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Epidemiology of paraneoplastic neurological syndromes: a population-based study



The epidemiology of paraneoplastic neurological syndromes (PNS) remains to be defined. We present here the first population-based incidence study and report the clinical spectrum and antibody profile of PNS in a large area in Northeastern Italy.


We performed a 9-year (2009–2017) population-based epidemiological study of PNS in the provinces of Udine, Pordenone and Gorizia, in the Friuli-Venezia Giulia region (983,190 people as of January 1, 2017). PNS diagnosis and subgroups were defined by the 2004 diagnostic criteria. Age- and sex-adjusted incidence rates were calculated.


We identified 89 patients with a diagnosis of definite PNS. Median age was 68 years (range 26–90), 52% were female. The incidence of PNS was 0.89/100,000 person-years. PNS incidence rates increased over time from 0.62/100,000 person-years (2009–2011), 0.81/100,000 person-years (2012–2014) to 1.22/100,000 person-years (2015–2017). The prevalence of PNS was 4.37 per 100,000. Most common PNS were limbic encephalitis (31%), cerebellar degeneration (28%) and encephalomyelitis (20%). Among antibody (Ab)-positive cases, most frequent specificities included: Yo (30%), Hu (26%), and Ma2 (22%), while the most frequent associated tumors were lung (17%) and breast cancer (16%), followed by lymphoma (12%). PNS developed in 1 in every 334 cancers in our region. Statistically significant associations were observed between cancer type and Ab-specificity (P < 0.001), and between neurological syndrome and Ab-specificity (P < 0.001).


This first population-based study found an incidence of PNS that approximates 1/100,000 person-years and a prevalence of 4/100,000. Moreover, the incidence of PNS is increasing over time, probably due to increased awareness and improved detection techniques.

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Data access, responsibility, and analysis

The corresponding author had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.


  1. Darnell RB, Posner JB (2003) Paraneoplastic syndromes involving the nervous system. N Engl J Med 349:1543–1554.

    Article  PubMed  CAS  Google Scholar 

  2. Honnorat J, Antoine J-C (2007) Paraneoplastic neurological syndromes. Orphanet J Rare Dis 2:22.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Dalmau J, Graus F (2018) Antibody-mediated encephalitis. N Engl J Med 378:840–851.

    Article  PubMed  Google Scholar 

  4. Graus F, Titulaer MJ, Balu R et al (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15:391–404.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Vogrig A, Joubert B, Ducray F et al (2018) Glioblastoma as differential diagnosis of autoimmune encephalitis. J Neurol 265:669–677.

    Article  PubMed  Google Scholar 

  6. Graus F, Delattre JY, Antoine JC et al (2004) Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 75:1135–1140.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Bettini M, Chaves M, Cristiano E et al (2017) Incidence of autoimmune myasthenia gravis in a health maintenance organization in Buenos Aires, Argentina. Neuroepidemiology 48:119–123.

    Article  PubMed  Google Scholar 

  8. Breiner A, Widdifield J, Katzberg HD et al (2016) Epidemiology of myasthenia gravis in Ontario, Canada. Neuromuscul Disord 26:41–46.

    Article  PubMed  Google Scholar 

  9. Martinka I, Fulova M, Spalekova M, Spalek P (2018) Epidemiology of myasthenia gravis in Slovakia in the years 1977–2015. Neuroepidemiology 50:153–159.

    Article  PubMed  Google Scholar 

  10. Popperud TH, Boldingh MI, Brunborg C et al (2017) Juvenile myasthenia gravis in Norway: a nationwide epidemiological study. Eur J Paediatr Neurol 21:312–317.

    Article  PubMed  CAS  Google Scholar 

  11. Monaco S, Turri E, Zanusso G, Maistrello B (2004) Treatment of inflammatory and paraproteinemic neuropathies. Curr Drug Targets Immune Endocr Metabol Disord 4:141–148

    Article  CAS  Google Scholar 

  12. Naing NN (2000) Easy way to learn standardization: direct and indirect methods. Malays J Med Sci 7:10–15

    PubMed  PubMed Central  CAS  Google Scholar 

  13. Keyfitz N (1966) Finite approximations in demography. Popul Stud (Camb) 19:281–295.

    Article  CAS  Google Scholar 

  14. Vogrig A, Joubert B, André-Obadia N et al (2019) Seizure specificities in patients with antibody-mediated autoimmune encephalitis. Epilepsia 60:1508–1525.

    Article  PubMed  Google Scholar 

  15. Kanikannan MA, Sirisha Y, Uppin MS et al (2015) Incidence and spectrum of paraneoplastic neurological syndromes: single center study. J Neurooncol 125:197–206.

    Article  PubMed  Google Scholar 

  16. Chan AM, Baehring JM (2019) Paraneoplastic neurological syndromes: a single institution 10-year case series. J Neurooncol 141:431–439.

    Article  PubMed  Google Scholar 

  17. Hayat MJ, Howlader N, Reichman ME, Edwards BK (2007) Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program. Oncologist 12:20–37.

