Polyneuropathy with anti-sulfatide and anti-MAG antibodies: Clinical, neurophysiological, pathological features and response to treatment Marta Campagnolo a , Sergio Ferrari b , Chiara Dalla Torre a , Ilaria Cabrini b , Mario Cacciavillani c , Marta Lucchetta a , Susanna Ruggero a , Elisabetta Toffanin a , Tiziana Cavallaro b , Chiara Briani a, ⁎ a Department of Neurosciences: Sciences NPSRR, University of Padova, Padova, Italy b Department of Neurological and Movement Sciences, University of Verona, Verona, Italy c CEMES, EMG Unit, Padova, Italy abstract article info Article history: Received 25 July 2014 Accepted 28 February 2015 Keywords: Myelin-associated glycoprotein (MAG) Sulfatide Polyneuropathy Demyelinating Indirect immunofluorescence Rituximab IgM paraproteins often present reactivity to myelin-associated glycoprotein (MAG) and sulfatide. We describe the clinical and neurophysiological findings, and therapy response in 21 patients with IgM paraproteinemic neuropathy (15 with anti-MAG antibodies, 1 with anti-sulfatide antibodies, and 5 with both reactivity), and in 2 with anti-sulfatide positivity and no hematological disease. All patients complained of sensory symptoms, the majority had demyelinating neuropathy. Indirect immunoflu- orescence on human normal sural nerves disclosed different staining patterns. Eight of 13 patients (6 anti-MAG, 1 anti-sulfatide, 1 both anti-sulfatide and anti-MAG antibodies) improved after Rituximab. IVIg, steroids and plasma-exchange were also administered with different responses. © 2015 Elsevier B.V. All rights reserved. 1. Introduction In more than 50% of patients with polyneuropathy and monoclonal gammopathy the IgMs present reactivity to several neural antigens, the most common being myelin-associated glycoprotein (MAG) and sulfatide (Nobile-Orazio, 2009). Anti-MAG antibody neuropathy presents with typical clinical, neurophysiological and pathological features. Sensory involvement is predominant with ataxia, paresthesias and tremor at upper limbs. The neuropathy is slowly progressive, with severe disability occurring only in long-term course. Neurophysiological studies reveal demyelinating neuropathy and are characterized by a disproportioned increase in distal motor latencies compared with motor conduction velocities (Kaku et al., 1994). Pathological data show segmental demyelination with deposits of IgM and complement in myelin sheaths and irregular widening of myelin lamellae (Monaco et al., 1990). Another IgM target, although less common, is sulfatide (Nobile-Orazio and Giannotta, 2011), that represents the major acidic glycosphingolipid in central and peripheral nerve myelin. Anti-sulfatide reactivity was first reported by Pestronk et al. (1991), who evaluated the cross-reactivity of anti-MAG antibodies with other compounds containing sulfate glucuronate epitopes in 64 patients with neuropathy. After the first report, several studies described anti-sulfatide anti- bodies in both axonal and demyelinating neuropathies including Guillain–Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and also in patients with multiple scle- rosis, chronic active hepatitis and idiopathic thrombocytopenic purpura (Carpo et al., 2000). However, the pathogenic role and the real diagnos- tic relevance of anti-sulfatide antibodies still remain unclear. Neuropa- thies with anti-sulfatide antibodies present with a heterogeneous spectrum of manifestations and different neurophysiological features. Anti-sulfatide antibodies have been associated with small fiber (Pestronk et al., 1991; Dabby et al., 2000), ataxic (Nobile-Orazio et al., 1994; Lopate et al., 1997; Carpo et al., 2000; Petratos et al., 2000) and painful sensory axonal neuropathies (Pestronk et al., 1991; Quattrini et al., 1992; Nemni et al., 1993; van den Berg et al., 1993). Carpo et al. showed that high titers of anti-sulfatide IgM antibodies are usually associated with chronic sensorimotor demyelinating neuropathy with secondary axonal loss, IgM monoclonal gammopathy, increased CSF protein levels and good response to immunotherapy (Carpo et al., 2000). Besides different clinical pictures, anti-sulfatide an- tibodies also show heterogeneous binding pattern. In a passive transfer study, Nardelli et al. showed that anti-sulfatide IgM antibodies from a patient with neuropathy bound to myelin sheaths of newborn rabbits with a pattern different from that found in anti-MAG neuropathy (Nardelli et al., 1995). Ferrari et al., examining sural nerve biopsies from 2 patients with sensorimotor and small fiber neuropathy and anti-sulfatide antibodies, demonstrated widely spaced myelin and Journal of Neuroimmunology 281 (2015) 1–4 ⁎ Corresponding author at: Department of Neurosciences: Sciences NPSRR, University of Padova, Via Giustiniani, 5, 35128 Padova, Italy. E-mail address: chiara.briani@unipd.it (C. Briani). http://dx.doi.org/10.1016/j.jneuroim.2015.02.009 0165-5728/© 2015 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim