Current Treatment Options in Neurology

, Volume 15, Issue 2, pp 185–200 | Cite as

Treatment of Paraneoplastic Cerebellar Degeneration

  • John E. Greenlee

Opinion statement

Paraneoplastic cerebellar degeneration is an uncommon autoimmune disorder characterized clinically by progressive, ultimately incapacitating ataxia and pathologically by destruction of cerebellar Purkinje cells, with variable loss of other cell populations. The disorder is most commonly associated with gynecological and breast carcinomas, small cell carcinoma of the lung, and Hodgkin’s disease and in most cases comes on prior to identification of the underlying neoplasm. The hallmark of paraneoplastic cerebellar degeneration is the presence of an immune response reactive with intracellular proteins of Purkinje or other neurons or, less commonly, against neuronal surface antigens. Evidence-based treatment strategies for paraneoplastic cerebellar degeneration do not exist; and approaches to therapy are thus speculative. Diagnosis and treatment of the underlying neoplasm is critical, and characterization of the antibody response involved may assist in tumor diagnosis. Most investigators have initiated treatment with corticosteroids, plasma exchange, or intravenous immunoglobulin G. Cyclophosphamide, tacrolimus, rituximab, or possibly mycophenolate mofetil may warrant consideration in patients who fail to stabilize or improve on less aggressive therapies. Plasma exchange has been of questionable benefit when used alone but should be considered at initiation of treatment to achieve rapid lowering of circulating paraneoplastic autoantibodies. Because the course of illness is one of relentless neuronal destruction, time is of the essence in initiating treatment. Likelihood of clinical improvement in patients with longstanding symptoms and extensive neuronal loss is poor.


Paraneoplastic Paraneoplastic cerebellar degeneration Breast neoplasms Ovarian neoplasms Uterine neoplasms Fallopian carcinoma Small cell cancer Hodgkin’s disease Lung neoplasms Autoantibodies T lymphocytes Prednisone Intravenous immunoglobulin G Cyclophosphamide Plasma exchange Rituximab Tacrolimus Mycophenolate mofetil Treatment 



Dr. Greenlee has received grant support from the US Department of Veterans Affairs. This article is an update of the article written by Dr. Greenlee and published in Current Treatment Options in Neurology. (“Treatment of Paraneoplastic Neurologic Disorders”) in 2010 (volume 12, issue 3).


