Skip to main content

Advertisement

SpringerLink
Log in

Novelties in Autoimmune and Paraneoplastic Cerebellar Ataxias: Twenty Years of Progresses

  • Review
  • Published:
The Cerebellum Aims and scope Submit manuscript

Abstract

Major advances in our knowledge concerning autoimmune and paraneoplastic cerebellar ataxias have occurred in the last 20 years. The discovery of several neural antibodies represents an undeniable contribution to this field, especially those serving as good biomarkers of paraneoplastic neurological syndromes and those showing direct pathogenic effects. Yet, many patients still lack detectable or known antibodies, and also many antibodies have only been reported in few patients, which makes it difficult to define in detail their clinical value. Nevertheless, a notable progress has additionally been made in the clinical characterization of patients with the main neural antibodies, which, although typically present with a subacute pancerebellar syndrome, may also show either hyperacute or chronic onsets that complicate the differential diagnoses. However, prodromal and transient features could be useful clues for an early recognition, and extracerebellar involvement may also be highly indicative of the associated antibody. Moreover, important advances in our understanding of the pathogenesis of cerebellar ataxias include the description of antibody effects, especially those targeting cell-surface antigens, and first attempts to isolate antigen-specific T-cells. Furthermore, genetic predisposition seems relevant, although differently involved according to cancer association, with particular HLA observed in non-paraneoplastic cases and genetic abnormalities in the tumor cells in paraneoplastic ones. Finally, immune checkpoint inhibitors used as cancer immunotherapy may rarely induce cerebellar ataxias, but even this undesirable effect may in turn serve to shed some light on their physiopathology. Herein, we review the principal novelties of the last 20 years regarding autoimmune and paraneoplastic cerebellar ataxias.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. de Silva RN, Vallortigara J, Greenfield J, Hunt B, Giunti P, Hadjivassiliou M. Diagnosis and management of progressive ataxia in adults. Pract Neurol. 2019;19:196–207.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hadjivassiliou M, Martindale J, Shanmugarajah P, Grünewald RA, Sarrigiannis PG, Beauchamp N, et al. Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients. J Neurol Neurosurg Psychiatry. 2017;88:301–9.

    Article  CAS  PubMed  Google Scholar 

  3. Mitoma H, Hadjivassiliou M, Honnorat J. Guidelines for treatment of immune-mediated cerebellar ataxias. Cerebellum Ataxias. 2015;2:14.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Gebus O, Montaut S, Monga B, Wirth T, Cheraud C, Alves Do Rego C, et al. Deciphering the causes of sporadic late-onset cerebellar ataxias: a prospective study with implications for diagnostic work. J Neurol. 2017;264:1118–26.

    Article  CAS  PubMed  Google Scholar 

  5. Joubert B 2019 Honnorat J. Nonparaneoplastic autoimmune cerebellar ataxias: Curr Opin Neurol 32:484–92

  6. Narayan RN, McKeon A, Fife TD. Autoimmune vestibulocerebellar syndromes. Semin Neurol. 2020;40:97–115.

    Article  PubMed  Google Scholar 

  7. Hadjivassiliou M, Graus F, Honnorat J, Jarius S, Titulaer M, Manto M, et al. Diagnostic criteria for primary autoimmune cerebellar ataxia-guidelines from an international task force on immune-mediated cerebellar ataxias. Cerebellum. 2020;19:605–10.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Mitoma H, Honnorat J, Yamaguchi K, Manto M. Fundamental mechanisms of autoantibody-induced impairments on ion channels and synapses in immune-mediated cerebellar ataxias. Int J Mol Sci. 2020;21:E4936.

    Article  PubMed  CAS  Google Scholar 

  9. Yshii L, Bost C, Liblau R. Immunological bases of paraneoplastic cerebellar degeneration and therapeutic implications. Front Immunol. 2020;11:991.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75:1135–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Trotter JL, Hendin BA, Osterland CK. Cerebellar degeneration with Hodgkin disease. An immunological study Arch Neurol. 1976;33:660–1.

    Article  CAS  PubMed  Google Scholar 

  12. Greenlee JE, Brashear HR. Antibodies to cerebellar Purkinje cells in patients with paraneoplastic cerebellar degeneration and ovarian carcinoma. Ann Neurol. 1983;14:609–13.

    Article  CAS  PubMed  Google Scholar 

  13. Cunningham J, Graus F, Anderson N, Posner JB. Partial characterization of the Purkinje cell antigens in paraneoplastic cerebellar degeneration. Neurology. 1986;36:1163–8.

    Article  CAS  PubMed  Google Scholar 

  14. Luque FA, Furneaux HM, Ferziger R, Rosenblum MK, Wray SH, Schold SC, et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol. 1991;29:241–51.

    Article  CAS  PubMed  Google Scholar 

  15. Solimena M, Folli F, Denis-Donini S, Comi GC, Pozza G, De Camilli P, et al. Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med. 1988;318:1012–20.

    Article  CAS  PubMed  Google Scholar 

  16. Solimena M, Piccolo G, Martino G, Folli F, Fratino P, De Camilli P. Autoantibodies directed against gabaergic nerve terminals in a patient with idiopathic late-onset cerebellar ataxia and type IB diabetes mellitus. Clin Neuropathol. 1988;7:211.

    Google Scholar 

  17. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, de Andres C, et al. Cerebellar ataxia with anti–glutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol. 2001;58:225–30.

    Article  CAS  PubMed  Google Scholar 

  18. Dalmau J, Geis C, Graus F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev. 2017;97:839–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Graus F, Vogrig A, Muñiz-Castrillo S, Antoine J-CG, Desestret V, Dubey D, et al. Updated diagnostic criteria for paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflammation. 2021;8.

  20. Shams’ili S, Grefkens J, de Leeuw B, van den Bent M, Hooijkaas H, van der Holt B, et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain. 2003;126:1409–18.

    Article  PubMed  Google Scholar 

  21. Ducray F, Demarquay G, Graus F, Decullier E, Antoine J-C, Giometto B, et al. Seronegative paraneoplastic cerebellar degeneration: the PNS Euronetwork experience. Eur J Neurol. 2014;21:731–5.

    Article  CAS  PubMed  Google Scholar 

  22. Jones AL, Flanagan EP, Pittock SJ, Mandrekar JN, Eggers SD, Ahlskog JE, et al. Responses to and outcomes of treatment of autoimmune cerebellar ataxia in adults. JAMA Neurol. 2015;72:1304–12.

    Article  PubMed  Google Scholar 

  23. Vogrig A, Gigli GL, Segatti S, Corazza E, Marini A, Bernardini A, et al. Epidemiology of paraneoplastic neurological syndromes: a population-based study. J Neurol. 2020;267:26–35.

    Article  CAS  PubMed  Google Scholar 

  24. Hébert J, Riche B, Vogrig A, Muñiz-Castrillo S, Joubert B, Picard G, et al. Epidemiology of paraneoplastic neurologic syndromes and autoimmune encephalitides in France. Neurol Neuroimmunol Neuroinflammation. 2020;7.

  25. Peterson K, Rosenblum MK, Kotanides H, Posner JB. Paraneoplastic cerebellar degeneration I A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology. 1992;42:1931–7.

