Fluorescein Angiography Findings in Susac Syndrome: A Multicenter Retrospective Case Series

Background: Susac syndrome is a vasculopathy, resulting in the classic triad of branch retinal artery occlusion (BRAO), inner ear ischemia, and brain ischemia. In this retrospective chart review, we characterize fluorescein angiography (FA) findings and other ancillary studies in Susac syndrome, including the appearance of persistent disease activity and the occurrence of new subclinical disease on FA. Methods: This multicenter, retrospective case series was institutional review board-approved and included patients with the complete triad of Susac syndrome evaluated with FA, contrasted MRI of the brain, and audiometry from 2010 to 2020. The medical records were reviewed for these ancillary tests, along with demographics, symptoms, visual acuity, visual field defects, and findings on fundoscopy. Clinical relapse was defined as any objective evidence of disease activity during the follow-up period after initial induction of clinical quiescence. The main outcome measure was the sensitivity of ancillary testing, including FA, MRI, and audiometry, to detect relapse. Results: Twenty of the 31 (64%) patients had the complete triad of brain, retinal, and vestibulocochlear involvement from Susac syndrome and were included. Median age at diagnosis was 43.5 years (range 21-63), and 14 (70%) were women. Hearing loss occurred in 20 (100%), encephalopathy in 13 (65%), vertigo in 15 (75%), and headaches in 19 (95%) throughout the course of follow-up. Median visual acuity at both onset and final visit was 20/20 in both eyes. Seventeen (85%) had BRAO at baseline, and 10 (50%) experienced subsequent BRAO during follow-up. FA revealed nonspecific leakage from previous arteriolar damage in 20 (100%), including in patients who were otherwise in remission. Of the 11 episodes of disease activity in which all testing modalities were performed, visual field testing/fundoscopy was abnormal in 4 (36.4%), MRI brain in 2 (18.2%), audiogram in 8 (72.7%), and FA in 9 (81.8%). Conclusions: New leakage on FA is the most sensitive marker of active disease. Persistent leakage represents previous damage, whereas new areas of leakage suggest ongoing disease activity that requires consideration of modifying immunosuppressive therapy.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Fluorescein Angiography Findings in Susac Syndrome: A Multicenter Retrospective Case Series Devon A. Cohen, MD, Deena Tajfirouz, MD, Ivana Vodopivec, MD, Kevin Kyle, MD, Marc A. Bouffard, MD, Shamik Bhattacharyya, MD, Vanja C. Douglas, MD, Nailyn Rasool, MD, M. Tariq Bhatti, MD, Andrew McKeon, MD, Sean Pittock, MD, Eoin P. Flanagan, MB BCh, Sashank Prasad, MD, Venna Nagagopal, MD, Robert A. Egan, MD, John J. Chen, MD, PhD, Bart K. Chwalisz, MD Background: Susac syndrome is a vasculopathy, resulting in the classic triad of branch retinal artery occlusion (BRAO), inner ear ischemia, and brain ischemia. In this retrospective chart review, we characterize fluorescein angiography (FA) findings and other ancillary studies in Susac syndrome, including the appearance of persistent disease activity and the occurrence of new subclinical disease on FA. Methods: This multicenter, retrospective case series was institutional review board–approved and included patients with the complete triad of Susac syndrome evaluated with FA, contrasted MRI of the brain, and audiometry from 2010 to 2020. The medical records were reviewed for these ancillary tests, along with demographics, symptoms, visual acuity, visual field defects, and findings on fundoscopy. Clinical relapse was defined as any objective evidence of disease activity during the follow-up period after initial induction of clinical quiescence. The main outcome measure was the sensitivity of ancillary testing, including FA, MRI, and audiometry, to detect relapse. Cleveland Clinic (DAC), Cleveland, Ohio; Mayo Clinic (DT, MTB, AM, SP, EPF, JJC), Rochester, Minnesota; Roche (IV), Basel, Switzerland; Massachusetts General Hospital (KK, VN, BKC), Boston, Massachusetts; Beth Israel