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Clinical features, diagnostic findings, and treatment of Susac syndrome: A case series

  • Ivana Vodopivec
    Correspondence
    Corresponding author at: Massachusetts General Hospital, Department of Neurology, 15 Parkman Street, Boston, MA 02114, United States.
    Affiliations
    Harvard Medical School, Boston, MA, United States

    Massachusetts General Hospital, Department of Neurology, 15 Parkman Street, Boston, MA 02114, United States

    Massachusetts Eye and Ear Infirmary, Neuro-Ophthalmology Service, 243 Charles St., Boston, MA 02114, United States
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  • Nagagopal Venna
    Affiliations
    Harvard Medical School, Boston, MA, United States

    Brigham and Women's Hospital, Department of Neurology, 75 Francis Street, Boston, MA 02115, United States
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  • Joseph F. Rizzo III
    Affiliations
    Harvard Medical School, Boston, MA, United States

    Massachusetts Eye and Ear Infirmary, Neuro-Ophthalmology Service, 243 Charles St., Boston, MA 02114, United States
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  • Sashank Prasad
    Affiliations
    Harvard Medical School, Boston, MA, United States

    Brigham and Women's Hospital, Department of Neurology, 75 Francis Street, Boston, MA 02115, United States
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      Highlights

      • Delayed diagnosis of Susac syndrome (SS) is common.
      • Callosal “snowball” lesions and T1 “holes” are not requisites for the diagnosis.
      • Brain MRI DWI and FA may be used to identify patients with active disease.
      • FA may have higher sensitivity for disease activity in its subacute stages.
      • Treatment with glucocorticoids and/or IVIg alone may be insufficient.

      Abstract

      Background

      Susac syndrome (SS) is a rare, presumed autoimmune condition characterized by the clinical triad of branch retinal artery occlusions (BRAOs), encephalopathy, and sensorineural hearing loss. The aim of this study was to evaluate clinical features, diagnostic results, treatment, and outcomes in SS.

      Methods

      Five patients with SS were referred to three tertiary care centers in Boston. The observation period across these patients was 7–57 months.

      Results

      At initial presentation, none of the patients demonstrated the complete triad of BRAO, sensorineural hearing loss, and encephalopathy. The interval between symptom onset and diagnosis of SS was 4–30 weeks.
      Brain MRI findings thought to be characteristic of SS (including callosal fluid-attenuated inversion recovery (FLAIR) hyperintense and T1 hypointense lesions) were frequently absent. Microinfarcts noted on diffusion-weighted imaging (DWI), BRAOs and vessel wall hyperfluorescence on fluorescein angiography (FA) were present in all cases in the acute encephalopathic phase.
      All patients treated with glucocorticoids and intravenous immunoglobulins (IVIg) alone experienced further clinical progression until additional immunosuppressive therapy was instituted.

      Conclusions

      The rarity of SS, its incomplete and variable presentation, and the nonspecific imaging findings invariably led to delayed diagnosis. DWI and FA should be used to identify the acute microvascular injury and monitor treatment response. Immunomodulatory agents more potent than glucocorticoids and IVIg might be required to control the disease.

      Abbreviations:

      SS (Susac syndrome), BRAOs (branch retinal artery occlusions), CNS (central nervous system), CSI (callosal–septal interface), FLAIR (fluid-attenuated inversion recovery), DWI (diffusion-weighted imaging), ADC (apparent diffusion coefficient), FA (fluorescein angiography), AECA (anti-endothelial cell antibodies), OCB (oligoclonal bands), ADEM (acute disseminated encephalomyelitis), MS (multiple sclerosis), IVIg (intravenous immunoglobulins), CYC (cyclophosphamide), MTX (methotrexate), MMF (mycophenolate mofetil), RTX (rituximab)