    Article  CAS  PubMed  Google Scholar 

  26. Linnoila J, Guo Y, Gadoth A, Raghunathan A, Parks B, McKeon A, et al. Purkinje cell cytoplasmic antibody type I (anti-Yo): predictive of gastrointestinal adenocarcinomas in men. J Neurol Neurosurg Psychiatry. 2018;89:1116–7.

    Article  PubMed  Google Scholar 

  27. Déchelotte B, Muñiz-Castrillo S, Joubert B, Vogrig A, Picard G, Rogemond V, et al. Diagnostic yield of commercial immunodots to diagnose paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflammation. 2020;7.

  28. Ruiz-García R, Martínez-Hernández E, Saiz A, Dalmau J, Graus F. The diagnostic value of onconeural antibodies depends on how they are tested. Front Immunol. 2020;11:1482.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Kråkenes T, Herdlevær I, Raspotnig M, Haugen M, Schubert M, Vedeler CA. CDR2L is the major Yo antibody target in paraneoplastic cerebellar degeneration. Ann Neurol. 2019;86:316–21.

    Article  PubMed  CAS  Google Scholar 

  30. Herdlevær I, Haugen M, Mazengia K, Totland C, Vedeler C. Paraneoplastic cerebellar degeneration: the importance of including CDR2L as a diagnostic marker. Neurol Neuroimmunol Neuroinflammation. 2021;8.

  31. McKeon A, Tracey JA, Pittock SJ, Parisi JE, Klein CJ, Lennon VA. Purkinje Cell Cytoplasmic Autoantibody Type 1 Accompaniments: The Cerebellum and Beyond. Arch Neurol. 2011;68:1282.

    Article  PubMed  Google Scholar 

  32. Bernal F, Shams’ili S, Rojas I, Sanchez-Valle R, Saiz A, Dalmau J, et al. Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin’s disease. Neurology. 2003;60:230–4.

    Article  CAS  PubMed  Google Scholar 

  33. Dubey D, Wilson MR, Clarkson B, Giannini C, Gandhi M, Cheville J, et al. Expanded clinical phenotype, oncological associations, and immunopathologic insights of paraneoplastic kelch-like protein-11 encephalitis. JAMA Neurol. 2020;77:1420–9.

    Article  PubMed  Google Scholar 

  34. Vogrig A, Péricart S, Pinto A-L, Rogemond V, Muñiz-Castrillo S, Picard G, et al. Immunopathogenesis and proposed clinical score for identifying Kelch-like protein-11 encephalitis. Brain Commun. 2021;3:fcab185.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Simard C, Vogrig A, Joubert B, Muñiz-Castrillo S, Picard G, Rogemond V, et al. Clinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibodies. Neurol Neuroimmunol Neuroinflammation. 2020;7.

  36. Pittock SJ, Lucchinetti CF, Lennon VA. Anti-neuronal nuclear autoantibody type 2: Paraneoplastic accompaniments. Ann Neurol. 2003;53:580–7.

    Article  CAS  PubMed  Google Scholar 

  37. Gadoth A, Kryzer TJ, Fryer J, McKeon A, Lennon VA, Pittock SJ. Microtubule-associated protein 1B: novel paraneoplastic biomarker: MAP1B IgG. Ann Neurol. 2017;81:266–77.

    Article  CAS  PubMed  Google Scholar 

  38. Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, Thiessen B, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain. 2004;127:1831–44.

    Article  PubMed  Google Scholar 

  39. Honnorat J, Cartalat-Carel S, Ricard D, Camdessanche JP, Carpentier AF, Rogemond V, et al. Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies. J Neurol Neurosurg Psychiatry. 2008;80:412–6.

    Article  PubMed  Google Scholar 

  40. Dubey D, Lennon VA, Gadoth A, Pittock SJ, Flanagan EP, Schmeling JE, et al. Autoimmune CRMP5 neuropathy phenotype and outcome defined from 105 cases. Neurology. 2018;90:e103–10.

    Article  CAS  PubMed  Google Scholar 

  41. Graus F, Vincent A, Pozo-Rosich P, Sabater L, Saiz A, Lang B, et al. Anti-glial nuclear antibody: Marker of lung cancer-related paraneoplastic neurological syndromes. J Neuroimmunol. 2005;165:166–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pittock SJ, Lucchinetti CF, Parisi JE, Benarroch EE, Mokri B, Stephan CL, et al. Amphiphysin autoimmunity: Paraneoplastic accompaniments. Ann Neurol. 2005;58:96–107.

    Article  PubMed  Google Scholar 

  43. Dubey D, Jitprapaikulsan J, Bi H, Do Campo RV, McKeon A, Pittock SJ, et al. Amphiphysin-IgG autoimmune neuropathy: A recognizable clinicopathologic syndrome. Neurology. 2019;93:e1873–80.

    Article  CAS  PubMed  Google Scholar 

  44. Graus F, Keime-Guibert F, Reñe R, Benyahia B, Ribalta T, Ascaso C, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain. 2001;124:1138–48.

    Article  CAS  PubMed  Google Scholar 

  45. Yu Z, Kryzer TJ, Griesmann GE, Kim K, Benarroch EE, Lennon VA. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol. 2001;49:146–54.

    Article  CAS  PubMed  Google Scholar 

  46. Graus F, Dalmau J, Valldeoriola F, Ferrer I, Reñé R, Marin C, et al. Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin’s disease. J Neuroimmunol. 1997;74:55–61.

    Article  CAS  PubMed  Google Scholar 

  47. de Graaff E, Maat P, Hulsenboom E, van den Berg R, van den Bent M, Demmers J, et al. Identification of delta/notch-like epidermal growth factor-related receptor as the Tr antigen in paraneoplastic cerebellar degeneration. Ann Neurol. 2012;71:815–24.

    Article  PubMed  CAS  Google Scholar 

  48. Mandel-Brehm C, Dubey D, Kryzer TJ, O’Donovan BD, Tran B, Vazquez SE, et al. Kelch-like protein 11 antibodies in seminoma-associated paraneoplastic encephalitis. N Engl J Med. 2019;381:47–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Maudes E, Landa J, Muñoz-Lopetegi A, Armangue T, Alba M, Saiz A, et al. Clinical significance of Kelch-like protein 11 antibodies. Neurol - Neuroimmunol Neuroinflammation. 2020;7:e666.

    Article  Google Scholar 

  50. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R, et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. 2008;131:2553–63.

    Article  PubMed  Google Scholar 

  51. Gresa-Arribas N, Ariño H, Martínez-Hernández E, Petit-Pedrol M, Sabater L, Saiz A, et al. Antibodies to inhibitory synaptic proteins in neurological syndromes associated with glutamic acid decarboxylase autoimmunity. PLOS ONE. 2015;10:e0121364.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Guasp M, Solà-Valls N, Martínez-Hernández E, Gil MP, González C, Brieva L, et al. Cerebellar ataxia and autoantibodies restricted to glutamic acid decarboxylase 67 (GAD67). J Neuroimmunol. 2016;300:15–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nanri K, Niwa H, Mitoma H, Takei A, Ikeda J, Harada T, et al. Low-titer anti-GAD-antibody-positive cerebellar ataxia. The Cerebellum. 2013;12:171–5.

    Article  CAS  PubMed  Google Scholar 

  54. Petrijan T, Menih M. Low-Titre GAD Antibody-associated late-onset cerebellar ataxia with a significant clinical response to intravenous immunoglobulin treatment. The Cerebellum. 2017;16:868–71.

    Article  CAS  PubMed  Google Scholar 

  55. Muñoz-Lopetegi A, de Bruijn MAAM, Boukhrissi S, Bastiaansen AEM, Nagtzaam MMP, Hulsenboom ESP, et al. Neurologic syndromes related to anti-GAD65: Clinical and serologic response to treatment. Neurol - Neuroimmunol Neuroinflammation. 2020;7:e696.

    Article  Google Scholar 

  56. Budhram A, Sechi E, Flanagan EP, Dubey D, Zekeridou A, Shah SS, et al. Clinical spectrum of high-titre GAD65 antibodies. J Neurol Neurosurg Psychiatry. 2021;92:645–54.

    Article  Google Scholar 

  57. Ariño H, Höftberger R, Gresa-Arribas N, Martínez-Hernández E, Armangue T, Kruer MC, et al. Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies. JAMA Neurol. 2015;72:874.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Hadjivassiliou M, Aeschlimann P, Strigun A, Sanders DS, Woodroofe N, Aeschlimann D. Autoantibodies in gluten ataxia recognize a novel neuronal transglutaminase. Ann Neurol. 2008;64:332–43.

    Article  CAS  PubMed  Google Scholar 

  59. Hadjivassiliou M, Aeschlimann P, Sanders DS, Mäki M, Kaukinen K, Grünewald RA, et al. Transglutaminase 6 antibodies in the diagnosis of gluten ataxia. Neurology. 2013;80:1740–5.

    Article  CAS  PubMed  Google Scholar 

  60. Hadjivassiliou M, Aeschlimann D, Grünewald RA, Sanders DS, Sharrack B, Woodroofe N. GAD antibody-associated neurological illness and its relationship to gluten sensitivity. Acta Neurol Scand. 2011;123:175–80.

    Article  CAS  PubMed  Google Scholar 

  61. Hadjivassiliou M, Sarrigiannis PG, Shanmugarajah PD, Sanders DS, Grünewald RA, Zis P, et al. Clinical characteristics and management of 50 patients with anti-GAD ataxia: gluten-free diet has a major impact. Cerebellum. 2021;20:179–85.

    Article  CAS  PubMed  Google Scholar 

  62. Zis P, Hadjivassiliou M. Treatment of Neurological manifestations of gluten sensitivity and coeliac disease. Curr Treat Options Neurol. 2019;21:10.

    Article  PubMed  Google Scholar 

  63. Hadjivassiliou M, Grϋnewald RA 2021 Gluten ataxia: an underdiagnosed condition. cerebellum

  64. Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis. Morvan’s syndrome and acquired neuromyotonia Brain. 2010;133:2734–48.

    PubMed  Google Scholar 

  65. Lancaster E, Huijbers MGM, Bar V, Boronat A, Wong A, Martinez-Hernandez E, et al. Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia. Ann Neurol. 2011;69:303–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. van Sonderen A, Petit-Pedrol M, Dalmau J, Titulaer MJ. The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis. Nat Rev Neurol. 2017;13:290–301.

    Article  PubMed  CAS  Google Scholar 

  67. Becker EBE, Zuliani L, Pettingill R, Lang B, Waters P, Dulneva A, et al. Contactin-associated protein-2 antibodies in non-paraneoplastic cerebellar ataxia. J Neurol Neurosurg Psychiatry. 2012;83:437–40.

    Article  PubMed  Google Scholar 

  68. Balint B, Regula JU, Jarius S, Wildemann B. Caspr2 antibodies in limbic encephalitis with cerebellar ataxia, dyskinesias and myoclonus. J Neurol Sci. 2013;327:73–4.

    Article  PubMed  Google Scholar 

  69. van Sonderen A, Ariño H, Petit-Pedrol M, Leypoldt F, Körtvélyessy P, Wandinger K-P, et al. The clinical spectrum of Caspr2 antibody–associated disease. Neurology. 2016;87:521–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Joubert B, Saint-Martin M, Noraz N, Picard G, Rogemond V, Ducray F, et al. Characterization of a subtype of autoimmune encephalitis with anti–contactin-associated protein-like 2 antibodies in the cerebrospinal fluid, prominent limbic symptoms, and seizures. JAMA Neurol. 2016;73:1115.

    Article  PubMed  Google Scholar 

  71. Muñiz-Castrillo S, Joubert B, Elsensohn M-H, Pinto A-L, Saint-Martin M, Vogrig A, et al. Anti-CASPR2 clinical phenotypes correlate with HLA and immunological features. J Neurol Neurosurg Psychiatry. 2020;91:1076–84.

    Article  PubMed  Google Scholar 

  72. Hutchinson M, Waters P, McHugh J, Gorman G, O’Riordan S, Connolly S, et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology. 2008;71:1291–2.

    Article  CAS  PubMed  Google Scholar 

  73. Boronat A, Gelfand JM, Gresa-Arribas N, Jeong H-Y, Walsh M, Roberts K, et al. Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6 a subunit of Kv42 potassium channels. Ann Neurol. 2013;73:120–8.

    Article  CAS  PubMed  Google Scholar 

  74. Sabater L, Gaig C, Gelpi E, Bataller L, Lewerenz J, Torres-Vega E, et al. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study. Lancet Neurol. 2014;13:575–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Gaig C, Graus F, Compta Y, Högl B, Bataller L, Brüggemann N, et al. Clinical manifestations of the anti-IgLON5 disease. Neurology. 2017;88:1736–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Honorat JA, Komorowski L, Josephs KA, Fechner K, St Louis EK, Hinson SR, et al. IgLON5 antibody: neurological accompaniments and outcomes in 20 patients. Neurol - Neuroimmunol Neuroinflammation. 2017;4:e385.

    Article  Google Scholar 

  77. Gaig C, Compta Y, Heidbreder A, Marti MJ, Titulaer MJ, Crijnen Y, et al. Frequency and characterization of movement disorders in anti-IgLON5 disease. Neurology. 2021. https://doi.org/10.1212/WNL.0000000000012639.

    Article  PubMed  Google Scholar 

  78. Carvajal-González A, Leite MI, Waters P, Woodhall M, Coutinho E, Balint B, et al. Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain. 2014;137:2178–92.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Piquet AL, Khan M, Warner JEA, Wicklund MP, Bennett JL, Leehey MA, et al. Novel clinical features of glycine receptor antibody syndrome: a series of 17 cases. Neurol - Neuroimmunol Neuroinflammation. 2019;6:e592.

    Article  Google Scholar 

  80. Hara M, Ariño H, Petit-Pedrol M, Sabater L, Titulaer MJ, Martinez-Hernandez E, et al. DPPX antibody–associated encephalitis: main syndrome and antibody effects. Neurology. 2017;88:1340–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tobin WO, Lennon VA, Komorowski L, Probst C, Clardy SL, Aksamit AJ, et al. DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients. Neurology. 2014;83:1797–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Poorthuis MHF, van Rooij JLM, Koch AH, Verdonkschot AEM, Leembruggen MM, Titulaer MJ. Cerebellar ataxia as a presenting symptom in a patient with anti-NMDA receptor encephalitis. Neurol Neuroimmunol Neuroinflammation. 2019;6:e579.

