Paraneoplastic cerebellar degeneration
- Josep Dalmau, MD, PhD
Josep Dalmau, MD, PhD
- ICREA Professor of Neurology
- Hospital Clinic/IDIBAPS, University of Barcelona, Spain
- Adjunct Professor of Neurology
- University of Pennsylvania
- Myrna R Rosenfeld, MD, PhD
Myrna R Rosenfeld, MD, PhD
- Professor of Neurology
- Hospital Clinic/IDIBAPS, University of Barcelona, Spain
- Adjunct Professor of Neurology
- University of Pennsylvania
Paraneoplastic neurologic syndromes are a heterogeneous group of neurologic disorders associated with systemic cancer and caused by mechanisms other than metastases, metabolic and nutritional deficits, infections, coagulopathy, or side effects of cancer treatment.
Paraneoplastic cerebellar degeneration is an uncommon disorder that can be associated with any cancer; the most commonly associated are lung cancer (particularly small cell lung cancer (SCLC)), gynecologic and breast cancer, and lymphoma (particularly Hodgkin disease) . The neurologic symptoms frequently precede the diagnosis of cancer, sometimes by an interval of years.
This topic discusses paraneoplastic cerebellar degeneration (PCD). An overview of paraneoplastic syndromes and other paraneoplastic disorders are discussed separately. (See "Overview of paraneoplastic syndromes of the nervous system" and "Paraneoplastic syndromes affecting peripheral nerve and muscle" and "Paraneoplastic syndromes affecting the spinal cord and dorsal root ganglia" and "Paraneoplastic and autoimmune encephalitis".)
The cerebellum is a frequent target of paraneoplastic autoimmunity. All paraneoplastic antibodies have been reported in association with PCD [2-17]. Some of these autoantibodies are associated with specific clinical settings (table 1) that may help focus the search for an underlying occult malignancy. Only two antibodies, anti-Yo and anti-Tr, predominantly associate with cerebellar dysfunction; the other paraneoplastic antibodies often associate with symptoms involving other areas of the nervous system.
●The most common among the associated antibodies, anti-Yo antibodies (also called Purkinje cell antibody type 1 or PCA-1) primarily occur in patients with PCD who have breast cancer or tumors of the ovary, endometrium, and fallopian tube (picture 1) [4,5,18-20]. Rare cases of anti-Yo associated PCD have been described in men with adenocarcinoma [21-25]. The target antigens of anti-Yo antibodies are the cdr proteins that are expressed by Purkinje cells and ovarian and breast cancers [6,7,26]. A cytotoxic T cell response against cdr2 has also been identified in these patients .
- Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol 2008; 7:327.
- Mason WP, Graus F, Lang B, et al. Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome. Brain 1997; 120 ( Pt 8):1279.
- Fukuda T, Motomura M, Nakao Y, et al. Reduction of P/Q-type calcium channels in the postmortem cerebellum of paraneoplastic cerebellar degeneration with Lambert-Eaton myasthenic syndrome. Ann Neurol 2003; 53:21.
- Furneaux HM, Rosenblum MK, Dalmau J, et al. Selective expression of Purkinje-cell antigens in tumor tissue from patients with paraneoplastic cerebellar degeneration. N Engl J Med 1990; 322:1844.
- Rojas-Marcos I, Rousseau A, Keime-Guibert F, et al. Spectrum of paraneoplastic neurologic disorders in women with breast and gynecologic cancer. Medicine (Baltimore) 2003; 82:216.
- Fathallah-Shaykh H, Wolf S, Wong E, et al. Cloning of a leucine-zipper protein recognized by the sera of patients with antibody-associated paraneoplastic cerebellar degeneration. Proc Natl Acad Sci U S A 1991; 88:3451.
- Albert ML, Darnell JC, Bender A, et al. Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med 1998; 4:1321.
- Graus F, Gultekin SH, Ferrer I, et al. 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 1998; 96:1.
- Bernal F, Shams'ili S, Rojas I, et al. Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin's disease. Neurology 2003; 60:230.
- Antoine JC, Honnorat J, Camdessanché JP, et al. Paraneoplastic anti-CV2 antibodies react with peripheral nerve and are associated with a mixed axonal and demyelinating peripheral neuropathy. Ann Neurol 2001; 49:214.
- Honnorat J, Antoine JC, Derrington E, et al. Antibodies to a subpopulation of glial cells and a 66 kDa developmental protein in patients with paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 1996; 61:270.