      Keywords

      1. Introduction

      Susac syndrome (SS) is a rare disease associated with microvascular occlusions in the retina, brain, and inner ear [
      • Dörr J.
      • Krautwald S.
      • Wildemann B.
      • Jarius S.
      • Ringelstein M.
      • Duning T.
      • et al.
      Characteristics of Susac syndrome: a review of all reported cases.
      ]. These occlusions result in the typical clinical triad of visual disturbances, encephalopathy and other manifestations of central nervous system (CNS) involvement, and inner ear dysfunction that can include deafness and vestibulopathy. First described in 1973 [
      • Pfaffenbach D.D.
      • Hollenhorst R.W.
      Microangiopathy of the retinal arterioles.
      ,
      • Weidauer H.
      • Tenner A.
      Bilateral acute hearing loss with transient occlusion of a branch of the retinal artery on both sides.
      ], more than 330 cases have now been reported [
      • Dörr J.
      • Krautwald S.
      • Wildemann B.
      • Jarius S.
      • Ringelstein M.
      • Duning T.
      • et al.
      Characteristics of Susac syndrome: a review of all reported cases.
      ,
      • Jarius S.
      • Kleffner I.
      • Dörr J.M.
      • Sastre-Garriga J.
      • Illes Z.
      • Eggenberger E.
      • et al.
      Clinical, paraclinical and serological findings in Susac syndrome: an international multicenter study.
      ]. Characteristic findings include branch retinal artery occlusions (BRAOs) sometimes in association with retinal arterial wall plaques at midarteriolar segments [
      • Egan R.A.
      • Ha Nguyen T.
      • Gass J.D.
      • Rizzo J.F.
      • Tivnan J.
      • Susac J.O.
      Retinal arterial wall plaques in Susac syndrome.
      ] and vessel wall hyperfluorescence on fluorescein angiography (FA), central callosal lesions evident on brain MRI, and sensorineural hearing loss detected on audiometry. Retinal arteriopathy alone or in combination with CNS or inner ear involvement represents a limited form of SS.
      In addition to the clinical features of SS, MRI imaging is often instrumental in establishing the diagnosis. Identifying specific, robust, and objective imaging markers for SS has long been of interest [
      • Susac J.O.
      • Murtagh F.R.
      • Egan R.A.
      • Berger J.R.
      • Bakshi R.
      • Lincoff N.
      • et al.
      MRI findings in Susac's syndrome.
      ,
      • White M.L.
      • Zhang Y.
      • Smoker W.R.
      Evolution of lesions in Susac syndrome at serial MR imaging with diffusion-weighted imaging and apparent diffusion coefficient values.
      ,
      • Rennebohm R.
      • Susac J.O.
      • Egan R.A.
      • Daroff R.B.
      Susac's Syndrome—update.
      ]. Predilection for the center of the corpus callosum has been well documented, with FLAIR hyperintense lesions occurring in more than 78% of patients [
      • Dörr J.
      • Krautwald S.
      • Wildemann B.
      • Jarius S.
      • Ringelstein M.
      • Duning T.
      • et al.
      Characteristics of Susac syndrome: a review of all reported cases.
      ]. Several morphologic variants of the central FLAIR hyperintense lesions have been described, including roundly shaped “snowballs”, linear “spokes”, and “icicles” which extend towards the callosal roof (superior or dorsal surface) [
      • Susac J.O.
      • Murtagh F.R.
      • Egan R.A.
      • Berger J.R.
      • Bakshi R.
      • Lincoff N.
      • et al.
      MRI findings in Susac's syndrome.
      ,
      • Rennebohm R.
      • Susac J.O.
      • Egan R.A.
      • Daroff R.B.
      Susac's Syndrome—update.
      ,
      • Oliveira P.
      • Mayeux J.
      Teaching neuroimages: snowball-like lesions with sudden hearing loss.
      ]. These lesions typically evolve into T1 hypointense “holes”. “Snowballs” and “holes” are regarded as pathognomonic findings by some authors [
      • Susac J.O.
      • Murtagh F.R.
      • Egan R.A.
      • Berger J.R.
      • Bakshi R.
      • Lincoff N.
      • et al.
      MRI findings in Susac's syndrome.
      ,
      • Rennebohm R.M.
      • Egan R.A.
      • Susac J.O.
      Treatment of Susac's syndrome.
      ]. The typical long-term consequence of these lesions is significant callosal atrophy [
      • Susac J.O.
      • Murtagh F.R.
      • Egan R.A.
      • Berger J.R.
      • Bakshi R.
      • Lincoff N.
      • et al.
      MRI findings in Susac's syndrome.
      ,
      • Wuerfel J.
      • Sinnecker T.
      • Ringelstein E.B.
      • Jarius S.
      • Schwindt W.
      • Niendorf T.
      • et al.
      Lesion morphology at 7 Tesla MRI differentiates Susac syndrome from multiple sclerosis.
      ].
      SS is believed to be an autoimmune condition, with evidence that at least some patients can have autoantibodies against endothelial cells (AECA) [
      • Jarius S.
      • Kleffner I.
      • Dörr J.M.
      • Sastre-Garriga J.
      • Illes Z.
      • Eggenberger E.
      • et al.
      Clinical, paraclinical and serological findings in Susac syndrome: an international multicenter study.
      ,
      • Magro C.M.
      • Poe J.C.
      • Lubow M.
      • Susac J.O.
      Susac syndrome: an organ-specific autoimmune endotheliopathy syndrome associated with anti-endothelial cell antibodies.
      ,
      • Jarius S.
      • Neumayer B.
      • Wandinger K.P.
      • Hartmann M.
      • Wildemann B.
      Anti-endothelial serum antibodies in a patient with Susac's syndrome.
      ]. AECA are a heterogeneous family of antibodies binding to various endothelial cell antigens [
      • Belizna C.
      • Duijvestijn A.
      • Hamidou M.
      • Tervaert J.W.
      Antiendothelial cell antibodies in vasculitis and connective tissue disease.
      ]. These antibodies have been reported in connective tissue diseases, vasculitides, and other inflammatory diseases. There are several methods to detect AECA, and the sensitivity and specificity of these antibodies as biomarkers of SS have not yet been established. Moreover, it remains unknown whether the complete and limited forms of SS have a distinct pathogenesis. In a single study investigating patients with limited SS characterized only by retinal pathology, none of 5 patients tested positive for AECA [
      • Jarius S.
      • Kleffner I.
      • Dörr J.M.
      • Sastre-Garriga J.
      • Illes Z.
      • Eggenberger E.
      • et al.
      Clinical, paraclinical and serological findings in Susac syndrome: an international multicenter study.
      ].
      Given the low prevalence of SS, therapeutic strategies have not been assessed in controlled trials. Individual patients are often treated with a variety of immunomodulatory agents in a non-standardized approach [
      • Rennebohm R.M.
      • Egan R.A.
      • Susac J.O.
      Treatment of Susac's syndrome.
      ]. Because the disease course can be unpredictable [
      • Dörr J.
      • Krautwald S.
      • Wildemann B.
      • Jarius S.
      • Ringelstein M.
      • Duning T.
      • et al.
      Characteristics of Susac syndrome: a review of all reported cases.
      ] and reliable disease biomarkers are lacking, an appropriate duration of treatment has not been well defined.
      Here, we provide a summary and detailed graphical analysis of the manifestations, clinical course, diagnostic findings, and therapeutic interventions in 5 patients with SS. We aim to compare our clinical experience with previously described clinical and radiographic features that have been regarded as diagnostic criteria for SS.