    Article  Google Scholar 

  83. Martinez-Hernandez E, Guasp M, García-Serra A, Maudes E, Ariño H, Sepulveda M, et al. Clinical significance of anti-NMDAR concurrent with glial or neuronal surface antibodies. Neurology. 2020;94:e2302–10.

    Article  CAS  PubMed  Google Scholar 

  84. Spatola M, Petit Pedrol M, Maudes E, Simabukuro M, Muñiz-Castrillo S, Pinto A-L, et al. Clinical features, prognostic factors, and antibody effects in anti-mGluR1 encephalitis. Neurology. 2020;95:e3012–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hoftberger R, van Sonderen A, Leypoldt F, Houghton D, Geschwind M, Gelfand J, et al. Encephalitis and AMPA receptor antibodies: novel findings in a case series of 22 patients. Neurology. 2015;84:2403–12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Joubert B, Kerschen P, Zekeridou A, Desestret V, Rogemond V, Chaffois M-O, et al. Clinical spectrum of encephalitis associated with antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor: case series and review of the literature. JAMA Neurol. 2015;72:1163.

    Article  PubMed  Google Scholar 

  87. Pettingill P, Kramer HB, Coebergh JA, Pettingill R, Maxwell S, Nibber A, et al. Antibodies to GABAA receptor a1 and g2 subunits: clinical and serological characterization. Neurology. 2015;84:1233–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Spatola M, Petit-Pedrol M, Simabukuro MM, Armangue T, Castro FJ, Barcelo Artigues MI, et al. Investigations in GABA A receptor antibody-associated encephalitis. Neurology. 2017;88:1012–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hoftberger R, Titulaer MJ, Sabater L, Dome B, Rozsas A, Hegedus B, et al. Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients. Neurology. 2013;81:1500–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Jeffery OJ, Lennon VA, Pittock SJ, Gregory JK, Britton JW, McKeon A. GABAB receptor autoantibody frequency in service serologic evaluation. Neurology. 2013;81:882–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12:157–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Graus F, Lang B, Pozo-Rosich P, Saiz A, Casamitjana R, Vincent A. P/Q type calcium-channel antibodies in paraneoplastic cerebellar degeneration with lung cancer. Neurology. 2002;59:764–6.

    Article  CAS  PubMed  Google Scholar 

  93. Smitt PS, Kinoshita A, De Leeuw B, Moll W, Coesmans M, Jaarsma D, et al. Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med. 2000;342:21–7.

    Article  Google Scholar 

  94. Marignier R, Chenevier F, Rogemond V, Sillevis Smitt P, Renoux C, Cavillon G, et al. Metabotropic glutamate receptor type 1 autoantibody–associated cerebellitis: a primary autoimmune disease? Arch Neurol. 2010;67:627–30.

    Article  PubMed  Google Scholar 

  95. Lopez-Chiriboga AS, Komorowski L, Kümpfel T, Probst C, Hinson SR, Pittock SJ, et al. Metabotropic glutamate receptor type 1 autoimmunity: clinical features and treatment outcomes. Neurology. 2016;86:1009–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Do LD, Gupton SL, Tanji K, Bastien J, Brugière S, Couté Y, et al. TRIM9 and TRIM67 are new targets in paraneoplastic cerebellar degeneration. Cerebellum Lond Engl. 2019;18:245–54.

    Article  CAS  Google Scholar 

  97. Zuliani L, Sabater L, Saiz A, Baiges JJ, Giometto B, Graus F. Homer 3 autoimmunity in subacute idiopathic cerebellar ataxia. Neurology. 2007;68:239–40.

    Article  CAS  PubMed  Google Scholar 

  98. Höftberger R, Sabater L, Ortega A, Dalmau J, Graus F. Patient with homer-3 antibodies and cerebellitis. JAMA Neurol. 2013;70:506–9.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Liu M, Ren H, Fan S, Zhang W, Xu Y, Zhao W, et al. Neurological Autoimmunity associated with Homer-3 antibody: a case series from China. Neurol Neuroimmunol Neuroinflammation. 2021;8:e1077.

    Article  Google Scholar 

  100. Landa J, Guasp M, Petit-Pedrol M, Martínez-Hernández E, Planagumà J, Saiz A, et al. Seizure-related 6 homolog like 2 autoimmunity: Neurologic syndrome and antibody effects. Neurol Neuroimmunol Neuroinflammation. 2021;8:e916.

    Article  Google Scholar 

  101. Yaguchi H, Yabe I, Takahashi H, Okumura F, Takeuchi A, Horiuchi K, et al. Identification of anti-Sez6l2 antibody in a patient with cerebellar ataxia and retinopathy. J Neurol. 2014;261:224–6.

    Article  PubMed  Google Scholar 

  102. Borsche M, Hahn S, Hanssen H, Münchau A, Wandinger K-P, Brüggemann N. Sez6l2-antibody-associated progressive cerebellar ataxia: a differential diagnosis of atypical parkinsonism. J Neurol. 2019;266:522–4.

    Article  PubMed  Google Scholar 

  103. Honorat JA, Lopez-Chiriboga AS, Kryzer TJ, Fryer JP, Devine M, Flores A, et al. Autoimmune septin-5 cerebellar ataxia. Neurol Neuroimmunol Neuroinflammation. 2018;5:e474.

    Article  Google Scholar 

  104. Herrero San Martin A, Amarante Cuadrado C, Gonzalez Arbizu M, Rábano-Suárez P, Ostos-Moliz F, Naranjo L, et al. Autoimmune septin-5 disease presenting as spinocerebellar ataxia and nystagmus. Neurology. 2021;97:291–2.

    Article  CAS  PubMed  Google Scholar 

  105. Bataller L, Sabater L, Saiz A, Serra C, Claramonte B, Graus F. Carbonic anhydrase-related protein VIII: autoantigen in paraneoplastic cerebellar degeneration. Ann Neurol. 2004;56:575–9.

    Article  CAS  PubMed  Google Scholar 

  106. Höftberger R, Sabater L, Velasco F, Ciordia R, Dalmau J, Graus F. Carbonic anhydrase-related protein VIII antibodies and paraneoplastic cerebellar degeneration. Neuropathol Appl Neurobiol. 2014;40:650–3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Prevezianou A, Tzartos JS, Dagklis IE, Bentenidi E, Angelopoulos P, Bostantjopoulou S. Paraneoplastic cerebellar degeneration in a patient with breast cancer associated with carbonic anhydrase-related protein VIII autoantibodies. J Neuroimmunol. 2020;344:577242.

    Article  CAS  PubMed  Google Scholar 

  108. Ruiz-García R, Martínez-Hernández E, Joubert B, Petit-Pedrol M, Pajarón-Boix E, Fernández V, et al. Paraneoplastic cerebellar ataxia and antibodies to metabotropic glutamate receptor 2. Neurol Neuroimmunol Neuroinflammation. 2020;7.

