Short Follow-up Bias Confounds Estimates of the "Typical" Clinical Course of Susac Syndrome

Aneurysmal volume expansion after endovascular treatment is caused by intra-aneurysmal thrombosis in the early postembolization period. Although postembolization mass effect on cranial nerves and other adjacent structures has been previously reported, we are unaware of reports involving the anterior visual pathway. A 66-year-old woman with a 2-week history of blurred vision without headache was found to have a large, unruptured anterior communicating artery aneurysm. One month after endovascular treatment of the aneurysm with coiling and flow diversion, the patient developed decreased vision in her right eye and a left homonymous hemianopia. Magnetic resonance imaging demonstrated compression of the right optic nerve, chiasm, and edema of the right optic tract. The patient was treated with a course of high dose corticosteroids, and over the course of several weeks, her vision improved and the optic tract edema resolved. We alert clinicians to this rare but potentially reversible visual complication of endovascular treatment of intracranial aneurysms.

Original Contribution Short Follow-up Bias Confounds Estimates of the "Typical" Clinical Course of Susac Syndrome Ivana Vodopivec, MD, PhD, Sashank Prasad, MD Background: To evaluate the validity of the prevailing concept that Susac syndrome (SS), a rare microvasculopathy of the brain, retina, and inner ear, is a self-limiting disease. Methods: We performed a literature search to identify all cases of SS reported between 1973 and October 2015. If available, we determined their demographics, duration of follow-up, and the clinical course that was labeled as monocyclic or polycyclic. We attempted to determine the number of relapses and the relapse rate in patients with polycyclic disease. Results: Our literature search yielded 185 relevant publications reporting 405 cases of SS. The duration of followup could be determined in 247/405 cases, with a range 0.5-312 months. The mean was 41 months but the distribution was skewed, with a median of 24 months. Defining the clinical course as monocyclic or polycyclic was possible in 102 patients who were followed for greater than 24 months; 53 were identified as having a polycyclic course. Patients labeled polycyclic were followed longer than those labeled monocyclic (median 62 vs 42 months, P , 0.001). The number or frequency of attacks per patient could not be determined. Conclusions: The follow-up of published cases of SS is short, creating an inherent bias toward the impression that the disease is self-limiting. Our findings suggest that stratification of SS into monocyclic, polycyclic, and chronic continuous courses may oversimplify the phenotype of SS; instead, the possibility of a relapsing-remitting course must be considered in all patients with this disorder. Journal of Neuro-Ophthalmology 2017;37:149-153 doi: 10.1097/WNO.0000000000000472 © 2016 by North American Neuro-Ophthalmology Society Department of Neurology (IV, SP), Brigham and Women's Hospital, Boston, MA; and Department of Neurology (IV, SP), Harvard Medical School, Boston, MA. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www.jneuro-ophthalmology.com). Address correspondence to Ivana Vodopivec, MD, PhD, Department of Neurology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115; E-mail: [e-mail] Vodopivec and Prasad: J Neuro-Ophthalmol 2017; 37: 149-153 S usac syndrome (SS) is a rare microvasculopathy characterized by retinal, brain, and cochlear involvement. Most often, this triad is not complete at presentation. The disease has been broadly characterized as having a monocyclic, polycyclic, or chronic continuous course. A monocyclic course is considered most common and it is frequently reported that the condition tends to show spontaneous resolution after 1-2 years (1,2). We sought to assess the validity of these assumptions. METHODS We collected all reported cases of SS published between 1973 and October 2015 by searching PubMed/MEDLINE and Google Scholar with the following terms: "Susac syndrome," "branch retinal artery occlusions" (BRAOs), and "recurrent BRAOs". We complemented the search by referencing the lists of publications compiled by Dörr et al (2), which is the largest retrospective review of SS, spanning publications from 1973 to December 2012, and by Johnson et al (3), which identified additional case reports of isolated recurrent BRAOs. The inclusion criterion was the final diagnosis of SS, which required that the report clearly described BRAOs and hyperfluorescence of vessel walls on fluorescein angiography (FA) that were