Abstract
The brain has traditionally been regarded as immunologically privileged because of the existence of the blood-brain barrier, the absence of conventional lymphatic drainage and the unusual tolerance of the brain to transplanted tissue. However, over the last decades, clinical evidence has accumulated indicating that the immune system may play an important role in some central nervous system diseases usually regarded as degenerative. The best-known example is paraneo-plastic cerebellar ataxia (PCA), which is thought to involve autoimmune cross-reaction between tumour and nervous system antigens. In the past 15 years, several antibodies directed against neuronal and tumoral antigens have been described in association with PCA, leading to the definition of different subtypes of PCA based on their associated antibodies, the clinical evolution and the type of tumour. Circulating antibodies have also been described in patients with non-paraneoplastic cerebellar ataxia (N-PCA), suggesting that the immune system may be involved in certain cases of sporadic cerebellar ataxia. In this review, the clinical presentation of the different subtypes of potentially immune-mediated PCA and N-PCA will be described, and the experimental approaches that have been developed in order to understand the pathogenic role of the immune system in these ataxias will be discussed.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Posner JB, Furneaux HM (1990) Paraneoplastic syndromes. In: Waksman BH (ed) Immunologic mechanisms in neurologic and psychiatric diseases. Raven Press, New York, pp 187–219
Brouwer B (1919) Beitrag zur Kenntnis der chronischen diffusen Kleinhirnerkrankungen. Neurol Centralbl 38:674–682
Brain WR, Daniel PM, Greenfield JG (1951) Subacute cortical cerebellar degeneration and its relation to carcinoma. J Neurol Neurosurg Psychiatry 14:59–75
Henson RA, Urich H (1982) Paraneoplastic disorders. In: Henson RA, Urich H, (ed) Cancer and the nervous system. Blackwell Scientific Publication, Oxford, pp 311–621
Anderson NE, Cunningham JM, Posner JB (1987) Autoimmune pathogenesis of para-neoplastic neurological syndromes. CRC Crit Rev Neurobiol 3:245–299
Verschnüren J, Chuang L, Rosenblum MK et al (1996) Inflammatory infiltrates and complete absence of Purkinje cells in anti-Yo associated paraneoplastic cerebellar degeneration. Acta Neuropathol 91:519–525
Russell DS (1961) Encephalomyelitis and carcinomatous neuropathy. In: Van Bogaert L, Radermecker J, Hozay J, Lowenthal A (eds) The encephalitides. Elsevier, Amsterdam, pp 131–135
Trotter JL, Hendin BA, Osterland CK (1976) Cerebellar degeneration with Hodgkin disease. Arch Neurol 33:660–661
Dalmau JO, Posner JB (1999) Paraneoplastic syndromes. Arch Neurol 56:405–408
Keime-Guibert F, Graus F, Fleury A et al (2000) Treatment of paraneoplastic neurological syndromes with anti-neuronal antibodies (anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide and methylprednisolone. J Neurol Neurosurg Psychiatry 68:479–482
Greenlee JE, Brashear HR (1983) Antibodies to cerebellar Purkinje cells in patients with paraneoplastic cerebellar degeneration and ovarian carcinoma. Ann Neurol 14:609–613
Jaeckle KA, Graus F, Houghton A et al (1985) Autoimmune response of patients with paraneoplastic degeneration to a Purkinje cell cytoplasmic protein antigen. Ann Neurol 18:592–600
Peterson K, Rosenblum MK, Kotanides H, Posner JB (1992) Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology 42:1931–1937