  109. Sabater L, Bataller L, Carpentier AF, Aguirre-Cruz ML, Saiz A, Benyahia B, et al. Protein kinase Cgamma autoimmunity in paraneoplastic cerebellar degeneration and non-small-cell lung cancer. J Neurol Neurosurg Psychiatry. 2006;77:1359–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Höftberger R, Kovacs GG, Sabater L, Nagy P, Racz G, Miquel R, et al. Protein kinase Cγ antibodies and paraneoplastic cerebellar degeneration. J Neuroimmunol. 2013;256:91–3.

    Article  PubMed  CAS  Google Scholar 

  111. Miske R, Scharf M, Stark P, Dietzel H, Bien CI, Borchers C, et al. Autoantibodies against the Purkinje cell protein RGS8 in paraneoplastic cerebellar syndrome. Neurol Neuroimmunol Neuroinflammation. 2021;8:e987.

    Article  Google Scholar 

  112. van Coevorden-Hameete MH, de Graaff E, Titulaer MJ, Hulsenboom E, Sabater L, Hoogenraad CC, et al. Plasticity-related gene 5: a novel surface autoantigen in paraneoplastic cerebellar degeneration. Neurol Neuroimmunol Neuroinflammation. 2015;2:e156.

    Article  Google Scholar 

  113. Landa J, Guasp M, Míguez-Cabello F, Guimarães J, Mishima T, Oda F, et al. Encephalitis with autoantibodies against the glutamate kainate receptors GluK2. Ann Neurol. 2021;90:101–17.

    Article  CAS  PubMed  Google Scholar 

  114. Miske R, Gross CC, Scharf M, Golombeck KS, Hartwig M, Bhatia U, et al. Neurochondrin is a neuronal target antigen in autoimmune cerebellar degeneration. Neurol Neuroimmunol Neuroinflammation. 2017;4:e307.

    Article  Google Scholar 

  115. Rommel FR, Miske R, Stöcker W, Arneth B, Neubauer BA, Hahn A. Chorea minor associated with anti-neurochondrin autoantibodies. Neuropediatrics. 2017;48:482–3.

    Article  PubMed  Google Scholar 

  116. Shelly S, Kryzer TJ, Komorowski L, Miske R, Anderson MD, Flanagan EP, et al. Neurochondrin neurological autoimmunity. Neurol Neuroimmunol Neuroinflammation. 2019;6.

  117. Weihua Z, Haitao R, Fang F, Xunzhe Y, Jing W, Hongzhi G. Neurochondrin antibody serum positivity in three cases of autoimmune cerebellar ataxia. Cerebellum. 2019;18:1137–42.

    Article  PubMed  CAS  Google Scholar 

  118. van Coevorden-Hameete MH, van Beuningen SFB, Perrenoud M, Will LM, Hulsenboom E, Demonet J-F, et al. Antibodies to TRIM46 are associated with paraneoplastic neurological syndromes. Ann Clin Transl Neurol. 2017;4:680–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Jarius S, Martínez-García P, Hernandez AL, Brase JC, Borowski K, Regula JU, et al. Two new cases of anti-Ca (anti-ARHGAP26/GRAF) autoantibody-associated cerebellar ataxia. J Neuroinflammation. 2013;10:7.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Doss S, Nümann A, Ziegler A, Siebert E, Borowski K, Stöcker W, et al. Anti-Ca/anti-ARHGAP26 antibodies associated with cerebellar atrophy and cognitive decline. J Neuroimmunol. 2014;267:102–4.

    Article  CAS  PubMed  Google Scholar 

  122. Wallwitz U, Brock S, Schunck A, Wildemann B, Jarius S, Hoffmann F. From dizziness to severe ataxia and dysarthria: new cases of anti-Ca/ARHGAP26 autoantibody-associated cerebellar ataxia suggest a broad clinical spectrum. J Neuroimmunol. 2017;309:77–81.

    Article  CAS  PubMed  Google Scholar 

  123. Bartels F, Prüss H, Finke C. Anti-ARHGAP26 autoantibodies are associated with isolated cognitive impairment. Front Neurol. 2018;9:656.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Jarius S, Scharf M, Begemann N, Stöcker W, Probst C, Serysheva II, et al. Antibodies to the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) in cerebellar ataxia. J Neuroinflammation. 2014;11:206.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Jarius S, Ringelstein M, Haas J, Serysheva II, Komorowski L, Fechner K, et al. Inositol 1,4,5-trisphosphate receptor type 1 autoantibodies in paraneoplastic and non-paraneoplastic peripheral neuropathy. J Neuroinflammation. 2016;13:278.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Fouka P, Alexopoulos H, Chatzi I, Dedos SG, Samiotaki M, Panayotou G, et al. Antibodies to inositol 1,4,5-triphosphate receptor 1 in patients with cerebellar disease. Neurol Neuroimmunol Neuroinflammation. 2017;4:e306.

    Article  Google Scholar 

  127. Berzero G, Hacohen Y, Komorowski L, Scharf M, Dehais C, Leclercq D, et al. Paraneoplastic cerebellar degeneration associated with anti-ITPR1 antibodies. Neurol - Neuroimmunol Neuroinflammation. 2017;4:e326.

    Article  Google Scholar 

  128. Alfugham N, Gadoth A, Lennon VA, Komorowski L, Scharf M, Hinson S, et al. ITPR1 autoimmunity: Frequency neurologic phenotype and cancer association. Neurol Neuroimmunol Neuroinflammation. 2018;5:e418.

    Article  Google Scholar 

  129. Honorat JA, Lopez-Chiriboga AS, Kryzer TJ, Komorowski L, Scharf M, Hinson SR, et al. Autoimmune gait disturbance accompanying adaptor protein-3B2-IgG. Neurology. 2019;93:e954–63.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Basal E, Zalewski N, Kryzer TJ, Hinson SR, Guo Y, Dubey D, et al. Paraneoplastic neuronal intermediate filament autoimmunity. Neurology. 2018;91:e1677–89.

    Article  PubMed  PubMed Central  Google Scholar 

  131. McKeon A, Shelly S, Zivelonghi C, Basal E, Dubey D, Flanagan E, et al. Neuronal intermediate filament IgGs in CSF: autoimmune axonopathy biomarkers. Ann Clin Transl Neurol. 2021;8:425–39.

    Article  CAS  PubMed  Google Scholar 

  132. Chan KH, Vernino S, Lennon VA. ANNA-3 anti-neuronal nuclear antibody: Marker of lung cancer-related autoimmunity. Ann Neurol. 2001;50:301–11.

    Article  CAS  PubMed  Google Scholar 

  133. Dubey D, Kryzer T, Guo Y, Clarkson B, Cheville JC, Costello BA, et al. Leucine zipper 4 autoantibody: a novel germ cell tumor and paraneoplastic biomarker. Ann Neurol. 2021;89:1001–10.

    Article  CAS  PubMed  Google Scholar 

  134. Do L-D, Moritz CP, Muñiz-Castrillo S, Pinto A-L, Tholance Y, Brugiere S, et al. Argonaute autoantibodies as biomarkers in autoimmune neurologic diseases. Neurol Neuroimmunol Neuroinflammation. 2021;8:e1032.

    Article  Google Scholar 

  135. Bataller L, Wade DF, Graus F, Stacey HD, Rosenfeld MR, Dalmau J. Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer. Neurology. 2004;62:778–82.

