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Journal of Clinical Immunology
Published in: Journal of Clinical Immunology 1/2014

Open Access 01-07-2014

MMN: From Immunological Cross-Talk to Conduction Block

Authors: Oliver Harschnitz, Bas A. Jongbloed, Hessel Franssen, Dirk C. G Straver, W. Ludo van der Pol, Leonard H. van den Berg

Published in: Journal of Clinical Immunology | Special Issue 1/2014

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Abstract

Multifocal motor neuropathy (MMN) is a rare inflammatory neuropathy characterized by progressive, asymmetric distal limb weakness and conduction block (CB). Clinically MMN is a pure motor neuropathy, which as such can mimic motor neuron disease. GM1-specific IgM antibodies are present in the serum of approximately half of all MMN patients, and are thought to play a key role in the immune pathophysiology. Intravenous immunoglobulin (IVIg) treatment has been shown to be effective in MMN in five randomized placebo-controlled trials. Despite long-term treatment with intravenous immunoglobulin (IVIg), which is efficient in the majority of patients, slowly progressive axonal degeneration and subsequent muscle weakness cannot be fully prevented. In this review, we will discuss the current understanding of the immune pathogenesis underlying MMN and how this may cause CB, available treatment strategies and future therapeutic targets.
Literature
1.
Cats EA, van der Pol WL, Piepers S, Franssen H, Jacobs BC, van den Berg-Vos RM, et al. Correlates of outcome and response to IVIg in 88 patients with multifocal motor neuropathy. Neurology. 2010;75(9):818–25.PubMedCrossRef
2.
3.
van Asseldonk JT, Franssen H, van den Berg-Vos RM, Wokke JH, van den Berg LH. Multifocal motor neuropathy. Lancet Neurol. 2005;4(5):309–19.PubMedCrossRef
4.
Vlam L, van der Pol WL, Cats EA, Straver DC, Piepers S, Franssen H, et al. Multifocal motor neuropathy: diagnosis, pathogenesis and treatment strategies. Nat Rev Neurol. 2012;8(1):48–58.
5.
Straver DC, van Asseldonk JT, Notermans NC, Wokke JH, van den Berg LH, Franssen H. Cold paresis in multifocal motor neuropathy. J Neurol. 2011;258(2):212–7.PubMedCentralPubMedCrossRef
6.
Chad DA, Hammer K, Sargent J. Slow resolution of multifocal weakness and fasciculation: a reversible motor neuron syndrome. Neurology. 1986;36(9):1260–3.PubMedCrossRef
7.
Roth G, Rohr J, Magistris MR, Ochsner F. Motor neuropathy with proximal multifocal persistent conduction block, fasciculations and myokymia. Evolution to tetraplegia. Eur Neurol. 1986;25(6):416–23.PubMedCrossRef
8.
Parry GJ, Clarke S. Multifocal acquired demyelinating neuropathy masquerading as motor neuron disease. Muscle Nerve. 1988;11(2):103–7.PubMedCrossRef
9.
Auer RN, Bell RB, Lee MA. Neuropathy with onion bulb formations and pure motor manifestations. Can J Neurol Sci. 1989;16(2):194–7.PubMed
10.
Kaji R, Oka N, Tsuji T, Mezaki T, Nishio T, Akiguchi I, et al. Pathological findings at the site of conduction block in multifocal motor neuropathy. Ann Neurol. 1993;33(2):152–8.PubMedCrossRef
11.
Corbo M, Abouzahr MK, Latov N, Iannaccone S, Quattrini A, Nemni R, et al. Motor nerve biopsy studies in motor neuropathy and motor neuron disease. Muscle Nerve. 1997;20(1):15–21.PubMedCrossRef
12.
Taylor BV, Dyck PJ, Engelstad J, Gruener G, Grant I, Dyck PJ. Multifocal motor neuropathy: pathologic alterations at the site of conduction block. J Neuropathol Exp Neurol. 2004;63(2):129–37.PubMed
13.
Pestronk A, Cornblath DR, Ilyas AA, Baba H, Quarles RH, Griffin JW, et al. A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann Neurol. 1988;24(1):73–8.PubMedCrossRef
14.
van Schaik IN, Bossuyt PM, Brand A, Vermeulen M. Diagnostic value of GM1 antibodies in motor neuron disorders and neuropathies: a meta-analysis. Neurology. 1995;45(8):1570–7.PubMedCrossRef
15.
Pestronk A, Choksi R, Blume G, Lopate G. Multifocal motor neuropathy: serum IgM binding to a GM1 ganglioside-containing lipid mixture but not to GM1 alone. Neurology. 1997;48(4):1104–6.PubMedCrossRef
16.
Galban-Horcajo F, Fitzpatrick AM, Hutton AJ, Dunn SM, Kalna G, Brennan KM, et al. Antibodies to heteromeric glycolipid complexes in multifocal motor neuropathy. Eur J Neurol. 2013;20(1):62–70.PubMedCrossRef
17.
Nobile-Orazio E, Giannotta C, Musset L, Messina P, Leger JM. Sensitivity and predictive value of anti-GM1/galactocerebroside IgM antibodies in multifocal motor neuropathy. J Neurol Neurosurg Psychiatry 2013.
18.
Taylor BV, Gross L, Windebank AJ. The sensitivity and specificity of anti-GM1 antibody testing. Neurology. 1996;47(4):951–5.PubMedCrossRef
19.
Piepers S, Jansen MD, Cats EA, van Sorge NM, van den Berg LH, van der Pol WL. IVIg inhibits classical pathway activity and anti-GM1 IgM-mediated complement deposition in MMN. J Neuroimmunol. 2010;229(1–2):256–62.PubMedCrossRef
20.
Vlam L, Cats EA, Willemse E, Franssen H, Medic J, Piepers S, et al. Pharmacokinetics of intravenous immunoglobulin in multifocal motor neuropathy. J Neurol Neurosurg Psychiatry 2013.
21.
Ogawa-Goto K, Funamoto N, Ohta Y, Abe T, Nagashima K. Myelin gangliosides of human peripheral nervous system: an enrichment of GM1 in the motor nerve myelin isolated from cauda equina. J Neurochem. 1992;59(5):1844–9.PubMedCrossRef
22.
Gong Y, Tagawa Y, Lunn MP, Laroy W, Heffer-Lauc M, Li CY, et al. Localization of major gangliosides in the PNS: implications for immune neuropathies. Brain. 2002;125(Pt 11):2491–506.PubMedCrossRef
23.
Svennerholm L, Bostrom K, Fredman P, Jungbjer B, Lekman A, Mansson JE, et al. Gangliosides and allied glycosphingolipids in human peripheral nerve and spinal cord. Biochim Biophys Acta. 1994;1214(2):115–23.PubMedCrossRef
24.
Ogawa-Goto K, Funamoto N, Abe T, Nagashima K. Different ceramide compositions of gangliosides between human motor and sensory nerves. J Neurochem. 1990;55(5):1486–93.PubMedCrossRef
25.
Corbo M, Quattrini A, Lugaresi A, Santoro M, Latov N, Hays AP. Patterns of reactivity of human anti-GM1 antibodies with spinal cord and motor neurons. Ann Neurol. 1992;32(4):487–93.PubMedCrossRef
26.
Corbo M, Quattrini A, Latov N, Hays AP. Localization of GM1 and Gal(beta 1–3)GalNAc antigenic determinants in peripheral nerve. Neurology. 1993;43(4):809–14.PubMedCrossRef
27.
Ganser AL, Kirschner DA, Willinger M. Ganglioside localization on myelinated nerve fibres by cholera toxin binding. J Neurocytol. 1983;12(6):921–38.PubMedCrossRef
28.
De Angelis MV, Di MA, Lupo S, Gambi D, Uncini A, Lugaresi A. Anti-GD1a antibodies from an acute motor axonal neuropathy patient selectively bind to motor nerve fiber nodes of Ranvier. J Neuroimmunol. 2001;121(1–2):79–82.PubMedCrossRef
29.
van Sorge NM, Yuki N, Jansen MD, Nishimoto Y, Susuki K, Wokke JH, et al. Leukocyte and complement activation by GM1-specific antibodies is associated with acute motor axonal neuropathy in rabbits. J Neuroimmunol. 2007;182(1–2):116–23.PubMedCrossRef
30.
