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. 2006 Apr 5;9(2):251–260. doi: 10.1111/j.1750-3639.1999.tb00224.x

The Neuropathology of Paraneoplastic Syndromes

Francesco Scaravilli 1,✉, Shu F An 1, Michael Groves 1, Maria Thom 1
PMCID: PMC8098626  PMID: 10219743

Abstract

The term “paraneoplastic neurological syndromes” encompasses a number of uncommon disorders associated with systemic malignancies. In order to be classified a paraneoplastic neurological syndrome, the malignancies must not invade, compress, or metastasize to the nervous system. They can either focally or diffusely involve the central and peripheral nervous system or the neuromuscular junction.

This paper reviews the neuropathology of the syndrome. It will first describe the clinical presentation and give an account of the systemic tumors most commonly associated with the various types of disorders. Then it will review the general pathological features that consist of an inflammatory process predominantly affecting the gray matter. Finally, it will describe in detail the main clinico‐pathological types, including 1) encephalomyelitis, 2) cortical cerebellar degeneration, 3) peripheral neuropathy, 4) opsoclonus‐myoclonus and 5) retinopathy. The Lambert‐Eaton myasthenie syndrome will be dealt with separately in another paper in this symposium.

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References

  • 1. Adamus G, Guy J, Schmied JL, Arendt A and Hargrave PA (1993) Role of anti‐recoverin autoantibodies in cancer‐associated retinopathy Invest Ophthalmol Vis Sci 34: 2626–33. [PubMed] [Google Scholar]
  • 2. Alajouanine T, Bertrand I and Samson M (1962) Deux observations anatomocliniques de neuropathie can‐céreuse. Rev Neurol 106: 318–23. [Google Scholar]
  • 3. Altman AJ and Baehner RL (1976) Favorable prognosis for survival in children with coincident opso‐myoclonus and neuroblastoma. Cancer 37: 846–52. [DOI] [PubMed] [Google Scholar]
  • 4. Anderson NE, Budde‐Steffen C, Rosenblum MK, Graus F, Ford D, Synek BJ and Posner JB (1988) Opsoclonus, myoclonus, ataxia and encephalopathy in adults with cancer: a distinct paraneoplastic syndrome. Medicine 67: 100–9. [DOI] [PubMed] [Google Scholar]
  • 5. Auché M (1890) Des névrites périphériques chez les can‐céreux. Rev Méd 10: 785–807. [Google Scholar]
  • 6. Barron SA and Heffner RR (1978) Weakness in malignancy: evidence for a remote effect of tumour on distal axons. Ann Neurol 4: 268–74. [DOI] [PubMed] [Google Scholar]
  • 7. Boeck K, Hofman S, Klopfer M, Ian U, Schmidt T, Engst R, Thirkill CE and Ring J (1997) Melanoma‐associated paraneoplastic retinopathy: case report and review of the literature. Brit J Dermatol 137: 457–60. [PubMed] [Google Scholar]
  • 8. Brain Lord, Croft PB and Wilkinson M (1965) Motor neurone disease as a manifestation of neoplasm (with a note on the course of classical motor neurone disease). Brain 88: 479–500. [DOI] [PubMed] [Google Scholar]
  • 9. Brain WR, Daniel PM and Greenfield JG (1951) Subacute cortical cerebellar degeneration and its relation to carcinoma. J Neurol Neurosurg Psychiaf14: 59–75. [DOI] [PMC free article] [PubMed]
  • 10. Brierley JB, Corsellis JAN, Hierons R and Nevin S (1960) Subacute encephalitis of later adult life, mainly affecting the limbic area. Brain 83: 357–68. [Google Scholar]