    Article  CAS  PubMed  Google Scholar 

  136. Sabater L, Bataller L, Suárez-Calvet M, Saiz A, Dalmau J, Graus F. ZIC antibodies in paraneoplastic cerebellar degeneration and small cell lung cancer. J Neuroimmunol. 2008;201–202:163–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Sabater L, Höftberger R, Boronat A, Saiz A, Dalmau J, Graus F. Antibody repertoire in paraneoplastic cerebellar degeneration and small cell lung cancer. Platten M editor PLoS ONE. 2013;8:e60438.

    Article  CAS  Google Scholar 

  138. Berridge G, Menassa DA, Moloney T, Waters PJ, Welding I, Thomsen S, et al. Glutamate receptor δ2 serum antibodies in pediatric opsoclonus myoclonus ataxia syndrome. Neurology. 2018;91:e714–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Armangue T, Titulaer MJ, Sabater L, Pardo-Moreno J, Gresa-Arribas N, Barbero-Bordallo N, et al. A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma. Ann Neurol. 2014;75:435–41.

    Article  PubMed  Google Scholar 

  140. Armangué T, Sabater L, Torres-Vega E, Martínez-Hernández E, Ariño H, Petit-Pedrol M, et al. Clinical and immunological features of opsoclonus-myoclonus syndrome in the era of neuronal cell surface antibodies. JAMA Neurol. 2016;73:417.

    Article  PubMed  PubMed Central  Google Scholar 

  141. Petit-Pedrol M, Guasp M, Armangue T, Lavarino C, Morales La Madrid A, Saiz A, et al. Absence of GluD2 antibodies in patients with opsoclonus-myoclonus syndrome. Neurology. 2021;96:e1082-7.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Vogrig A, Bernardini A, Gigli GL, Corazza E, Marini A, Segatti S, et al. Stroke-like presentation of paraneoplastic cerebellar degeneration: a single-center experience and review of the literature. The Cerebellum. 2019;18:976–82.

    Article  CAS  PubMed  Google Scholar 

  143. Dalmau J, Gonzalez RG, Lerwill MF. Case 4–2007: A 56-year-old woman with rapidly progressive vertigo and ataxia. N Engl J Med. 2007;356:612–20.

    Article  CAS  PubMed  Google Scholar 

  144. Ogawa E, Sakakibara R, Kawashima K, Yoshida T, Kishi M, Tateno F, et al. VGCC antibody-positive paraneoplastic cerebellar degeneration presenting with positioning vertigo. Neurol Sci. 2011;32:1209–12.

    Article  PubMed  Google Scholar 

  145. Matsumoto S. Acute attacks and brain stem signs in a patient with glutamic acid decarboxylase autoantibodies. J Neurol Neurosurg Psychiatry. 2002;73:345–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Ariño H, Gresa-Arribas N, Blanco Y, Martínez-Hernández E, Sabater L, Petit-Pedrol M, et al. Cerebellar ataxia and glutamic acid decarboxylase antibodies: immunologic profile and long-term effect of immunotherapy. JAMA Neurol. 2014;71:1009.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Muñiz-Castrillo S, Vogrig A, Joubert B, Pinto A-L, Gonçalves D, Chaumont H, et al. Transient neurological symptoms preceding cerebellar ataxia with glutamic acid decarboxylase antibodies. Cerebellum. 2020;19:715–21.

    Article  PubMed  CAS  Google Scholar 

  148. Joubert B, Gobert F, Thomas L, Saint-Martin M, Desestret V, Convers P, et al. Autoimmune episodic ataxia in patients with anti-CASPR2 antibody-associated encephalitis. Neurol - Neuroimmunol Neuroinflammation. 2017;4:e371.

    Article  Google Scholar 

  149. van Broekhoven PCA, Frens MA, Sillevis Smitt PA, van der Geest JN. Eye movements as a marker for cerebellar damage in paraneoplastic neurological syndromes. Parkinsonism Relat Disord. 2007;13(Suppl 3):S296-300.

    Article  PubMed  Google Scholar 

  150. Bataller L, Dalmau J. Neuro-ophthalmology and paraneoplastic syndromes. Curr Opin Neurol. 2004;17:3–8.

    Article  PubMed  Google Scholar 

  151. Bohm PE, Chen JJ, Bhatti TM, Eggenberger ER. Neuro-ophthalmic features of autoimmune encephalitides. J Neuro-Ophthalmol Off J North Am Neuro-Ophthalmol Soc. 2020;40:385–97.

    Article  Google Scholar 

  152. Wray SH, Martinez-Hernandez E, Dalmau J, Maheshwari A, Chen A, King S, et al. Paraneoplastic upbeat nystagmus. Neurology. 2011;77:691–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Martins AI, Carvalho JN, Amorim AM, Geraldo A, Eggenberger E, Lemos J. Disabling central paroxysmal positioning upbeat nystagmus and vertigo associated with the presence of anti–glutamic acid decarboxylase antibodies. J Neuroophthalmol. 2018;38:32–5.

    Article  PubMed  Google Scholar 

  154. Tilikete C, Vighetto A, Trouillas P, Honnorat J. Anti-GAD antibodies and periodic alternating nystagmus. Arch Neurol. 2005;62:1300.

    Article  PubMed  Google Scholar 

  155. Bohm P, Eggenberger ER, Dubey D, Kim HW, Lopez Chiriboga AS. Teaching video neuroimages: periodic alternating nystagmus in paraneoplastic KLHL11 rhomboencephalitis. Neurology. 2021;96:e2668–9.

    Article  PubMed  Google Scholar 

  156. Muñiz-Castrillo S, Vogrig A, Montagnac C, Joubert B, Benaiteau M, Casez O, et al. Familial autoimmunity in neurological patients with GAD65 antibodies: an interview-based study. J Neurol. 2021;268:2515–22.

    Article  PubMed  CAS  Google Scholar 

  157. Muñiz-Castrillo S, Vogrig A, Honnorat J. Associations between HLA and autoimmune neurological diseases with autoantibodies. Autoimmun Highlights. 2020;11:2.

    Article  Google Scholar 

  158. Vogrig A, Muñiz-Castrillo S, Desestret V, Joubert B, Honnorat J. Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors. Ther Adv Neurol Disord. 2020;13:1756286420932797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Graus F, Illa I, Agusti M, Ribalta T, Cruz-Sanchez F, Juarez C. Effect of intraventricular injection of an anti-Purkinje cell antibody (anti-Yo) in a guinea pig model. J Neurol Sci. 1991;106:82–7.

    Article  CAS  PubMed  Google Scholar 

  160. Greenlee JE, Clawson SA, Hill KE, Wood BL, Tsunoda I, Carlson NG. Purkinje cell death after uptake of anti-Yo antibodies in cerebellar slice cultures. J Neuropathol Exp Neurol. 2010;69:997–1007.

    Article  CAS  PubMed  Google Scholar 

  161. Greenlee JE, Clawson SA, Hill KE, Wood B, Clardy SL, Tsunoda I, et al. Anti-Yo antibody uptake and interaction with its intracellular target antigen causes Purkinje cell death in rat cerebellar slice cultures: a possible mechanism for paraneoplastic cerebellar degeneration in humans with gynecological or breast cancers. PloS One. 2015;10:e0123446.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Schubert M, Panja D, Haugen M, Bramham CR, Vedeler CA. Paraneoplastic CDR2 and CDR2L antibodies affect Purkinje cell calcium homeostasis. Acta Neuropathol (Berl). 2014;128:835–52.