Deaconess (MAB), Boston, Massachusetts; Brigham and Women’s Hospital (SB, SP), Boston, Massachusetts; UCSF (VD, NR), San Francisco, California; and Eye and Vascular Neurology (RE), Carlton, Oregon. I. Vodopivec is an employee at Roche; A. McKeon received research funding from Alexion, Grifols, and MedImmune and has patents pending for the following IgGs as biomarkers of autoimmune neurological disorders (septin-5, Kelch-like protein 11, GFAP, PDE10A, and MAP1B); S. J Pittock is an inventor on patents related to functional AQP4/NMO-IgG assays and NMO-IgG as a cancer marker, consulted for Alexion and MedImmune, and received research support from Grifols, MedImmune, and Alexion; compensation paid directly to Mayo Clinic; E. P. Flanagan is a site principal investigator in a randomized placebo-controlled clinical trial of inebilizumab (a CD19 inhibitor) in neuromyelitis optica spectrum disorders funded by MedImmune/Viela Bio. J. J. Chen and B. K. Chwalisz are cosenior authors. Address correspondence to Bart K. Chwalisz, MD, MGH Neurology, WACC 835, 15 Parkman Street, Boston, MA 02130; E-mail: [e-mail] Cohen et al: J Neuro-Ophthalmol 2023; 43: 481-490 Results: Twenty of the 31 (64%) patients had the complete triad of brain, retinal, and vestibulocochlear involvement from Susac syndrome and were included. Median age at diagnosis was 43.5 years (range 21–63), and 14 (70%) were women. Hearing loss occurred in 20 (100%), encephalopathy in 13 (65%), vertigo in 15 (75%), and headaches in 19 (95%) throughout the course of follow-up. Median visual acuity at both onset and final visit was 20/20 in both eyes. Seventeen (85%) had BRAO at baseline, and 10 (50%) experienced subsequent BRAO during follow-up. FA revealed nonspecific leakage from previous arteriolar damage in 20 (100%), including in patients who were otherwise in remission. Of the 11 episodes of disease activity in which all testing modalities were performed, visual field testing/ fundoscopy was abnormal in 4 (36.4%), MRI brain in 2 (18.2%), audiogram in 8 (72.7%), and FA in 9 (81.8%). Conclusions: New leakage on FA is the most sensitive marker of active disease. Persistent leakage represents previous damage, whereas new areas of leakage suggest ongoing disease activity that requires consideration of modifying immunosuppressive therapy. Journal of Neuro-Ophthalmology 2023;43:481–490 doi: 10.1097/WNO.0000000000001826 © 2023 by North American Neuro-Ophthalmology Society I n 1979, Susac et al (1) described a novel triad of microangiopathy of the retina, brain, and inner ear, resulting in vision changes, encephalopathy, and hearing loss in 2 women, that now bears his name, Susac syndrome (SS). Although an earlier report by Pfaffenbach and Hollenhorst described 2 women with microangiopathy of the retinal arterioles, which was attributed to systemic lupus erythematosus (SLE), Susac et al distinguished their findings from SLE (2). Since that time, accumulating clinical experience has proposed the pathophysiology of the disease to be the result of a vasculopathy of small- to medium-sized vessels, 481 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution with a clinical course of remissions and relapses, and treatment targeted toward immunosuppression (3–12). Multiple criteria have been set forth to help distinguish Susac syndrome based on the clinical and paraclinical manifestations (13,14). Nevertheless, the challenge to distinguish Susac syndrome from other vasculitides and systemic autoimmune disorders remains. Moreover, only 13% of patients present with the complete triad, which can take up to 2 years to develop (15). Efficient diagnosis is critical, given the risk of recurrent multiorgan infarction when treatment is inadequate (16). Complicating the matter is the challenge of determining disease activity or relapses because limited information is available on the relative utility of diagnostic monitoring modalities: fluorescein angiography (FA), visual field testing, fundoscopy, brain MRI, and audiogram (8,11,17). We therefore set out to establish their sensitivity to detect clinical relapse or subclinical