      2. Methods

      Five patients treated at three tertiary care centers (Massachusetts General Hospital, Brigham and Women's Hospital, and Massachusetts Eye and Ear Infirmary, Boston, MA) between January 2009 and October 2013 were included in this retrospective study. The observation period was 7–57 months. Case 1 was previously discussed by D.C. Bienfang et al. [
      • Bienfang D.C.
      • McKenna M.J.
      • Papaliodis G.N.
      • Gonzalez R.G.
      • Stemmer-Rachamimov A.
      Case records of the Massachusetts General Hospital. Case 24-2011. A 36-year-old man with headache, memory loss, and confusion.
      ] and case 3 was reported by A.M. Allmendinger et al. [
      • Allmendinger A.M.
      • Viswanadhan N.
      • Klufas R.A.
      • Hsu L.
      Diffuse cauda equina enhancement in a middle aged male with Susac syndrome and symptomatic cauda equina syndrome.
      ]. Both case reports focused on initial clinical features alone without discussing treatment approaches and outcomes.
      We analyzed the following demographic and clinical features: age, gender, ethnicity, past medical history, details of initial presentation, diagnostic methods, differential diagnoses, clinical course, treatment strategies, and outcomes.
      Brain MRI, FA, and audiometry, which are the studies required to establish a diagnosis of SS, were available in all cases. The MRI findings that were specifically analyzed included: (i) central callosal T1 hypointense lesions (“holes”), (ii) FLAIR/T2 hyperintense lesions, including round central callosal lesions (“snowballs”) and deep gray matter lesions, (iii) punctuate DWI hyperintense lesions with corresponding ADC hypointensity (microinfarcts), (iv) parenchymal enhancement, and (v) leptomeningeal enhancement. In addition, callosal thickness was evaluated in the mid-sagittal plane at 2–4-month intervals over a course of approximately 12 months. FA studies were evaluated for hyperfluorescence of vessel walls indicative of active vasculitis and retinal vascular occlusions including proximal BRAOs and distal capillary hypoperfusion. Isolated peripheral hypoperfusion was considered a sequela of the vasculitis rather than a manifestation of its acute phase. Ancillary diagnostic studies included CSF analysis (performed in all patients), AECA testing by indirect immunofluorescence assay (IFA using human cutaneous endothelial cell culture; performed in 2 patients, at the Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY [
      • Magro C.M.
      • Poe J.C.
      • Lubow M.
      • Susac J.O.
      Susac syndrome: an organ-specific autoimmune endotheliopathy syndrome associated with anti-endothelial cell antibodies.
      ]) skin biopsy (performed in 2 patients who developed rash), and brain biopsy (performed in 2 patients).
      Once the diagnosis was established, the duration of treatment was planned to extend for at least 2 years after the resolution of diagnostic findings indicative of active disease. The course was determined based on the literature defining the 2-year time period of active disease as the critical parameter that separates the monocyclic course from the polycyclic and chronic–continuous forms of SS [
      • Rennebohm R.M.
      • Egan R.A.
      • Susac J.O.
      Treatment of Susac's syndrome.
      ].
      Outcome measures included adverse events and subjective and objective evidence of disease sequelae, including neuropsychological testing, neuro-ophthalmologic evaluations, and audiometry.
      We created a graphical representation of the clinical features, diagnostic findings, and treatment regimens for each case of SS. The charts were designed to visually characterize the sequence of symptoms, their severity (represented by the width of each bar), and the time points of various diagnostic studies and therapeutic interventions (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5) [
      • Bui A.
      • Hsu W.
      Medical Imaging Informatics.
      ].
      Figure thumbnail gr1