No potential conflicts of interest relevant to this article were reported.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Henson RA, Urich H. Cortical cerebellar degeneration. In: Henson RA, Urich H, editors. Cancer and the nervous system: the neurological manifestations of systemic malignant disease. Oxford: Blackwell Scientific Publications; 1982. p. 346–67.Google Scholar
  2. 2.
    Brain WR, Damiel PM, Greenfield JG. Subacute cortical cerebellar degeneration and its relation to cancer. J Neurol Neurosurg Psychiatry. 1951;14:59–75.PubMedCrossRefGoogle Scholar
  3. 3.
    Greenfield JG. Subacute cerebellar degeneration associated with neoplasms. Brain. 1934;57:161–76.CrossRefGoogle Scholar
  4. 4.
    Brain L, Wilkinson M. Subacute cerebellar degeneration associated with neoplasms. Brain. 1965;88:465–78.PubMedCrossRefGoogle Scholar
  5. 5.
    Peterson K, Rosenblum MK, Kotanides H, et al. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology. 1992;42:1931–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Greenlee JE, Dalmau J, Lyons T, et al. Association of anti-Yo (type I) antibody with paraneoplastic cerebellar degeneration in the setting of transitional cell carcinoma of the bladder: detection of Yo antigen in tumor tissue, and fall in antibody titers following tumor removal. Ann Neurol. 1999;45:805–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7:327–40.PubMedCrossRefGoogle Scholar
  8. 8.
    Pellkofer HL, Voltz R, Goebels N, et al. Cross-reactive T-cell receptors in tumor and paraneoplastic target tissue. Arch Neurol. 2009;66:655–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Pellkofer H, Schubart AS, Hoftberger R, et al. Modelling paraneoplastic CNS disease: T-cells specific for the onconeuronal antigen PNMA1 mediate autoimmune encephalomyelitis in the rat. Brain. 2004;127:1822–30.PubMedCrossRefGoogle Scholar
  10. 10.
    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.PubMedCrossRefGoogle Scholar
  11. 11.
    Bien CG, Vincent A, Barnett MH, et al. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain. 2012;135:1622–38.PubMedCrossRefGoogle Scholar
  12. 12.
    Zuliani L, Graus F, Giometto B, et al. Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition. J Neurol Neurosurg Psychiatry. 2012;83:638–45.PubMedCrossRefGoogle Scholar
  13. 13.
    Graus F, Saiz A, Dalmau J. Antibodies and neuronal autoimmune disorders of the CNS. J Neurol. 2009;509–17.Google Scholar
  14. 14.
    Mason WP, Graus F, Lang B, et al. Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome. Brain. 1997;120:1279–300.PubMedCrossRefGoogle Scholar
  15. 15.
    Sillevis Smitt P, Kinoshita A, De Leeuw B, et al. Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med. 2000;342:21–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Marignier R, Chenevier F, Rogemond V, et al. Metabotropic glutamate receptor type 1 autoantibody-associated cerebellitis: a primary autoimmune disease? Arch Neurol. 2010;67:627–30.PubMedCrossRefGoogle Scholar
  17. 17.
    Honnorat J, Trouillas P, Thivolet C, et al. Autoantibodies to glutamate decarboxylase in a patient with cerebellar cortical atrophy, peripheral neuropathy, and slow eye movements. Arch Neurol. 1995;52:462–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Greenlee JE. Treatment of paraneoplastic neurologic disorders. Curr Treat Options Neurol. 2010;12:212–30.PubMedCrossRefGoogle Scholar
  19. 19.
    Keime-Guibert F, Graus F, Fleury A, et al. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (Anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry. 2000;68:479–82.Google Scholar
  20. 20.
    Vedeler CA, Antoine JC, Giometto B, et al. Management of paraneoplastic neurological syndromes: report of an EFNS Task Force. Eur J Neurol. 2006;13:682–90.PubMedCrossRefGoogle Scholar
  21. 21.
    Candler PM, Hart PE, Barnett M, et al. A follow up study of patients with paraneoplastic neurological disease in the United Kingdom. J Neurol Neurosurg Psychiatry. 2004;75:1411–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Vernino S, O'Neill BP, Marks RS, et al. Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neuro-Oncol. 2004;6:55–62.PubMedCrossRefGoogle Scholar
  23. 23.
    Shams'ili S, Grefkens J, De Leeuw B, et al. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain. 2003;126:1409–18.PubMedCrossRefGoogle Scholar