Susuki K, Rasband MN, Tohyama K, Koibuchi K, Okamoto S, Funakoshi K, et al. Anti-GM1 antibodies cause complement-mediated disruption of sodium channel clusters in peripheral motor nerve fibers. J Neurosci. 2007;27(15):3956–67.PubMedCrossRef
31.
McGonigal R, Rowan EG, Greenshields KN, Halstead SK, Humphreys PD, Rother RP, et al. Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain. 2010;133(Pt 7):1944–60.PubMedCrossRef
32.
O’Hanlon GM, Humphreys PD, Goldman RS, Halstead SK, Bullens RW, Plomp JJ, et al. Calpain inhibitors protect against axonal degeneration in a model of anti-ganglioside antibody-mediated motor nerve terminal injury. Brain. 2003;126(Pt 11):2497–509.PubMedCrossRef
33.
Goodfellow JA, Bowes T, Sheikh K, Odaka M, Halstead SK, Humphreys PD, et al. Overexpression of GD1a ganglioside sensitizes motor nerve terminals to anti-GD1a antibody-mediated injury in a model of acute motor axonal neuropathy. J Neurosci. 2005;25(7):1620–8.PubMedCrossRef
34.
Halstead SK, Humphreys PD, Goodfellow JA, Wagner ER, Smith RA, Willison HJ. Complement inhibition abrogates nerve terminal injury in Miller Fisher syndrome. Ann Neurol. 2005;58(2):203–10.PubMedCrossRef
35.
Yuki N, Shahrizaila N. Keeping it simple: is there a need for the various subtyping of axonal forms of Guillain-Barre syndrome? J Neurol Neurosurg Psychiatry. 2011;82(6):592.PubMedCrossRef
36.
Andrew SM, Titus JA. Fragmentation of immunoglobulin M. Curr Protoc Immunol. 2001 May;Chapter 2:Unit.
37.
Shimizu F, Sano Y, Abe MA, Maeda T, Ohtsuki S, Terasaki T, et al. Peripheral nerve pericytes modify the blood-nerve barrier function and tight junctional molecules through the secretion of various soluble factors. J Cell Physiol. 2011;226(1):255–66.PubMedCrossRef
38.
Shimizu F, Omoto M, Sano Y, Mastui N, Miyashiro A, Tasaki A, et al. Sera from patients with multifocal motor neuropathy disrupt the blood-nerve barrier. J Neurol Neurosurg Psychiatry 2013.
39.
Thomas PD, Brewer GJ. Gangliosides and synaptic transmission. Biochim Biophys Acta. 1990;1031(3):277–89.PubMedCrossRef
40.
Fewou SN, Plomp JJ, Willison HJ. The pre-synaptic motor nerve terminal as a site for antibody-mediated neurotoxicity in autoimmune neuropathies and synaptopathies. J Anat. 2014;224(1):36–44.PubMedCrossRef
41.
Zitman FM, Todorov B, Jacobs BC, Verschuuren JJ, Furukawa K, Furukawa K, et al. Neuromuscular synaptic function in mice lacking major subsets of gangliosides. Neuroscience. 2008;156(4):885–97.PubMedCrossRef
42.
Zitman FM, Todorov B, Verschuuren JJ, Jacobs BC, Furukawa K, Furukawa K, et al. Neuromuscular synaptic transmission in aged ganglioside-deficient mice. Neurobiol Aging. 2011;32(1):157–67.PubMedCrossRef
43.
Plomp JJ, Molenaar PC, O’Hanlon GM, Jacobs BC, Veitch J, Daha MR, et al. Miller Fisher anti-GQ1b antibodies: alpha-latrotoxin-like effects on motor end plates. Ann Neurol. 1999;45(2):189–99.PubMedCrossRef
44.
Terenghi F, Allaria S, Scarlato G, Nobile-Orazio E. Multifocal motor neuropathy and Campylobacter jejuni reactivity. Neurology. 2002;59(2):282–4.PubMedCrossRef
45.