  • 11. Brower B (1919) Beitrag zur Kenntis der chronischen diffusen Kleinhirnerkrankngen. Mendels neurol Zentralblatt 38: 674–82. [Google Scholar]
  • 12. Brower B and Biemond A (1938) Les affections parenchymateuses du cervelet et leur signification du point de vue de l'anatomie et la physiologie de cet organe. J Bel Neurol Psychiat 38: 691–757. [Google Scholar]
  • 13. Brownell B and Hughes JT (1975) Degeneration of muscle in association with carcinoma of the bronchus. J Neurol Neurosurg Psychiat 38: 363–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Cher LM, Hochberg FH, Teruya J, Nischke M and Valenzuela RF (1995) Therapy for paraneoplastic neurologic syndromes in six patients with protein A column immunoadsorption. Cancer 75: 1678–83. [DOI] [PubMed] [Google Scholar]
  • 15. Corsellis JAN, Goldberg GJ and Norton AR (1968) ‘Limbic encephalitis’ and its association with carcinoma. Brain 91: 481–96. [DOI] [PubMed] [Google Scholar]
  • 16. Croft PB and Wilkinson M (1965) The incidence of carcinomatous neuromyopathy in patients with various types of carcinoma. Brain 88: 427–34. [DOI] [PubMed] [Google Scholar]
  • 17. Croft PB and Wilkinson M (1969) The course and prognosis in some types of carcinomatous neuromyopathy. Brain 92: 1–8. [DOI] [PubMed] [Google Scholar]
  • 18. Crotf CR, Urich H and Wilkinson M (1967) Peripheral neuropayhy of sensorimotor type associated with malignant disease. Brain 90: 31–66. [DOI] [PubMed] [Google Scholar]
  • 19. Dalmau J, Graus F, Rosenblum MK and Posner JB (1992) Anti‐Hu‐associated paraneoplastic encephalomyelitis/ sensory neuropathy. A clinical study of 71 patients. Medicine 71:59–72. [DOI] [PubMed] [Google Scholar]
  • 20. Dalmau J, Graus G, Cheung NK, Rosenblum MK and Ho A (1995) Major histocompatibility proteins, anti‐Hu antibodies and paraneoplastic encephalomyelitis in neuroblastoma and small cell lung cancer. Cancer 75: 99–109. [DOI] [PubMed] [Google Scholar]
  • 21. Denny‐Brown D (1948) Primary sensory neuropathy with muscular changes associated with carcinoma. J Neurol Neurosurg Psychiat 11: 73–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Digre KB (1986) Opsoclonus in adults. Arch Neurol 43: 1165–75. [DOI] [PubMed] [Google Scholar]
  • 23. Dirr LY, Elster AD, Donofrio PD and Smith M (1990) Evolution of brain MRI abnormalities in limbic encephalitis. Neurology 40: 1304–06. [DOI] [PubMed] [Google Scholar]
  • 24. Dorfman LJ and Forno LS (1972) Paraneoplsatic encephalomyelitis. Acta Neurologica Scandinavica 48: 556–74. [DOI] [PubMed] [Google Scholar]
  • 25. Dropcho EJ (1998) Neurologic paraneoplastic syndromes. J Neurol Sci 153: 264–78. [DOI] [PubMed] [Google Scholar]
  • 26. Eltabbakh GH, Hoogerland DL and Kay L (1995) Paraneoplastic retinopathy associated with uterine sarcoma. Gynecol Oncol 58: 120–23. [DOI] [PubMed] [Google Scholar]
  • 27. Evans BK, Fagan C, Arnold T, Dropcho EJ and Oh SJ (1990) Paraneoplastic motor neuron disease and renal cell carcinoma: improvement after nephrectomy. Neurology 40: 960–62. [DOI] [PubMed] [Google Scholar]
  • 28. Fisher PG, Wechsler DS and Singer HS (1994) Anti‐Hu antibody in a neuroblastoma‐associated paraneoplastic syndrome. Pediatr Neurol 10: 309–12. [DOI] [PubMed] [Google Scholar]
  • 29. Graus F and Delattre JY (1995) Immune modulation of paraneoplastic neurologic disorders. Clin Neurol Neurosurg 97: 112–16. [DOI] [PubMed] [Google Scholar]