recurrence and to determine the rate on FA of persistent arteriolar wall hyperfluorescence secondary to previous arteriolar damage in a multicenter cohort of patients. METHODS Standard Protocol Approvals, Registrations, and Patient Consents The study was approved by the Mass General Brigham Institutional Review Board (IRB) (Protocol #: 2020P003119) and the Mayo Clinic IRB (Protocol #: 08006647). The institutional review boards approved the study with a waiver of informed consent because of the retrospective nature of the study. The research adhered to the tenets of the Declaration of Helsinki and the requirements of the United States Health Insurance Portability and Accountability Act. Patient Identification All patients evaluated by neuro-ophthalmologists between 2010 and 2020 at Mass General Brigham, Beth Israel Deaconess, Mayo Clinic, Eye and Vascular Neurology Oregon, and UCSF were retrospectively reviewed. Inclusion criteria were (1) complete triad of retinal, brain, and cochlear manifestations of Susac syndrome with no alternative diagnosis; (2) patients evaluated with FA, brain MRI, and audiogram. To best ensure diagnostic accuracy, included patients possessed the complete triad within 2 years of presentation, apart from one who was lost to follow-up for 5 years but had the complete triad on return to clinical care. Data Collection The medical records were reviewed in detail to determine the sensitivity of ancillary testing to detect relapses in patients with Susac syndrome along with the presence of persistent leakage on FA in clinically silent disease. Collected data included best-corrected visual acuity at 482 presentation and final follow-up (with Snellen conversion to logarithm of the minimum angle of resolution for analysis), Humphrey visual field defects at presentation and final follow-up, and dilated funduscopic examination findings, FA findings at presentation and subsequent follow-up examinations, brain MRI findings at presentation and subsequent follow-up studies, and audiogram findings at presentation and subsequent follow-up studies. Given that this was a multicenter, retrospective study, there was inherent inhomogeneity among the testing modalities. The MRI scans were performed on different machines, with different magnetic strength and without consistent image sequence protocols. FA was performed on Optos or Spectralis without uniform protocols nor consistently wide-field. For Spectralis FA, sweeps of the periphery were performed to best capture disease activity. Audiograms were also performed based on institution-specific standards. New vs Persistent Fluorescein Angiogram Leakage Definition Persistent leakage in the retinal arterioles on FA was defined as wall hyperfluorescence in areas that have had previous arteriolar damage, particularly in patients with a previous branch retinal artery occlusion (BRAO), which did not disappear regardless of acute or chronic treatment. This old damage is typically seen at end terminals out in the periphery at areas of previous retinal artery occlusion and poor perfusion. It will be persistent and unchanged on repeat FAs despite treatment. New leakage was defined as areas of leakage that were not seen on previous FA studies. New leakage could occur with or without a concomitant, new BRAO. Disease Activity and Relapse Definition Episodes of disease activity were defined by objective evidence of clinical or subclinical disease activity on at least one of the following: history and examination (visual field testing and/or fundoscopy), FA, MRI, and audiogram. Clinical relapses were defined as episodes of symptomatic disease worsening based on the subspecialist documentation of a new abnormality seen on at least one of the following: history, ophthalmic examination, FA, MRI, and audiogram, after initial induction of remission. Relapses detected by ophthalmic history and examination were based on the patient’s symptoms (i.e., new scotoma), Humphrey visual field defects, and funduscopic abnormalities (i.e., retinal edema consistent with arteriolar occlusion and rarely Gass plaques). FA relapses were