Rojas I, Graus F, Keime-Guibert F et al (2000) Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 55:713–715
Felician O, Renard JL, Vega F et al (1995) Paraneoplastic cerebellar degeneration with anti-Yo antibody in man. Neurology 45:1226–1227
Krakauer J, Balmaceda C, Gluck JT et al (1996) Anti-Yo-associated paraneoplastic cerebellar degeneration in a man with adenocarcinoma of unknown origin. Neurology 46:1486–1487
Anderson NE, Rosenblum MK, Posner JB (1988) Paraneoplastic cerebellar degeneration: clinical-immunological correlation. Ann Neurol 24:559–567
Furneaux HM, Reich L, Posner JB (1990) Autoantibody synthesis in the central nervous system of patients with paraneoplastic syndromes. Neurology 40:1085–1091
Giometto B, Marchiori GC, Nicolao P et al (1997) Subacute cerebellar degeneration with anti-Yo autoantibodies: immunohistochemical analysis of the immune reaction in the central nervous system. Neuropathol Appl Neurobiol 23:468–474
Chen YT, Rettig WJ, Yenamandra AK et al (1990) Cerebellar degeneration related (CDR) antigen: a highly conserved neuroectodermal marker mapped to chromosomes X in human mouse. Proc Natl Acad Sci 87:3077–3081
Fatallah-Shaykh H, Wolf S, Wong E et al (1991) Cloning of a leucine-zipper protein recognized by the sera of patients with antibody-associated paraneoplastic cerebellar degeneration. Proc Natl Acad Sci USA 88:3451–3454
Sakai K, Mitchell DJ, Tsukamoto T, Steinman L (1990) Isolation of a complementary DNA clone encoding an autoantigen recognized by an anti-neuronal cell antibody from a patient with paraneoplastic cerebellar degeneration. Ann Neurol 28:692–698
Darnell JC, Albert ML, Darnell RB (2000) Cdr2, a target antigen of naturally occurring human tumor immunity, is widely expressed in gynecological tumors. Cancer Res 60:2136–2139
Okano HJ, Park WY, Corradi JP, Darnell RB (1999) The cytoplasmic Purkinje onconeural antigen cdr2 down-regulates c-Myc function: implications for neuronal and tumor cell survival. Genes Dev 16:2087–2097
Sakai K, Ogasawara T, Hirose G et al (1993) Analysis of autoantibody binding to 52-kd paraneoplastic cerebellar degeneration-associated antigen expressed in recombinant proteins. Ann Neurol 33:373–380
Borges LF, Elliot PJ, Gill R et al (1985) Selective extraction of small and large molecules from the cerebrospinal fluid by Purkinje neurons. Science 228:346–348
Fabian RH, Petroff G (1987) Intraneuronal IgG in the central nervous system: uptake by retrograde axonal transport. Neurology 37:1780–1784
Graus F, Ilia I, Agusti M, Ribalta T et al (1991) Effect of intraventricular injection of anti-Purkinje cell antibody (anti-Yo) in a guinea pig model. J Neurol Sci 106:82–87
Jaeckle KA, Stroop WG (1986) Intraventricular injection of paraneoplastic anti-Purkinje cell antibody in a rat model. Neurology 36 (Suppl 1):332
Greenlee JE, Burns JB, Rose JW et al (1995) Uptake of systematically administered human anti-cerebellar antibody by rat Purkinje cells following blood brain barrier disruption. Acta Neuropathol 89:341–345
Sakai K, Gofuku M, Kitagawa Y et al (1995) Induction of anti-Purkinje cell antibodies in vivo by immunizing with a recombinant 52 kDa paraneoplastic cerebellar degeneration associated protein. J Neuroimmunol 60:135–141
Tanaka M, Tanaka K, Onoreda O, Tsuji S (1995) Trial to establish an animal model of paraneoplastic cerebellar degeneration with anti-Yo antibody: 1. Mouse strains bearing different MHC molecules produce antibodies on immunization with recombinant Yo protein, but do not cause Purkinje cell loss. Clin Neurol Neurosurg 97:95–100