associated with central nervous system (CNS) manifestations and/or vestibulocochlear impairment (1,2). The diagnosis was not established if clinical, laboratory (e.g., positive antiphospholipid antibodies), or neuroimaging features suggested an alternative diagnosis to SS. We also evaluated cases of reportedly isolated idiopathic recurrent BRAOs to assess whether additional clinical manifestations were present to suggest a diagnosis of SS (1,2). These articles were excluded by Dörr et al (2) because the authors suspected that this syndrome may represent a separate clinical entity, but we chose to evaluate the clinical features of these reported cases to judge if they met our inclusion criteria. Exclusion criteria included duplicate reports of a single case in multiple publications, lack of demographic and/or clinical data on individual patients, and cases in which the diagnosis was uncertain based on the aforementioned criteria. 149 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Flowchart showing the selection process for Susac syndrome (SS) publications (A) and analysis of follow-up time in cases with confirmed SS (B). Where it was possible, we identified or calculated the duration of follow-up for each published case. For cases in which the length of follow-up exceeded 24 months, we recorded the reported classification as monocyclic, polycyclic, or chronic continuous (2,4). A monocyclic course was defined as the cessation of clinical relapses after a period of 24 months after the initial symptoms (2,4). We compared the reported duration of follow-up for the monocyclic and polycyclic groups of patients using the Mann-Whitney U test. We analyzed all reports of patients with a polycyclic course to attempt to determine the number and frequency of relapses per patient. 150 RESULTS The search retrieved 297 reports (Fig. 1A). Twenty-six publications were identified by the search but were not actually related to SS and were excluded. Eighteen publications were unavailable to us; of these, 17 (including 15 conference abstracts) had been included by Dörr et al (2). Fifty-one publications were excluded because they did not present original cases. Seventeen publications were excluded because of diagnostic uncertainty; of these, 4 were case reports included in analysis by Dörr et al (2,5-8). These Vodopivec and Prasad: J Neuro-Ophthalmol 2017; 37: 149-153 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Histogram showing individual follow-up periods in 247 cases of Susac syndrome. The distribution is positively skewed, with a mean (6SD) of 41 6 52 months, and a median of 24 months. Each column represents number of patients per a 2-month interval. cases either did not have BRAOs with hyperfluorescence of vessel walls on FA or had an alternative diagnosis, such as Behçet's disease or antiphospholipid syndrome. For the final review, we included 184 journal publications and 1 conference abstract, which comprised 155 reports in English, 9 in German, 13 in French, 5 in Spanish, 1 in Portuguese, 1 in FIG. 3. Length of follow-up in cases of Susac syndrome with a polycyclic and a monocyclic course. Only cases with follow-up greater than 24 months are shown. The median follow-up time, marked with the horizontal lines, was 62 months in the polycyclic group (N = 53) and 42 months in the monocyclic group (N = 49). ***indicates a P , 0.001 comparing the 2 groups. Vodopivec and Prasad: J Neuro-Ophthalmol 2017; 37: 149-153 Hungarian, and 1 in Chinese (Fig. 1A). Forty-five of these articles were published after the review by Dörr et al, between December 2012 and October 2015. The 185 reports included in our study encompassed a total of 419 individual cases (Fig. 1B). Of these, we excluded 14 from our analysis because they did not meet our prespecified criteria for the diagnosis of SS. Case No 1 was excluded from the series by Pfaffenbach and Hollenhorst (9) because the clinical features were suggestive of systemic lupus erythematosus rather than SS and FA was not available. Case No 2 in the series by Kalisa et al (10) was excluded as the patient had a single isolated BRAO without other FA abnormalities, vestibulocochlear dysfunction, or abnormalities on brain MRI and was, therefore, excluded. Cases Nos 7, 11, 21, 25, and 27 in the series by Mateen et al (11) were excluded as they had no visual symptoms and neither their funduscopic examination nor FA findings were reported. We identified a total of 23 cases of reportedly isolated idiopathic recurrent BRAOs in 9 publications (3,12-19). Sixteen of these cases met our predefined criteria for the diagnosis of SS as they not only had BRAOs, but also at least one other reported