Cats EA, Bertens AS, Veldink JH, van den Berg LH, van der Pol WL. Associated autoimmune diseases in patients with multifocal motor neuropathy and their family members. J Neurol. 2012;259(6):1137–41.PubMedCentralPubMedCrossRef
46.
Laki J, Lundstrom E, Snir O, Ronnelid J, Ganji I, Catrina AI, et al. Very high levels of anti-citrullinated protein antibodies are associated with HLA-DRB1*15 non-shared epitope allele in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64(7):2078–84.PubMedCrossRef
47.
van den Berg LH, Franssen H, Wokke JH. The long-term effect of intravenous immunoglobulin treatment in multifocal motor neuropathy. Brain. 1998;121(Pt 3):421–8.PubMedCrossRef
48.
Pestronk A, Chuquilin M, Choksi R. Motor neuropathies and serum IgM binding to NS6S heparin disaccharide or GM1 ganglioside. J Neurol Neurosurg Psychiatry. 2010;81(7):726–30.PubMedCrossRef
49.
Willison HJ, Goodyear CS. Glycolipid antigens and autoantibodies in autoimmune neuropathies. Trends Immunol. 2013;34(9):453–9.PubMedCrossRef
50.
Lingwood D, Binnington B, Rog T, Vattulainen I, Grzybek M, Coskun U, et al. Cholesterol modulates glycolipid conformation and receptor activity. Nat Chem Biol. 2011;7(5):260–2.PubMedCrossRef
51.
Franssen H, Straver DC. Pathophysiology of immune-mediated demyelinating neuropathies–part II: neurology. Muscle Nerve. 2014;49(1):4–20.PubMedCrossRef
52.
Susuki K, Baba H, Tohyama K, Kanai K, Kuwabara S, Hirata K, et al. Gangliosides contribute to stability of paranodal junctions and ion channel clusters in myelinated nerve fibers. Glia. 2007;55(7):746–57.PubMedCrossRef
53.
Suzuki N, Kato S, Kato M, Warita H, Mizuno H, Kato M, et al. FUS/TLS-immunoreactive neuronal and glial cell inclusions increase with disease duration in familial amyotrophic lateral sclerosis with an R521C FUS/TLS mutation. J Neuropathol Exp Neurol. 2012;71(9):779–88.PubMedCrossRef
54.
Kaji R. Physiology of conduction block in multifocal motor neuropathy and other demyelinating neuropathies. Muscle Nerve. 2003;27(3):285–96.PubMedCrossRef
55.
Kiernan MC, Walters RJ, Andersen KV, Taube D, Murray NM, Bostock H. Nerve excitability changes in chronic renal failure indicate membrane depolarization due to hyperkalaemia. Brain. 2002;125(Pt 6):1366–78.PubMedCrossRef
56.
Priori A, Cinnante C, Pesenti A, Carpo M, Cappellari A, Nobile-Orazio E, et al. Distinctive abnormalities of motor axonal strength-duration properties in multifocal motor neuropathy and in motor neurone disease. Brain. 2002;125(Pt 11):2481–90.PubMedCrossRef
57.
Priori A, Bossi B, Ardolino G, Bertolasi L, Carpo M, Nobile-Orazio E, et al. Pathophysiological heterogeneity of conduction blocks in multifocal motor neuropathy. Brain. 2005;128(Pt 7):1642–8.PubMedCrossRef
58.
Boerio D, Creange A, Hogrel JY, Gueguen A, Bertrand D, Lefaucheur JP. Nerve excitability changes after intravenous immunoglobulin infusions in multifocal motor neuropathy and chronic inflammatory demyelinating neuropathy. J Neurol Sci. 2010;292(1–2):63–71.PubMedCrossRef
59.
van Asseldonk JT, van den Berg LH, van den Berg-Vos RM, Wieneke GH, Wokke JH, Franssen H. Demyelination and axonal loss in multifocal motor neuropathy: distribution and relation to weakness. Brain. 2003;126(Pt 1):186–98.PubMedCrossRef
60.
Cats EA, Jacobs BC, Yuki N, Tio-Gillen AP, Piepers S, Franssen H, et al. Multifocal motor neuropathy: association of anti-GM1 IgM antibodies with clinical features. Neurology. 2010;75(22):1961–7.PubMedCrossRef
61.
