Susac syndrome – A Portuguese experience

Mariana Portela; Vanda Nogueira; Marco Liverani; Luís Figueira; Jeniffer Jesus; Tiago Lorga; Margarida Baptista; Marta Guedes

doi:10.4103/pajo.pajo_57_22

ORIGINAL ARTICLE

Year : 2023 | Volume : 5 | Issue : 1 | Page : 1

Susac syndrome – A Portuguese experience

Mariana Portela¹, Vanda Nogueira², Marco Liverani³, Luís Figueira⁴, Jeniffer Jesus⁵, Tiago Lorga⁶, Margarida Baptista¹, Marta Guedes¹
¹ Department of Ophthalmology, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal
² Department of Ophthalmology, Instituto de Oftalmologia Gama Pinto, Lisbon, Portugal
³ Department of Ophthalmology, Hospital de Vila Franca de Xira, Lisbon, Portugal
⁴ Department of Ophthalmology, Centro Hospitalar Universitário de São João; Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Lisbon, Portugal
⁵ Department of Ophthalmology, Centro Hospitalar Entre Douro e Vouga, Lisbon, Portugal
⁶ Department of Neuroradiology, Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal

Date of Submission	11-Oct-2022
Date of Decision	15-Oct-2022
Date of Acceptance	17-Oct-2022
Date of Web Publication	19-Feb-2023

Correspondence Address:
Mariana Portela
Rua Da Junqueira 126, 1349-019 Lisbon
Portugal

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/pajo.pajo_57_22

Abstract

Introduction: Susac syndrome (SS) is characterized by microvascular occlusions in the brain, retina, and inner ear. Despite significant advances in understanding this disorder, it remains an under- and misdiagnosed entity in the clinical setting.
Methods: This study was retrospective review of clinical records.
Results: We present the cases of three young adults complaining of visual loss, hearing impairment, and headache. In all patients, the fundoscopy and fluorescein angiography revealed nonperfused arteriolar segments and multifocal arterial vasculitis. The brain magnetic resonance imaging demonstrated characteristic white matter brain lesions and the audiometry revealed low-frequency hearing loss. The diagnosis of SS was therefore established. We present and discuss the different treatment regimens applied and the course and outcomes of each case.
Conclusion: SS is a rare and complex disease with possibly severe consequences that must be promptly diagnosed and treated. However, as no prospective or randomized controlled trials exist, empirical treatment strategies are still the norm, mainly based on the case reports and series.

Keywords: Mycophenolate mofetil, retinal artery occlusion, rituximab, Susac syndrome

How to cite this article:
Portela M, Nogueira V, Liverani M, Figueira L, Jesus J, Lorga T, Baptista M, Guedes M. Susac syndrome – A Portuguese experience. Pan Am J Ophthalmol 2023;5:1

How to cite this URL:
Portela M, Nogueira V, Liverani M, Figueira L, Jesus J, Lorga T, Baptista M, Guedes M. Susac syndrome – A Portuguese experience. Pan Am J Ophthalmol [serial online] 2023 [cited 2023 Mar 26];5:1. Available from: https://www.thepajo.org/text.asp?2023/5/1/1/369996

Introduction

Susac syndrome (SS) is a rare microangiopathy characterized by microvascular occlusions in the brain, retina, and inner ear. While the exact pathophysiology remains unknown, an autoimmune-mediated endotheliopathy of small-to-medium-size vessels is presumed to be the underlying cause. It classically presents with a pathognomonic clinical triad, including visual disturbances due to branch retinal artery occlusions (BRAOs), sensorineural hearing loss, and encephalopathy mainly due to callosal lesions best seen on brain magnetic resonance imaging (MRI). This triad, however, is present in only 13% of patients at disease onset and may take up to 2 years to fully develop, leading to misdiagnosing and significant delay in treatment initiation.^[1]

Isolated cases of SS were first reported in 1973, but the term was only coined 6 years later, after Susac.^[2] Since then, fewer than 300 cases have been reported in the literature.^[3] There is a female preponderance with an estimated male: female ratio of about 1:3. The typical age at disease onset varies between 21 and 35 years.^[3] The syndrome can be empirically divided into three characteristic clinical courses: monocyclic, polycyclic, and chronic continuous. Most patients present with a fluctuating condition with remission intervals that self-limits itself after no more than 2 years (monocyclic course) or relapses beyond a 2 years (polycyclic course). A chronic continuous path with no remission phase is far less common (4%).