symptom indicative of neurological or vestibulocochlear dysfunction. Seven of the excluded cases consisted of truly isolated idiopathic recurrent BRAOs (3,12,14,18), but even in these cases it was not evident that the diagnostic evaluation sufficiently excluded CNS and vestibulocochlear abnormalities over the course of the disease. The 405 individual cases of SS included in our review are compiled in Supplemental Digital Content (see Table E1, http://links.lww.com/WNO/A214). For the purpose of follow-up analysis, we eliminated all case series that reported the group range of follow-up time, rather than follow-up time for each individual patient (20- 25). The duration of follow-up was determined in 247 cases 151 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution and ranged from 0.5 to 312 months. The distribution was skewed; the mean duration (6SD) was 41 6 52 months, whereas the median duration was 24 months (Fig. 2). One hundred-two of the 247 reported cases included a description of the clinical course beyond 24 months from initial symptoms (Fig. 1B). Of these, 53 cases were classified as polycyclic and 49 cases were classified as monocyclic. The patients labeled as having a polycyclic course were followed longer (median 62 months) than the patients with a monocyclic course (median 42 months, P , 0.001; Fig. 3). There was scant evidence to support a chronic continuous subtype of SS. Among the 53 patients with a polycyclic course, there was a single case described with a chronic continuous course with steroid dependence (26). The course may possibly be characterized as chronic continuous in another patient, Case No 3 in the report by Bernard et al (27), where the authors reported that "the disease had a progressive course for the next 5 years." The exact clinical trajectory was not made clear. In 3 patients characterized as chronic continuous by Dörr et al (2), we could not confirm the actual clinical course, either because the original publications reported incomplete information (28,29), or the followup was limited to less than 24 months and additional therapy was introduced at the end of the follow-up period (30). Twenty patients were followed for 10 or more years; in 3 of these, the clinical course was unclear (11,31), but in 15 of the remaining 17 (88%), the course was polycyclic. Of note, relapses in these patients occurred up to 23 years after the disease onset (32). In 7 patients, the interval between relapses was 10 years or longer (18,32-37). Insufficient and vague information (for example, "multiple recurrent BRAOs" (38), "she continued to have one or 2 exacerbations per year" (39)) did not permit calculation of the total number and frequency of relapses among patients with SS. DISCUSSION It has been 43 years since the initial reports (9,40) of the rare condition that is now called SS (1). The goal of our study was to assess the validity of commonly accepted concepts about the clinical course of SS, within the limitations of analysis restricted to case reports, including publication bias toward cases with a severe and protracted course. By identifying and analyzing 405 reported cases of this disease, we have been able to make several observations. Our first major finding is that the distribution of followup time in reported cases of SS is skewed, with most cases having short follow-up. This asymmetry necessarily produces a discrepancy between the mean and the median. Although the large case series by Dörr et al (2) reported that the mean follow-up time (6SD) was 41 6 46 months, the median follow-up time was not reported. In our analysis of all reported cases of SS, we found that the median follow-up was only 24 months. It is critical to acknowledge the bias toward short follow-up in the existing literature, because it 152 invalidates conclusions that the disease is typically monocyclic and remits within 24 months. Second, only 102 of the 405 patients had follow-up that extended beyond 24 months and a clinical course that was sufficiently described to allow classification as monocyclic or polycyclic. As expected, patients with a relapsing (polycyclic) course beyond 24 months were followed longer than those reported to have a monocyclic course. Seven cases showed an interrelapse period of a decade or longer, suggesting that the follow-up of reportedly monocyclic cases is frequently terminated prematurely. Among patients with reported follow-up for more than 10 years, the majority had relapses indicative of a polycyclic course. Third, based on our retrospective analysis, we did not find sufficient information to determine the number and frequency of relapses per patient. Adding