vessel Vasculitis on Temporal Artery Biopsies

Background: Giant cell arteritis (GCA) is the most common type of systemic vasculitis in the elderly. Untreated, it can lead to irreversible blindness. Its diagnosis relies on a temporal artery biopsy (TAB). However, a proportion of patients have small vessel vasculitis (SVV) on biopsy; the prognosis of which remains unclear. The aim of this study is to compare the clinical presentation and long-term outcomes of those with SVV with negative and positive biopsies to determine whether long-term corticosteroid therapy can be avoided in these patients. Methods: Post hoc analysis of patients with suspected GCA who underwent TAB and fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scan as part of a prospective GCA and PET cohort. Patients were divided in to 3 groups based on TAB result: positive (inflammation in the main artery wall), negative (no inflammation), and SVV (isolated vasa vasorum or periadventitial SVV). Clinical, serological, and PET/CT data of patients with SVV were compared with those with positive and those with negative biopsies. Results: For the 58 eligible patients recruited between May 2016 and December 2017, 11 had SVV, 12 had positive, and 35 had negative biopsies. Patients with SVV had similar clinical, serological, and PET/CT findings to those with negative biopsies. Compared with those with positive biopsies, patients with SVV had lower erythrocyte sedimentation rate (25 vs 78 mm/hour; P = 0.02), platelet count (296 vs 385 ×109/L; P = 0.03), and a lower median total vascular score on PET/CT scan (1.0 vs 13.5; P = 0.01). Median prednisone dose was lower (4.8 vs 11.7 mg; P = 0.015) and fewer were on steroid-sparing agents (20% vs 67%; P = 0.043) at 6 months. The percentage of patients with a clinical diagnosis of GCA was similar between those with SVV (3/11, 27.3%) and those with negative biopsies (5/35, 14.3%; P = 0.374). Conclusions: Patients with SVV on TAB had similar clinical features, PET/CT findings, and 6-month outcomes to those with negative biopsies. Small vessel vasculitis can be treated as equivalent to a negative biopsy when being considered for diagnosis and treatment of GCA.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD The Clinical Significance of Small Vessel Vasculitis on Temporal Artery Biopsies Julian Quigley, MBBS, Anthony Michael Sammel, PhD, Rodger Laurent, MD, Janice Brewer, MD, Edward Hsiao, MBChB, Geoffrey Schembri, MBBS, Clare L. Fraser, FRANZCO, Background: Giant cell arteritis (GCA) is the most common type of systemic vasculitis in the elderly. Untreated, it can lead to irreversible blindness. Its diagnosis relies on a temporal artery biopsy (TAB). However, a proportion of patients have small vessel vasculitis (SVV) on biopsy; the prognosis of which remains unclear. The aim of this study is to compare the clinical presentation and long-term outcomes of those with SVV with negative and positive biopsies to determine whether long-term corticosteroid therapy can be avoided in these patients. Methods: Post hoc analysis of patients with suspected GCA who underwent TAB and fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scan as part of a prospective GCA and PET cohort. Patients were divided in to 3 groups based on TAB result: positive (inflammation in the main artery wall), negative (no inflammation), and SVV (isolated vasa vasorum or periadventitial SVV). Clinical, serological, and PET/CT data of patients with SVV were compared with those with positive and those with negative biopsies. Results: For the 58 eligible patients recruited between May 2016 and December 2017, 11 had SVV, 12 had positive, and 35 had negative biopsies. Patients with SVV had similar clinical, serological, and PET/CT findings to those with negative biopsies. Compared with those with positive biopsies, patients with SVV had lower erythrocyte sedimentation rate (25 vs 78 mm/hour; P = 0.02), platelet count (296 vs 385 ·109/L; P = 0.03), and a lower median Department of Intensive Care (JQ), Chris O’Brien Lifehouse, Sydney, Australia; Department of Rheumatology (AMS), Prince of Wales Hospital, Randwick, Sydney, Australia; Prince of Wales Clinical School (AMS), University of New South Wales, Randwick, Sydney, Australia; Departments of Rheumatology (RL, JB, EH, GS), Nuclear Medicine and Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, Australia; Northern Clinical School (RL, GS), University of Sydney, St Leonards, Sydney, Australia; and Save Sight Institute (CLF), Faculty of Health and Medicine, The University of Sydney, Sydney, Australia. Supported by Arthritis Australia provided funding for the PET/CT scans. The authors report no conflicts of interest. Address correspondence to Julian Quigley, MBBS, Department of Intensive Care, 119-143 Missenden Rd, Camperdown NSW 2050, Australia; E-mail: [e-mail] 212 total vascular score on PET/CT scan (1.0 vs 13.5; P = 0.01). Median prednisone dose was lower (4.8 vs 11.7 mg; P = 0.015) and fewer were on steroid-sparing agents (20% vs 67%; P = 0.043) at 6 months. The percentage of patients with a clinical diagnosis of GCA was similar between those with SVV (3/11, 27.3%) and those with negative biopsies (5/35, 14.3%; P = 0.374). Conclusions: Patients with SVV on TAB had similar clinical features, PET/CT findings, and 6-month outcomes to those with negative biopsies. Small vessel vasculitis can be treated as equivalent to a negative biopsy when being considered for diagnosis and treatment of GCA. Journal of Neuro-Ophthalmology 2022;42:212–217 doi: 10.1097/WNO.0000000000001505 © 2022 by North American Neuro-Ophthalmology Society G iant cell arteritis (GCA) is the most common primary systemic vasculitis in older adults, with an incidence of approximately 20/100,000 in people older than 50 years (1). The major risk factors are increasing age and female gender (2,3). The mainstay of GCA treatment is high-dose systemic glucocorticoids; however, most patients experience at least 1 drug-related adverse event (4). Giant cell arteritis typically affects the temporal arteries but often involves multiple cranial and extracranial medium and large vessels (5,6). Using [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET), imaging glucose metabolism in vessels is possible, allowing for the identification of inflammatory foci of GCA (7). The gold standard diagnosis of GCA is temporal artery biopsy (TAB). Historically, a positive biopsy consisted of transmural infiltration of predominantly lymphocytes and histiocytes, with multinucleated giant cells present in approximately half of cases (8). Recently, a more limited vasculitic histological variant has been recognized, with inflammation restricted to the smaller periadventitial vessels or the vasa vasorum that supplies an unaffected temporal Quigley et al: J Neuro-Ophthalmol 2022; 42: 212-217 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution artery. However, the clinical significance of this small vessel vasculitis (SVV) variant remains unclear. Studies have reported a link with polymyalgia rheumatica (9), other groups reported that SVV should be treated as a negative biopsies (10) or that it may be a normal finding with ageing (11). In contrast, a large case series indicated that patients with SVV have clinical outcomes and neuroophthalmological events similar to those with a positive biopsy and thus warrant treatment (12,13). The PET/computed tomography (CT) findings for patients with SVV have not been systemically examined. The aim of this study was to assess the significance of SVV using clinical, serological and, uniquely, incorporating FDG-PET/CT findings. Patients with SVV were compared with those with typical positive and negative biopsies. METHODS clinician and expert reviewer diagnoses (blinded to PET/CT result), biopsy result, and corticosteroid dose. If consensus was not reached between the treating clinician and at least 1 of the 2 reviewers, a panel of 4 rheumatologists made the diagnosis. Additional details are published elsewhere (7). Relapses were reported by the treating clinician or by patients during telephone surveys, with the treating clinician determining whether a true relapse had occurred. Relapses were grouped into 2 categories: 1) any relapse and 2) relapse with clinical features of ischemia (European League Against Rheumatism [EULAR] major relapse (15)). EULAR major relapse is defined as recurrence of active disease with either of the following: 1) clinical features of ischemia (including jaw claudication, visual symptoms, visual loss attributable to GCA) or 2) evidence of active aortic inflammation resulting in progressive aortic or large vessel dilatation, stenosis, or