defined as new leakage away from a site of previous arteriolar damage, as determined by ophthalmologists and neuro-ophthalmologists. MRI brain relapses were defined as new central callosal or white matter lesions and/or leptomeningeal enhancement as confirmed by neuroradiologists. Relapses on audiogram were determined by otolaryngologists at each institution without Cohen et al: J Neuro-Ophthalmol 2023; 43: 481-490 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution specific metrics required, given the retrospective, multicenter nature of this study. Data Availability Anonymized data not published within this article will be made available by request from any qualified investigator. RESULTS Twenty of the 31 (64%) patients with the full triad of brain, retinal, and vestibulocochlear involvement were included in the analysis (Table 1). All patients had this triad within 2 years of presentation, except for in 1 patient who was lost to follow-up for 5 years, at which point they were confirmed to have the triad. Of the 17 patients who had all testing modalities performed at presentation, 16 had abnormalities on comprehensive ophthalmic examination, FA, MRI brain, and audiogram, whereas 1 patient only lacked audiogram manifestations. The median age at diagnosis was 43.5 years (range 21–63), and 14 (70%) were women. The median duration between presentation and final follow-up was 41 months. Hearing loss occurred in 20 (100%), encephalopathy in 13 (65%), vertigo in 15 (75%), and headaches in 19 (95%) throughout follow-up. Median visual acuity at both onset and final follow-up was 20/20 in both eyes. Visual fields were abnormal in 12 (60%). Seventeen (85%) had a BRAO at baseline, and 10 (50%) experienced subsequent BRAO during follow-up. Seven of these 10 patients had a BRAO at baseline, and 3 did not; thus, all patients had a BRAO during the course of the disease. Relapses generally occurred during times of nonadherence or suboptimal treatment with immune suppression. For example, 1 patient developed new arteriolar leakage without other disease activity while transitioning from cyclophosphamide to mycophenolate mofetil (MMF) and again while being tapered off the MMF (Patient 10). Details of Fluorescein Angiography FA revealed areas of leakage from previous arteriolar damage in all 20 patients, including in patients who were otherwise in remission. Many of these areas did not resolve throughout the course of follow-up FAs, despite immunotherapy. This was often present in the peripheral retina in areas of previous arteriolar damage (Figs. 1, 2). Areas of new pathologic leakage on FA were present in all patients at either diagnosis or a relapse (Figs. 1, 2). This tended to occur in the posterior pole along the arteriolar arcades and usually occurred at areas away from previous damage. These areas of new pathologic leakage tended to resolve with treatment, but some became areas of persistent leakage. Cohen et al: J Neuro-Ophthalmol 2023; 43: 481-490 Details of MRI Brain Consistent abnormalities reported among the centers included in this retrospective multicenter study were midcallosal and white matter lesions in addition to leptomeningeal enhancement, which were used to define neuroimaging relapses. Presenting MRI brain with and without contrast showed midcallosal lesions in 18 patients, white matter lesions in 20 (6 with associated enhancement), and leptomeningeal enhancement in 8. MRI brain performed during relapses demonstrated midcallosal lesions in 4 and white matter lesions in 12 (7 with associated enhancement). Sensitivity of Testing Modalities Overall Sensitivity Among the 28 total visits (including initial presentation) in which each testing modality was performed: Clinical history and examination (visual field testing/fundoscopy) was abnormal in 21 (75%), MRI brain in 19 (68%), audiogram in 24 (86%), and FA in 26 (93%). Of the 11 episodes of disease activity in which all 4 testing modalities were performed: History and visual field testing/fundus examination was abnormal in 4 (36.4%), MRI brain in 2 (18.2%), audiogram in 8 (72.7%), and FA in 9 (81.8%). Two patients had episodes with only changes on audiogram. One patient had a relapse of worsening dizziness associated with characteristic MRI changes but without new leakage on FA; FA changes were present during all the other relapses. There were 16 occasions in which an FA was performed in conjunction with either an examination and/or another testing modality, and it was the only positive finding. Active disease was demonstrated on FA in 9 undertreated patients with stable MRI scans; 5 of these patients were asymptomatic. Sensitivity for Symptomatic Relapses The sensitivity of the modalities to detect clinical symptomatic relapses (i.e., subspecialist documentation of any new abnormality, as defined above) was FA 91.4% (32 of 35), audiogram 80% (8 of 10), history and examination 58.3% (21 of 35), and MRI 46.4% (13 of 28). The overall sensitivity of the testing modalities to detect active disease (both at presentation and during relapses) was FA 93.5% (58 of 62), audiogram 82% (27 of 33), history and examination 63.6% (42 of 66), and MRI 58.6% (34 of 58). The sensitivity of the modalities to detect ongoing disease activity after presentation was FA 91.1% (41 of 45), audiogram 64.3% (9 of 14), history and ophthalmic examination 47.8% (22 of 46), and MRI 37.8% (14 of 37). There were no instances of MRI brain being the only positive test when performed in conjunction with examination or other ancillary testing modalities. DISCUSSION This is the first systematic study comparing the sensitivity of testing modalities in Susac syndrome with detailed findings 483 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Changes on Changes Audiogram Changes on Seen on MRI Clinical During x # Seen Examination Fluorescein of During x # of Changes on During x # With Complete Relapses Corresponding of FA Seen Relapses Nonspecific Duration Triad Symptoms With During x # of Relapses With Leakage in Between of Brain, Reported With MRI Audiogram Relapses Examination BRAO Presentation Areas of Initial and Retinal, and Performed Performed During x # of With FA Performed # of Final BRAO at Since and Final f/u Previous Vestibulocochlear Relapses (%) (%) (%) Performed (%) (%) Damage Relapses (d) BCVA Initial and Final VF Baseline Baseline Involvement Symptoms Cohen et al: J Neuro-Ophthalmol 2023; 43: 481-490 Patient No. Age at Diagnosis/ Sex 1 51/M HL, Cog, Yes and HA 2 54/M HL, HA, Yes and vertigo 3 23/F Yes HL, HA, and vertigo 4 21/M HL, Cog, Yes and HA 20/30-1 Persistent superonasal OD, defect 20/20 (scotoma) OD OS; 20/15-1 OD, 20/ 15-2 OS 20/20-1 Inferonasal depression OD, OD, superonasal 20/20 depression OS, OS; nasal 20/20-1 constriction OD, 20/ 20-3 OS OD, and superonasal constriction OS Inferior paracentral 20/20 defect OD, OD, superior 20/15 altitudinal OS; defect OS, 20/15-3 superior OU arcuate and inferior paracentral defects OD, and superior altitudinal defect OS 20/25 Inferior field OD, defects OU and 20/30 generalized OS; construction to 20/15 confrontation OD, 20/ OU 15-1 OS Suspected Cause of Relapse Yes No 155 Yes 0 NA NA NA NA NA NA Yes No 1235 Yes 0 NA NA NA NA NA NA Yes Yes 1259 Yes 5 1/5 (20%) 4/5 (80%) 0/3 (0%) 1/3 (33%) 4/5 (80%) Yes Yes 3584 Yes 1 1/1 (100%) 1/1 (100%) 1/1 1/1 1/1 (100%) (100%) (100%) Steroid tapers, medication noncompliance with recurrent relapse during reinitiation MMF initiation Original Contribution 484 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 1. Summary of cases Cohen et al: J Neuro-Ophthalmol 2023; 43: 481-490 Changes on Changes Audiogram Changes on Seen on MRI Clinical During x # Seen Examination Fluorescein of During x # of Changes on During x # With Complete Relapses Corresponding of FA Seen Relapses Nonspecific Duration Triad Symptoms With During x # of Relapses With Leakage in Between of Brain, Reported With MRI Audiogram Relapses Examination Retinal, and Initial and BRAO Presentation Areas of Performed Performed During x # of With FA Performed # of Vestibulocochlear Final BRAO at Since and Final f/u Previous Relapses (%) (%) (%) Performed (%) (%) Damage Relapses (d) Involvement BCVA Initial and Final VF