  24. 24.
    Hammack J, Kotanides H, Rosenblum MK, et al. Paraneoplastic cerebellar degeneration. II. Clinical and immunologic findings in 21 patients with Hodgkin’s disease. Neurology. 1992;42:1938–43.PubMedCrossRefGoogle Scholar
  25. 25.
    Poepel A, Jarius S, Heukamp LC, et al. Neurological course of long-term surviving patients with SCLC and anti-Hu syndrome. J Neurol Sci. 2007;263:145–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Voltz R. Intravenous immunoglobulin therapy in paraneoplastic neurological syndromes. J Neurol. 2006;253 Suppl 5:V33–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Stark E, Wurster U, Patzgold U, et al. Immunological and clinical response to immunosupressive treatment in paraneoplastic cerebellar degeneration. Arch Neurol. 1995;52:814–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Uchuya M, Graus F, Vega F, et al. Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies. J Neurol Neurosurg Psychiatry. 1996;60:388–92.PubMedCrossRefGoogle Scholar
  29. 29.
    Bataller L, Graus F, Saiz A, et al. Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain. 2001;124:437–43.Google Scholar
  30. 30.
    Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol. 1991;29:241–51.PubMedCrossRefGoogle Scholar
  31. 31.
    Digre KB. Opsoclonus in adults: report of 3 cases and review of the literature. Arch Neurol. 1986;43:1165–75.PubMedCrossRefGoogle Scholar
  32. 32.
    Pittock SJ, Lucchinetti CF, Lennon VA. Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol. 2003;53:580–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Moll JWB, Henzen-Logmans SC, Van der Merche FGA, et al. Early diagnosis and intravenous immune globulin therapy in paraneoplastic cerebellar degeneration [letter]. J Neurol Neurosurg Psychiatry. 1994;56:112.CrossRefGoogle Scholar
  34. 34.••
    Orange D, Frank M, Tian S, et al. Cellular immune suppression in paraneoplastic neurologic syndromes targeting intracellular antigens. Arch Neurol. 2012;69:1132–40. This recent article details the use of the immunosuppressive agent, tacrolimus, in treatment of paraneoplastic disorders including paraneoplastic cerebellar degeneration. The article outlines a carefully considered approach to treatment. However, the drug had only limited effectiveness in the population studied.PubMedCrossRefGoogle Scholar
  35. 35.
    Esposito M, Penza P, Orefice G, et al. Successful treatment of paraneoplastic cerebellar degeneration with Rituximab. J Neurooncol. 2008;86:363–4.PubMedCrossRefGoogle Scholar
  36. 36.
    Shams'ili S, de Beukelaar J, Gratama JW, et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol. 2006;253:16–20.PubMedCrossRefGoogle Scholar
  37. 37.•
    Yeo KK, Walter AW, Miller RE, et al. Rituximab as potential therapy for paraneoplastic cerebellar degeneration in pediatric Hodgkin disease. Pediatr Blood Cancer. 2012;58:986–7. This recent single case report also suggests a possible role for ritximab in the treatment of paraneoplastic cerebellar degeneration.PubMedCrossRefGoogle Scholar
  38. 38.
    Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. New Engl J Med. 2012;367:2015-25.Google Scholar
  39. 39.
    Koffman BM, Dalakas MC. Effect of high-dose intravenous immunoglobulin on serum chemistry, hematology, and lymphocyte subpopulations: assessments based on controlled treatment trials in patients with neurological diseases. Muscle Nerve. 1997;20:1102–7.PubMedCrossRefGoogle Scholar
  40. 40.
    Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med. 1994;121:259–62.PubMedGoogle Scholar
  41. 41.
    Jayabose S, Mahmoud M, Levendoglu-Tugal O, et al. Corticosteroid prophylaxis for neurologic complications of intravenous immunoglobulin G therapy in childhood immune thrombocytopenic purpura. J Pediatr Hematol Oncol. 1999;21:514–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Evangelou N, Littlewood T, Anslow P, et al. Transverse sinus thrombosis and IVIg treatment: a case report and discussion of risk-benefit assessment for immunoglobulin treatment. J Clin Pathol. 2003;56:308–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology. 1994;44:223–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Eibl MM. Intravenous immunoglobulins in neurological disorders: safety issues. Neurol Sci. 2003;24 Suppl 4:S222–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Zwerner J, Fiorentino D. Mycophenolate mofetil. Dermatol Ther. 2007;20:229–38.PubMedCrossRefGoogle Scholar