dissection (15). This study is a post hoc analysis of a prospective, doubleblind, cross-sectional study (7). Positron Emission Tomography/Computed Tomography Scan Patients Patients suspected of having GCA were referred from 13 centres across Sydney, Australia between May 2016 and December 2017. Inclusion criteria were 1) age .50 years, 2) satisfied at least two 1990 American College of Rheumatology (ACR) classification criteria for GCA (14), 3) received ,72 hours of corticosteroids before PET/CT scan, and 4) not undergone TAB before enrolment. The ACR criteria consist of age at disease onset ($50), new headache, temporal artery abnormality on examination, elevated erythrocyte sedimentation rate (ESR), and abnormal artery biopsy. Exclusion criteria were active malignancy, preexisting connective tissue disease or vasculitis, and corticosteroid use for longer than 1 week in the preceding 6 months (7). Only patients who completed TAB were included in this analysis. This study was conducted in accordance with the revised Declaration of Helsinki and following the Australian National Health and Medical Research Council statement of ethical conduct in research involving humans. Patients provided written informed consent. The project was approved by the local health district human ethics committee (HREC/16/HAWKE/68). Clinical Assessment All patients underwent a standardized survey and clinical examination at enrolment. The ESR (Westergren method), C-reactive protein (CRP), and platelet count measured closest to the start of corticosteroid commencement was recorded. Follow-up was a standardized telephone survey at 2 weeks, 3 months, and 6 months, with ESR, CRP, and platelet count recorded at these times. Patients were asked about symptoms, daily corticosteroid dose, use of steroid-sparing agents, and relapses. The final clinical diagnosis was based on treating Quigley et al: J Neuro-Ophthalmol 2022; 42: 212-217 Time of flight FDG-PET/CT scans were performed before TAB. Each scan was independently reported by 2 nuclear medicine physicians who were blinded to all clinical, imaging, and biopsy data. The primary reporting outcome was a subjective global assessment of the scan as positive or negative for GCA; this was based on the intensity and distribution of FDG uptake. The intensity of FDG uptake compared with background blood pool was reported for 18 artery segments based on an established grading system (7,16): 0 = no uptake (normal), 1 = equivocally increased uptake, 2 = clearly increased uptake, and 3 = very marked uptake. Discordant results were resolved by a consensus. Scores were summed to give a total, large, and cranial vascular scores (17). The large vessel score was out of 30, being the sum of scores from 10 segments: ascending, arch, and descending aorta, brachiocephalic artery, and bilateral carotid, subclavian, and axillary arteries. The cranial vessel score encompassed bilateral temporal, maxillary, occipital, and vertebral arteries, with a maximum score of 24. Total vascular score was the sum of large vessel score and cranial vessel score. Temporal Artery Biopsy Clinically guided unilateral TAB was performed within 4 weeks of enrolment. Specimens were placed into 10% neutral buffered formalin for up to 12 hours. These were routinely processed, cut transversely into 2-mm segments, embedded side by side in a single paraffin block for each patient, which was then sectioned at 0.25-mm increments. The 4-mm transverse sections at each level were mounted on Superfrost slides and stained with hematoxylin and eosin. One of 2 anatomical pathologists reviewed all sections for inflammation; they were blinded to PET/CT findings but not clinical details. 