Tanaka K, Tanaka M, Igarashi S et al (1995) Trial to estabUsh an animal model of para-neoplastic cerebellar degeneration with anti-Yo antibody: 2. Passive transfer of murine mononuclear cells activated with recombinant Yo protein to paraneoplastic cerebellar degeneration lymphocytes in severe combined immunodeficiency mice. Clin Neurol Neurosurg 97:101–105
Albert ML, Darnell JC, Bender A et al (1998) Tumor-specific killer cells in paraneo-plastic cerebellar degeneration. Nature Med 11:1321–1324
Albert ML, Austin L, Darnell RB (2000) Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration. Ann Neurol 47:9–17
Voltz RD, Posner JB, Dalmau J, Graus F (1997) Paraneoplastic encephalomyelitis: an update of the effects of the anti-Hu immune response on the nervous system and tumour. J Neurol Neurosurg Psychiatry 63:133–136
Graus F, Cordon-Cardo C, Posner JB (1985) Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology 35:538–543
Dalmau J, Graus F, Rosenblum MK, Posner JB (1992) Anti-Hu associated paraneoplastic encephalomyelitis/sensory neuropathy. Medicine 71:59–72
Mason WP, Graus F, Lang B et al (1997). Paraneoplastic cerebellar degeneration and small cell lung cancer. Brain 120:1279–1300
Dalmau J, Furneaux HM, Rosenblum MK et al (1991) Detection of the anti-Hu anti-body in specific regions of the nervous system and tumor from patients with paraneoplastic encephalomyelitis and sensory neuropathy. Neurology 41:1757–1764
Greenlee JE, Parks TN, Jaeckle KA (1993) Type IIa (anti-Hu) antineuronal antibodies produce destruction of rat cerebellar granule neurons in vitro. Neurology 43:2049–2054
Hormigo A, Lieberman F (1994) Nuclear localization of anti-Hu antibody is not associated with in vitro cytotoxicity. J Neuroimmunol 55:205–212
Sillevis Smitt PAE, Manley GT, Posner JB (1995) Immunization with the paraneoplastic encephalomyelitis antigen HuD does not cause neurologic disease in mice. Neurology 45:1873–1878
Panegyres PK, Reading MC, Esiri MM (1993) The inflammatory reaction of paraneoplastic ganglionitis and encephalitis: an immunohistochemical study. J Neurol 240:93–97
Jean WC, Dalmau J, Ho A, Posner JB (1994) Analysis of the IgG subclass distribution and inflammatory infiltrates in patients with anti-Hu associated paraneoplastic encephalomyelitis. Neurology 44:140–147
Szabo A, Dalmau J, Mauley G et al (1991) HuD, a paraneoplastic encephalomyelitis antigen, contains RNA-binding domains and is homologous to ELAV and sex-lethal. Cell 67:325–333
Dropcho EJ, King PH (1994) Autoantibodies against the Hel-Nl RNA-binding protein among patients with lung carcinoma: an association with type I anti-neuronal nuclear antibodies. Ann Neurol 36:200–205
Sakai K, Gofuku M, Kitagawa Y et al (1994) A hippocampal protein associated with paraneoplastic neurologic syndrome and small cell lung carcinoma. Biochem Biophys Res Commun 199:1200–1208
Marusich M, Furneaux H, Henion P, Weston J (1994) Hu neuronal proteins are expressed in proliferating neurogenic cells. J Neurobiol 25:143–155
Akamatsu W, Okano HJ, Osumi N et al (1999) Mammalian ELAV-like neuronal RNA-binding proteins HuB and HuC promote neuronal development in both the central and the peripheral nervous systems. Proc Natl Acad Sci 96:9885–9890
Carpentier AF, Rosenfeld MR, Delattre JY et al (1998) DNA vaccination with HuD inhibits growth of a neuroblastoma in mice. Clin Cancer Res 4:2819–2824
Voltz RD, Dalmau J, Posner JB, Rosenfeld MR (1998) T-cell receptor analysis in anti-Hu associated paraneoplastic encephalomyelitis. Neurology 51:1146–1150
Benyahia B, Liblau R, Merle-Béral H et al (1999) Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies. Ann Neurol 45:162–167
Tanaka K, Tanaka M, Inuzuka T et al (1999) Cytotoxic T lymphocyte-mediated cell death in paraneoplastic sensory neuropathy with anti-Hu antibody. J Neurol Sci 163:159–162
Antoine JC, Honnorat J, Koenig F et al (1993) Posterior uveitis and paraneoplastic encephalomyelitis with auto-antibodies reacting against cytoplasmic proteins of brain and retina. J Neurol Sci 117:215–223
Honnorat J, Antoine JC, Derrington E et al (1996) Antibodies to a subpopulation of glial cells and a 66 kD developmental protein in patients with paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 61:270–278
Honnorat J, Aguera M, Zalc B et al (1998) POP66, a paraneoplastic encephalomyelitis related antigen is a marker of aduh oligodendrocytes. J Neuropathol Exp Neurol 57:311–322
Rogemond V, Honnorat J (2000) Anti-CV2 autoantibodies and paraneoplastic neurological syndromes. Clin Rev Allergol Immunol 19:48–57
De la Sayette V, Bertran F, Honnorat J et al (1998) Paraneoplastic cerebellar syndrome and optic neuritis with anti-CV2 antibodies: clinical response to excision of the primary tumor. Arch Neurol 55:405–408
Honnorat J, Byk T, Küsters I et al (1999) Ulip/CRMP proteins are recognized by autoan-tibodies in paraneoplastic neurological syndromes. Eur J Neurosci 11:4226–4232
Wang LH, Strittmatter SM (1996) A family of rat CRMP genes is differentially expressed in the nervous system. J Neurosci 16:6197–207
Goshima Y, Nakamura F, Strittmatter P, Strittmatter SM (1995) Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature 376:509–14
Honnorat J, Guillon B, De Ferron E et al (1997) Association of anti-neural autoanti-bodies in a patient with paraneoplastic cerebellar syndrome and small cell lung carcinoma. J Neurol Neurosurg Psy 62:425–426
Antoine JC, Honnorat J, Camdessanche JP et al (2001) Paraneoplastic anti-CV2 anti-bodies react with peripheral nerve and are associated with a peripheral neuropathy different from that of anti-Hu syndromes. Ann Neurol 49:214–221
Telander RL, Smithson WA, Groover RV (1989) Clinical outcome in children with acute cerebellar encephalopathy and neuroblastoma. J Pediatr Surg 24:11–14
Anderson NE, Budde-Steffen C, Rosenblum MC et al (1988) Opsoclonus, myoclonus, ataxia and encephalopathy in adults with cancer: a distinct paraneoplastic syndrome. Medicine (Baltimore) 67:100–109
Hersh B, Dalmau J, Dangond F et al (1994) Paraneoplastic opsoclonus-myoclonus associated with anti-Hu antibody. Neurology 44:1754–1755
Cher LM, Hochberg FH, Teruya J et al (1995) Therapy for paraneoplastic neurological syndromes in six patients with protein A column immunoadsorption. Cancer 75:1678–1683
Honnorat J, Trillet M, Antoine JC et al (1997) Paraneoplastic opsomyoclonus, cerebellar ataxia and encephalopathy associated with anti-Purkinje cell antibodies. J Neurol 244:333–339
Luque FA, Furneaux HM, Ferziger R et al (1991) Anti-Ri: an autoantibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol 29:241–251
Hormigo A, Dalmau J, Rosenblum MK et al (1994) Immunological and pathological study of anti-Ri associated encephalopathy. Ann Neurol 36:896–902
Buckanovich ARJ, Yang YYL, Darnell RB (1993) The onconeural antigen Nova-1 is a neuron RNA-binding protein and is specifically expressed in the developing motor system. Neuron 11:657–672