  46. 46.
    Watorek E, Boratynska M, Smolska D, et al. Malignancy after renal transplantation in the new era of immunosuppression. Ann Transplant. 2011;16:14–8.PubMedGoogle Scholar
  47. 47.
    Cowlrick I, Delventhal H, Kaipainen K, et al. Three-year follow-up of malignancies in tacrolimus-treated renal recipients–an analysis of European multicenter studies. Clin Transplant. 2008;22:372–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Graves D, Vernino S. Immunotherapies in neurologic disorders. Med Clin N Am. 2012;96:497–523.PubMedCrossRefGoogle Scholar
  49. 49.
    Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358:676–88.PubMedCrossRefGoogle Scholar
  50. 50.
    Cross AH, Stark JL, Lauber J, et al. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol. 2006;180:63–70.PubMedCrossRefGoogle Scholar
  51. 51.
    Petereit HF, Moeller-Hartmann W, Reske D, et al. Rituximab in a patient with multiple sclerosis–effect on B cells, plasma cells and intrathecal IgG synthesis. Acta Neurol Scand. 2008;117:399–403.PubMedCrossRefGoogle Scholar
  52. 52.
    Pranzatelli MR, Tate ED, Travelstead AL, et al. Long-term cerebrospinal fluid and blood lymphocyte dynamics after rituximab for pediatric Opsoclonus-Myoclonus. J Clin Immunol. 2010;30:106-13.Google Scholar
  53. 53.
    Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicenter trial. Lancet. 2011;378:1779–87.PubMedCrossRefGoogle Scholar
  54. 54.
    Fernandez O, Alvarez-Cermeno JC, Arroyo-Gonzalez R, et al. Review of the novelties presented at the 27th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (II). Rev Neurol. 2012;54:734–49.PubMedGoogle Scholar
  55. 55.
    Jacob A, Weinshenker BG, Violich I, et al. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol. 2008;65:1443–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Min L, Zwerling J, Ocava LC, et al. Reversible posterior leukoencephalopathy in connective tissue diseases. Semin Arthritis Rheum. 2006;35:388–95.PubMedCrossRefGoogle Scholar
  57. 57.
    Wolach O, Shpilberg O, Lahav M. Neutropenia after rituximab treatment: new insights on a late complication. Curr Opin Hematol. 2012;19:32–8.PubMedCrossRefGoogle Scholar
  58. 58.
    Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009;113:4834–40.PubMedCrossRefGoogle Scholar
  59. 59.
    Sharma M, Moore J, Nguyen V, et al. Fatal CMV pneumonitis in a lymphoma patient treated with rituximab. Am J Hematol. 2009;84:614–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Levi ME, Quan D, Ho JT, et al. Impact of rituximab-associated B-cell defects on West Nile virus meningoencephalitis in solid organ transplant recipients. Clin Transplant. 2009;24:223-8.Google Scholar
  61. 61.
    Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000;47:85–118.PubMedCrossRefGoogle Scholar
  62. 62.
    Hehir MK, Burns TM, Alpers J, et al. Mycophenolate mofetil in AChR-antibody-positive myasthenia gravis: outcomes in 102 patients. Muscle Nerve. 2010;41:593–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Hanisch F, Wendt M, Zierz S. Mycophenolate mofetil as second line immunosuppressant in Myasthenia gravis–a long-term prospective open-label study. Eur J Med Res. 2009;14:364–6.PubMedCrossRefGoogle Scholar
  64. 64.
    Mirabelli-Badenier M, Morana G, Pinto F, et al. Anti-glutamic acid decarboxylase limbic encephalitis without epilepsy evolving into dementia with cerebellar ataxia. Arch Neurol. 2012;69:1064–6.PubMedCrossRefGoogle Scholar
  65. 65.
    Cornelius JR, Pittock SJ, McKeon A, et al. Sleep manifestations of voltage-gated potassium channel complex autoimmunity. Arch Neurol. 2011;68:733–8.PubMedCrossRefGoogle Scholar
  66. 66.
    Saidha S, Murphy S, Ronayne A, et al. Treatment of anti-glutamic acid decarboxylase antibody-associated limbic encephalitis with mycophenolate mofetil. J Neurol. 2010;257:1035–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Wong SH, Saunders MD, Larner AJ, et al. An effective immunotherapy regimen for VGKC antibody-positive limbic encephalitis. J Neurol Neurosurg Psychiatry. 2010;81:1167–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Hegde S, Annamalai R, Biswas J. Extensive herpes zoster involvement following mycophenolate mofetil therapy for sarcoidosis. J Ophthalmic Inflamm Infect. 2012;2:47–8.PubMedCrossRefGoogle Scholar