213 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution A positive biopsy for GCA was defined as that demonstrating inflammatory infiltrate with lymphocytes and/or histiocytes through 1 or more layers of the main artery wall. In keeping with previous reports, SVV was defined as lymphocytic predominant inflammation comprising $15 cells (18) limited to the region around small periadventitial vessels or the adventitial vasa vasorum. Biopsies with ,15 cells were considered negative. Patients with both positive and SVV findings on biopsy were considered as positive. Statistical Analysis The study population was divided into 3 groups based on biopsy results. The group of patients with SVV were separately compared with those with positive and negative biopsies. Statistical analysis was performed using SPSS (version 26, IBM Corp), and for all comparisons, a P value of ,0.05 was considered statistically significant. Statistical tests included the independent samples t test for normally distributed continuous variables, Mann– Whitney U test for non-normally distributed variables, and Fisher exact test for nominal variables. A post hoc power analysis was performed using G*Power (version 3.1.9.4), with an alpha value set at 0.05. RESULTS Ninety-six patients were referred, and 64 met inclusion criteria, of which 58 proceeded to have TAB performed and were included in this analysis. They were divided into 3 groups by biopsy result: SVV (11 patients), biopsy positive (12 patients), and biopsy negative (35 patients). The mean biopsy length (±SD) was similar in all groups, with SVV of 19.2 ± 7.4 mm, positive of 20.2 ± 5.0 mm, and negative of 19.2 ± 6.0 mm. Baseline Demographics Female subjects comprised 70.7% of the cohort. This female predominance was seen in the biopsy positive (9/12 patients, 75.0%) and biopsy negative (27/35 patients, 77.1%) TAB subcohorts but not in the SVV group (5/11 patients, 45.5%). The mean age was 70.4 ± 0.3 years. There was no significant difference in mean age between the SVV group (67.3 ±9.6) and the biopsy positive (73.3 ±8.4; P = 0.120) or biopsy negative (70.4 ±11.1; P = 0.405) groups. Giant Cell Arteritis Symptoms and Signs There was no difference in the incidence of headache, constitutional symptoms, Polymyalgia rheumatica (PMR) symptoms, scalp tenderness, temporal artery examination abnormality, or limb claudication between the SVV group and the biopsy-positive or biopsy-negative groups. No patients in the SVV group reported jaw claudication, compared with 31% in biopsy-negative group and 50% in the biopsy-positive group (P = 0.04 and P = 0.014 respectively). 214 The ESR and platelet count were similar in the SVV and biopsy-negative groups; both were significantly lower than the biopsy-positive group. There was no significant difference in CRP (Table 1). Subjective nonspecific visual symptoms were reported in 2 of 11 (18.2%) SVV, 4 of 12 (33.3%) biopsy-positive, and 9 of 35 (25.7%) biopsy-negative patients. Diplopia was reported in none with SVV but reported in 1 (8.3%) biopsy-positive and 2 (5.7%) biopsy-negative patients. Transient monocular vision loss was experienced by none with SVV but experienced by 1 (8.3%) biopsy-positive and 1 (2.9%) biopsy-negative patient. There was no significant difference in visual symptoms between SVV and positive (P = 0.355) or negative biopsy (P = 0.780) groups. Positron Emission Tomography/Computed Tomography Findings The PET/CT scan was reported positive for GCA in 2 patients (18.2%) with SVV and 5 patients (14.3%) with a negative biopsy, a nonsignificant difference (P = 1.0). The PET/CT positive rate in the SVV group was significantly lower than that in the biopsy-positive group (18.2% vs 91.7%; P = 0.001). These findings were reflected in both cranial and large vessel subregions with PET scores similar for SVV and biopsy-negative groups. Details are presented in Table 2. Six-Month Follow-up Data Fifty-five patients were followed up at 6 months. One patient in the SVV group had died from metastatic lung cancer. Two biopsy-negative patients were lost to follow-up. All patients in the biopsy-positive group were reviewed. The clinical diagnoses at 6 months are presented in Table 3. Three patients in the SVV group (27.3%) and 5 patients in the biopsy-negative group (14.3%) were diagnosed with clinical GCA, a nonsignificant difference (P = 0.374). All 12 patients in the biopsy-positive group were diagnosed with GCA, which was a significantly higher when compared with SVV group (P , 0.001). Clinical relapse occurred in 2 patients with SVV (20%), 6 with positive biopsies (50%; P = 0.204), and 9 with negative biopsies (27.3%; P = 1.0). None of the patients with SVV had a relapse with clinical features of ischemia, compared with 5 patients in the biopsy-positive group (41.7%; P = 0.040). Of 58 patients, 56 received empirical corticosteroids during their GCA workup, but at 6 months of follow-up, 5 (50.0%) with SVV, 19 (57.6%) with negative biopsies, and 