At the clinical onset, any of the three organs may be affected. The brain is commonly involved, and most patients present with headaches.^[4] Other central nervous system (CNS) symptoms such as impaired cognition and memory loss can develop later. At least half of the cases are characterized by visual disturbances as the first clinical manifestation, which varies among sudden reduction of visual acuity, photopsia, scintillating scotomas, or visual field defects, depending on the number and location of the affected retinal branches. Otolaryngological symptoms differ between hearing loss, mainly low-to-moderate frequencies, or jerk nystagmus, and can be unilateral or bilateral.

The diagnosis of SS is based on clinical presentation, laboratory tests, and ancillary studies such as MRI, fluorescein angiography (FA), and audiometry. Since the clinical triad is rarely complete at onset, many disorders are typically considered in the differential diagnosis.

Management guidelines are still lacking, and treatment choice is mainly based on case reports and case series results.^[5] It usually consists of corticosteroids and intravenous immunoglobulin (IVIG). Immunosuppressants, including mycophenolate mofetil (MMF), cyclophosphamide, methotrexate, and azathioprine, have been successfully used. Rituximab has recently been referred to as helpful, especially in refractory cases.^[6],[7]

Despite significant advances in understanding this disorder, it remains an under- and misdiagnosed entity in the clinical setting, consequently delaying appropriate treatment initiation.

Aim

Our work aimed to analyze the ophthalmic, clinical, and imaging signs of SS in three patients and to report our experience with the treatment. This study was retrospective and multicentric and included patients from three Portuguese hospitals. All patients have given informed consent to participate in this research.

Case series

Case one

A 30-year-old man was admitted to the emergency room, due to 3-day history of right eye (RE) temporal hemifield loss accompanied by right hearing loss and tinnitus. The ophthalmological examination showed a bilateral best-corrected visual acuity (BCVA) of 20/20. On RE fundoscopy, multiple paramacular retinal whitening areas were seen as consistent with BRAO [Figure 1]a. The FA of the RE revealed numerous arteriolar occlusions and nonperfused segments [Figure 1]b. Some arteriolar portions presented with a fluorescent wall and late-phase leakage. Brain MRI showed multiple hyperintense white matter lesions in T2 and fluid-attenuated inversion recovery sequences with predominant affection of the corpus callosum. An audiogram revealed right low-frequency hearing loss.

Figure 1: (a) Retinography of the RE showing multiple paramacular retinal whitening areas consistent with branch retinal artery occlusions. (b) Fluorescein angiography of the RE with numerous nonperfused arteriolar segments. RE = Right eye

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A diagnosis of SS was established, and the patient was started on intravenous (IV) methylprednisolone (1 g/day) for 3 days and hyperbaric oxygen followed by oral prednisolone (1 mg/kg) and cyclophosphamide (150 mg/day) with rapid fundoscopy and visual field improvement. Two weeks later, the patient returned to the ER with complaints of scintillating scotomas on the left eye (LE) and a numbness sensation on the face and mouth. The fundoscopy and a new FA revealed LE involvement with a superotemporal arteriolar occlusion [Figure 2]. The patient was again treated with IV methylprednisolone (1 g/day) for 3 days, followed by a single dose of rituximab (500 mg) which was repeated after 6 months. Six months later, a new brain MRI showed initial lesions to be smaller or absent, and 18 months later, the patient is still under rituximab maintenance therapy and relapse-free.