  • 30. Graus F, Dalmau J, Valldeoriola F, Ferrer I, Rene R, Marin C, Vecht CJ, Arbizu T, Targa C and Moll JW (1997) Immunological characterization of a neuronal antibody (anti‐Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin's disease. J Neuroimmunol 74: 55–61. [DOI] [PubMed] [Google Scholar]
  • 31. Greenfield JG (1934) Subacute spinocerebellar degeneration occurring in elderly patients. Brain 57: 161–76. [Google Scholar]
  • 32. Hammack J, Kimmel DW, O'Neill BP O'Neill BP and Lennon VA (1990) Paraneoplastic cerebellar degeneration: a clinic comparison of patients with and without Purkinje cell cytoplasmic antibodies. Mayo Clin Proc 65: 1423–31. [DOI] [PubMed] [Google Scholar]
  • 33. Hammack J, Kotanides H, Rosenblum MK and Posner JB (1992) Paraneoplastic cerebellar degeneration: II. Clinical and immunologic findings in 21 patients with Hodgkin's disease. Neurology 42: 1938–43. [DOI] [PubMed] [Google Scholar]
  • 34. Hammerstein W, Jurgens H and Gobel U (1991) Retinal degeneration and embryonal rhabdomyosarcoma of the thorax. Fortschr Ophthalmol 88: 463–65. [PubMed] [Google Scholar]
  • 35. Harris W (1926) Neuritis and Neuralgia. Oxford Univ press, Oxford , p 38. [Google Scholar]
  • 36. Henson RA (1970) Non‐metastatic neurological manifestations of malignant diseases. In Modern Trends in Neurology, Williams D ed, Butterworth, London pp 209–25. [PubMed] [Google Scholar]
  • 37. Henson RA and Urich H (1979) Remote effects of malignant disease: certain intracranial disorders. In Handbook of Clinical Neurology, Vinken PJ and Bruyn GW eds, North Holland Publishing Co, Amsterdam , vol 38, pp 625–68. [Google Scholar]
  • 38. Henson RA and Urich H (1982) Cancer and the Nervous System. Blackwell Scientific, London . [Google Scholar]
  • 39. Henson RA, Russell DS and Wilkinson M (1954) Carcinomatous neuropathy and myopathy A clinical and pathological study. Brain 77: 82–121. [DOI] [PubMed] [Google Scholar]
  • 40. Hersh B, Dalmau J, Dangond F, Gultekin S, Geller E and Wen PY (1994) Paraneoplastic opsoclonus‐myoclonus associated with anti‐Hu antibody. Neurology 44: 1754–55. [DOI] [PubMed] [Google Scholar]
  • 41. Hormigo A, Dalmau J, Rosenblum MK, River ME and Posner JB (1994) Immunological and pathological study of an anti‐Ri‐associated encephalopathy Ann Neurol 36: 896–902. [DOI] [PubMed] [Google Scholar]
  • 42. Huober J, Holz FG, Schmid H, Nolle B, Bellmann C, Krastel H, Wallwiener D and Bastert G (1997) Paraneoplastic retinopathy in 2 patients with breast carcinoma. Zentralbl Gynakol 119: 278–81. [PubMed] [Google Scholar]
  • 43. Jacobson DM, Thirkill CE and Tipping SJ (1990) A clinical triad to diagnose paraneoplsatic retinopathy. Ann Neurol 28: 162–67. [DOI] [PubMed] [Google Scholar]
  • 44. Johnson PC, Roluk LA, Hamilton RH and Laguna JF (1979) Paraneoplastic vasculitis of nerve: a remote effect of cancer. Ann Neurol 5: 437–44. [DOI] [PubMed] [Google Scholar]
  • 45. Khwaja S, Sripathi N, Ahmad BK and Lennon VA (1998) Paraneoplastic motor neuron disease with type 1 Purkinje cell antibody. Muscle Nerve 21: 943–45. [DOI] [PubMed] [Google Scholar]
  • 46. Lafeuillade A, Quilichini R, Chiozza R, Pellegrino P and Thirkill CE (1993) Rétinopathie paranéoplasique (CAR syndrome) révélatrice d'un cancer prostatique. Presse Méd 22: 35. [PubMed] [Google Scholar]