11 (91.7%) with positive biopsies were still taking prednisone. Those with positive biopsies were on a significantly higher mean daily dose at 6 months than those with SVV (11.7 ±6.3 mg vs 4.8 ±5.8 mg; P = 0.043). Patients with negative biopsies had similar mean prednisone doses to those with SVV (5.1 ±5.4 mg; P = 1.0). Quigley et al: J Neuro-Ophthalmol 2022; 42: 212-217 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Symptoms, signs, and inflammatory markers at baseline SVV Positive Negative P value (SVV vs Positive) P value (SVV vs Negative) 10/11 (90.9%) 0/11 (0%) 1/10 (9.1%) 2/11 (18.2%) 2/11 (18.2%) 7/11 (63.6%) 0/11 (0%) 6/11 (54.5%) 11/12 (91.7%) 6/12 (50%) 3/12 (25%) 4/12 (33.3%) 7/12 (58.3%) 7/12 (58.3%) 1/12 (8.3%) 5/12 (41.2%) 32/35 (91.4%) 11/35 (31.4%) 4/35 (11.4%) 6/35 (17.1%) 10/35 (28.6%) 18/35 (51.4%) 0/35 (0%) 22/35 (62.9%) 1.00 0.014 0.590 0.640 0.089 1.00 1.00 0.374 1.00 0.044 1.00 1.00 0.701 0.514 N/A 0.654 25 ± 62 33 ± 34 296 ± 154 95 ± 106 78 ± 73 385 ± 211 9 ± 40 40 ± 52 265 ± 63 0.059 0.019 0.032 0.151 0.780 0.800 Variable New headache Jaw claudication Weight loss Fevers/night sweats PMR Scalp tenderness Limb claudication Temporal artery examination abnormality CRP (median ± IQR, mg/L) ESR (median ± IQR, mm/hr) Platelet count (median ± IQR, ·109) CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IQR, Interquartile range; SVV, small vessel vasculitis. Two patients in the SVV group (20%) and 6 in the biopsy-negative group (18%; P = 1.0) were on a steroidsparing agent at 6 months compared with 8 (66.7%; P = 0.043) in the biopsy-positive group. Methotrexate was used in all cases except for 1 SVV patient on azathioprine and 1 biopsy-positive patient on leflunomide. CONCLUSION Our study is the first to compare the clinical characteristics, PET/CT findings, and 6-month outcomes for patients with SVV with those with mural inflammation and those with no inflammation. We found that patients with SVV had equivalent outcome measures to the those with a negative TAB. The clinical significance of SVV has been investigated previously, with conflicting results and management recommendations. Our study enrolled a prospective cohort of untreated, newly suspected GCA patients and our rigorous biopsy sectioning and reporting methodology ensured that all temporal artery biopsies were properly reviewed to identify SVV. We also had the benefit of being able to compare groups using blinded PET/CT scan findings. Overall, our patient demographics were consistent with the existing literature. Interestingly, the substantial female gender bias commonly found in GCA was not present in our patients with SVV, with only 45% of patients with SVV being female. This gender discrepancy has also been noted in other cohorts with female subejcts accounting for 37%– 53% of SVV biopsies compared with 67%–78% for positive biopsies (9,11,18,19). The mean age for our SVV cohort was similar to other patients and was in keeping with the published literature (11,18,19). While most GCA-associated symptoms were similar between the SVV, biopsy-positive, and biopsy-negative groups, the exception was jaw claudication, which was not reported in any of our patients with SVV. Historically, the odds of a positive TAB are up to 9· higher in a patient with jaw claudication, making it one of the most specific symptoms (20,21); this supports the idea that SVV is not a true subset of biopsy-positive GCA. Another area of controversy has been whether SVV may represent a PMR-associated biopsy finding (9,19). Our study would refute this hypothesis because only 2 of the patients with SVV had PMR symptoms at presentation and none received a final clinical diagnosis of PMR. TABLE 2. PET scores at baseline Score (Median ± IQR) Type of PET Score Total vascular score Large vessel score Cranial vessel score P value SVV Positive Negative SVV vs Positive SVV vs Negative 1.0 ± 4.0 1.0 ± 4.0 0 ± 1.0 13.5 ± 20.0 9.0 ± 16.0 5.0 ± 9.0 1.0 ± 3.0 1.0 ± 3.0 0 ± 1.0 0.001 0.002 ,0.001 0.899 0.800 0.939 IQR, Interquartile range; PET, positron emission tomography; SVV, small vessel vasculitis. Quigley et al: J Neuro-Ophthalmol 2022; 42: 212-217 215 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 3. Final diagnosis at 6 months Clinical Diagnosis Giant cell arteritis Cervicogenic headache Polymyalgia rheumatica Self-limiting