Figure 2: Retinography of the LE revealing a superotemporal arteriolar occlusion. LE = Left eye

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Case two

A 26-year-old woman presented to the ER with a 2-week history of vertigo, dizziness, and hearing loss. Her past medical history was unremarkable. A brain MRI showed multiple hyperintense foci in T2 sequences, some hypointense in T1, mainly affecting the corpus callosum but also the corona radiata, centrum semiovale, periventricular, and subcortical white matter of the frontal and parietal lobes [Figure 3]a and [Figure 3]b. The ophthalmological examination revealed a bilateral BCVA of 20/20, but with bilateral BRAO visible on fundoscopy and confirmed by FA. The patient was started on IV methylprednisolone (1 g/day) for 3 days, followed by MMF (3000 mg/day), and remained relapse-free for 4 years.

Figure 3: Brain MRI demonstrating multiple hyperintense lesions in the corpus callosum in sagital (a) and axial (b) planes. MRI = magnetic resonance imaging

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A sudden LE visual loss characterized her first SS recurrence. The LE fundoscopy revealed a new small superotemporal arteriolar branch occlusion, which the FA confirmed. In addition, the brain MRI showed an increase in the number of CNS lesions, mainly affecting the corpus callosum and the periventricular white matter of the frontal lobe. Treatment was reinitiated with IV methylprednisolone (1 g/day) for 3 days and IVIG (2 g/kg/day), followed by oral prednisolone (1 mg/kg), cyclophosphamide (150 mg/day), and IVIg (0.4 mg/kg/month). MMF was also reinitiated (3000 mg/day), and the patient remained relapse-free.

After another 4 years, new complaints of a sudden LE visual loss arose, accompanied by recent headaches. The ophthalmological examination demonstrated a bilateral BCVA of 20/20, but the fundoscopy revealed a new superonasal arteriolar branch occlusion with inferior macula edema confirmed by FA. This episode was assumed as a second SS recurrence, and the patient was restarted on IV methylprednisolone (1 g/day) for 3 days, followed by an oral tapering course of prednisolone (started at 1 mg/kg/day). The daily dose of MMF remained at 3000 mg.

Since then (4-year follow-up), the patient has had no more recurrences or new lesions in the brain MRI. She is being treated with MMF (3000 mg/day) and prednisolone (5 mg/every other day). A bilateral cochlear implant was also necessary due to severe hearing loss, and additional neurological findings developed, including cognitive dysfunction with memory loss, confusion, and decreased executive function.

Case three

A 24-year-old woman was admitted to the ER with a 2-day history of intense headaches and a LE scotoma. Apart from aphthous stomatitis, her medical history was unremarkable. However, when questioned, she also complained of hearing impairment over the previous years. Her ophthalmological examination showed a BCVA of 20/20 in both eyes, but the fundoscopy revealed areas of retinal whitening in the perimacular region of both eyes. The FA demonstrated fluorescein leakage in multiple arteriolar segments with abrupt flow interruption in some arterioles [Figure 4]a and [Figure 4]b. The optical coherence tomography showed thickening of the inner retina layers corresponding to the white paramacular areas consistent with acute retinal ischemia. It also showed areas of focal retinal atrophy, revealing previous episodes of retinal ischemia and supporting long-standing disease. The audiometry testing revealed a bilateral sensorineural hearing loss in the low-to-mid-tone range. The MRI brain scanning showed multiple areas of high signal in T2 in the corpus callosum, right centrum semiovale, and globi pallidi. SS was diagnosed, and on admission, she was started on 3 daily pulses of IV methylprednisolone (1 g/day) followed by tapering oral prednisolone started on 1 mg/kg, aspirin 100 mg, and IVIG 2 g/kg/month. The patient remained relapse-free.

Figure 4: (a) Retinography of both eyes showing an inferotemporal arteriolar branch occlusion of the RE and a superotemporal arteriolar branch occlusion of the LE. (b) Fluorescein angiography of both eyes revealed numerous arteriolar occlusions with nonperfused segments and segmental arteriolar wall hyperfluorescence. RE = Right eye; LE = Left eye

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Eight months later, she presented to the ER with a 2-week history of headaches and tinnitus. The audiometry showed a progression of her sensorineural hearing loss, and the FA demonstrated new areas of arterial occlusive vasculitis in both eyes. As a result, the patient was restarted on IV methylprednisolone (1 g/day) for 3 days, followed by oral prednisolone (1 mg/kg). In addition, MMF (2000 mg/day) was started as a steroid-sparing agent with a rapid symptomatic improvement.