  • 47. Lamarche J and Vital C (1987) Carcinomatous neuropathy. An ultrastructural study of 10 cases. Ann Pathol 7: 98–105. [PubMed] [Google Scholar]
  • 48. Lenman JAR, Fleming AM, Robertson MAH et al (1981) Peripheral nerve function in patients with bronchial carcinoma. Comparison with matched controls and effects of treatment. J Neurol Neurosurg Psychiat 44: 54–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Lhermitte F, Gray F, Lyon‐Caen O, Pertuiset BF and Bernard P (1980) Paralysie du tube digestif avec lésions des plexus myentériques. Nouveau syndrome paranéoplasique. Rev Neurol 136: 825–36. [PubMed] [Google Scholar]
  • 50. Lipton RB, Galer BS, Dutcher JP, Portenoy RK, Berger A, Arezzo JC, Mizruchi M, Wiernik PH and Schaumburg HH (1987) Quantitative sensory testing demonstrates that subclinical sensory neuropathy is prevalent in patients with cancer. Arch Neurol 44: 944–6. [DOI] [PubMed] [Google Scholar]
  • 51. Luque A, Furneaux HM, Ferziger R, Rosenblum MK and Wray S (1991) Anti‐Ri: an antibody with paraneoplstic opsoclonus and breast cancer. Ann Neurol 29: 241–51. [DOI] [PubMed] [Google Scholar]
  • 52. McLeod JG (1993) Paraneoplastic neuropathies. In Periphearl Neuropathy, Dick PJ and Thomas PK eds, 3rd ed WB Saunders Co, Philadelphia , pp 1583–90. [Google Scholar]
  • 53. Mellgren SI, Mørk S and Nyland H (1978) Malignant glioma and sensorimotor neuropathy. J Neurol 48: 1–6. [DOI] [PubMed] [Google Scholar]
  • 54. Milam AH, Saari JC, Jacobson SG, Lubinski WP, Feun LG and Alexander KR (1993) Autoantibodies against retinal bipolar cells in cutaneous melanoma‐associated retinopathy. Invest Ophthalmol Vis Sci 34: 91–100. [PubMed] [Google Scholar]
  • 55. Moll JW, Antoine JC, Brashear HR, Delattre J, Drlicek M and Dropcho EJ (1995) Guidelines on the detection of paraneoplastic anti‐neuronal‐specific antibodies. Neurology 45: 1937–41. [DOI] [PubMed] [Google Scholar]
  • 56. Moody JF (1965) Electrophysiological investigations in the neurological complications of carcinoma. Brain 88: 1023–36. [DOI] [PubMed] [Google Scholar]
  • 57. Moossy J, Todd Troost B. and Durkan J (1980) Chronic brainstem‐cerebellar encephalitis: a delayed remote effect of breast carcinoma Neurology 30: 430. [Google Scholar]
  • 58. Norris FH jr (1979) Remote effects of cancer on the spinal cord. In Handbook of Clinical Neurology, Vinken PJ and Bruyn GW eds, North Holland Publishing Company, Amsterdam , vol 38, pp 669–77. [Google Scholar]
  • 59. Norris FH jr and Engel WK (1965) Carcinomatous amyotrophic lateral sclerosis. In The Remote Effect of Cancer of the Nervous System, Lord Brain and Norris HF jr eds, Grune and Stratton, New York , pp 24–34. [Google Scholar]
  • 60. Norris FH jr, McMenemey WH and Barnard RO (1969) Anterior horn pathology in carcinomatous neuromyopathy compared with other forms of motor neuron disease. In Motor Neuron Disease, Norris FH jr and Kurland LT eds, Grune and Stratton, New York , pp 100–11. [Google Scholar]
  • 61. Norris FH jr, Rudolph JH and Barney MO (1964) Carcinomatous neuropathy. Rare complication of cancer of the cervix uteri. Neurology 14: 202–05. [DOI] [PubMed] [Google Scholar]
  • 62. Ongerboer de Visser BW, Feltkamp‐Wroom TM and Feltkamp CA (1983) Sural nerve immune deposits in polyneuropathy as a remote effect of malignancy. Ann Neurol 14: 261–66. [DOI] [PubMed] [Google Scholar]
  • 63. Oppenheim H (1911) Textbook of Nervous Diseases. 5th ed, Edinburgh .