- de la Sayette V, Bertran F, Honnorat J, et al. Paraneoplastic cerebellar syndrome and optic neuritis with anti-CV2 antibodies: clinical response to excision of the primary tumor. Arch Neurol 1998; 55:405.
- Bataller L, Wade DF, Graus F, et al. Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer. Neurology 2004; 62:778.
- Vernino S, Lennon VA. New Purkinje cell antibody (PCA-2): marker of lung cancer-related neurological autoimmunity. Ann Neurol 2000; 47:297.
- Chan KH, Vernino S, Lennon VA. ANNA-3 anti-neuronal nuclear antibody: marker of lung cancer-related autoimmunity. Ann Neurol 2001; 50:301.
- 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.
- Bataller L, Sabater L, Saiz A, et al. Carbonic anhydrase-related protein VIII: autoantigen in paraneoplastic cerebellar degeneration. Ann Neurol 2004; 56:575.
- 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.
- Rojas I, Graus F, Keime-Guibert F, et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 2000; 55:713.
- McKeon A, Tracy JA, Pittock SJ, et al. Purkinje cell cytoplasmic autoantibody type 1 accompaniments: the cerebellum and beyond. Arch Neurol 2011; 68:1282.
- Sutton IJ, Fursdon Davis CJ, Esiri MM, et al. Anti-Yo antibodies and cerebellar degeneration in a man with adenocarcinoma of the esophagus. Ann Neurol 2001; 49:253.
- Meglic B, Graus F, Grad A. Anti-Yo-associated paraneoplastic cerebellar degeneration in a man with gastric adenocarcinoma. J Neurol Sci 2001; 185:135.
- Krakauer J, Balmaceda C, Gluck JT, et al. Anti-Yo-associated paraneoplastic cerebellar degeneration in a man with adenocarcinoma of unknown origin. Neurology 1996; 46:1486.
- Matschke J, Kromminga A, Erbersdobler A, et al. Paraneoplastic cerebellar degeneration and anti-Yo antibodies in a man with prostatic adenocarcinoma. J Neurol Neurosurg Psychiatry 2007; 78:775.
- Debes JD, Lagarde SM, Hulsenboom E, et al. Anti-Yo-associated paraneoplastic cerebellar degeneration in a man with adenocarcinoma of the gastroesophageal junction. Dig Surg 2007; 24:395.
- Totland C, Aarskog NK, Eichler TW, et al. CDR2 antigen and Yo antibodies. Cancer Immunol Immunother 2011; 60:283.
- 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.
- Clouston PD, Saper CB, Arbizu T, et al. Paraneoplastic cerebellar degeneration. III. Cerebellar degeneration, cancer, and the Lambert-Eaton myasthenic syndrome. Neurology 1992; 42:1944.
- Graus F, Lang B, Pozo-Rosich P, et al. P/Q type calcium-channel antibodies in paraneoplastic cerebellar degeneration with lung cancer. Neurology 2002; 59:764.
- Greene M, Lai Y, Baella N, et al. Antibodies to Delta/notch-like epidermal growth factor-related receptor in patients with anti-Tr, paraneoplastic cerebellar degeneration, and Hodgkin lymphoma. JAMA Neurol 2014; 71:1003.
- Hammack J, Kotanides H, Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration. II. Clinical and immunologic findings in 21 patients with Hodgkin's disease. Neurology 1992; 42:1938.
- Geromin A, Candoni A, Marcon G, et al. Paraneoplastic cerebellar degeneration associated with anti-neuronal anti-Tr antibodies in a patient with Hodgkin's disease. Leuk Lymphoma 2006; 47:1960.
- Briani C, Vitaliani R, Grisold W, et al. Spectrum of paraneoplastic disease associated with lymphoma. Neurology 2011; 76:705.
- de Graaff E, Maat P, Hulsenboom E, 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.
- Brieva-Ruíz L, Diaz-Hurtado M, Matias-Guiu X, et al. Anti-Ri-associated paraneoplastic cerebellar degeneration and breast cancer: an autopsy case study. Clin Neurol Neurosurg 2008; 110:1044.
- de Andrés C, Esquivel A, de Villoria JG, et al. Unusual magnetic resonance imaging and cerebrospinal fluid findings in paraneoplastic cerebellar degeneration: a sequential study. J Neurol Neurosurg Psychiatry 2006; 77:562.
- Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol 2001; 49:146.
