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. 2004 Aug;75(8):1135–1140. doi: 10.1136/jnnp.2003.034447

Recommended diagnostic criteria for paraneoplastic neurological syndromes

F Graus 1, J Delattre 1, J Antoine 1, J Dalmau 1, B Giometto 1, W Grisold 1, J Honnorat 1, P Smitt 1, C Vedeler 1, J Verschuuren 1, A Vincent 1, R Voltz 1
PMCID: PMC1739186  PMID: 15258215

Abstract

Background: Paraneoplastic neurological syndromes (PNS) are defined by the presence of cancer and exclusion of other known causes of the neurological symptoms, but this criterion does not separate "true" PNS from neurological syndromes that are coincidental with a cancer.

Objective: To provide more rigorous diagnostic criteria for PNS.

Methods: An international panel of neurologists interested in PNS identified those defined as "classical" in previous studies. The panel reviewed the existing diagnostic criteria and recommended new criteria for those in whom no clinical consensus was reached in the past. The panel reviewed all reported onconeural antibodies and established the conditions to identify those that would be labelled as "well characterised". The antibody information was obtained from published work and from unpublished data from the different laboratories involved in the study.

Results: The panel suggest two levels of evidence to define a neurological syndrome as paraneoplastic: "definite" and "possible". Each level can be reached combining a set of criteria based on the presence or absence of cancer and the definitions of "classical" syndrome and "well characterised" onconeural antibody.