  69. 69.
    Sato A, Amada N, Kikuchi H, et al. Pneumonia due to varicella-zoster virus reinfection in a renal transplant recipient. Transplant Proc. 2009;41:3959–61.PubMedCrossRefGoogle Scholar
  70. 70.
    Lauzurica R, Bayes B, Frias C, et al. Disseminated varicella infection in adult renal allograft recipients: role of mycophenolate mofetil. Transplant Proc. 2003;35:1758–9.PubMedCrossRefGoogle Scholar
  71. 71.
    Eisen HJ, Kobashigawa J, Keogh A, et al. Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. J Heart Lung Transplant. 2005;24:517–25.PubMedCrossRefGoogle Scholar
  72. 72.
    Pavlovic AM, Bonaci-Nikolic B, Kozic D, et al. Progressive multifocal leukoencephalopathy associated with mycophenolate mofetil treatment in a woman with lupus and CD4+ T-lymphocyte deficiency. Lupus. 2012;21:100–2.PubMedCrossRefGoogle Scholar
  73. 73.
    Tamaki H, Kawakami M, Ikegame K, et al. Successful treatment of tacrolimus (FK506)-related leukoencephalopathy with cerebral hemorrhage in a patient who underwent nonmyeloablative stem cell transplantation. Int J Hematol. 2004;80:291–4.PubMedCrossRefGoogle Scholar
  74. 74.
    Lehmann HC, Hartung HP, Hetzel GR, et al. Plasma exchange in neuroimmunological disorders: part 1: rationale and treatment of inflammatory central nervous system disorders. Arch Neurol. 2006;63:930–5.PubMedCrossRefGoogle Scholar
  75. 75.
    Graus F, Abos J, Roquer J, et al. Effect of plasmapheresis on serum and CSF autoantibody levels in CNS paraneoplastic syndromes. Neurology. 1990;40:1621–3.PubMedCrossRefGoogle Scholar
  76. 76.
    Furneaux HM, Reich L, Posner JB. Autoantibody synthesis in the central nervous system of patients with paraneoplastic syndromes. Neurology. 1990;40:1085–91.PubMedCrossRefGoogle Scholar
  77. 77.
    David YB, Warner E, Levitan M, et al. Autoimmune paraneoplastic cerebellar degeneration in ovarian carcinoma patients treated with plasmapheresis and immunoglobulin. A case report. Cancer. 1996;78:2153–6.PubMedCrossRefGoogle Scholar
  78. 78.
    O'Brien TJ, Pasaliaris B, D'Apice A, et al. Anti-Yo positive paraneoplastic cerebellar degeneration: a report of 3 cases and review of the literature. J Clin Neurosci. 1995;2:316–20.PubMedCrossRefGoogle Scholar
  79. 79.
    McCrystal M, Anderson NE, Jones RW, et al. Paraneoplastic cerebellar degeneration in a patient with chemotherapy-responsive ovarian cancer. Int J Gynecol Cancer. 1995;5:396–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Cehreli C, Payzin B, Undar B, et al. Paraneoplastic cerebellar degeneration in association with Hodgkin’s disease: a report of 2 cases. Acta Haematol. 1995;94:210–3.PubMedCrossRefGoogle Scholar
  81. 81.
    Blumenfeld AM, Recht LD, Chad DA, et al. Coexistence of Lambert-Eaton myasthenic syndrome and subacute cerebellar degeneration: differential effects of treatment. Neurology. 1991;41:1682–5.PubMedCrossRefGoogle Scholar
  82. 82.
    Weinstein R. Therapeutic apheresis in neurological disorders. J Clin Apher. 2000;15:74–128.PubMedCrossRefGoogle Scholar
  83. 83.
    Shemin D, Briggs D, Greenan M. Complications of therapeutic plasma exchange: a prospective study of 1,727 procedures. J Clin Apher. 2007;22:270–6.PubMedCrossRefGoogle Scholar
  84. 84.
    Schlake HP, Husstedt IW, Grotemeyer KH, et al. Paraneoplastic subacute cerebellar degeneration in Hodgkin’s disease. Report of 3 cases and review of the literature. Clin Neurol Neurosurg. 1989;91:329–35.PubMedCrossRefGoogle Scholar
  85. 85.
    Banugaria SG, Prater SN, McGann JK, et al. Bortezomib in the rapid reduction of high sustained antibody titers in disorders treated with therapeutic protein: lessons learned from Pompe disease. Genet Med. 2012;13:729-36.Google Scholar
  86. 86.
    Gomez AM, Vrolix K, Martinez-Martinez P, et al. Proteasome inhibition with bortezomib depletes plasma cells and autoantibodies in experimental autoimmune myasthenia gravis. J Immunol. 2011;186:2503–13.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York (outside the USA) 2013

Authors and Affiliations

  1. 1.Clinical Neuroscience CenterUniversity of UtahSalt Lake CityUSA

Personalised recommendations