After a 6-year follow-up, the patient is still under maintenance therapy with MMF (2000 mg/day) and relapse-free.

Discussion

There is still no consensus regarding the optimal treatment for SS, particularly in refractory or relapsing disease, as there are no prospective or randomized controlled trials on this matter. Furthermore, as the organs affected are easily and irreversibly injured, this condition must be quickly and entirely suppressed, preferably before the development of the complete clinical triad. Empirical treatment regimens are based on the hypothesis of an autoimmune inflammatory etiology.^[8],[9] According to the literature, many different treatment strategies have been proposed with variable success rates, including corticosteroids, IVIG, cyclophosphamide, MMF, azathioprine, and methotrexate.^[5],[9] Biologic agents were first used for refractory SS in the mid-2000s, and agents such as rituximab^[10],[11] and infliximab^[12] may play an essential role in the setting of refractory disease.

In our sample, IV methylprednisolone and oral prednisolone were started in all cases. In addition, patient one was treated with hyperbaric oxygen, cyclophosphamide, and rituximab; in case two, we also used cyclophosphamide, IVIg, and MMF; and patient three was also given aspirin, IVIg, and MMF.

Corticosteroids and IVIg are strongly recommended when treating a patient with SS.^[5] In addition, other immunosuppressants such as MMF or rituximab should be considered if relapses are observed. Cyclophosphamide may be added if the previous treatment fails.^[5]

In SS, the occlusive retinal lesions lead to hypoxic environments, which cause toxin accumulation and tissue damage. The hyperbaric oxygen counterbalances the retina and reduced oxygen levels, resulting in less destruction, and has therefore been used in some cases of visual loss related to SS.^[13] It was first mentioned by Li et al.,^[13] who reported a case of a young woman with effective posttreatment visual acuity and visual field improvement. It was also suggested by Meca-Lallana et al.,^[14] who documented a case of a young woman that showed improved ophthalmological symptoms and no visual sequelae after hyperbaric oxygen. In our sample, case one was given hyperbaric oxygen on diagnosis with substantial visual field and fundoscopy improvement.

MMF is a prodrug of mycophenolic acid which depletes guanosine nucleotides preferentially in T and B lymphocytes, inhibiting their proliferation. It thereby suppresses cell-mediated immune responses and antibody formation.^[15] Various treatment approaches for SS, including MMF, have been reported in the literature.^[9] In case three, on the diagnosis of SS, the treatment was started with steroids and IVIg, which rapidly improved the clinical situation. However, it was only after the introduction of MMF that we observed no more relapses in a 6-year follow-up. On the other hand, case one was also treated with MMF from the start but had two relapses, one on a higher dose of MMF (3000 mg/day).

Rituximab is a chimeric anti-CD20 monoclonal antibody originally developed to treat B-cell non-Hodgkin's lymphoma and is now used to treat multiple autoimmune diseases. The pathogenesis of SS remains uncertain, but recently, antiendothelial cell antibodies (AECAs) have been associated with SS and postulated as a possible disease biomarker.^[8] Rituximab eliminates autoantibody-producing plasma cell precursors and suppresses autoantigen presentation to CD4 T-cells, which may, in this syndrome, block the pathogenic action of AECAs.^[16] Different treatment regimens with rituximab have been suggested and administered for SS patients with different outcomes. In one case, it was introduced to treat a relapse along with MMF with rapid delirium recovery and partial regression of brain lesions on MRI.^[17] In another case of a SS relapse during pregnancy, rituximab was introduced after induced delivery, along with cyclophosphamide, IVIG, and tapered oral prednisolone, which led to mental status, gait improvement, and no relapses over a 1.5-year follow-up.^[10] Furthermore, among two patients who received rituximab as first-line therapy, only one needed additional treatment with azathioprine due to severe sensorineural hearing loss.^[6],[7] In our sample, patient 1 was treated with rituximab. It was only started after one disease relapse, and the patient was kept under maintenance therapy for a long time. We report a reasonably positive outcome in this case with no relapses after starting this drug. Because SS is a severe disease with an unpredictable course, choosing rituximab to treat refractory disease, or even as first-line therapy along with steroids, may be a reasonable decision to wholly and rapidly suppress the course of the disease, preventing further complications and relapses.