- Dalmau J, Gultekin SH, Voltz R, et al. Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders. Brain 1999; 122 ( Pt 1):27.
- Rosenfeld MR, Eichen JG, Wade DF, et al. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 2001; 50:339.
- Sabater L, Bataller L, Suárez-Calvet M, et al. ZIC antibodies in paraneoplastic cerebellar degeneration and small cell lung cancer. J Neuroimmunol 2008; 201-202:163.
- 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.
- Sabater L, Bataller L, Carpentier AF, et al. Protein kinase Cgamma autoimmunity in paraneoplastic cerebellar degeneration and non-small-cell lung cancer. J Neurol Neurosurg Psychiatry 2006; 77:1359.
- Greenlee JE, Clawson SA, Hill KE, et al. Antineuronal autoantibodies in paraneoplastic cerebellar degeneration associated with adenocarcinoma of the prostate. J Neurol Sci 2010; 291:74.
- 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.
- Aye MM, Kasai T, Tashiro Y, et al. CD8 positive T-cell infiltration in the dentate nucleus of paraneoplastic cerebellar degeneration. J Neuroimmunol 2009; 208:136.
- Henson, RA, Urich, H. Cancer and the Nervous System. Blackwell Scientific, Oxford 1982. p.314.
- Dalmau J, Gonzalez RG, Lerwill MF. Case records of the Massachusetts General Hospital. Case 4-2007. A 56-year-old woman with rapidly progressive vertigo and ataxia. N Engl J Med 2007; 356:612.
- Choi KD, Kim JS, Park SH, et al. Cerebellar hypermetabolism in paraneoplastic cerebellar degeneration. J Neurol Neurosurg Psychiatry 2006; 77:525.
- Scheid R, Voltz R, Briest S, et al. Clinical insights into paraneoplastic cerebellar degeneration. J Neurol Neurosurg Psychiatry 2006; 77:529.
- Saiz A, Graus F, Dalmau J, et al. Detection of 14-3-3 brain protein in the cerebrospinal fluid of patients with paraneoplastic neurological disorders. Ann Neurol 1999; 46:774.
- Marchand V, Graveleau J, Lanctin-Garcia C, et al. A rare gynecological case of paraneoplastic cerebellar degeneration discovered by FDG-PET. Gynecol Oncol 2007; 105:545.
- Cao Y, Abbas J, Wu X, et al. Anti-Yo positive paraneoplastic cerebellar degeneration associated with ovarian carcinoma: case report and review of the literature. Gynecol Oncol 1999; 75:178.
- 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.
- 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.
- Esposito M, Penza P, Orefice G, et al. Successful treatment of paraneoplastic cerebellar degeneration with Rituximab. J Neurooncol 2008; 86:363.
- 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.
- Blaes F, Strittmatter M, Merkelbach S, et al. Intravenous immunoglobulins in the therapy of paraneoplastic neurological disorders. J Neurol 1999; 246:299.
- Taniguchi Y, Tanji C, Kawai T, et al. A case report of plasmapheresis in paraneoplastic cerebellar ataxia associated with anti-Tr antibody. Ther Apher Dial 2006; 10:90.
- Mowzoon N, Bradley WG. Successful immunosuppressant therapy of severe progressive cerebellar degeneration and sensory neuropathy: a case report. J Neurol Sci 2000; 178:63.
- Counsell CE, McLeod M, Grant R. Reversal of subacute paraneoplastic cerebellar syndrome with intravenous immunoglobulin. Neurology 1994; 44:1184.
- Thöne J, Hohaus A, Lamprecht S, et al. Effective immunosuppressant therapy with cyclophosphamide and corticosteroids in paraneoplastic cerebellar degeneration. J Neurol Sci 2008; 272:171.
- Phuphanich S, Brock C. Neurologic improvement after high-dose intravenous immunoglobulin therapy in patients with paraneoplastic cerebellar degeneration associated with anti-Purkinje cell antibody. J Neurooncol 2007; 81:67.
- Widdess-Walsh P, Tavee JO, Schuele S, Stevens GH. Response to intravenous immunoglobulin in anti-Yo associated paraneoplastic cerebellar degeneration: case report and review of the literature. J Neurooncol 2003; 63:187.
- Graus F, Dalmau J, Valldeoriola F, et al. Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin's disease. J Neuroimmunol 1997; 74:55.
- Honnorat J, Cartalat-Carel S, Ricard D, 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 2009; 80:412.