to this challenge is the lack of accepted definitions for an attack duration or interrelapse period. Occurrence of new symptoms a few months from the onset of initial symptoms may reflect uninterrupted disease activity rather than a separate attack. Conversely, some attacks, including those in the retina, may be asymptomatic (2) and, therefore, the true relapse rate may be underreported. In summary, we objectively assessed the assumption that SS is a self-limiting disease and found that short follow-up bias in reported cases confounds a true estimation of the disease course. After early reports had suggested that the condition typically has a 1-2 year course (1), subsequent reports and reviews (22,41) have frequently perpetuated this notion, despite a lack of sufficient follow-up time to judge its veracity. Our analysis suggests that, in contrast, it is prudent to assume that the disease has a high probability of being relapsing-remitting. This concept abandons the proposed stratification of SS into distinct monocyclic, polycyclic, and chronic continuous courses. Furthermore, it raises questions about current recommendations for duration of treatment and implies that lifelong follow-up should be considered. A multicenter patient registry with long-term follow-up at regular intervals is necessary to determine the true clinical course and risk of relapses in patients with SS (42,43). STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: I. Vodopivec and S. Prasad; b. Acquisition of data: I. Vodopivec and S. Prasad; c. Analysis and interpretation: I. Vodopivec and S. Prasad. Category 2: a. Drafting the manuscript: I. Vodopivec and S. Prasad; b. Revising the manuscript for intellectual content: I. Vodopivec and S. Prasad. Category 3: a. Final approval of the completed manuscript: I. Vodopivec and S. Prasad. ACKNOWLEDGMENTS The authors thank Stephanie Friree from Massachusetts Eye and Ear Infirmary Library and Judy Walls from Brigham & Women's Hospital Library for aid in acquiring the full text of articles. Vodopivec and Prasad: J Neuro-Ophthalmol 2017; 37: 149-153 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution REFERENCES 1. Susac JO. Susac's syndrome: the triad of microangiopathy of the brain and retina with hearing loss in young women. Neurology. 1994;44:591-593. 2. Dorr J, Krautwald S, Wildemann B, Jarius S, Ringelstein M, Duning T, Aktas O, Ringelstein EB, Paul F, Kleffner I. Characteristics of Susac syndrome: a review of all reported cases. Nat Rev Neurol. 2013;9:307-316. 3. Johnson MW, Thomley ML, Huang SS, Gass JD. Idiopathic recurrent branch retinal arterial occlusion. Natural history and laboratory evaluation. Ophthalmology. 1994;101:480-489. 4. Rennebohm RM, Susac JO. Treatment of Susac's syndrome. J Neurol Sci. 2007;257:215-220. 5. Matamoros N, BenEzra D. Bilateral retinopathy and encephalopathy. Graefes Arch Clin Exp Ophthalmol. 1989;227:39-41. 6. Sbai A, Wechsler B, Papo T, Godeau P, Piette JC. Aphthous ulcers have their secrets. [in French]. Rev Med Interne. 2001;22(suppl 2):227s-229s. 7. Bucciarelli S, Cervera R, Martinez M, Latorre X, Font J. Susac's syndrome or catastrophic antiphospholipid syndrome? Lupus. 2004;13:607-608. 8. Assuras S, Lacy M. Psychiatric presentation in possible Susac's syndrome. J Neuropsychiatry Clin Neurosci. 2011;23:E30. 9. Pfaffenbach DD, Hollenhorst RW. Microangiopathy of the retinal arterioles. JAMA. 1973;225:480-483. 10. Kalisa P, Constantinides G, Bodson-Halleux M, De Laey JJ. Small infarctions of cochlear, retinal and encephalic tissue (SICRET syndrome). Bull Soc Belge Ophtalmol. 2001;282:5-12. 11. Mateen FJ, Zubkov AY, Muralidharan R, Fugate JE, Rodriguez FJ, Winters JL, Petty GW. Susac syndrome: clinical characteristics and treatment in 29 new cases. Eur J Neurol. 2012;19:800-811. 12. Gass JD, Tiedeman J, Thomas MA. Idiopathic recurrent branch retinal arterial occlusion. Ophthalmology. 1986;93:1148-1157. 13. Johnson MW, Flynn HW Jr, Gass JD. Idiopathic recurrent branch retinal arterial occlusion. Arch Ophthalmol. 1989;107:757. 14. Capone A Jr, Meredith TA. Profound central visual loss and ocular neovascularization in idiopathic recurrent branch retinal arterial occlusion. Retina. 1990;10:265-268. 15. Barak N, Ferencz JR, Freund M, Mekori Y. Urticaria in idiopathic bilateral recurrent branch retinal arterial occlusion. Acta Ophthalmol Scand. 1997;75:107-108. 16. Beversdorf D, Stommel E, Allen C, Stevens R, Lessell S. Recurrent branch retinal infarcts in association with migraine. Headache. 1997;37:396-399. 17. Trevino R, Pearlman R. Idiopathic recurrent branch retinal arterial occlusion in a young adult. Optom Vis Sci. 1998;75:11-16. 