Conclusion

SS is a rare and complex disease with possibly severe consequences that must be promptly diagnosed and treated. A high index of suspicion is needed to recognize this condition, and a close follow-up is necessary to detect relapses and adjust therapy. Due to the rarity of this disorder, empirical treatment strategies are still the norm as no prospective or randomized controlled trials exist and an individual approach is recommended.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Pawate S, Agarwal A, Moses H, Sriram S. The spectrum of Susac's syndrome. Neurol Sci 2009;30:59-64.
2.	Susac JO. Susac's syndrome: The triad of microangiopathy of the brain and retina with hearing loss in young women. Neurology 1994;44:591-3.
3.	Dörr J, Krautwald S, Wildemann B, Jarius S, Ringelstein M, Duning T, et al. Characteristics of Susac syndrome: A review of all reported cases. Nat Rev Neurol 2013;9:307-16.
4.	Gross M, Eliashar R. Update on Susac's syndrome. Curr Opin Neurol 2005;18:311-4.
5.	Egan RA. Diagnostic criteria and treatment algorithm for Susac syndrome. J Neuroophthalmol 2019;39:60-7.
6.	Gertner E, Rosenbloom MH. Susac syndrome with prominent dermatological findings and a prompt response to intravenous immunoglobulin, steroids, and rituximab: A case report. J Med Case Rep 2016;10:137.
7.	Monferrer-Adsuara C, Remolí-Sargues L, Hernández-Bel L, Gracia-García A, Hernández-Garfella ML, Cervera-Taulet E. Rituximab in the treatment of Susac's syndrome: Report of a case. Eur J Ophthalmol 2021;31:NP48-52.
8.	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;136:903-12.
9.	Dörr J, Radbruch H, Bock M, Wuerfel J, Brüggemann A, Wandinger KP, et al. Encephalopathy, visual disturbance and hearing loss-recognizing the symptoms of Susac syndrome. Nat Rev Neurol 2009;5:683-8.
10.	Deane KD, Tyler KN, Johnson DW, Tanabe JL, Oskarrson BE, Nitka EE, et al. Susac syndrome and pregnancy: Disease management. J Clin Rheumatol 2011;17:83-8.
11.	Mateen FJ, Zubkov AY, Muralidharan R, Fugate JE, Rodriguez FJ, Winters JL, et al. Susac syndrome: Clinical characteristics and treatment in 29 new cases. Eur J Neurol 2012;19:800-11.
12.	Fernando SL, Boyle T, Smith A, Parratt JD. The successful use of infliximab in a relapsing case of Susac's syndrome. Case Rep Neurol Med 2020;2020:9317232.
13.	Li HK, Dejean BJ, Tang RA. Reversal of visual loss with hyperbaric oxygen treatment in a patient with Susac syndrome. Ophthalmology 1996;103:2091-8.
14.	Meca-Lallana JE, Martín JJ, Lucas C, Marín J, Gomariz J, Valenti JA, et al. Susac syndrome: Clinical and diagnostic approach. A new case report. Rev Neurol 1999;29:1027-32.
15.	Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus 2005;14 Suppl 1:s2-8.
16.	Gross CC, Meyer C, Bhatia U, Yshii L, Kleffner I, Bauer J, et al. CD8+T cell-mediated endotheliopathy is a targetable mechanism of neuro-inflammation in Susac syndrome. Nat Commun 2019;10:5779.
17.	Betend R, Humm AM, Medlin F. Delirium as presentation of late-onset and relapsing Susac syndrome. BMJ Case Rep 2017;2017:bcr2017220494.