Conclusions: The proposed criteria should help clinicians in the classification of their patients and the prospective and retrospective analysis of PNS cases.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson N. E., Budde-Steffen C., Rosenblum M. K., Graus F., Ford D., Synek B. J., Posner J. B. Opsoclonus, myoclonus, ataxia, and encephalopathy in adults with cancer: a distinct paraneoplastic syndrome. Medicine (Baltimore) 1988 Mar;67(2):100–109. doi: 10.1097/00005792-198803000-00003. [DOI] [PubMed] [Google Scholar]
  2. Angstwurm K., Schielke E., Zimmer C., Kivelitz D., Weber J. R. Superficial siderosis of the central nervous system: response to steroid therapy. J Neurol. 2002 Sep;249(9):1223–1225. doi: 10.1007/s00415-002-0815-0. [DOI] [PubMed] [Google Scholar]
  3. Antoine J. C., Absi L., Honnorat J., Boulesteix J. M., de Brouker T., Vial C., Butler M., De Camilli P., Michel D. Antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors. Arch Neurol. 1999 Feb;56(2):172–177. doi: 10.1001/archneur.56.2.172. [DOI] [PubMed] [Google Scholar]
  4. Antoine J. C., Mosnier J. F., Honnorat J., Convers P., Absi L., Lapras J., Michel D. Paraneoplastic demyelinating neuropathy, subacute sensory neuropathy, and anti-Hu antibodies: clinicopathological study of an autopsy case. Muscle Nerve. 1998 Jul;21(7):850–857. doi: 10.1002/(sici)1097-4598(199807)21:7<850::aid-mus2>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  5. Antoine J. C., Mosnier J. F., Lapras J., Convers P., Absi L., Laurent B., Michel D. Chronic inflammatory demyelinating polyneuropathy associated with carcinoma. J Neurol Neurosurg Psychiatry. 1996 Feb;60(2):188–190. doi: 10.1136/jnnp.60.2.188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bernal F., Shams'ili S., Rojas I., Sanchez-Valle R., Saiz A., Dalmau J., Honnorat J., Sillevis Smitt P., Graus F. Anti-Tr antibodies as markers of paraneoplastic cerebellar degeneration and Hodgkin's disease. Neurology. 2003 Jan 28;60(2):230–234. doi: 10.1212/01.wnl.0000041495.87539.98. [DOI] [PubMed] [Google Scholar]
  7. Bohan A., Peter J. B., Bowman R. L., Pearson C. M. Computer-assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine (Baltimore) 1977 Jul;56(4):255–286. doi: 10.1097/00005792-197707000-00001. [DOI] [PubMed] [Google Scholar]
  8. Camdessanché Jean-Philippe, Antoine Jean-Christophe, Honnorat Jérôme, Vial Christophe, Petiot Philippe, Convers Philippe, Michel Daniel. Paraneoplastic peripheral neuropathy associated with anti-Hu antibodies. A clinical and electrophysiological study of 20 patients. Brain. 2002 Jan;125(Pt 1):166–175. doi: 10.1093/brain/awf006. [DOI] [PubMed] [Google Scholar]
  9. Chalk C. H., Windebank A. J., Kimmel D. W., McManis P. G. The distinctive clinical features of paraneoplastic sensory neuronopathy. Can J Neurol Sci. 1992 Aug;19(3):346–351. [PubMed] [Google Scholar]
  10. Chan K. H., Vernino S., Lennon V. A. ANNA-3 anti-neuronal nuclear antibody: marker of lung cancer-related autoimmunity. Ann Neurol. 2001 Sep;50(3):301–311. doi: 10.1002/ana.1127. [DOI] [PubMed] [Google Scholar]
  11. Chinn J. S., Schuffler M. D. Paraneoplastic visceral neuropathy as a cause of severe gastrointestinal motor dysfunction. Gastroenterology. 1988 Nov;95(5):1279–1286. doi: 10.1016/0016-5085(88)90362-9. [DOI] [PubMed] [Google Scholar]
  12. Croft P. B., Urich H., Wilkinson M. Peripheral neuropathy of sensorimotor type associated with malignant disease. Brain. 1967 Mar;90(1):31–66. doi: 10.1093/brain/90.1.31. [DOI] [PubMed] [Google Scholar]
  13. Darnell R. B. Onconeural antigens and the paraneoplastic neurologic disorders: at the intersection of cancer, immunity, and the brain. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4529–4536. doi: 10.1073/pnas.93.10.4529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Darnell Robert B., Posner Jerome B. Paraneoplastic syndromes involving the nervous system. N Engl J Med. 2003 Oct 16;349(16):1543–1554. doi: 10.1056/NEJMra023009. [DOI] [PubMed] [Google Scholar]
  15. Drlicek M., Bianchi G., Bogliun G., Casati B., Grisold W., Kolig C., Liszka-Setinek U., Marzorati L., Wondrusch E., Cavaletti G. 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 Feb;244(2):85–89. doi: 10.1007/s004150050054. [DOI] [PubMed] [Google Scholar]
