Download PDF
CC BY-NC-ND 4.0 · Neurology International Open 2017; 01(01): E56-E60
DOI: 10.1055/s-0043-102455
Review
© Georg Thieme Verlag KG Stuttgart · New York

The New Entity of Paranodopathies: A Target Structure with Therapeutic Consequences

Kathrin Doppler
1   Neurological Clinic, University Hospital Würzburg
,
Claudia Sommer
1   Neurological Clinic, University Hospital Würzburg
› Author Affiliations
Further Information

Publication History

Publication Date:
13 April 2017 (online)

   Permissions and Reprints

Abstract

Autoimmune neuropathies with autoantibodies against paranodal proteins have been described in the last few years. They comprise a subgroup of inflammatory neuropathies with IgG4 autoantibodies against the paranodal proteins neurofascin-155, contactin-1 and caspr-1. Although this subtype of autoimmune neuropathy represents less than 10% of all patients diagnosed with CIDP, it is of high interest as they show a different response to treatment. Even though there are no therapeutic studies available due to the limited number of patients identified so far, all case reports published so far report an excellent response to treatment with rituximab, and in most cases no response to treatment with IVIG, the standard therapy of CIDP. The typical clinical picture of patients with autoantibodies against paranodal proteins is characterized by an acute onset of a severe predominantly motor neuropathy, often accompanied by action tremor and sensory ataxia, with demyelinating features in the nerve conduction studies but an axonal histological phenotype. The latter may be explained by the pathogenetic concept of a paranodopathy/nodopathy, a disease of the paranode/node of Ranvier.

