Clinical, paraclinical and serological findings in Susac syndrome: an international multicenter study

Journal of Neuroinflammation

Brigitte Wildemann⁹  Friedemann Paul³  Erich B Ringelstein⁵  Winfried Stöcker⁷  Kai Fechner⁷  Xavier Montalban⁴  Orhan Aktas¹  Marius Ringelstein¹  Colin Chalk⁶  Eric Eggenberger²  Zsolt Illes⁸  Jaume Sastre-Garriga⁴  Jan M Dörr³  Ilka Kleffner⁵  Sven Jarius⁹ 

[1] Department of Neurology, University of Düsseldorf, Düsseldorf, Germany;Department of Neurology and Ophthalmology, Michigan State University, East Lansing, MI, USA;NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Department of Neurology, Charité-Universitätsmedizin, Berlin, Germany;Servei de Neurologia/Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron (HUVH), Barcelona, Spain;Department of Neurology, University of Heidelberg, Münster, Germany;Department of Neurology and Neurosurgery, McGill University, Montreal, Canada;Institute for Experimental Immunology, affiliated to Euroimmun, Luebeck, Germany;Department of Neurology, Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark;Molecular Neuroimmunology, Department of Neurology, University of Heidelberg, Heidelberg, Germany

关键词: BRAO;    branch retinal artery occlusion;    visual impairment;    hearing loss;    encephalopathy;    laboratory test;    indirect immunofluorescence;    AECA;    anti-endothelial cell antibodies;    Susac’s syndrome;    Susac syndrome;   

Others  :  812075
DOI  :  10.1186/1742-2094-11-46

 received in 2013-08-24, accepted in 2014-02-13,  发布年份 2014

【 摘 要 】

Background

Susac syndrome (SuS) is a rare disorder thought to be caused by autoimmune-mediated occlusions of microvessels in the brain, retina and inner ear leading to central nervous system (CNS) dysfunction, visual disturbances due to branch retinal artery occlusions (BRAO), and hearing deficits. Recently, a role for anti-endothelial cell antibodies (AECA) in SuS has been proposed.

Objectives

To report the clinical and paraclinical findings in the largest single series of patients so far and to investigate the frequency, titers, and clinical relevance of AECA in SuS.

Patients and methods

A total of 107 serum samples from 20 patients with definite SuS, 5 with abortive forms of SuS (all with BRAO), and 70 controls were tested for AECA by immunohistochemistry employing primate brain tissue sections.

Results

IgG-AECA >1:100 were detected in 25% (5/20) of patients with definite SuS and in 4.3% (3/70) of the controls. Median titers were significantly higher in SuS (1:3200, range 1:100 to 1:17500) than in controls (1:100, range 1:10 to 1:320); IgG-AECA titers >1:320 were exclusively present in patients with SuS; three controls had very low titers (1:10). Follow-up samples (n = 4) from a seropositive SuS patient obtained over a period of 29 months remained positive at high titers. In all seropositive cases, AECA belonged to the complement-activating IgG1 subclass. All but one of the IgG-AECA-positive samples were positive also for IgA-AECA and 45% for IgM-AECA. SuS took a severe and relapsing course in most patients and was associated with bilateral visual and hearing impairment, a broad panel of neurological and neuropsychological symptoms, and brain atrophy in the majority of cases. Seropositive and seronegative patients did not differ with regard to any of the clinical or paraclinical parameters analyzed.

Conclusions

SuS took a severe and protracted course in the present cohort, resulting in significant impairment. Our finding of high-titer IgG1 and IgM AECA in some patients suggest that humoral autoimmunity targeting the microvasculature may play a role in the pathogenesis of SuS, at least in a subset of patients. Further studies are warranted to define the exact target structures of AECA in SuS.