      Fig. 1Case 1. A. Symbol + indicates a study with abnormalities suggestive of active disease, symbol − indicates a negative study. Circled symbol denotes the imaging studies shown in panel B. The diagnosis was established 30 weeks after the initial symptom onset (large asterisk). B. Callosal T1 “holes” were absent throughout the observation period. FLAIR hyperintense lesions affected the callosal–septal interface and did not meet criteria for “snowballs”. Microinfarcts, noted on diffusion-weighted imaging (DWI), accompanied encephalopathy. Branch retinal artery occlusions (BRAOs; arrows) and vessel wall hyperfluorescence (arrowheads) persisted from week 27 to 59. Hyperfluorescence with peripheral filling defects were last detected 2 years and 7 months after the disease onset. FA normalized by the end of observation period. Δ: changes, *: fever, chills, diarrhea, A: ataxia, DA: dysarthria, N: numbness, R: rash, SD: sphincter dysfunction, sx: symptoms, T: tinnitus, w: weeks.
      Figure thumbnail gr2
      Fig. 2Case 2. A. Symbol + indicates a study with abnormalities suggestive of active disease, symbol − indicates a negative study. Circled symbol denotes the imaging studies shown in panel B. The diagnosis was established 10 weeks after the initial symptom onset (large asterisk). B. T1 “holes” were detected at the disease onset. FLAIR hyperintense “snowballs” and punctate areas of restricted diffusion (microinfarcts) were noted during active disease dominated by encephalopathy. Fluorescein angiography (FA) exhibited branch retinal artery occlusions (BRAOs; arrows) and vessel wall hyperfluorescence (arrowheads) were last detected in week 38. Few areas of hypoperfusion were noted at the end of observation period, 42 weeks after the onset of first symptoms. Δ: changes, A: ataxia, BD: bladder dysfunction, BP: back pain, N: numbness, S: spasticity, SD: sphincter dysfunction, sx: symptoms, T: tinnitus, W: weakness (paresis), w: weeks.
      Figure thumbnail gr3
      Fig. 3Case 3. A. Symbol + indicates a study with abnormalities suggestive of active disease, symbol − indicates a negative study. Circled symbol denotes the imaging studies shown in panel B. Visual symptoms were absent throughout the course of the disease. The diagnosis was established 9 weeks after the initial symptom onset (large asterisk). B. T1 “holes” were detected at the disease onset. FLAIR hyperintense “snowballs” and punctate areas of restricted diffusion (microinfarcts) were noted during active disease dominated by encephalopathy. Fluorescein angiography (FA) exhibited asymptomatic branch retinal artery occlusions (BRAOs; arrows) and vessel wall hyperfluorescence (arrowheads), which persisted until the end of the observation period, 29 weeks after the disease onset. Δ: changes, aph: aphasia, CE: cauda equina syndrome, R: rash, sx: symptoms, T: tinnitus, w: weeks.
      Figure thumbnail gr4
      Fig. 4Case 4. A. Symbol + indicates a study with abnormalities suggestive of active disease, symbol − indicates a negative study. Circled symbol denotes the imaging studies shown in panel B. The diagnosis of SS was established 10 weeks after the initial symptom onset (large asterisk). B. T1 “holes” were detected at the disease onset. Microinfarcts, noted on diffusion-weighted imaging (DWI), accompanied encephalopathy. Callosal FLAIR hyperintense “snowballs” were absent; lesions along the callosal–septal interface, in the gray matter and internal capsule were present instead. Fluorescein angiography (FA) demonstrated branch retinal artery occlusions (BRAOs; arrows) and prominent vessel wall hyperfluorescence until week 24. These were replaced by peripapillary hyperfluorescence and atrophy. Δ: changes, A: ataxia, CI: cochlear implant, SD: sphincter dysfunction, sx: symptoms, T: tinnitus, w: weeks.
      Figure thumbnail gr5
      Fig. 5Case 5. A. Symbol + indicates a study with abnormalities suggestive of active disease, symbol − indicates a negative study. Circled symbol denotes the imaging studies shown in panel B. The characteristic clinical triad developed within the first 3 weeks from the onset of headache. The diagnosis of SS was established 4 weeks after the initial symptom onset (large asterisk). B. Callosal T1 “holes” were absent throughout the observation period. FLAIR hyperintense lesions that affected the callosal–septal interface were inconspicuous at the disease onset and became apparent by the end of observation period. Punctate areas of restricted diffusion (microinfarcts) were noted on diffusion-weighted imaging (DWI) only during active disease dominated by encephalopathy. Branch retinal artery occlusions (BRAOs; arrows) and vessel wall hyperfluorescence (arrowheads) persisted from week 4 through 14 from disease onset. Isolated areas of hypoperfusion were last detected in week 31. Δ: changes, sx: symptoms, T: tinnitus, w: weeks.

      3. Results

      3.1 Clinical presentation

      Table 1 summarizes the demographic data of the 5 patients with SS. There were 4 men and 1 woman. Age of onset ranged from 21 to 52 years. All patients were Caucasian. Panel A in Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5 depicts the evolution and the severity of the clinical features in each case. In all patients, the clinical triad of deficits was incomplete at presentation. Migraine-like headache was a heralding symptom in all patients. In addition to headache, the main neurologic deficits were cognitive and behavioral abnormalities, accompanied by marked confusion at disease peak in all cases. Other CNS manifestations included aphasia, dysarthria, upper motor neuron signs, ataxia, and numbness. Two patients had marked sphincter dysfunction with fecal and urinary incontinence and urinary retention.
      Table 1Demographic data, clinical features, CSF profile, and MRI findings in patients with Susac syndrome.
      Case no.SexAge at onset (y)Differential diagnosisSymptom onset to diagnosis (w)CSF WBC (#/μL)CSF protein (mg/dL)CC FLAIR “snowballs”CC T1 “holes”Deep gray matter lesionsParenchymal enhancementLeptomeningea enhancement
      1M36ADEM, MS, IVL, PACNS308, 2, 7266, 211, 257+
      2M33ADEM, MS, PACNS1013, 5219, 130++++
      3M43ADEM, PACNS98, 4, 1, 2104, 53, 78, 113++++
      4M21ADEM, MS, CADASIL, PACNS104, 2187, 46++
      5F52Labyrinthitis, Ménière43, 4142++
      y: years; w: weeks; IVL: intravascular lymphoma; PACNS: primary angiitis of CNS; CC: corpus callosum.
      Visual disturbances were described as blurring, partial visual field deficits or blind spots, and flashing lights (photopsias). Inner ear dysfunction manifested as tinnitus and hearing loss in all patients. Vertigo, as a sign of vestibulopathy, occurred in one patient (case 5). Non-neurological manifestations included rash during active disease in two patients (case 1 and 3). Patient 1 developed transient erythematous macular eruption that involved the trunk alone. Patient 3 developed transient erythematous maculopapular rash over the trunk, neck, face, and extensor extremity surfaces.
      The diagnosis of SS in these patients was established only once the full triad was recognized, 4 to 30 weeks after the onset of symptoms (Table 1, panel A in all figures). Acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), primary angiitis of CNS, intravascular lymphoma, and Meniere's disease were initially considered as leading differential diagnoses (Table 1).

      3.2 Diagnostic evaluations

      3.2.1 Imaging

      Brain MRI in all cases revealed punctate areas of restricted diffusion (DWI hyperintense/ADC hypointense) only during the acute stage dominated by encephalopathy (Table 2, panel B in all figures). Callosal FLAIR hyperintense “snowball” lesions were absent in 3 patients and T1 hypointense “holes” were absent in 2 patients (Table 1). In contrast, all patients (even those without “snowballs” or “holes”) had FLAIR hyperintense lesions involving the callosal–septal interface (CSI; Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5). Case 4 had extensive FLAIR hyperintensities of the gray matter (basal ganglia and thalamus) and subcortical white matter, rather than in the corpus callosum (Fig. 4). Parenchymal and leptomeningeal enhancement was inconsistently detected during the active phase (Table 1). Callosal atrophy became apparent by 12 months after the onset of initial symptoms (Fig. 6). Generalized brain parenchymal volume loss with resulting ex vacuo dilatation of lateral ventricles was conspicuous in case 4 (Fig. 4).
      Table 2Treatment and clinical course in patients with Susac syndrome.
      Case no.InductionResponse to initial treatmentFinal treatmentMedication SETime to neg DWI MRI (mo)Time to resolution of vasculitis on FA (mo)
      1MP; MP + CYCFailedCYC + MP × 24 mo + P taper × 10 mo → MMF × 31 moCushing, hypogonadism>6.5>25
      2MP + IVIgFailedRTX × 4 → P  × taper × 12 mo + MMF × 30 moCushing>4>9
      3MP + IVIgFailedP taper × 12 mo + CYC + IVIg Qmo + MPCushing>2.5>7 (present)
      4IVIg; MPFailedMMF (relapse) → CYC + MP × 18 mo + P taper × 7.5 mo → MTX × 32 moCushing>6>6
      5MP + RTX × 4RemissionP taper × 12 mo + MMF × 24 moCushing, Candida esophagitis>2>3.5
      SE; side effect; Neg: negative; mo: months; MP: methylprednisolone; CYC: cyclophosphamide; IVIg: intravenous immunoglobulins; RTX: rituximab; P: prednisone; MMF: mycophenolate mofetil; MTX: methotrexate.
      Figure thumbnail gr6
      Fig. 6Development of callosal atrophy over a course of 12 months. Mid-sagittal T1-weighted MRI scans demonstrate progressive decrease in callosal thickness in all cases. A. Case 1. B. Case 2. C. Case 3. D. Case 4. E. Case 5.

      3.2.2 Retinal fluorescein angiography

      FA revealed hyperfluorescent vessel walls, BRAOs, and retinal filling defects during the acute symptomatic phase with encephalopathy in all cases. Hyperfluorescence of the vessel walls with peripheral filling defects with or without BRAOs were noted for the entire duration that DWI abnormalities were present and persisted longer than DWI abnormalities in 3 patients (Table 2). They remained present in patient 3 at the end of the observation period, 29 weeks after the disease onset (Fig. 3). Peripheral hypoperfusion without hyperfluorescence or BRAOs persisted until the end of the observation period (42 weeks after the onset of the first symptoms) in case 2.

      3.2.3 Spinal fluid studies

      CSF analysis showed elevated total protein with or without mild lymphocytic pleocytosis in all patients (Table 1). Of 5 CSF samples obtained from 3 patients, 1 tested positive for 2 oligoclonal bands (OCBs; case 1). Normal IgG index (0.48), indicating absence of intrathecal IgG synthesis, was reported in 1 patient (case 2).

      3.2.4 Antiendothelial cell serum antibodies

      AECA were tested and detected in both patients (cases 3 and 4) during the encephalopathic stage of disease.

      3.2.5 Pathology

      Brain histopathology in the 2 biopsied cases demonstrated nonspecific pauci-inflammatory microangiopathy characterized by swollen endothelial cells, scant mononuclear-cell perivascular infiltration, and hyaline thrombi in the small vessels [
      • Bienfang D.C.
      • McKenna M.J.
      • Papaliodis G.N.
      • Gonzalez R.G.
      • Stemmer-Rachamimov A.
      Case records of the Massachusetts General Hospital. Case 24-2011. A 36-year-old man with headache, memory loss, and confusion.
      ,
      • Allmendinger A.M.
      • Viswanadhan N.
      • Klufas R.A.
      • Hsu L.
      Diffuse cauda equina enhancement in a middle aged male with Susac syndrome and symptomatic cauda equina syndrome.
      ]. Histopathology of a transient skin rash in 2 patients revealed nonspecific inflammatory changes.

      3.3 Treatment strategies

      Pursued treatment strategies in the acute phase consisted of pulse doses of methylprednisolone (all patients), intravenous immunoglobulins (IVIg; 4 patients), and/or rituximab (RTX; 1 patient; Table 2). Of the 4 patients treated with corticosteroids and IVIg alone, all experienced further clinical progression until additional immunosuppressive agents were instituted. These included cyclophosphamide (CYC; 3 patients), methotrexate (MTX; 1 patient), mycophenolate mofetil (MMF; 4 patients), and/or RTX (1 patient). One patient (case 4) continued to progress despite MMF, and was thus transitioned to CYC. Case 1 was continued on multimodal immunosuppressive therapy for 4.5 years and is the only patient in whom treatment was fully discontinued during the observation period.

      3.4 Outcomes

      Residual cognitive weaknesses were noted in 2 patients (Fig. 1, Fig. 2, Fig. 3, Fig. 4, Fig. 5). They were mild and not associated with any objective deficits in formal neuropsychological evaluation in 1 patient (case 5). In another patient (case 4), with a premorbid history of polysubstance abuse and affective disorder, neuropsychological testing identified significant difficulties with sustained attention, executive functioning, and memory. Headaches persisted in 2 patients, sphincter dysfunction in 2 patients, and prominent upper motor neuron signs (spastic paraparesis, hyperreflexia) in one patient. All patients retained good visual acuity despite minor visual field defects; 2 patients reported small residual areas of deficient vision (i.e. scotomas) at the end of the observation period. Three patients developed permanent hearing loss managed with a hearing aid in case 2 and a cochlear implant in case 4. All patients experienced Cushing syndrome from glucocorticoids. One patient treated with MMF developed Candida esophagitis (Table 2).