Key words

neuropathy - node of Ranvier - autoantibody - CIDP
 

  • References

  • 1 Mathey EK, Park SB, Hughes RA. et al. Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype. J Neurol Neurosurg Psychiatry 2015; 86: 973-985
    CrossrefPubMedGoogle Scholar
  • 2 Quarles RH, Weiss MD. Autoantibodies associated with peripheral neuropathy. Muscle Nerve 1999; 22: 800-822
    CrossrefPubMedGoogle Scholar
  • 3 Querol L, Illa I. Paranodal and other autoantibodies in chronic inflammatory neuropathies. Curr Opin Neurol 2015; 28: 474-479
    CrossrefPubMedGoogle Scholar
  • 4 Salzer JL, Brophy PJ, Peles E. Molecular domains of myelinated axons in the peripheral nervous system. Glia 2008; 56: 1532-1540
    CrossrefPubMedGoogle Scholar
  • 5 Rosenbluth J. Multiple functions of the paranodal junction of myelinated nerve fibers. J Neurosci Res 2009; 87: 3250-3258
    CrossrefPubMedGoogle Scholar
  • 6 Doppler K, Werner C, Sommer C. Disruption of nodal architecture in skin biopsies of patients with demyelinating neuropathies. J Peripher Nerv Syst 2013; 18: 168-176
    CrossrefPubMedGoogle Scholar
  • 7 Doppler K, Werner C, Henneges C. et al. Analysis of myelinated fibers in human skin biopsies of patients with neuropathies. J Neurol 2012; 259: 1879-1887
    CrossrefPubMedGoogle Scholar
  • 8 Li J, Bai Y, Ghandour K. et al. Skin biopsies in myelin-related neuropathies: bringing molecular pathology to the bedside. Brain 2005; 128: 1168-1177
    CrossrefPubMedGoogle Scholar
  • 9 Cifuentes-Diaz C, Dubourg O, Irinopoulou T. et al. Nodes of ranvier and paranodes in chronic acquired neuropathies. PLoS One 2011; 6: e14533
    CrossrefPubMedGoogle Scholar
  • 10 Peltier AC, Myers MI, Artibee KJ. et al. Evaluation of dermal myelinated nerve fibers in diabetes mellitus. J Peripher Nerv Syst 2013; 18: 162-167
    CrossrefPubMedGoogle Scholar
  • 11 Allt G, Cavanagh JB. Ultrastructural changes in the region of the node of ranvier in the rat caused by diphtheria toxin. Brain 1969; 92: 459-468
    CrossrefPubMedGoogle Scholar
  • 12 Allt G. Repair of segmental dehyelination in peripheral nerves: an electron microscope study. Brain 1969; 92: 639-646
    CrossrefPubMedGoogle Scholar
  • 13 Weller RO, Nester B. Early changes at the node of Ranvier in segmental demyelination. Histochemical and electron microscopic observations. Brain 1972; 95: 665-674
    CrossrefPubMedGoogle Scholar
  • 14 Devaux JJ, Odaka M, Yuki N. Nodal proteins are target antigens in Guillain-Barre syndrome. J Peripher Nerv Syst 2012; 17: 62-71
    CrossrefPubMedGoogle Scholar
  • 15 Devaux JJ. Antibodies to gliomedin cause peripheral demyelinating neuropathy and the dismantling of the nodes of Ranvier. Am J Pathol 2012; 181: 1402-1413
    CrossrefPubMedGoogle Scholar
  • 16 Querol L, Nogales-Gadea G, Rojas-Garcia R. et al. Antibodies to contactin-1 in chronic inflammatory demyelinating polyneuropathy. Ann Neurol 2013; 73: 370-380
    CrossrefPubMedGoogle Scholar
  • 17 Ng JK, Malotka J, Kawakami N. et al. Neurofascin as a target for autoantibodies in peripheral neuropathies. Neurology 2012; 79: 2241-2248
    CrossrefPubMedGoogle Scholar
  • 18 Pruss H, Schwab JM, Derst C. et al. Neurofascin as target of autoantibodies in Guillain-Barre syndrome. Brain 2011; 134: e173
    CrossrefPubMedGoogle Scholar
  • 19 Mathey EK, Derfuss T, Storch MK. et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. J Exp Med 2007; 204: 2363-2372
    CrossrefPubMedGoogle Scholar
  • 20 Querol L, Nogales-Gadea G, Rojas-Garcia R. et al. Neurofascin IgG4 antibodies in CIDP associate with disabling tremor and poor response to IVIg. Neurology 2014; 82: 879-886
    CrossrefPubMedGoogle Scholar
  • 21 Devaux JJ, Miura Y, Fukami Y. et al. Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy. Neurology 2016; 86: 800-807
    CrossrefPubMedGoogle Scholar
  • 22 Ogata H, Yamasaki R, Hiwatashi A. et al. Characterization of IgG4 anti-neurofascin 155 antibody-positive polyneuropathy. Ann Clin Transl Neurol 2015; 2: 960-971
    CrossrefPubMedGoogle Scholar
  • 23 Kawamura N, Yamasaki R, Yonekawa T. et al. Anti-neurofascin antibody in patients with combined central and peripheral demyelination. Neurology 2013; 81: 714-722
    CrossrefPubMedGoogle Scholar
  • 24 Vural A, Gocmen R, Kurne AT. et al. Fulminant central plus peripheral nervous system demyelination without antibodies to neurofascin. Can J Neurol Sci 2016; 43: 149-156
    CrossrefPubMedGoogle Scholar
  • 25 Doppler K, Appeltshauser L, Wilhelmi K. et al. Destruction of paranodal architecture in inflammatory neuropathy with anti-contactin-1 autoantibodies. J Neurol Neurosurg Psychiatry 2015; 86: 720-728
    CrossrefPubMedGoogle Scholar
  • 26 Miura Y, Devaux JJ, Fukami Y. et al. Contactin 1 IgG4 associates to chronic inflammatory demyelinating polyneuropathy with sensory ataxia. Brain 2015; 138: 1484-1491
    CrossrefPubMedGoogle Scholar
  • 27 Doppler K, Appeltshauser L, Villmann C. et al. Auto-antibodies to contactin-associated protein 1 (Caspr) in two patients with painful inflammatory neuropathy. Brain 2016; 139: 2617-2630
    CrossrefPubMedGoogle Scholar
  • 28 Cortese A, Devaux JJ, Zardini E. et al. Neurofascin-155 as a putative antigen in combined central and peripheral demyelination. Neurol Neuroimmunol Neuroinflamm 2016; 3: e238
    PubMedGoogle Scholar
  • 29 Kadoya M, Kaida K, Koike H. et al. IgG4 anti-neurofascin155 antibodies in chronic inflammatory demyelinating polyradiculoneuropathy: Clinical significance and diagnostic utility of a conventional assay. J Neuroimmunol 2016; 301: 16-22
    CrossrefPubMedGoogle Scholar
  • 30 Uncini A. A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Exp Neurol 2012; 235: 513-516
    CrossrefPubMedGoogle Scholar
  • 31 Uncini A, Susuki K, Yuki N. Nodo-paranodopathy: beyond the demyelinating and axonal classification in anti-ganglioside antibody-mediated neuropathies. Clin Neurophysiol 2013; 124: 1928-1934
    CrossrefPubMedGoogle Scholar
  • 32 Labasque M, Hivert B, Nogales-Gadea G. et al. Specific contactin N-glycans are implicated in neurofascin binding and autoimmune targeting in peripheral neuropathies. J Biol Chem 2014; 289: 7907-7918
    CrossrefPubMedGoogle Scholar
  • 33 Tao MH, Smith RI, Morrison SL. Structural features of human immunoglobulin G that determine isotype-specific differences in complement activation. J Exp Med 1993; 178: 661-667
    CrossrefPubMedGoogle Scholar
  • 34 Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol 2014; 5: 520
    PubMedGoogle Scholar
  • 35 Yuki N, Watanabe H, Nakajima T. et al. IVIG blocks complement deposition mediated by anti-GM1 antibodies in multifocal motor neuropathy. J Neurol Neurosurg Psychiatry 2011; 82: 87-91
    CrossrefPubMedGoogle Scholar
  • 36 Piepers S, Jansen MD, Cats EA. et al. IVIg inhibits classical pathway activity and anti-GM1 IgM-mediated complement deposition in MMN. J Neuroimmunol 2010; 229: 256-262
    CrossrefPubMedGoogle Scholar
  • 37 Appeltshauser L, Weishaupt A, Sommer C et al. Complement deposition induced by binding of anti-contactin-1 auto-antibodies is modified by immunoglobulins. Exp Neurol 2016
    PubMed
  • 38 Manso C, Querol L, Mekaouche M et al. Contactin-1 IgG4 antibodies cause paranode dismantling and conduction defects. Brain 2016
    PubMed
  • 39 Querol L, Rojas-Garcia R, Diaz-Manera J. et al. Rituximab in treatment-resistant CIDP with antibodies against paranodal proteins. Neurol Neuroimmunol Neuroinflamm 2015; 2: e149
    PubMedGoogle Scholar
  • 40 Boyle ME, Berglund EO, Murai KK. et al. Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron 2001; 30: 385-397
    CrossrefPubMedGoogle Scholar