  • 64. Posner JB (1991) Paraneoplastic syndromes. Neurologic Clinics 9: 919–36. [PubMed] [Google Scholar]
  • 65. Posner JB (1993) Paraneoplastic cerebellar degeneration. Can J Neurol Sci 20 (suppl 3): 117–22. [PubMed] [Google Scholar]
  • 66. Posner JB and Dalmau J (1995) Clinical enigmas of paraneoplastic neurologic disorders. Clin Neurol Neurosurg 97:61–70. [DOI] [PubMed] [Google Scholar]
  • 67. Ridley A, Kennard C, Scholtz CL Büttner‐Ennever JA, Summer B and Turnbull A (1987) Omnipause neurons in two cases of opsoclonus associated with oat cell carcinoma of the lung. Brain 110: 1699–709. [DOI] [PubMed] [Google Scholar]
  • 68. Russell DS (1961) Encephalomyelitis and carcinomatous neuropathy. In The encephalitides, van Bogaert L, Radermecker J, Hozay J and Lowenthal eds, Elsevier, Amsterdam , pp 131–35. [Google Scholar]
  • 69. Schmid AH and Riede UN (1974) A morphometric study of the cerebellar cortex from patients with carcinoma. Acta Neuropathol 28: 343–52. [DOI] [PubMed] [Google Scholar]
  • 70. Sculier J‐P, Feld R, Evans WK, De Boer G, Shepherd FA, Payne DG, Pringle JF, Yeoh JL, Quirt IC, Curtis JE et al (1987) Neurologic disorders in patients with small cell lung cancer. Cancer 60: 2275–83. [DOI] [PubMed] [Google Scholar]
  • 71. Shaw PJ, Ince PG, Slade J, Burn J and Cartlidge NEF (1991) Lower motor neuron degeneration and familial predisposition to colonic neoplasia in two adult siblings. J Neurol Neurosurg Psychiat 54: 993–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72. Shy GM and Silverstein I (1965) A study of the effects upon the motor unit by remote malignancy. Brain 88: 515–28. [DOI] [PubMed] [Google Scholar]
  • 73. Sodhi N, Camilleri M, Camoriano JK, Low PA, Fealey RD and Perry MC (1989) Autonomie function and motility in intestinal pseudoobstruction caused by paraneoplastic syndrome. Dig Dis Sci 34: 1937–42. [DOI] [PubMed] [Google Scholar]
  • 74. Telander RL, Smithson WA and Groover RV (1989) Clinical outcome in children with acute cerebellar encephalopathy and neuroblastoma. J Pediatr Surg 24: 11–14. [DOI] [PubMed] [Google Scholar]
  • 75. Teräväinen H and Larsen A (1977) Some features of the neuromuscular complications of pulmonary carcinoma. Ann Neurol 2: 495–502. [DOI] [PubMed] [Google Scholar]
  • 76. Trojaborg W, Frentzen E and Anderson I (1969) Peripheral neuropathy and myopathy associated with carcinoma of the lung. Brain 92: 71–82. [DOI] [PubMed] [Google Scholar]
  • 77. Van Oosterhout AG, Van de Pol M, Ten Velde GPM and Twijnstra A (1996) Neurologic disorders in 203 consecutive patients with small cell lung cancer. Cancer 77:1434–41. [DOI] [PubMed] [Google Scholar]
  • 78. Verma A, Berger JR, Snodgrass S and Petito C (1996) Motor neuron disease: a paraneoplastic process associated with anti‐Hu antibody and small cell lung carcinoma. Ann Neurol 40: 112–16. [DOI] [PubMed] [Google Scholar]
  • 79. Vincent D, Dubas F, Hauw JJ, Godeau P, Lhermitte F, Buge A and Castaigne P (1986) Nerve and muscle microvasculitis in peripheral neuropathy: a remote effect of cancer J Neurol Neurosurg Psychiat 49: 1007–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80. Weber FP and Hill TR (1933) Complete degeneration of the posterior columns of the spinal cord with chronic polyneuritis in a case of widespread carcinomatous disease. J Neurol Psychopathol 14: 57–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81. Wessel K, Diener HC, Dichgans J and Thron A (1988) Cerebellar dysfucnction in patients with brochogenic carcinoma: clinical and post‐urographic findings. J Neurol 235: 290–6. [DOI] [PubMed] [Google Scholar]
  • 82. Wyburn‐Mason R (1948) Bronchial carcinoma presenting as a polyneuritis. Lancet 1: 203–206. [PubMed] [Google Scholar]
  • 83. Younger DS, Rowland LP, Latov N, Hays AP, Lange DJ, Sherman W, Inghirami G, Pesce MA, Kniowles DM, Powers J, Miller JR, Fetell MR and Lovelace RE (1991) Lymphoma, motor neuron disease and amyotrophic lateral sclerosis. Ann Neurol 29: 78–86. [DOI] [PubMed] [Google Scholar]

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