Eftimov F, Vermeulen M, de Haan RJ, van den Berg LH, van Schaik IN. Subcutaneous immunoglobulin therapy for multifocal motor neuropathy. J Peripher Nerv Syst. 2009;14(2):93–100.PubMedCrossRef
62.
Leger JM, Chassande B, Musset L, Meininger V, Bouche P, Baumann N. Intravenous immunoglobulin therapy in multifocal motor neuropathy: a double-blind, placebo-controlled study. Brain. 2001;124(Pt 1):145–53.PubMedCrossRef
63.
van Schaik IN, van den Berg LH, de Haan R, Vermeulen M. Intravenous immunoglobulin for multifocal motor neuropathy. Cochrane Database Syst Rev. 2005;(2):CD004429.
64.
Piepers S, Berg-Vos R, van der Pol WL, Franssen H, Wokke J, Van den Berg L. Mycophenolate mofetil as adjunctive therapy for MMN patients: a randomized, controlled trial. Brain. 2007;130(Pt 8):2004–10.PubMedCrossRef
65.
Fitzpatrick AM, Mann CA, Barry S, Brennan K, Overell JR, Willison HJ. An open label clinical trial of complement inhibition in multifocal motor neuropathy. J Peripher Nerv Syst. 2011;16(2):84–91.PubMedCrossRef
66.
Phongsisay V, Susuki K, Matsuno K, Yamahashi T, Okamoto S, Funakoshi K, et al. Complement inhibitor prevents disruption of sodium channel clusters in a rabbit model of Guillain-Barre syndrome. J Neuroimmunol. 2008;205(1–2):101–4.PubMedCrossRef
67.
Chaudhry V, Cornblath DR. An open-label trial of rituximab (Rituxan(R)) in multifocal motor neuropathy. J Peripher Nerv Syst. 2010;15(3):196–201.PubMedCrossRef
68.
Pestronk A, Florence J, Miller T, Choksi R, Al-Lozi MT, Levine TD. Treatment of IgM antibody associated polyneuropathies using rituximab. J Neurol Neurosurg Psychiatry. 2003;74(4):485–9.PubMedCentralPubMedCrossRef
69.
Stork AC, Notermans NC, van den Berg LH, Schellevis RD, Niermeijer JM, Nederend M, et al. Fcgamma receptor IIIA genotype is associated with rituximab response in antimyelin-associated glycoprotein neuropathy. J Neurol Neurosurg Psychiatry 2014.
70.
Reinhart WH, Berchtold PE. Effect of high-dose intravenous immunoglobulin therapy on blood rheology. Lancet. 1992;339(8794):662–4.PubMedCrossRef
71.
Kuitwaard K, de Gelder J, Tio-Gillen AP, Hop WC, van Gelder T, van Toorenenbergen AW, et al. Pharmacokinetics of intravenous immunoglobulin and outcome in Guillain-Barre syndrome. Ann Neurol. 2009;66(5):597–603.PubMedCrossRef
72.
Wasserman RL, Melamed I, Stein MR, Gupta S, Puck J, Engl W, et al. Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency. J Allergy Clin Immunol. 2012;130(4):951–7.PubMedCrossRef
73.
Bergin PS, Miller DH, Hirsch NP, Murray NM. Failure of 3,4-diaminopyridine to reverse conduction block in inflammatory demyelinating neuropathies. Ann Neurol. 1993;34(3):406–9.PubMedCrossRef
74.
Russell JW, Windebank AJ, Harper Jr CM. Treatment of stable chronic demyelinating polyneuropathy with 3,4-diaminopyridine. Mayo Clin Proc. 1995;70(6):532–9.PubMedCrossRef
Metadata
Title
MMN: From Immunological Cross-Talk to Conduction Block
Authors
Oliver Harschnitz
Bas A. Jongbloed
Hessel Franssen
Dirk C. G Straver
W. Ludo van der Pol
Leonard H. van den Berg
Publication date
01-07-2014
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue Special Issue 1/2014
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-014-0026-3

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