Yang YL, Lin Yin G, Darnell RB (1998) The neuronal RNA-binding protein Nova-2 is implicated as the autoantigen targeted in POMA patients with dementia. Proc Nad Acad Sci USA 95:13254–13259
Jensen KB, Dredge BK, Stefani G et al (2000) Nova-1 regulates neuron-specific alter-native splicing and is essential for neuronal viability. Neuron 25:359–371
Polyrides AD, Okano HJ, Yang YY et al (2000) A brain-enriched polyrimidine tract-binding protein antagonizes the ability of NOVA to regulate neuron-specific alternative splicing. Proc Natl Acad Sci USA 97:6350–6355
Buckanovich ARJ, Posner JB, Darnell RB (1996) Nova, the paraneoplastic Ri antigen is homogous to an RNA-binding protein, the activity of which is inhibited by paraneoplastic antibodies. J Neurosci 16:1114–1122
Buckanovich RJ, Darnell RB (1997) The neuronal RNA binding protein NOVA 1 recognizes specific RNA targets in vitro and in vivo. Mol Cell Biol 17:3194–3201
Ryan SG, Buckwalter MS, Lynch JW et al (1994) A missense mutation in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor in the spasmodic mouse. Nat Genet 7:131–135
Saul B, Schmieden V, Kling C et al (1994) Point mutation of glycine receptor alpha 1 subunit in the spasmodic mouse affects agonist responses. FEBS Lett 350:71–76
Malamud N (1957) Atlas of neuropathology. University of California Press, Berkeley, pp 118
Hammack J, Kotanides H, Rosenblum MK, Posner JB (1992) Paraneoplastic cerebellar degeneration. II. Clinical and immunologic findings in 21 patients with Hodgkin’s disease. Neurology 42:1938–1943
Sillevis-Smitt P, Kinoshita A, De Leeuw B et al (2000) Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med 342:21–27
Graus F, Dalmau J, Valldeoriola F et al (1997) Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin’s disease. J Neuroimmunol 74:55–61
Graus F, Gultekin SH, Ferrer I et al (1998) Localization of the neuronal antigen recognized by anti-Tr antibodies from patients with paraneoplastic cerebellar degeneration and Hodgkin’s disease in the rat nervous system. Acta Neuropathol 96:1–7
Motomura M, Lang B, Johnston I et al (1997) Incidence of serum anti-P/O-type and anti-N-type calcium channel autoantibodies in the Lambert-Eaton myasthenic syndrome. J Neurol Sci 147:35–42
Lennon VA, Kryzer TJ, Griesmann GE et al (1995) Calcium-channel antibodies in the Lambert-Eaton syndrome and other paraneoplastic syndromes. N Engl J Med 332:1467–1474
Clouston PD, Saper CB, Arbizu T et al (1992) Paraneoplastic cerebellar degeneration. III. Cerebellar degeneration, cancer, and the Lambert-Eaton myasthenic syndrome. Neurology 42:1944–1950
Greenberg DA (1997) Calcium channels in neurological disease. Ann Neurol 42:275–282
Restituito S, Thompson RM, Eliet J et al (2000) The polyglutamine expansion in spinocerebellar ataxia type 6 causes a beta subunit-specific enhanced activation of P/Q-type calcium channels in Xenopus oocytes. J Neurosci 20:6394–6403
Pinto A, Gillard S, Moss F et al (1998) Human autoantibodies specific for the alpha 1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons. Proc Natl Acad Sci 95:8328–8333
Antoine JC, Absi L, Honnorat J et al (1999) Anti-amphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumours. Arch Neurol 56:172–177
Dalmau JO, Gultekin SH, Voltz R et al (1999) Mal, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders. Brain 122:27–39
Darnell RB, Furneaux HM, Posner JB (1991) Antiserum from a patient with cerebellar degeneration identifies a novel protein in Purkinje cells, cortical neurons, and neuroectodermal tumors. J Neurosci 11:1224–1230
