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Overview of paraneoplastic syndromes of the nervous system

Josep Dalmau, MD, PhD
Myrna R Rosenfeld, MD, PhD
Section Editor
Lisa M DeAngelis, MD, FAAN, FANA
Deputy Editor
April F Eichler, MD, MPH


Paraneoplastic neurologic syndromes are a heterogeneous group of disorders caused by mechanisms other than metastases, metabolic and nutritional deficits, infections, coagulopathy, or side effects of cancer treatment. These syndromes may affect any part of the nervous system, from cerebral cortex to neuromuscular junction and muscle (table 1), either damaging one area (eg, Purkinje cell, presynaptic cholinergic synapses) or multiple areas (eg, encephalomyelitis).

This topic provides an overview of the pathogenesis, diagnosis, and treatment of paraneoplastic disorders. Individual syndromes are discussed separately. (See "Paraneoplastic syndromes affecting peripheral nerve and muscle" and "Paraneoplastic syndromes affecting the spinal cord and dorsal root ganglia" and "Paraneoplastic and autoimmune encephalitis" and "Paraneoplastic cerebellar degeneration" and "Opsoclonus myoclonus syndrome" and "Paraneoplastic visual syndromes".)


Although the pathogenesis of paraneoplastic neurologic syndromes is incompletely understood, immunologic factors are believed to be important because antibody and T-cell responses against nervous system antigens have been described for many of these disorders. The immunologic response is directed against shared antigens that are ectopically expressed by the tumor, but otherwise exclusively expressed by the nervous system (picture 1) [1,2], or rarely by the nervous system and testes [3]. For unknown reasons, the immune system identifies these antigens as foreign and mounts an immune attack against them. One report suggests that the immune system can mount a T-cell response to a normal protein when it is expressed in a cancer cell, suggesting that normal self-antigens may be processed differently in cancer cells than in the normal cells [4].

Antibodies that occur in paraneoplastic disorders have been divided in two categories depending on the location of the antigen.

Antibodies directed against intracellular neuronal proteins (called classical paraneoplastic or onconeuronal antibodies) – These antibodies belong to the category of "well-characterized" paraneoplastic antibodies (table 2 and table 3), and their detection almost always indicates the presence of an underlying tumor. Examples include Hu (also known as type 1 anti-neuronal nuclear antibody [ANNA-1]), Ri (also known as type 2 anti-neuronal nuclear antibody [ANNA-2]), Yo (also known as Purkinje cell cytoplasmic antibody type 1 [PCA-1]), amphiphysin, Ma2, Tr (also known as delta/notch-like epidermal growth factor-related receptor [DNER]), collapsin response-mediator protein-5 (CRMP-5), and recoverin. These antibodies are surrogate markers of the paraneoplastic disorder, but in most of these disorders, the pathogenic mechanism is believed to be mediated by cytotoxic T-cells.