Baseline Baseline Symptoms Patient No. Age at Diagnosis/ Sex 5 43/M HL, Cog, Yes and HA 6 40/F HL, Yes Vertigo 7 59/F HL, Cog, Yes and HA 8 52/F Yes HL, vertigo, Cog, and HA 9 23/F Yes HL, vertigo, and HA 10 47/F Yes HL, vertigo, Cog, and HA 11 57/F Yes HL, vertigo, Cog, and HA Remains full OU 20/20 OD, 20/25 OS; 20/20 OU 20/15-1 Remains full OU OD, 20/ 20+2 OS; 20/20 OD, 20/ 20-2 OS 20/40 Remains full OU OD, 20/ 200 OS; 20/20 OU 20/20-1 Remains full OU OU; 20/25-2 OD, 20/ 25 OS Dense inferonasal 20/20 scotoma OD, OU; small nasal 20/20-1 edge defect OS, OU inferonasal depression OD, and full OS Persistent mild 20/20 nasal and OD, superior 20/20depression OS, 1 OS; full OD 20/20 OU 20/25-1 Remains full OU OU, 20/20 OU Suspected Cause of Relapse Yes Yes 1197 Yes 2 0/2 (0%) 2/2 (100%) 0/2 (0%) 0/1 (0%) 0/2 (0%) CP initiation Yes No 521 Yes 0 NA NA NA NA NA NA Yes Yes 432 Yes 1 0/1 (0%) 1/1 (100%) 0/1 (0%) NA 0/1 (0%) Steroid taper/ immuno suppressant increase Yes No 3006 Yes 0 NA NA NA NA NA NA Yes No 714 Yes 0 NA NA NA NA NA NA Yes No 1468 Yes 2 1/2 (50%) 2/2 (100%) NA NA 1/2 (50%) Transition from CP to MMF Yes No 1976 Yes 5 3/5 (60%) 4/5 (80%) 3/5 (60%) 1/1 4/5 (80%) (100%) Medication initiation and transitions Original Contribution 485 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Changes on Changes Audiogram Changes on Seen on MRI Clinical During x # Seen Examination Fluorescein of During x # of Changes on During x # With Complete Relapses Corresponding of FA Seen Relapses Nonspecific Duration Triad Symptoms With During x # of Relapses With Leakage in Between of Brain, Reported With MRI Audiogram Relapses Examination Retinal, and Initial and BRAO Presentation Areas of Performed Performed During x # of With FA Performed # of Vestibulocochlear Final BRAO at Since and Final f/u Previous Relapses (%) (%) (%) Performed (%) (%) Damage Relapses (d) Involvement BCVA Initial and Final VF Baseline Baseline Symptoms Cohen et al: J Neuro-Ophthalmol 2023; 43: 481-490 Patient No. Age at Diagnosis/ Sex 12 54/F HL, Yes vertigo, Cog, and HA 13 33/F HL, Yes vertigo, and HA 14 27/M HL, Yes vertigo, and HA 15 44/F HL, Cog, Yes and HA 16 63/F Yes HL, vertigo, Cog, and HA Yes Yes 20/20 Full OU OU (final visit not performed) Not performed 20/20 OD, 20/201 OS; 20/30+1 OD, 20/ 25+2 OS 20/20 Superonasal loss OD, OD, inferonasal 20/20loss OS; 1 OS; superior and 20/20-1 inferior OD, 20/ scotoma OD, and inferior 20 OS altitudinal defect OS Mild superior loss 20/20 OD, OU; superonasal 20/20 loss OS, inferior OD, 20/ . superior 15 OS loss, OD . OS 20/20-2 Not performed OD, 20/402 OS; 20/20-2 OD, 20/ 40-2 OS; 20/20 OD, 20/202 OS; 1251 Yes Suspected Cause of Relapse Yes Yes 872 Yes 4 2/4 (50%) 3/3 (100%) 1/4 (25%) 1/1 2/4 (50%) (100%) Steroid tapers, medication initiation Yes No 4504 Yes 5 0/5 (0%) 5/5 (100%) 1/2 (50%) 0/2 (0%) 0/5 (0%) Medication noncompliance and initiation Yes Yes 4144 Yes 6 3/6 (50%) 6/6 (100%) 1/5 (20%) 1/1 1/5 (20%) (100%) Steroid taper, IVIG discontinuation, medication initiation, and transitions Yes No 1373 Yes 1 NA NA 1/2 NA (100%) Medication initiation 7 6/9 7/9 (78%) (67%) 5/7 (71%) 2/2 6/9 (67%) (100%) Medication initiation and transitions 1/1 (100%) Original Contribution 486 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Cohen et al: J Neuro-Ophthalmol 2023; 43: 481-490 Changes on Changes Audiogram Changes on Seen on MRI Clinical During x # Seen Examination Fluorescein of During x # of Changes on During x # With Complete Relapses Corresponding of FA Seen Relapses Nonspecific Duration Triad Symptoms With During x # of Relapses With Leakage in Between of Brain, Reported With MRI Audiogram Relapses Examination Retinal, and Initial and BRAO Presentation Areas of Performed Performed During x # of With FA Performed # of Vestibulocochlear Final BRAO at Since and Final f/u Previous Relapses (%) (%) (%) Performed (%) (%) Damage Relapses (d) Involvement BCVA Initial and Final VF Baseline Baseline Symptoms Patient No. Age at Diagnosis/ Sex 17 53/M HL, Yes vertigo, Cog, and HA 18 30/F Yes HL, vertigo, and HA 19 22/F Yes HL, vertigo, Cog, and HA 20 38/F Yes