      4. Discussion

      SS is typically characterized by a triad of encephalopathy, visual disturbances, and hearing loss attributed to a pauci-inflammatory vasculopathy of the brain, eye, and inner ear. Our case series depicts the heterogeneity of the clinical presentation and course. We detected migraine-like headache as the initial symptom in all patients. Encephalopathy, characterized by cognitive impairment or marked confusion, was an early feature in our series.
      SS is commonly mimicked by many other conditions at its presentation. Most frequently considered diagnoses included ADEM, MS primary angiitis of CNS, intravascular lymphoma, and Ménière's disease. Our study emphasizes the previously reported prolonged time to accurate diagnosis [
      • Dörr J.
      • Krautwald S.
      • Wildemann B.
      • Jarius S.
      • Ringelstein M.
      • Duning T.
      • et al.
      Characteristics of Susac syndrome: a review of all reported cases.
      ]. We believe the explanation for this delay relates to the low prevalence of the disease and the heterogeneous clinical presentations with an incomplete clinical triad at disease onset. Although the imaging findings have certain characteristic features, there is significant variability and the findings are not completely specific.
      In the absence of specific biologic markers, the diagnosis of SS is based on the clinical and radiologic features. Here, we demonstrate that previously described MRI findings of central callosal FLAIR snowball-like lesions and T1 “holes” [
      • Susac J.O.
      • Murtagh F.R.
      • Egan R.A.
      • Berger J.R.
      • Bakshi R.
      • Lincoff N.
      • et al.
      MRI findings in Susac's syndrome.
      ,
      • Rennebohm R.M.
      • Egan R.A.
      • Susac J.O.
      Treatment of Susac's syndrome.
      ] are frequently absent, and are therefore not the sine qua non of SS. Equally remarkable is the fact that all patients in our case series were noted to have FLAIR hyperintense lesions involving the CSI. This challenges previous studies that regard this finding as a feature that excludes the diagnosis of SS [
      • Susac J.O.
      • Murtagh F.R.
      • Egan R.A.
      • Berger J.R.
      • Bakshi R.
      • Lincoff N.
      • et al.
      MRI findings in Susac's syndrome.
      ,
      • Rennebohm R.
      • Susac J.O.
      • Egan R.A.
      • Daroff R.B.
      Susac's Syndrome—update.
      ] and suggests MS or ADEM [
      • Simon J.H.
      • Holtås S.L.
      • Schiffer R.B.
      • Rudick R.A.
      • Herndon R.M.
      • Kido D.K.
      • et al.
      Corpus callosum and subcallosal-periventricular lesions in multiple sclerosis: detection with MR.
      ,
      • Gean-Marton A.D.
      • Vezina L.G.
      • Marton K.I.
      • Stimac G.K.
      • Peyster R.G.
      • Taveras J.M.
      • et al.
      Abnormal corpus callosum: a sensitive and specific indicator of multiple sclerosis.
      ,
      • Uchino A.
      • Takase Y.
      • Nomiyama K.
      • Egashira R.
      • Kudo S.
      Acquired lesions of the corpus callosum: MR imaging.
      ,
      • Yousem D.
      • Grossman R.
      White matter diseases.
      ,
      • Palmer S.
      • Bradley W.G.
      • Chen D.Y.
      • Patel S.
      Subcallosal striations: early findings of multiple sclerosis on sagittal, thin-section, fast FLAIR MR images.
      ].
      Among all available diagnostic findings, two were consistently detected in all patients with active disease: punctate ADC/DWI signal changes indicative of microinfarcts and hyperfluorescence of vessel walls on FA. It should also be noted that in 1 case the acute FA abnormalities were present in an asymptomatic patient (case 3), which supports the use of the diagnostic technique in this clinical context even when visual symptoms are absent. Perivascular hyperfluorescence and BRAOs detected on FA always accompany DWI abnormalities, and the hyperfluorescence may persist longer than the DWI changes. FA thus not only has a role in identifying patients early in the disease course, as highlighted previously [
      • Dörr J.
      • Krautwald S.
      • Wildemann B.
      • Jarius S.
      • Ringelstein M.
      • Duning T.
      • et al.
      Characteristics of Susac syndrome: a review of all reported cases.
      ], but also in long-term surveillance. Together, brain MRI and FA may be used to guide treatment decisions and follow response to treatment. The extent to which these findings, particularly isolated retinal pathology, should guide ongoing therapy requires further investigation.
      AECA testing holds promise as a diagnostic tool in SS but its use is still hindered by several methodological limitations [
      • Belizna C.
      • Duijvestijn A.
      • Hamidou M.
      • Tervaert J.W.
      Antiendothelial cell antibodies in vasculitis and connective tissue disease.
      ]. A recent study using primate CNS tissue-based IFA demonstrated that AECA were present at a titer of >1:100 in 25% (5/20) of patients with the encephalopathic form of SS and were absent in its limited form [
      • Jarius S.
      • Kleffner I.
      • Dörr J.M.
      • Sastre-Garriga J.
      • Illes Z.
      • Eggenberger E.
      • et al.
      Clinical, paraclinical and serological findings in Susac syndrome: an international multicenter study.
      ]. The specificity of these antibodies for SS is also limited, as they were detected in 3/70 control patients (2 patients with MS and 1 patient with connective tissue disease). Two patients in our series were tested for serum AECA using a different method and both showed positive results. It remains unknown, however, whether these antibodies have direct pathogenicity or are an epiphenomenon of the disease. There is no direct evidence of an association between AECA seropositivity or titers and disease activity. It has not been demonstrated whether passive transfer of AECA produces a Susac-type syndrome in animal models.
      Brain biopsy findings in SS may include endothelial injury, microinfarctions, and scant perivascular lymphocytic infiltration [
      • Magro C.M.
      • Poe J.C.
      • Lubow M.
      • Susac J.O.