    Article  CAS  Google Scholar 

  163. Panja D, Vedeler CA, Schubert M. Paraneoplastic cerebellar degeneration: Yo antibody alters mitochondrial calcium buffering capacity. Neuropathol Appl Neurobiol. 2019;45:141–56.

    Article  CAS  PubMed  Google Scholar 

  164. Herdlevaer I, Kråkenes T, Schubert M, Vedeler CA. Localization of CDR2L and CDR2 in paraneoplastic cerebellar degeneration. Ann Clin Transl Neurol. 2020;7:2231–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Mitoma H, Song SY, Ishida K, Yamakuni T, Kobayashi T, Mizusawa H. Presynaptic impairment of cerebellar inhibitory synapses by an autoantibody to glutamate decarboxylase. J Neurol Sci. 2000;175:40–4.

    Article  CAS  PubMed  Google Scholar 

  166. Hampe CS, Petrosini L, De Bartolo P, Caporali P, Cutuli D, Laricchiuta D, et al. Monoclonal antibodies to 65kDa glutamate decarboxylase induce epitope specific effects on motor and cognitive functions in rats. Orphanet J Rare Dis. 2013;8:82.

    Article  PubMed  PubMed Central  Google Scholar 

  167. Manto MU, Hampe CS, Rogemond V, Honnorat J. Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia. Orphanet J Rare Dis. 2011;6:3.

    Article  PubMed  PubMed Central  Google Scholar 

  168. Sabater L, Planagumà J, Dalmau J, Graus F. Cellular investigations with human antibodies associated with the anti-IgLON5 syndrome. J Neuroinflammation. 2016;13:226.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Patterson KR, Dalmau J, Lancaster E. Mechanisms of Caspr2 antibodies in autoimmune encephalitis and neuromyotonia. Ann Neurol. 2018;83:40–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Saint-Martin M, Pieters A, Déchelotte B, Malleval C, Pinatel D, Pascual O, et al. Impact of anti-CASPR2 autoantibodies from patients with autoimmune encephalitis on CASPR2/TAG-1 interaction and Kv1 expression. J Autoimmun. 2019;103:102284.

    Article  CAS  PubMed  Google Scholar 

  171. Yaguchi H, Yabe I, Takahashi H, Watanabe M, Nomura T, Kano T, et al. Anti-Sez6l2 antibody detected in a patient with immune-mediated cerebellar ataxia inhibits complex formation of GluR1 and Sez6l2. J Neurol. 2018;265:962–5.

    Article  CAS  PubMed  Google Scholar 

  172. Crisp SJ, Dixon CL, Jacobson L, Chabrol E, Irani SR, Leite MI, et al. Glycine receptor autoantibodies disrupt inhibitory neurotransmission. Brain. 2019;142:3398–410.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Coesmans M, Smitt PAS, Linden DJ, Shigemoto R, Hirano T, Yamakawa Y, et al. Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies. Ann Neurol. 2003;53:325–36.

    Article  CAS  PubMed  Google Scholar 

  174. Martín-García E, Mannara F, Gutiérrez-Cuesta J, Sabater L, Dalmau J, Maldonado R, et al. Intrathecal injection of P/Q type voltage-gated calcium channel antibodies from paraneoplastic cerebellar degeneration cause ataxia in mice. J Neuroimmunol. 2013;261:53–9.

    Article  PubMed  CAS  Google Scholar 

  175. Liao YJ, Safa P, Chen Y-R, Sobel RA, Boyden ES, Tsien RW. Anti-Ca2+ channel antibody attenuates Ca2+ currents and mimics cerebellar ataxia in vivo. Proc Natl Acad Sci U S A. 2008;105:2705–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Storstein A, Krossnes BK, Vedeler CA. Morphological and immunohistochemical characterization of paraneoplastic cerebellar degeneration associated with Yo antibodies. Acta Neurol Scand. 2009;120:64–7.

    Article  CAS  PubMed  Google Scholar 

  177. Aye MM, Kasai T, Tashiro Y, Xing HQ, Shirahama H, Mitsuda M, et al. CD8 positive T-cell infiltration in the dentate nucleus of paraneoplastic cerebellar degeneration. J Neuroimmunol. 2009;208:136–40.

    Article  CAS  PubMed  Google Scholar 

  178. Ishida K, Mitoma H, Wada Y, Oka T, Shibahara J, Saito Y, et al. Selective loss of Purkinje cells in a patient with anti-glutamic acid decarboxylase antibody-associated cerebellar ataxia. J Neurol Neurosurg Psychiatry. 2007;78:190–2.

    Article  PubMed  Google Scholar 

  179. Piccolo G, Tavazzi E, Cavallaro T, Romani A, Scelsi R, Martino G. Clinico-pathological findings in a patient with progressive cerebellar ataxia, autoimmune polyendocrine syndrome, hepatocellular carcinoma and anti-GAD autoantibodies. J Neurol Sci. 2010;290:148–9.

    Article  PubMed  Google Scholar 

  180. Albert ML, Darnell JC, Bender A, Francisco LM, Bhardwaj N, Darnell RB. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med. 1998;4:1321–4.

    Article  CAS  PubMed  Google Scholar 

  181. Carpenter EL, Vance BA, Klein RS, Voloschin A, Dalmau J, Vonderheide RH. Functional analysis of CD8+ T cell responses to the onconeural self protein cdr2 in patients with paraneoplastic cerebellar degeneration. J Neuroimmunol. 2008;193:173–82.

    Article  CAS  PubMed  Google Scholar 

  182. Costa M, Saiz A, Casamitjana R, Castañer MF, Sanmartí A, Graus F, et al. T-cell reactivity to glutamic acid decarboxylase in stiff-man syndrome and cerebellar ataxia associated with polyendocrine autoimmunity. Clin Exp Immunol. 2002;129:471–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Albert ML, Austin LM, Darnell RB. Detection and treatment of activated T cells in the cerebrospinal fluid of patients with paraneoplastic cerebellar degeneration. Ann Neurol. 2000;47:9–17.

    Article  CAS  PubMed  Google Scholar 

  184. Yshii LM, Gebauer CM, Pignolet B, Mauré E, Quériault C, Pierau M, et al. CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model. Brain. 2016;139:2923–34.

    Article  PubMed  Google Scholar 

  185. Yshii L, Pignolet B, Mauré E, Pierau M, Brunner-Weinzierl M, Hartley O, et al. IFN-γ is a therapeutic target in paraneoplastic cerebellar degeneration. JCI Insight. 2019;4:127001.

    Article  PubMed  Google Scholar 

  186. Gaig C, Ercilla G, Daura X, Ezquerra M, Fernández-Santiago R, Palou E, et al. HLA and microtubule-associated protein tau H1 haplotype associations in anti-IgLON5 disease. Neurol - Neuroimmunol Neuroinflammation. 2019;6:e605.