【 授权许可】

   
2014 Jarius et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]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.
• [2]Dorr J, Jarius S, Wildemann B, Ringelstein EB, Schwindt W, Deppe M, Wandinger KP, Promesberger J, Paul F, Kleffner I: [Susac syndrome: an interdisciplinary challenge]. Nervenarzt 2011, 82:1250-1263.
• [3]Kleffner I, Duning T, Lohmann H, Deppe M, Basel T, Promesberger J, Dorr J, Schwindt W, Ringelstein EB: A brief review of Susac syndrome. J Neurol Sci 2012, 322:35-40.
• [4]Dorr J, Radbruch H, Bock M, Wuerfel J, Bruggemann A, Wandinger KP, Zeise D, Pfueller CF, Zipp F, Paul F: Encephalopathy, visual disturbance and hearing loss-recognizing the symptoms of Susac syndrome. Nat Rev Neurol 2009, 5:683-688.
• [5]Wildemann B, Schulin C, Storch-Hagenlocher B, Hacke W, Dithmar S, Kirchhof K, Jansen O, Breitbart A: Susac’s syndrome: improvement with combined antiplatelet and calcium antagonist therapy. Stroke 1996, 27:149-151.
• [6]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.
• [7]Rennebohm RM, Susac JO: Treatment of Susac’s syndrome. J Neurol Sci 2007, 257:215-220.
• [8]Susac JO, Egan RA, Rennebohm RM, Lubow M: Susac’s syndrome: 1975–2005 microangiopathy/autoimmune endotheliopathy. J Neurol Sci 2007, 257:270-272.
• [9]Jarius S, Neumayer B, Wandinger KP, Hartmann M, Wildemann B: Anti-endothelial serum antibodies in a patient with Susac’s syndrome. J Neurol Sci 2009, 285:259-261.
• [10]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.
• [11]Jarius S, Franciotta D, Bergamaschi R, Wright H, Littleton E, Palace J, Hohlfeld R, Vincent A: NMO-IgG in the diagnosis of neuromyelitis optica. Neurology 2007, 68:1076-1077.
• [12]Jarius S, Wandinger KP, Horn S, Heuer H, Wildemann B: A new Purkinje cell antibody (anti-Ca) associated with subacute cerebellar ataxia: immunological characterization. J Neuroinflammation 2010, 7:21. BioMed Central Full Text
• [13]Jarius S, Probst C, Borowski K, Franciotta D, Wildemann B, Stoecker W, Wandinger KP: Standardized method for the detection of antibodies to aquaporin-4 based on a highly sensitive immunofluorescence assay employing recombinant target antigen. J Neurol Sci 2010, 291:52-56.
• [14]Jarius S, Wildemann B: Aquaporin-4 Antibodies (NMO-IgG) as a serological marker of neuromyelitis optica: a critical review of the literature. Brain Pathol 2013, 23:661-683.
• [15]Jarius S, Franciotta D, Paul F, Bergamaschi R, Rommer PS, Ruprecht K, Ringelstein M, Aktas O, Kristoferitsch W, Wildemann B: Testing for antibodies to human aquaporin-4 by ELISA: Sensitivity, specificity, and direct comparison with immunohistochemistry. J Neurol Sci 2012, 320:32-37.
• [16]Egan RA, Ha Nguyen T, Gass JD, Rizzo JF 3rd, Tivnan J, Susac JO: Retinal arterial wall plaques in Susac syndrome. Am J Ophthalmol 2003, 135:483-486.
• [17]Reiber H: Flow rate of cerebrospinal fluid (CSF)–a concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases. J Neurol Sci 1994, 122:189-203.
• [18]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.
• [19]Jarius S, Paul F, Franciotta D, Waters P, Zipp F, Hohlfeld R, Vincent A, Wildemann B: Mechanisms of disease: aquaporin-4 antibodies in neuromyelitis optica. Nat Clin Pract Neurol 2008, 4:202-214.
• [20]Jarius S, Wildemann B: AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol 2010, 6:383-392.
• [21]Jarius S, Ruprecht K, Wildemann B, Kuempfel T, Ringelstein M, Geis C, Kleiter I, Kleinschnitz C, Berthele A, Brettschneider J, Hellwig K, Hemmer B, Linker RA, Lauda F, Mayer CA, Tumani H, Melms A, Trebst C, Stangel M, Marziniak M, Hoffmann F, Schippling S, Faiss JH, Neuhaus O, Ettrich B, Zentner C, Guthke K, Hofstadt-van Oy U, Reuss R, Pellkofer H, et al.: Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J Neuroinflammation 2012, 9:14. BioMed Central Full Text
• [22]Wildemann B, Jarius S: The expanding range of autoimmune disorders of the nervous system. Lancet Neurol 2013, 12:22-24.
• [23]Jarius S, Franciotta D, Paul F, Ruprecht K, Bergamaschi R, Rommer PS, Reuss R, Probst C, Kristoferitsch W, Wandinger KP, Wildemann B: Cerebrospinal fluid antibodies to aquaporin-4 in neuromyelitis optica and related disorders: frequency, origin, and diagnostic relevance. J Neuroinflammation 2010, 7:52. BioMed Central Full Text
• [24]Jarius S, Paul F, Franciotta D, Ruprecht K, Ringelstein M, Rommer P, Bergamaschi R, Kleiter I, Stich O, Reuss R, Rauer S, Zettl UK, Wandinger KP, Melms A, Aktas O, Kristoferitsch W, Wildemann B: Cerebrospinal fluid findings in aquaporin-4 antibody positive neuromyelitis optica: results from 211 lumbar punctures. J Neurol Sci 2011, 306:82-90.
• [25]Kalluri SR, Illes Z, Srivastava R, Cree B, Menge T, Bennett JL, Berthele A, Hemmer B: Quantification and functional characterization of antibodies to native aquaporin 4 in neuromyelitis optica. Arch Neurol 2010, 67:1201-1208.
• [26]Jarius S, Hoffmann L, Clover L, Vincent A, Voltz R: CSF findings in patients with voltage gated potassium channel antibody associated limbic encephalitis. J Neurol Sci 2008, 268:74-77.
• [27]Jarius S, Eichhorn P, Wildemann B, Wick M: Usefulness of antibody index assessment in cerebrospinal fluid from patients negative for total-IgG oligoclonal bands. Fluids Barriers CNS 2012, 9:14. BioMed Central Full Text
• [28]Psimaras D, Carpentier AF, Rossi C: Cerebrospinal fluid study in paraneoplastic syndromes. J Neurol Neurosurg Psychiatry 2010, 81:42-45.
• [29]Jarius S, Aboul-Enein F, Waters P, Kuenz B, Hauser A, Berger T, Lang W, Reindl M, Vincent A, Kristoferitsch W: Antibody to aquaporin-4 in the long-term course of neuromyelitis optica. Brain 2008, 131:3072-3080.
• [30]Mano K, Takegami T, Okamoto S, Takahashi A: Remission of myasthenia gravis: clinical, electrophysiological and immunological studies. Nagoya J Med Sci 1993, 55:103-113.
• [31]Yurasov S, Tiller T, Tsuiji M, Velinzon K, Pascual V, Wardemann H, Nussenzweig MC: Persistent expression of autoantibodies in SLE patients in remission. J Exp Med 2006, 203:2255-2261.