      Susac syndrome: an organ-specific autoimmune endotheliopathy syndrome associated with anti-endothelial cell antibodies.
      ,
      • Petty G.W.
      • Engel A.G.
      • Younge B.R.
      • Duffy J.
      • Yanagihara T.
      • Lucchinetti C.F.
      • et al.
      Retinocochleocerebral vasculopathy.
      ,
      • Mateen F.J.
      • Zubkov A.Y.
      • Muralidharan R.
      • Fugate J.E.
      • Rodriguez F.J.
      • Winters J.L.
      • et al.
      Susac syndrome: clinical characteristics and treatment in 29 new cases.
      ]. Brain biopsy in 2 cases in this series showed subtle non-specific histopathological abnormalities. Histopathologic features that were not present included necrotizing vasculitis, fibrinoid necrosis, or recruitment of other cell types (such as histiocytes, plasma cells, neutrophils, and eosinophils). Thus, the brain biopsy findings helped narrow the differential diagnosis, although they did not demonstrate specific features that confirmed the diagnosis of SS. This high-risk procedure should therefore be avoided if other investigations support the diagnosis.
      The CSF profile in patients with SS is nonspecific. In this series, the CSF showed minimal or no pleocytosis, with elevated protein. Oligoclonal bands were found in only 1 of 3 patients. CSF-restricted OCB were previously reported in 4–13% of available cases [
      • Dörr J.
      • Krautwald S.
      • Wildemann B.
      • Jarius S.
      • Ringelstein M.
      • Duning T.
      • et al.
      Characteristics of Susac syndrome: a review of all reported cases.
      ,
      • Jarius S.
      • Kleffner I.
      • Dörr J.M.
      • Sastre-Garriga J.
      • Illes Z.
      • Eggenberger E.
      • et al.
      Clinical, paraclinical and serological findings in Susac syndrome: an international multicenter study.
      ]. Both histopathology and CSF results in our case series suggest the pauci-inflammatory nature of the disease.
      In cases of SS including severe encephalopathy, as represented in this series, treatment with glucocorticoids and/or IVIg alone appears to be insufficient to halt the progression of disease. These two agents are the initial preferred empiric treatment options in patients with SS, used in 27/29 and 14/29 patients, respectively, in the study by Mateen et al., which is the largest series analyzing treatment and outcomes [
      • Mateen F.J.
      • Zubkov A.Y.
      • Muralidharan R.
      • Fugate J.E.
      • Rodriguez F.J.
      • Winters J.L.
      • et al.
      Susac syndrome: clinical characteristics and treatment in 29 new cases.
      ]. It should be noted that in that series, the 7 patients in whom the treatment was limited to glucocorticoids and/or IVIg had a high risk of poor outcomes, with a median modified Rankin scale score at last follow-up of 4 (range 2 to 4). All 7 patients in that series who were asymptomatic at the end of the observation period (modified Rankin scale score 0) had received additional treatments, including plasma exchange (PLEX), CYC, and azathioprine (AZA). In light of those reported outcomes, one patient (case 4) in our series received RTX in combination with methylprednisolone as immediate induction treatment. The severity of impairments and recurrence of symptoms prompted escalation of immunosuppressive therapy in the remaining patients in our series. In addition to CYC, MTX, MMF, RTX, other agents whose use is reported as an adjunct to glucocorticoids include cyclosporine A and TNF-alpha inhibitors (etanercept and infliximab) [
      • Rennebohm R.M.
      • Egan R.A.
      • Susac J.O.
      Treatment of Susac's syndrome.
      ,
      • Mateen F.J.
      • Zubkov A.Y.
      • Muralidharan R.
      • Fugate J.E.
      • Rodriguez F.J.
      • Winters J.L.
      • et al.
      Susac syndrome: clinical characteristics and treatment in 29 new cases.
      ,
      • Hardy T.A.
      • Garsia R.J.
      • Halmagyi G.M.
      • Lewis S.J.
      • Harrisberg B.
      • Fulham M.J.
      • et al.
      Tumour necrosis factor (TNF) inhibitor therapy in Susac's syndrome.
      ]. Ultimately, recovery and clinical stability was achieved in all patients in our series. The patients had some persistent deficits that included cognitive disturbances, headaches, mild visual deficits, or hearing loss. An important unanswered question is the extent to which earlier initiation of high-level immunosuppression improves long term prognosis and prevents accrual of radiographic abnormalities such as residual FLAIR hyperintensities or callosal atrophy.
      Several limitations of our study should be addressed. This was a retrospective case series that relied on surveillance of medical records, which may have incorrectly or inconsistently reported relevant patient information. Incomplete data, such as biopsies and AECA testing in only two patients further limit any meaningful conclusions about the pathology of the disease. The retrospective nature of the study and the small sample size prohibit any causal inference based on the observed phenomena. Furthermore, the case series likely reflects more severe forms of SS, given that most patients were referred to tertiary care centers for their care.
      Despite these limitations, this case series underscores the variability in clinical presentations and diagnostic findings among patients with SS. At this time, SS remains the clinician's challenge, relying on the history, examination, and ability to recognize the subtle radiographic features that distinguish SS from other acute and subacute conditions that predominantly involve the white matter. Avenues for immediate future study include research into the pathogenic role of AECA, and the discovery of disease biomarkers and more robust imaging tools that will enable early and accurate diagnosis. Prospective studies of the immunomodulatory strategies, in conjunction with analyses of the clinical and radiographic long-term outcomes, are needed to optimize the treatment and disease outcomes.

      Conflict of interest

      None.

      Acknowledgments

      The authors wish to thank Dr. Robert Egan, Dr. Cynthia Magro, and Dr. Rebecca Folkerth for their clinical contributions.

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