ophthalmological disease Inflammatory ocular disease Malignancy Pneumonia Infection (other) Rheumatic disease (other) Herpes zoster Stroke/TIA Chronic ophthalmological disorder Neurological disease (other) Sinusitis Headache (not otherwise specified) Unknown Dental abscess Thyroiditis SVV Negative Positive 3 (27.3%) — — — 2 (18.2%) 2 (18.2%) 1 (9.1%) — — 1 (9.1%) — — — — — — 1 (9.1%) 1 (9.1%) 5 (14.3%) 8 (22.9%) 5 (14.3%) 4 (11.4%) — 1 (2.9%) 2 (5.7%) 2 (5.7%) 2 (5.7%) — 1 (2.9%) 1 (2.9%) 1 (2.9%) 1 (2.9%) 1 (2.9%) 1 (2.9%) — — 12 (100%) — — — — — — — — — — — — — — — — — SVV, small vessel vasculitis; TIA, Transient ischaemic attack. The inflammatory marker and platelet count profile of patients with SVV was similar to those with a negative biopsy and lower than those for patients with a positive biopsy, arguing against SVV representing a forme fruste of GCA-associated biopsy finding. This is the first study comparing FDG-PET/CT vessel uptake in patients with SVV with those with positive or negative biopsies. Patients with SVV had PET/CT findings similar to those with negative biopsies. Only 2 of 11 patients with SVV (18%) had a globally positive PET/CT for GCA, which was comparable to 14% for patients who had a negative biopsy. Patients with SVV had low vascular uptake scores in both cranial and large arteries, thereby arguing against the proposal that SVV represents a localized form of arteritis, a segment of artery adjacent to a skip lesion (13), or that it is an intermediate stage in the pathway to transmural inflammation. The final clinical diagnosis in our study relied on clinical data, acute phase markers, biopsy, and follow-up data from enrolment to 6 months. The majority of patients with SVV (73%) had an alternate diagnosis at month 6 (8/11%, 72.7%) similar to those with a negative biopsy (86%). There were a range of diagnoses among patients with SVV, indicating that the finding is not specific for a particular alternative condition. Ischemic relapse is a key concern with GCA. In our cohort, none of the patients with SVV experienced relapse with ischemic features compared with 5 of 12 patients (42%) in the biopsy-positive group. This provides reassurance that patients with SVV are unlikely to demonstrate an aggressive clinical course. Our study has several strengths, including its prospective design, standardized clinical assessment, correlation with PET/CT scan, and rigorous sectioning of the TAB. The 216 main limitation is the relatively small sample size for each group, although post hoc analysis indicated that the study was adequately powered ($0.80) for all significant outcomes aside from the use of steroid-sparing agents (0.61). Another limitation is that the rates and timing of patient follow-up visits will have been affected by the treatment schedule chosen by the treating physician, which may have introduced some bias into the conclusions about follow-ups. Given the similarities between the SVV and biopsynegative groups in almost all variables, we propose that the finding of SVV on a TAB should be treated the same as if negative, provided that adequate length and examination of segments are performed. It is important to note, however, that a negative biopsy does not exclude GCA; it has been well documented that approximately 20% of patients with GCA have a negative TAB (20,21). In summary, our study has shown that a finding of SVV on TAB does not support a diagnosis GCA. In the absence of alternative clinical or imaging evidence of medium-large vessel vasculitis, these patients are unlikely to require longterm corticosteroid therapy. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. Quigley, A. M. Sammel, and C. L. Fraser; b. Acquisition of data: A. M. Sammel; c. Analysis and interpretation of data: J. Quigley, A. M. Sammel, C. L. Fraser, R. Laurent, J. Brewer, E. Hsiao, and G. Schembri. Category 2: a. Drafting the manuscript: J. Quigley, A. M. Sammel, and C. L. Fraser; b. Revising it for intellectual content: J. Quigley, A. M. Sammel, and C. L. Fraser. Category 3: a. Final approval of the completed manuscript: J. Quigley, A. M. Sammel, R. Laurent, J. Brewer, E. Hsiao, G. Schembri, and C. L. Fraser. Quigley et al: J Neuro-Ophthalmol 2022; 42: 212-217 Copyright © North American Neuro-Ophthalmology Society. 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