HL, vertigo, Cog, and HA 20/15-2 Full OU, enlarged blind spot in OD, superior field 20/25 OD, full OS + 1; 20/20 OU 20/20-1 Full OU (final visit OU; not performed) 20/20-1 OU 20/20 Superior . inferior OU; arcuate defect 20/20 OU OD, Superior . inferior arcuate defect OS (only performed at final f/u) 20/20-1 Persistent superotemporal OU; and nasal 20/20-1 defects OD, full OU OS Suspected Cause of Relapse Yes No 130 Yes 2 2/2 (100%) 2/2 (100%) 0/2 (0%) NA 1/2 (50%) Medication initiation No Yes 1791 Yes 1 1/1 (100%) 1/1 (100%) 0/1 (0%) 1/1 1/1 (100%) (100%) Steroid taper No Yes 66 Yes 1 0/1 (0%) 1/1 NA (100%) No Yes 257 Yes 2 2/2 (100%) 2/2 (100%) 1/1 (100%) NA 0/1 (0%) 1/1 2/2 (100%) (100%) Steroid taper Was off immunotherapy in remission for 7 years before BRAO BCVA, best corrected visual acuity; BRAO, branch retinal artery occlusion; CP, cyclophosphamide; FA, fluorescein angiography; HA, headache; HL, hearing loss; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; OD, right eye; OS, left eye; OU, both eye; VF = visual fields. Original Contribution 487 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Original Contribution FIG. 1. Patient 3: A 26-year-old woman (diagnosed at age 23 years) who was asymptomatic while increasing mycophenolate mofetil (MMF) after a period of medication noncompliance. The fluorescein angiography (FA) in panels (A and B) was performed on January 10, 2018, and in panels (C and D) was performed April 2, 2019. FA showed (A and C) leakage in the right eye at subsequent visits with (B and D) new leakage in the left eye. (E) Audiogram showed stable bilateral sensorineural hearing loss, and (F) MRI brain redemonstrated a stable single T1-hypointense spot in the body of corpus callosum. on FA. We found that FA was the most sensitive marker of active disease, followed by audiogram and comprehensive ophthalmic history and examination, whereas MRI brain was the least sensitive testing modality. Pathologic leakage on FA was present in all patients. New areas of leakage along the arcades even without a BRAO correlated with undertreated disease or medication noncompliance in this cohort. To avoid making a circular argument in which we defined a relapse based on the presence of disease activity on ancillary testing, we additionally performed a set of calculations that only included clinical symptomatic relapse episodes with overall worsening of a patient’s Susac disease. This calculation also showed FA to be the most sensitive marker of relapses, followed by audiogram (although fewer were performed), then history and examination, and MRI remained the least sensitive. Moreover, all included episodes of new leakage were considered clinically significant even among asymptomatic patients without associated changes on audiogram or MRI because they specifically occurred during medication transitions, tapering of immunotherapy, or in the setting of 488 medication noncompliance. This again suggests that new leakage on FA is both sensitive and specific for active disease. Immunotherapy should be escalated in a patient with new leakage in the posterior pole away from a site of previous damage if they are symptomatic or other ancillary tests show abnormalities. If there is isolated new leakage on FA in an asymptomatic patient, immunosuppressant optimization should be considered or at a minimum the patient should be closely followed. This emphasizes the importance of interval FA follow-up studies to help prevent vision loss in Susac patients. The interval of surveillance in Susac patients depends on the severity and activity of the disease. In symptomatic patients, ancillary testing and monitoring should be performed in short intervals to try to achieve remission. By contrast, patients with isolated asymptomatic leakage on FA without other symptoms or abnormalities on other ancillary tests can be followed in 1–3 months to look for worsening disease. Once complete quiescence is achieved on all testing modalities, we usually follow patients every 6–12 months, depending on the clinical context. However, prospective investigations are ultimately