Tanaka K, Yamazaki M, Sata S et al (1986) Antibodies to brain proteins in paraneo-plastic cerebellar degeneration. Neurology 36:1169–1172
Yoon JW, Yoon CS, Lim HW et al (1999) Control of autoimmune diabetes in NOD mice by GAD expression or suppression in beta cells. Science 284:1183–1187
Baekkeskov S, Aanstoot HJ, Christgau S et al (1990) Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347:151–156
Solimena M, Folli F, Aparisi R et al (1990) Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 322:1555–1560
Grimaldi LM, Martino G, Braghi S et al (1993) Heterogeneity of autoantibodies in stiff-man syndrome. Ann Neurol 34:57–64
Solimena M, De Camilli P (1991) Autoimmunity to glutamic acid decarboxylase (GAD) in stiff-man syndrome and insulin-dependent diabetes mellitus. Trends Neurosci 14:452–457
Honnorat J, Trouillas P, Thivolet C et al (1995) Autoantibodies to glutamate decar-boxylase in a patient with cerebellar cortical atrophy, peripheral neuropathy, and slow eye movements. Arch Neurol 52:462–468
Giometto B, Miotto D, Faresin F et al (1996) Anti-GABAergic neuron autoantibodies in a patient with stiff-man syndrome and ataxia. J Neurol Sci 143:57–59
Saiz A, Arpa J, Sagasta A et al (1997) Autoantibodies to glutamic acid decarboxylase in three patients with cerebellar ataxia, late-onset insulin dependent diabetes mellitus, and polyendocrine autoimmunity. Neurology 49:1026–1030
Abele M, Weller M, Mescheriakov S et al (1999) Cerebellar ataxia with glutamic acid decarboxylase autoantibodies. Neurology 52:857–859
Honnorat J, Saiz A, Giometto B et al (2001) Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of a series of 14 patients. Arch Neurol 58:225–230
Ishida K, Mitoma H, Song SY et al (1999) Selective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase. Ann Neurol 46:263–267
Brashear HR, Login IS, Mathe SA, Phillips LH (1997) Cerebellar disorder in stiff-man syndrome [abstract]. Neurology 48:A433
Dinkel K, Meinck HM, Jury KM et al (1998) Inhibition of y-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol 44:194–201
Hadjivassiliou M, Grünewald RA, Chattopadhyay AK et al (1998) Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet 352:1582-1585
Pellecchia MT, Scala R, Filla A et al (1999) Idiopathic cerebellar ataxia associated with celiac disease: lack of distinctive neurological features. J Neurol Neurosurg Psychiatry 66:32–35
Gahring LC, Rogers SW, Twyman RE (1997) Autoantibodies to glutamate receptor subunit GluR2 in non familial olivopontocerebellar degeneration. Neurology 48:494–500
Ito H, Sayama S, Irie S et al (1994) Antineuronal antibodies in acute cerebellar ataxia following Epstein-Barr virus infection. Neurology 44:1506–1507
Fritzler MJ, Kerfoot SM, Feasby TE et al (2000) Autoantibodies from patients with idiopathic ataxia bind to M-phase phosphoprotein-1 (MPP1). J Invest Med 48:28–39
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Springer-Verlag Italia
About this chapter
Cite this chapter
Honnorat, J. (2002). Clinical Presentation and Mechanisms of Immune-Mediated Cerebellar Ataxia. In: Vincent, A., Martino, G. (eds) Autoantibodies in Neurological Diseases. Topics in Neuroscience. Springer, Milano. https://doi.org/10.1007/978-88-470-2097-9_9
Download citation
DOI: https://doi.org/10.1007/978-88-470-2097-9_9
Publisher Name: Springer, Milano
Print ISBN: 978-88-470-2163-1
Online ISBN: 978-88-470-2097-9
eBook Packages: Springer Book Archive