    Article  PubMed  Google Scholar 

  18. Ducray F, Graus F, Vigliani MC et al (2010) Delayed onset of a second paraneoplastic neurological syndrome in eight patients. J Neurol Neurosurg Psychiatry 81:937–939.

    Article  PubMed  Google Scholar 

  19. Dubey D, Pittock SJ, Kelly CR et al (2018) Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 83:166–177.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Talbott EO, Malek AM, Lacomis D (2016) The epidemiology of amyotrophic lateral sclerosis. Handb Clin Neurol 138:225–238.

    Article  PubMed  CAS  Google Scholar 

  21. Zarei S, Carr K, Reiley L et al (2015) A comprehensive review of amyotrophic lateral sclerosis. Surg Neurol Int.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Giometto B, Grisold W, Vitaliani R et al (2010) Paraneoplastic neurologic syndrome in the PNS Euronetwork database: a European study from 20 centers. Arch Neurol 67:330–335.

    Article  PubMed  Google Scholar 

  23. Vogrig A, Ferrari S, Tinazzi M et al (2015) Anti-Ma-associated encephalomyeloradiculopathy in a patient with pleural mesothelioma. J Neurol Sci 350:105–106.

    Article  PubMed  Google Scholar 

  24. Dalmau J (2004) Clinical analysis of anti-Ma2-associated encephalitis. Brain 127:1831–1844.

    Article  PubMed  Google Scholar 

  25. Vogrig A, Joubert B, Maureille A et al (2018) Motor neuron involvement in anti-Ma2-associated paraneoplastic neurological syndrome. J Neurol 266:398–410.

    Article  PubMed  CAS  Google Scholar 

  26. Vogrig A, Fouret M, Joubert B et al (2019) Increased frequency of anti-Ma2 encephalitis associated with immune checkpoint inhibitors. Neurol Neuroimmunol Neuroinflamm 6:e604.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Maureille A, Fenouil T, Joubert B et al (2018) Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis. J Neurol.

    Article  PubMed  Google Scholar 

  28. Vogrig A, Pauletto G, Belgrado E et al (2018) Effect of thymectomy on refractory autoimmune status epilepticus. J Neuroimmunol 317:90–94.

    Article  PubMed  CAS  Google Scholar 

  29. Camdessanché J-P, Jousserand G, Ferraud K et al (2009) The pattern and diagnostic criteria of sensory neuronopathy: a case-control study. Brain 132:1723–1733.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Shams’ili S, Grefkens J, de Leeuw B et al (2003) Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients. Brain 126:1409–1418

    Article  Google Scholar 

  31. McKeon A, Tracy JA, Pittock SJ et al (2011) Purkinje cell cytoplasmic autoantibody type 1 accompaniments: the cerebellum and beyond. Arch Neurol 68:1282–1289.

    Article  PubMed  Google Scholar 

  32. Ventura L, Giorgi D, Giordano L et al (2015) Mammographic breast cancer screening in Italy: 2011–2012 survey. Epidemiol Prev 39:21–29

    PubMed  Google Scholar 

  33. Vogrig A, Zanoni T, Moretto G (2016) Nystagmus and lower extremity hyperalgesia after colectomy. JAMA 316:1488–1489.

    Article  PubMed  Google Scholar 

  34. Do L-D, Chanson E, Desestret V et al (2017) Characteristics in limbic encephalitis with anti-adenylate kinase 5 autoantibodies. Neurology 88:514–524.

    Article  PubMed  CAS  Google Scholar 

  35. Spatola M, Petit-Pedrol M, Simabukuro MM et al (2017) Investigations in GABAA receptor antibody-associated encephalitis. Neurology 88:1012–1020.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Gaig C, Graus F, Compta Y et al (2017) Clinical manifestations of the anti-IgLON5 disease. Neurology 88:1736–1743.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Hara M, Ariño H, Petit-Pedrol M et al (2017) DPPX antibody–associated encephalitis: main syndrome and antibody effects. Neurology 88:1340–1348.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Mandel-Brehm C, Dubey D, Kryzer TJ et al (2019) Kelch-like protein 11 antibodies in seminoma-associated paraneoplastic encephalitis. N Engl J Med 381:47–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations



Study concept and design: AV. Acquisition of data: AV, SS, EC, AM, AB, MF, PP and MR. Analysis and interpretation of data: AV, GLG, SS, EC, AM, AB, FV, MF, FC, FB, DI, PP, MR, JH and MV. Drafting of the manuscript: AV. Critical revision of the manuscript for important intellectual content: AV, GLG, SS, EC, AM, AB, FV, MF, FC, FB, DI, PP, MR, JH and MV. Study supervision: GLG and MV. All authors read and approved the final manuscript.

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Correspondence to Alberto Vogrig.

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All procedures were performed in accordance with the institutional ethics committee and the Declaration of Helsinki.

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Vogrig, A., Gigli, G.L., Segatti, S. et al. Epidemiology of paraneoplastic neurological syndromes: a population-based study. J Neurol 267, 26–35 (2020).

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  • Paraneoplastic syndromes
  • Epidemiology
  • Incidence
  • Prevalence
  • Encephalitis
  • Autoimmune