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Literature review current through: Nov 2017. | This topic last updated: Dec 06, 2016.
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  1. Dalmau J, Gultekin HS, Posner JB. Paraneoplastic neurologic syndromes: pathogenesis and physiopathology. Brain Pathol 1999; 9:275.
  2. Dalmau J, Furneaux HM, Cordon-Cardo C, Posner JB. The expression of the Hu (paraneoplastic encephalomyelitis/sensory neuronopathy) antigen in human normal and tumor tissues. Am J Pathol 1992; 141:881.
  3. Rosenfeld MR, Eichen JG, Wade DF, et al. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 2001; 50:339.
  4. Savage PA, Vosseller K, Kang C, et al. Recognition of a ubiquitous self antigen by prostate cancer-infiltrating CD8+ T lymphocytes. Science 2008; 319:215.
  5. Graus F, Saiz A, Dalmau J. Antibodies and neuronal autoimmune disorders of the CNS. J Neurol 2010; 257:509.
  6. Leypoldt F, Armangue T, Dalmau J. Autoimmune encephalopathies. Ann N Y Acad Sci 2015; 1338:94.
  7. Lang B, Newsom-Davis J, Wray D, et al. Autoimmune aetiology for myasthenic (Eaton-Lambert) syndrome. Lancet 1981; 2:224.
  8. Drachman DB. Myasthenia gravis. N Engl J Med 1994; 330:1797.
  9. Dalmau J, Gleichman AJ, Hughes EG, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7:1091.
  10. Hughes EG, Peng X, Gleichman AJ, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 2010; 30:5866.
  11. Planagumà J, Leypoldt F, Mannara F, et al. Human N-methyl D-aspartate receptor antibodies alter memory and behaviour in mice. Brain 2015; 138:94.
  12. Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 2009; 65:424.
  13. Peng X, Hughes EG, Moscato EH, et al. Cellular plasticity induced by anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis antibodies. Ann Neurol 2015; 77:381.
  14. Vernino S, Low PA, Fealey RD, et al. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000; 343:847.
  15. Ohguro H, Nakazawa M. Pathological roles of recoverin in cancer-associated retinopathy. Adv Exp Med Biol 2002; 514:109.
  16. Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol 2014; 13:276.
  17. Ohkawa T, Fukata Y, Yamasaki M, et al. Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors. J Neurosci 2013; 33:18161.
  18. Boronat A, Gelfand JM, Gresa-Arribas N, et al. Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels. Ann Neurol 2013; 73:120.
  19. Balint B, Jarius S, Nagel S, et al. Progressive encephalomyelitis with rigidity and myoclonus: a new variant with DPPX antibodies. Neurology 2014; 82:1521.
  20. Tobin WO, Lennon VA, Komorowski L, et al. DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients. Neurology 2014; 83:1797.
  21. Piepgras J, Höltje M, Michel K, et al. Anti-DPPX encephalitis: pathogenic effects of antibodies on gut and brain neurons. Neurology 2015; 85:890.
  22. Geis C, Weishaupt A, Hallermann S, et al. Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain 2010; 133:3166.
  23. Dalakas MC. Invited article: inhibition of B cell functions: implications for neurology. Neurology 2008; 70:2252.
  24. Darnell RB, DeAngelis LM. Regression of small-cell lung carcinoma in patients with paraneoplastic neuronal antibodies. Lancet 1993; 341:21.
  25. Graus F, Dalmou J, Reñé R, et al. Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival. J Clin Oncol 1997; 15:2866.
  26. Maddison P, Newsom-Davis J, Mills KR, Souhami RL. Favourable prognosis in Lambert-Eaton myasthenic syndrome and small-cell lung carcinoma. Lancet 1999; 353:117.
  27. Wirtz PW, Lang B, Graus F, et al. P/Q-type calcium channel antibodies, Lambert-Eaton myasthenic syndrome and survival in small cell lung cancer. J Neuroimmunol 2005; 164:161.
  28. Graus F, Keime-Guibert F, Reñe R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001; 124:1138.
  29. Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu--associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore) 1992; 71:59.
  30. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology 1998; 50:652.
  31. Sillevis Smitt P, Grefkens J, de Leeuw B, et al. Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol 2002; 249:745.
  32. 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.
  33. Monstad SE, Drivsholm L, Storstein A, et al. Hu and voltage-gated calcium channel (VGCC) antibodies related to the prognosis of small-cell lung cancer. J Clin Oncol 2004; 22:795.
  34. 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.
  35. Benyahia B, Liblau R, Merle-Béral H, et al. Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies. Ann Neurol 1999; 45:162.
  36. Tanaka M, Tanaka K, Shinozawa K, et al. Cytotoxic T cells react with recombinant Yo protein from a patient with paraneoplastic cerebellar degeneration and anti-Yo antibody. J Neurol Sci 1998; 161:88.
  37. Posner JB. Neurologic Complications of Cancer, FA Davis, Philadelphia 1995.
  38. Gozzard P, Woodhall M, Chapman C, et al. Paraneoplastic neurologic disorders in small cell lung carcinoma: A prospective study. Neurology 2015; 85:235.
  39. Rudnicki SA, Dalmau J. Paraneoplastic syndromes of the spinal cord, nerve, and muscle. Muscle Nerve 2000; 23:1800.
  40. Graus F, Delattre JY, Antoine JC, et al. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004; 75:1135.