    Article  Google Scholar 

  187. Muñiz-Castrillo S, Ambati A, Dubois V, Vogrig A, Joubert B, Rogemond V, et al. Primary DQ effect in the association between HLA and neurological syndromes with anti-GAD65 antibodies. J Neurol. 2020;267:1906–11.

    Article  PubMed  CAS  Google Scholar 

  188. Hillary RP, Ollila HM, Lin L, Desestret V, Rogemond V, Picard G, et al. Complex HLA association in paraneoplastic cerebellar ataxia with anti-Yo antibodies. J Neuroimmunol. 2018;315:28–32.

    Article  CAS  PubMed  Google Scholar 

  189. Small M, Treilleux I, Couillault C, Pissaloux D, Picard G, Paindavoine S, et al. Genetic alterations and tumor immune attack in Yo paraneoplastic cerebellar degeneration. Acta Neuropathol (Berl). 2018;135:569–79.

    Article  CAS  Google Scholar 

  190. Vialatte de Pémille C, Berzero G, Small M, Psimaras D, Giry M, Daniau M, et al. Transcriptomic immune profiling of ovarian cancers in paraneoplastic cerebellar degeneration associated with anti-Yo antibodies. Br J Cancer. 2018;119:105–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Rojas-Marcos I, Picard G, Chinchón D, Gelpi E, Psimaras D, Giometto B, et al. Human epidermal growth factor receptor 2 overexpression in breast cancer of patients with anti-Yo–associated paraneoplastic cerebellar degeneration. Neuro-Oncol. 2012;14:506–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378:158–68.

    Article  CAS  PubMed  Google Scholar 

  194. Dubey D, David WS, Reynolds KL, Chute DF, Clement NF, Cohen JV, et al. Severe neurological toxicity of immune checkpoint inhibitors: growing spectrum. Ann Neurol. 2020;87:659–69.

    Article  PubMed  Google Scholar 

  195. Yshii LM, Hohlfeld R, Liblau RS. Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives. Nat Rev Neurol. 2017;13:755–63.

    Article  CAS  PubMed  Google Scholar 

  196. Marini A, Bernardini A, Gigli GL, Valente M, Muñiz-Castrillo S, Honnorat J, et al. Neurologic adverse events of immune checkpoint inhibitors: a systematic review. Neurology. 2021;96:754–66.

    Article  CAS  PubMed  Google Scholar 

  197. Kao JC, Liao B, Markovic SN, Klein CJ, Naddaf E, Staff NP, et al. Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol. 2017;74:1216–22.

    Article  PubMed  PubMed Central  Google Scholar 

  198. Kawamura R, Nagata E, Mukai M, Ohnuki Y, Matsuzaki T, Ohiwa K, et al. Acute cerebellar ataxia induced by nivolumab. Intern Med Tokyo Jpn. 2017;56:3357–9.

    Article  Google Scholar 

  199. Naito T, Osaki M, Ubano M, Kanzaki M, Uesaka Y. Acute cerebellitis after administration of nivolumab and ipilimumab for small cell lung cancer. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol. 2018;39:1791–3.

    Google Scholar 

  200. Vitt JR, Kreple C, Mahmood N, Dickerson E, Lopez GY, Richie MB. Autoimmune pancerebellitis associated with pembrolizumab therapy. Neurology. 2018;91:91–3.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Zurko J, Mehta A. Association of Immune-Mediated Cerebellitis With Immune Checkpoint Inhibitor Therapy. Mayo Clin Proc Innov Qual Outcomes. 2018;2:74–7.

    Article  PubMed  PubMed Central  Google Scholar 

  202. Saikawa H, Nagashima H, Maeda T, Maemondo M. Acute cerebellar ataxia due to Epstein-Barr virus under administration of an immune checkpoint inhibitor. BMJ Case Rep. 2019;12:e231520.

    Article  PubMed  PubMed Central  Google Scholar 

  203. Monteiro A, Gouveia E, Garcez D, Donato S, Martins-Branco D, Marques J, et al. Challenges of new approaches in metastatic merkel cell carcinoma. Case Rep Oncol. 2020;13:501–7.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Vogrig A, Muñiz-Castrillo S, Joubert B, Picard G, Rogemond V, Marchal C, et al. Central nervous system complications associated with immune checkpoint inhibitors. J Neurol Neurosurg Psychiatry. 2020;91:772–8.

    Article  PubMed  Google Scholar 

  205. Iyer SG, Khakoo NS, Aitcheson G, Perez C. Case of anti-Zic4 antibody-mediated cerebellar toxicity induced by dual checkpoint inhibition in head and neck squamous cell carcinoma. BMJ Case Rep. 2020;13:e235607.

    Article  PubMed  PubMed Central  Google Scholar 

  206. Segal Y, Bukstein F, Raz M, Aizenstein O, Alcalay Y, Gadoth A 2021 PD-1-inhibitor-induced PCA-2 (MAP1B) autoimmunity in a patient with renal cell carcinoma. Cerebellum

  207. Hardwick M, Nolan L, Nicoll JAR, Jogai S, Arriola E, Joseph-Pietras D, et al 2021 CD8 T-cell-mediated cerebellitis directed against Purkinje cell antigen after ipilimumab for small cell lung cancer. Neuropathol Appl Neurobiol

Download references

Acknowledgements

Figure 3 was created using images from the Smart site (https://smart.servier.com).

Funding

This work is supported by research grants from Fondation pour la recherche médicale (reference DQ20170336751) and has been developed within the BETPSY project, which is supported by a public grant overseen by the French national research agency (Agence nationale de la recherche, ANR), as part of the second “Investissements d´Avenir” program (reference ANR-18-RHUS-0012), and has been performed within the framework of the LABEX CORTEX (ANR-11-LABX-0042) of Université de Lyon operated by the ANR.

Author information

Authors and Affiliations

  1. French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, 59 Boulevard Pinel, 69677, Bron Cedex, France

    Sergio Muñiz-Castrillo, Alberto Vogrig, Nicolás Lundahl Ciano-Petersen, Macarena Villagrán-García, Bastien Joubert & Jérôme Honnorat

  2. SynatAc Team, Institut NeuroMyoGène, INSERM U1217, CNRS, UMR 5310, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France

    Sergio Muñiz-Castrillo, Alberto Vogrig, Nicolás Lundahl Ciano-Petersen, Macarena Villagrán-García, Bastien Joubert & Jérôme Honnorat

Authors
  1. Sergio Muñiz-Castrillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alberto Vogrig
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicolás Lundahl Ciano-Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Macarena Villagrán-García
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bastien Joubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jérôme Honnorat
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SMC and JH conceptualized and designed the review. SMC, AV, NLCP, MVG, and BJ collected, analyzed, and interpreted the data. SMC and AV drafted the manuscript. All authors revised the manuscript. JH supervised the review.

Corresponding author

Correspondence to Jérôme Honnorat.

Ethics declarations

Ethics Approval

Not applicable.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Muñiz-Castrillo, S., Vogrig, A., Ciano-Petersen, N.L. et al. Novelties in Autoimmune and Paraneoplastic Cerebellar Ataxias: Twenty Years of Progresses. Cerebellum 21, 573–591 (2022). https://doi.org/10.1007/s12311-021-01363-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12311-021-01363-3

Keywords

Search

Navigation