18. Egan RA, Hills WL, Susac JO. Gass plaques and fluorescein leakage in Susac syndrome. J Neurol Sci. 2010;299:97-100. 19. Seamone ME, Fielden M. A case of isolated Susac occlusive retinal vasculitis. J Neuroophthalmol. 2013;33:260-262. 20. Aubart-Cohen F, Klein I, Alexandra JF, Bodaghi B, Doan S, Fardeau C, Lavallée P, Piette JC, Hoang PL, Papo T. Long-term outcome in Susac syndrome. Medicine (Baltimore). 2007;86:93-102. 21. Martinet N, Fardeau C, Adam R, Bodaghi B, Papo T, Piette JC, Lehoang P. Fluorescein and indocyanine green angiographies in Susac syndrome. Retina. 2007;27:1238-1242. 22. Magro CM, Poe JC, Lubow M, Susac JO. Susac syndrome: an organ-specific autoimmune endotheliopathy syndrome associated with anti-endothelial cell antibodies. Am J Clin Pathol. 2011;136:903-912. 23. Wuerfel J, Sinnecker T, Ringelstein EB, Jarius S, Schwindt W, Niendorf T, Paul F, Kleffner I, Dorr J. Lesion morphology at 7 Tesla MRI differentiates Susac syndrome from multiple sclerosis. Mult Scler. 2012;18:1592-1599. 24. Jarius S, Kleffner I, Dörr JM, Sastre-Garriga J, Illes Z, Eggenberger E, Chalk C, Ringelstein M, Aktas O, Montalban X, Vodopivec and Prasad: J Neuro-Ophthalmol 2017; 37: 149-153 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. Fechner K, Stöcker W, Ringelstein EB, Paul F, Wildemann B. Clinical, paraclinical and serological findings in Susac syndrome: an international multicenter study. J Neuroinflammation. 2014;11:46. Ringelstein M, Albrecht P, Kleffner I, Buhn B, Harmel J, Muller AK, Finis D, Guthoff R, Bergholz R, Duning T, Kramer M, Paul F, Brandt A, Oberwahrenbrock T, Mikolajczak J, Wildemann B, Jarius S, Hartung HP, Aktas O, Dorr J. Retinal pathology in Susac syndrome detected by spectral-domain optical coherence tomography. Neurology. 2015;85:610- 618. Finis D, Stammen J, Gonnermann J. Retinal arteritis in pregnancy [in German]. Ophthalmologe. 2011;108:676- 682. Bernard JT, Romero R, Agrawal K, Jager R, Rezania K. Optical coherence tomography in Susac's syndrome. Mult Scler Relat Disord. 2014;3:110-116. Delaney WV Jr, Torrisi PF. Occlusive retinal vascular disease and deafness. Am J Ophthalmol. 1976;82:232-236. Vila N, Graus F, Blesa R, Santamaria J, Ribalta T, Tolosa E. Microangiopathy of the brain and retina (Susac's syndrome): two patients with atypical features. Neurology. 1995;45:1225-1226. Saux A, Niango G, Charif M, Morales R, Mura F, Bonafe A, Mourand I. Susac's syndrome, a rare, potentially severe or lethal neurological disease. J Neurol Sci. 2010;297:71- 73. Brandt AU, Zimmermann H, Kaufhold F, Promesberger J, Schippling S, Finis D, Aktas O, Geis C, Ringelstein M, Ringelstein EB, Hartung HP, Paul F, Kleffner I, Dorr J. Patterns of retinal damage facilitate differential diagnosis between Susac syndrome and MS. PLoS One. 2012;7: e38741. Feresiadou A, Eriksson U, Larsen HC, Raininko R, Nygren I, Melberg A. Recurrence of susac syndrome following 23 years of remission. Case Rep Neurol. 2014;6:171-175. Robles-Cedeno R, Ramio-Torrenta L, Laguillo G, Gich J, Castellanos M. Long-term clinical and radiological evolution in one case of Susac's syndrome. Neurol Sci. 2012;33:1407- 1410. Karelle S, Demanez L, Zangerle PF, Blaise P, Moonen G, Poirrier AL. Sudden sensorineural hearing loss: when ophthalmology meets otolaryngology. B-ENT. 2012;8:135-139. Pawate S, Agarwal A, Moses H, Sriram S. The spectrum of Susac's syndrome. Neurol Sci. 2009;30:59-64. Skacel M, Bardy FB, Pereira MB, Mendes MH. Susacs syndrome: case report [in Portuguese]. Arq Neuropsiquiatr. 2000;58:1128-1132. Petty GW, Matteson EL, Younge BR, McDonald TJ, Wood CP. Recurrence of Susac syndrome (retinocochleocerebral vasculopathy) after remission of 18 years. Mayo Clin Proc. 2001;76:958-960. Li HK, Dejean BJ, Tang RA. Reversal of visual loss with hyperbaric oxygen treatment in a patient with Susac syndrome. Ophthalmology. 1996;103:2091-2098. Nicolle MW, McLachlan RS. Microangiopathy with retinopathy, encephalopathy, and deafness (RED-M) and systemic features. Semin Arthritis Rheum. 1991;21:123-128. Weidauer H, Tenner A. Bilateral acute hearing loss with transient occlusion of a branch of the retinal artery on both sides [in German]. Z Laryngol Rhinol Otol. 1973;52:121-128. Rennebohm RM, Egan RA, Susac JO. Treatment of Susac's syndrome. Curr Treat Options Neurol. 2008;10:67-74. Diseases and Conditions: Susac Syndrome. Available at: http://my.clevelandclinic.org/health/diseases_conditions/ susac-syndrome. Accessed August 2, 2016. Blankshain KD, Moss HE. Research registries: a tool to advance understanding of rare neuro-ophthalmic diseases. J Neuroophthalmol. 2016;26:317-323. 153 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.