  41. 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.
  42. Vitaliani R, Mason W, Ances B, et al. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 2005; 58:594.
  43. McKeon A, Pittock SJ, Lennon VA. CSF complements serum for evaluating paraneoplastic antibodies and NMO-IgG. Neurology 2011; 76:1108.
  44. Motomura M, Johnston I, Lang B, et al. An improved diagnostic assay for Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry 1995; 58:85.
  45. Pozo-Rosich P, Clover L, Saiz A, et al. Voltage-gated potassium channel antibodies in limbic encephalitis. Ann Neurol 2003; 54:530.
  46. Solimena M, Folli F, Aparisi R, et al. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990; 322:1555.
  47. Folli F, Solimena M, Cofiell R, et al. Autoantibodies to a 128-kd synaptic protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med 1993; 328:546.
  48. Drlicek M, Bianchi G, Bogliun G, et al. Antibodies of the anti-Yo and anti-Ri type in the absence of paraneoplastic neurological syndromes: a long-term survey of ovarian cancer patients. J Neurol 1997; 244:85.
  49. Dalmau J, Furneaux HM, Gralla RJ, et al. Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer--a quantitative western blot analysis. Ann Neurol 1990; 27:544.
  50. Bataller L, Wade DF, Graus F, et al. Antibodies to Zic4 in paraneoplastic neurologic disorders and small-cell lung cancer. Neurology 2004; 62:778.
  51. Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 2004; 56:715.
  52. McKeon A, Tracy JA, Pittock SJ, et al. Purkinje cell cytoplasmic autoantibody type 1 accompaniments: the cerebellum and beyond. Arch Neurol 2011; 68:1282.
  53. Knudsen A, Monstad SE, Dørum A, et al. Ri antibodies in patients with breast, ovarian or small cell lung cancer determined by a sensitive immunoprecipitation technique. Cancer Immunol Immunother 2006; 55:1280.
  54. Monstad SE, Storstein A, Dørum A, et al. Yo antibodies in ovarian and breast cancer patients detected by a sensitive immunoprecipitation technique. Clin Exp Immunol 2006; 144:53.
  55. McKeon A, Lennon VA, Lachance DH, et al. Ganglionic acetylcholine receptor autoantibody: oncological, neurological, and serological accompaniments. Arch Neurol 2009; 66:735.
  56. 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.
  57. Voltz R, Carpentier AF, Rosenfeld MR, et al. P/Q-type voltage-gated calcium channel antibodies in paraneoplastic disorders of the central nervous system. Muscle Nerve 1999; 22:119.
  58. Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004; 127:1831.
  59. Basu S, Alavi A. Role of FDG-PET in the clinical management of paraneoplastic neurological syndrome: detection of the underlying malignancy and the brain PET-MRI correlates. Mol Imaging Biol 2008; 10:131.
  60. Choi KD, Kim JS, Park SH, et al. Cerebellar hypermetabolism in paraneoplastic cerebellar degeneration. J Neurol Neurosurg Psychiatry 2006; 77:525.
  61. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014; 13:167.
  62. Psimaras D, Carpentier AF, Rossi C, PNS Euronetwork. Cerebrospinal fluid study in paraneoplastic syndromes. J Neurol Neurosurg Psychiatry 2010; 81:42.
  63. Rees JH, Hain SF, Johnson MR, et al. The role of [18F]fluoro-2-deoxyglucose-PET scanning in the diagnosis of paraneoplastic neurological disorders. Brain 2001; 124:2223.
  64. Younes-Mhenni S, Janier MF, Cinotti L, et al. FDG-PET improves tumour detection in patients with paraneoplastic neurological syndromes. Brain 2004; 127:2331.
  65. McKeon A, Apiwattanakul M, Lachance DH, et al. Positron emission tomography-computed tomography in paraneoplastic neurologic disorders: systematic analysis and review. Arch Neurol 2010; 67:322.
  66. Patel RR, Subramaniam RM, Mandrekar JN, et al. Occult malignancy in patients with suspected paraneoplastic neurologic syndromes: value of positron emission tomography in diagnosis. Mayo Clin Proc 2008; 83:917.
  67. Linke R, Schroeder M, Helmberger T, Voltz R. Antibody-positive paraneoplastic neurologic syndromes: value of CT and PET for tumor diagnosis. Neurology 2004; 63:282.
  68. Titulaer MJ, Soffietti R, Dalmau J, et al. Screening for tumours in paraneoplastic syndromes: report of an EFNS task force. Eur J Neurol 2011; 18:19.
  69. Leyhe T, Schüle R, Schwärzler F, et al. Second primary tumor in anti-Ma1/2-positive paraneoplastic limbic encephalitis. J Neurooncol 2006; 78:49.
  70. Pranzatelli MR, Tate ED, Travelstead AL, et al. Rituximab (anti-CD20) adjunctive therapy for opsoclonus-myoclonus syndrome. J Pediatr Hematol Oncol 2006; 28:585.
  71. Buckley C, Vincent A. Autoimmune channelopathies. Nat Clin Pract Neurol 2005; 1:22.
  72. Levine TD. Rituximab in the treatment of dermatomyositis: an open-label pilot study. Arthritis Rheum 2005; 52:601.
  73. Vernino S, O'Neill BP, Marks RS, et al. Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neuro Oncol 2004; 6:55.
  74. 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.
  75. 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.
  76. Rosenfeld MR, Dalmau J. Current Therapies for Paraneoplastic Neurologic Syndromes. Curr Treat Options Neurol 2003; 5:69.
  77. Ducray F, Graus F, Vigliani MC, et al. Delayed onset of a second paraneoplastic neurological syndrome in eight patients. J Neurol Neurosurg Psychiatry 2010; 81:937.