  16. Dropcho E. J., Kline L. B., Riser J. Antineuronal (anti-Ri) antibodies in a patient with steroid-responsive opsoclonus-myoclonus. Neurology. 1993 Jan;43(1):207–211. doi: 10.1212/wnl.43.1_part_1.207. [DOI] [PubMed] [Google Scholar]
  17. Folli F., Solimena M., Cofiell R., Austoni M., Tallini G., Fassetta G., Bates D., Cartlidge N., Bottazzo G. F., Piccolo G. Autoantibodies to a 128-kd synaptic protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med. 1993 Feb 25;328(8):546–551. doi: 10.1056/NEJM199302253280805. [DOI] [PubMed] [Google Scholar]
  18. Graus F., Bonaventura I., Uchuya M., Valls-Solé J., Reñ R., Leger J. M., Tolosa E., Delattre J. Y. Indolent anti-Hu-associated paraneoplastic sensory neuropathy. Neurology. 1994 Dec;44(12):2258–2261. doi: 10.1212/wnl.44.12.2258. [DOI] [PubMed] [Google Scholar]
  19. Graus F., Dalmau J., Valldeoriola F., Ferrer I., Reñe R., Marin C., Vecht C. J., Arbizu T., Targa C., Moll J. W. Immunological characterization of a neuronal antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin's disease. J Neuroimmunol. 1997 Apr;74(1-2):55–61. doi: 10.1016/s0165-5728(96)00205-6. [DOI] [PubMed] [Google Scholar]
  20. Graus F., Dalmou J., Reñ R., Tora M., Malats N., Verschuuren J. J., Cardenal F., Viñolas N., Garcia del Muro J., Vadell C. Anti-Hu antibodies in patients with small-cell lung cancer: association with complete response to therapy and improved survival. J Clin Oncol. 1997 Aug;15(8):2866–2872. doi: 10.1200/JCO.1997.15.8.2866. [DOI] [PubMed] [Google Scholar]
  21. Graus F., Elkon K. B., Lloberes P., Ribalta T., Torres A., Ussetti P., Valls J., Obach J., Agusti-Vidal A. Neuronal antinuclear antibody (anti-Hu) in paraneoplastic encephalomyelitis simulating acute polyneuritis. Acta Neurol Scand. 1987 Apr;75(4):249–252. doi: 10.1111/j.1600-0404.1987.tb07928.x. [DOI] [PubMed] [Google Scholar]
  22. Graus F., Keime-Guibert F., Reñe R., Benyahia B., Ribalta T., Ascaso C., Escaramis G., Delattre J. Y. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain. 2001 Jun;124(Pt 6):1138–1148. doi: 10.1093/brain/124.6.1138. [DOI] [PubMed] [Google Scholar]
  23. 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 Sep 10;59(5):764–766. doi: 10.1212/wnl.59.5.764. [DOI] [PubMed] [Google Scholar]
  24. Gultekin S. H., Rosenfeld M. R., Voltz R., Eichen J., Posner J. B., Dalmau J. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain. 2000 Jul;123(Pt 7):1481–1494. doi: 10.1093/brain/123.7.1481. [DOI] [PubMed] [Google Scholar]
  25. Henson R. A., Hoffman H. L., Urich H. Encephalomyelitis with carcinoma. Brain. 1965 Sep;88(3):449–464. doi: 10.1093/brain/88.3.449. [DOI] [PubMed] [Google Scholar]
  26. Honnorat J., Antoine J. C., Derrington E., Aguera M., Belin M. F. Antibodies to a subpopulation of glial cells and a 66 kDa developmental protein in patients with paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 1996 Sep;61(3):270–278. doi: 10.1136/jnnp.61.3.270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Hormigo A., Dalmau J., Rosenblum M. K., River M. E., Posner J. B. Immunological and pathological study of anti-Ri-associated encephalopathy. Ann Neurol. 1994 Dec;36(6):896–902. doi: 10.1002/ana.410360615. [DOI] [PubMed] [Google Scholar]
  28. Horwich M. S., Cho L., Porro R. S., Posner J. B. Subacute sensory neuropathy: a remote effect of carcinoma. Ann Neurol. 1977 Jul;2(1):7–19. doi: 10.1002/ana.410020103. [DOI] [PubMed] [Google Scholar]
  29. Mason W. P., Graus F., Lang B., Honnorat J., Delattre J. Y., Valldeoriola F., Antoine J. C., Rosenblum M. K., Rosenfeld M. R., Newsom-Davis J. Small-cell lung cancer, paraneoplastic cerebellar degeneration and the Lambert-Eaton myasthenic syndrome. Brain. 1997 Aug;120(Pt 8):1279–1300. doi: 10.1093/brain/120.8.1279. [DOI] [PubMed] [Google Scholar]
  30. O'Neill J. H., Murray N. M., Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain. 1988 Jun;111(Pt 3):577–596. doi: 10.1093/brain/111.3.577. [DOI] [PubMed] [Google Scholar]
  31. Oh S. J., Slaughter R., Harrell L. Paraneoplastic vasculitic neuropathy: a treatable neuropathy. Muscle Nerve. 1991 Feb;14(2):152–156. doi: 10.1002/mus.880140210. [DOI] [PubMed] [Google Scholar]