needed to confirm these recommendations. Cohen et al: J Neuro-Ophthalmol 2023; 43: 481-490 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Patient 14: A 34-year-old man (diagnosed at age 27 years) with clinical Susac relapse consisting of headaches and encephalopathy, without vision changes, taking IVMP 1G and IVIG 0.4 g/kg every 3 weeks along with azathioprine 250 mg daily. Fluorescein angiography (FA) showed (A) persistent leakage in the far periphery from previous damage in addition to (B) new leakage inferonasally in the right eye with accompanying blockage in addition to trace leakage superior to the superior arcade and (C) new leakage along the inferotemporal arcade with accompanying blockage in the left eye. D. MRI brain showed stable periventricular T2 hyperintensities, and (E) audiogram demonstrated bilateral high-frequency sensorineural hearing loss in the setting of reportedly chronic hearing loss without subjective worsening. IVIG, intravenous immunoglobulin; IVMP, IV (intravenous) methylprednisolone. Our study supports the finding that persistent leakage on FA occurs in areas of previous arteriolar damage, particularly after BRAO and does not require treatment if it is not associated with visual field changes. Limitations Limitations of our study include its multicenter, retrospective design that precluded a standardized approach to testing at each visit and resulted in inhomogeneity of testing machines, protocols, and sequences. Each testing modality was not performed at every visit, thereby limiting our sensitivity analysis. There is inherent selection bias in that most patients underwent FA, whereas other modalities were performed in smaller percentages. FA is more sensitive than dilated fundus examination alone, so we believe that it should be performed as part of baseline and follow-up testing. We recognize that this might be uncommon practice in clinics with less access to FA, but it is an important diagnostic modality in patients with Susac syndrome. Cohen et al: J Neuro-Ophthalmol 2023; 43: 481-490 Different FA machines were used among the different sites included in our study (Optos, Spectralis), potentially resulting in imperfect comparison. Additional diagnostic modalities that may occasionally be useful (e.g., vestibular testing or MRI spine) were not included. Future prospective studies should standardize this process. In addition, only patients with the full triad of Susac syndrome were included, and therefore, some of these sensitivities may not apply to patients with the incomplete triad of Susac syndrome. Conclusions New leakage on FA was the most sensitive marker of active disease. However, persistent leakage in areas of previous damage is very common in Susac syndrome. It is therefore necessary to distinguish between old and new areas of FA leakage to accurately assess disease activity and the indication for adjustments to immunosuppressant therapy. A prospective investigation of FA in Susac syndrome is needed to confirm the significance of new asymptomatic leakage on FA in patients with Susac syndrome. 489 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution STATEMENT OF AUTHORSHIP Conception and design: D. A. Cohen, D. Tajfirouz, J. J. Chen, B. K. Chwalisz; Acquisition of data: D. A. Cohen, D. Tajfirouz, I. Vodopivec, K. Kyle, M. A. Bouffard, S. Bhattacharyya, V. C. Douglas, N. Rasool, M. T. Bhatti, A. McKeon, S. Pittock, E. P. Flanagan, S. Prasad, V. Nagagopal, R. A. Egan, J. J. Chen, B. K. Chwalisz; Analysis and interpretation of data: D. A. Cohen, J. J. Chen, B. K. Chwalisz. Drafting the manuscript: D. A. Cohen, J. J. Chen, B. K. Chwalisz; Revising the manuscript for intellectual content: D. A. Cohen, D. Tajfirouz, I. Vodopivec, K. Kyle, M. A. Bouffard, S. Bhattacharyya, V. C. Douglas, N. Rasool, M. T. Bhatti, A. McKeon, S. Pittock, E. P. Flanagan, S. Prasad, V. Nagagopal, R. A. Egan, J. J. Chen, B. K. Chwalisz. Final approval of the completed manuscript: D. A. Cohen, D. Tajfirouz, I. Vodopivec, K. Kyle, M. A. Bouffard, S. Bhattacharyya, V. C. Douglas, N. 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