  32. Overeem S., Dalmau J., Bataller L., Nishino S., Mignot E., Verschuuren J., Lammers G. J. Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis. Neurology. 2004 Jan 13;62(1):138–140. doi: 10.1212/01.wnl.0000101718.92619.67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Perego L., Previtali S. C., Nemni R., Longhi R., Carandente O., Saibene A., Sciolla R., Villa A., Gai P., Panzeri C. Autoantibodies to amphiphysin I and amphiphysin II in a patient with sensory-motor neuropathy. Eur Neurol. 2002;47(4):196–200. doi: 10.1159/000057898. [DOI] [PubMed] [Google Scholar]
  34. Peterson K., Rosenblum M. K., Kotanides H., Posner J. B. Paraneoplastic cerebellar degeneration. I. A clinical analysis of 55 anti-Yo antibody-positive patients. Neurology. 1992 Oct;42(10):1931–1937. doi: 10.1212/wnl.42.10.1931. [DOI] [PubMed] [Google Scholar]
  35. Pittock Sean J., Lucchinetti Claudia F., Lennon Vanda A. Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol. 2003 May;53(5):580–587. doi: 10.1002/ana.10518. [DOI] [PubMed] [Google Scholar]
  36. Pozo-Rosich Patricia, Clover Linda, Saiz Albert, Vincent Angela, Graus Francesc. Voltage-gated potassium channel antibodies in limbic encephalitis. Ann Neurol. 2003 Oct;54(4):530–533. doi: 10.1002/ana.10713. [DOI] [PubMed] [Google Scholar]
  37. Rojas-Marcos Iñigo, Rousseau Audrey, Keime-Guibert Florence, Reñ Ramón, Cartalat-Carel Stéphanie, Delattre Jean Yves, Graus Francesc. Spectrum of paraneoplastic neurologic disorders in women with breast and gynecologic cancer. Medicine (Baltimore) 2003 May;82(3):216–223. doi: 10.1097/01.md.0000076004.64510.ce. [DOI] [PubMed] [Google Scholar]
  38. Rojas I., Graus F., Keime-Guibert F., Reñ R., Delattre J. Y., Ramón J. M., Dalmau J., Posner J. B. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology. 2000 Sep 12;55(5):713–715. doi: 10.1212/wnl.55.5.713. [DOI] [PubMed] [Google Scholar]
  39. Rosenfeld M. R., Eichen J. G., Wade D. F., Posner J. B., Dalmau J. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol. 2001 Sep;50(3):339–348. [PubMed] [Google Scholar]
  40. Saiz A., Dalmau J., Butler M. H., Chen Q., Delattre J. Y., De Camilli P., Graus F. Anti-amphiphysin I antibodies in patients with paraneoplastic neurological disorders associated with small cell lung carcinoma. J Neurol Neurosurg Psychiatry. 1999 Feb;66(2):214–217. doi: 10.1136/jnnp.66.2.214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Shams'ili Setareh, Grefkens Joost, de Leeuw Bertie, van den Bent Martin, Hooijkaas Herbert, van der Holt Bronno, Vecht Charles, Sillevis Smitt Peter. Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain. 2003 Jun;126(Pt 6):1409–1418. doi: 10.1093/brain/awg133. [DOI] [PubMed] [Google Scholar]
  42. Sillevis Smitt P., Kinoshita A., De Leeuw B., Moll W., Coesmans M., Jaarsma D., Henzen-Logmans S., Vecht C., De Zeeuw C., Sekiyama N. Paraneoplastic cerebellar ataxia due to autoantibodies against a glutamate receptor. N Engl J Med. 2000 Jan 6;342(1):21–27. doi: 10.1056/NEJM200001063420104. [DOI] [PubMed] [Google Scholar]
  43. Sutton I. J., Barnett M. H., Watson J. D. G., Ell J. J., Dalmau J. Paraneoplastic brainstem encephalitis and anti-Ri antibodies. J Neurol. 2002 Nov;249(11):1597–1598. doi: 10.1007/s00415-002-0863-5. [DOI] [PubMed] [Google Scholar]
  44. Vernino S., Lennon V. A. New Purkinje cell antibody (PCA-2): marker of lung cancer-related neurological autoimmunity. Ann Neurol. 2000 Mar;47(3):297–305. [PubMed] [Google Scholar]
  45. Vernino Steven, Tuite Paul, Adler Charles H., Meschia James F., Boeve Bradley F., Boasberg Peter, Parisi Joseph E., Lennon Vanda A. Paraneoplastic chorea associated with CRMP-5 neuronal antibody and lung carcinoma. Ann Neurol. 2002 May;51(5):625–630. doi: 10.1002/ana.10178. [DOI] [PubMed] [Google Scholar]
  46. Vincent Angela, Buckley Camilla, Schott Jonathan M., Baker Ian, Dewar Bonnie-Kate, Detert Niels, Clover Linda, Parkinson Abigail, Bien Christian G., Omer Salah. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain. 2004 Feb 11;127(Pt 3):701–712. doi: 10.1093/brain/awh077. [DOI] [PubMed] [Google Scholar]
  47. Yu Z., Kryzer T. J., Griesmann G. E., Kim K., Benarroch E. E., Lennon V. A. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol. 2001 Feb;49(2):146–154. [PubMed] [Google Scholar]

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