Paraneoplastic Encephalomyelitis 

  • Author: David S Liebeskind, MD; Chief Editor: Stephen A Berman, MD, PhD, MBA   more...
 
Updated: Aug 13, 2010
 

Background

Paraneoplastic encephalomyelitis (PEM) is a multifocal inflammatory disorder of the central nervous system (CNS) associated with remote neoplasia. Frequently, the disorder is accompanied by subacute sensory neuronopathy (SSN) due to involvement of the dorsal root ganglia. Anti-Hu antibodies may be detected in both of these conditions. Although various malignancies have been reported in PEM, 80% of cases are associated with bronchial cancer, typically small cell lung carcinoma. Neurologic manifestations commonly precede the diagnosis of cancer, although variable presentations have been reported. Symptoms usually progress over the course of weeks to months, reaching a plateau of neurologic disability. Neurologic impairment may be more debilitating than the associated cancer. No effective therapeutic approaches have been established, although immunosuppressive therapies are commonly used.

Paraneoplastic encephalomyelitis. Paraneoplastic encephalomyelitis. Paraneoplastic encephalomyelitis. Paraneoplastic encephalomyelitis.
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Pathophysiology

Neurologic dysfunction probably results from an autoimmune reaction directed against onconeural antigens in the human nervous system. Polyclonal immunoglobulin G (IgG) anti-Hu antibodies or type 1 antineuronal nuclear antibodies are most prevalent (~50%), although several other circulating autoantibodies have been identified. Some patients have no identifiable paraneoplastic antibodies. These markers of paraneoplasia have an undetermined pathogenic role. Cytotoxic T cell–mediated neuronal damage is suspected, although no animal models have been developed to confirm this.[1]

Almost all cases of PEM with anti-Hu antibodies are related to small-cell lung carcinoma. These antibodies react with a group of 35- to 40-kilodalton neuronal RNA-binding proteins, including HuD[2] , PLE21/HuC, and Hel-N1. Nuclear and cytoplasmic staining of CNS neurons demonstrates the presence of these antibodies. A ubiquitous protein, HuR, is also an antigenic target. The neuronal proteins are homologous to the embryonic lethal abnormal visual (ELAV) protein in Drosophila species. Anti-Hu antibodies may alter the production of these proteins, which are essential for the development, maturation, and maintenance of the vertebrate nervous system. Intrathecal synthesis of anti-Hu antibodies may represent an autoimmune cross-reaction with neurologic tissue, triggered by a remote carcinoma. Recent work has focused on the detection of neuron-specific ELAV mRNA in peripheral blood of SCLC patients using real-time quantitative polymerase chain reaction (PCR).[3]

In a recent report, a subset of patients with limbic encephalitis associated with a systemic neoplasm previously attributed to antibodies against voltage gated potassium channel antibodies actually recognize LGI1 protein complex epitopes and do not represent a channelopathy. The authors propose the term limbic encephalitis associated with LGI1 antibodies.[4]

Other PEM antibodies include anti-CV2, anti-Yo, anti-Ma1, anti-Ta or anti-Ma2, anti-LGI1, and several other atypical antibodies. The targets of such antibodies may be quite varied, including neuropil and intraneuronal sites.

Nonneuronal autoantibodies, such as antinuclear antibodies and anticytoplasmic antibodies, are frequently detected in cases with anti-Hu antibodies or anti-Yo antibodies. The presence of such nonneuronal autoantibodies, however, does not correlate with particular clinical characteristics.[5]

Voltage-gated potassium channel antibodies may be associated with nonparaneoplastic limbic encephalitis.

Recent reports have noted detection of the prion-related 14-3-3 protein[6] and of herpes simplex virus[7] by PCR in the cerebrospinal fluid (CSF) of patients with PEM. The significance of these findings is unclear.

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Epidemiology

Frequency

United States

The incidence of PEM is unknown. PEM affects approximately 0.4% of patients with bronchial carcinoma. Increased recognition of clinical manifestations may provide estimates of incidence in the future.

International

The incidence of PEM is unknown.

Mortality/Morbidity

  • PEM has a variable and unpredictable course.
  • Progressive evolution of neurologic dysfunction may lead to coma and death in a few patients.
  • Most patients experience severe neurologic impairment with susceptibility to related medical complications.

Race

No racial predilection has been reported.

Sex

Anti-Hu–associated PEM has a slight female predominance.[8]

Age

  • PEM occurs most frequently in middle-aged or older adults with small-cell lung carcinoma.
  • It may occur in younger individuals with other types of cancer.
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Contributor Information and Disclosures
Author

David S Liebeskind, MD  Associate Professor of Neurology, Program Director, Vascular Neurology Residency Program, University of California, Los Angeles, David Geffen School of Medicine; Neurology Director, Stroke Imaging Program, Co-Medical Director, Cerebral Blood Flow Laboratory, Associate Neurology Director, UCLA Stroke Center

David S Liebeskind, MD is a member of the following medical societies: American Academy of Neurology, American Heart Association, American Medical Association, American Society of Neuroimaging, American Society of Neuroradiology, National Stroke Association, and Stroke Council of the American Heart Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Frederick M Vincent Sr, MD  Clinical Professor, Department of Neurology and Ophthalmology, Michigan State University Colleges of Human and Osteopathic Medicine

Frederick M Vincent Sr, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American College of Forensic Examiners, American College of Legal Medicine, American College of Physicians, and Michigan State Medical Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Jorge C Kattah, MD  Head, Associate Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria

Jorge C Kattah, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, and New York Academy of Sciences

Disclosure: Biogen Honoraria Consulting; Bayer Corporation Honoraria Consulting

Selim R Benbadis, MD  Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting

Chief Editor

Stephen A Berman, MD, PhD, MBA  Professor of Neurology, University of Central Florida College of Medicine

Stephen A Berman, MD, PhD, MBA is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, and Phi Beta Kappa

Disclosure: Nothing to disclose.

References

  1. Graus F, Saiz A, Lai M, Bruna J, López F, Sabater L, et al. Neuronal surface antigen antibodies in limbic encephalitis: clinical-immunologic associations. Neurology. Sep 16 2008;71(12):930-6. [Medline].

  2. Benyahia B, Liblau R, Merle-Beral H, et al. Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies. Ann Neurol. Feb 1999;45(2):162-7. [Medline].

  3. D'Alessandro V, Muscarella LA, Copetti M, Zelante L, Carella M, Vendemiale G. Molecular detection of neuron-specific ELAV-like-positive cells in the peripheral blood of patients with small-cell lung cancer. Cell Oncol. 2008;30(4):291-7. [Medline].

  4. Lai M, Huijbers MG, Lancaster E, Graus F, Bataller L, Balice-Gordon R, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. Aug 2010;9(8):776-85. [Medline].

  5. Aguirre-Cruz L, Charuel JL, Carpentier AF, et al. Clinical relevance of non-neuronal auto-antibodies in patients with anti-Hu or anti-Yo paraneoplastic diseases. J Neurooncol. Jan 2005;71(1):39-41. [Medline].

  6. Saiz A, Graus F, Dalmau J. Detection of 14-3-3 brain protein in the cerebrospinal fluid of patients with paraneoplastic neurological disorders. Ann Neurol. Nov 1999;46(5):774-7. [Medline].

  7. Sharshar T, Auriant I, Dorandeu A, et al. Association of herpes simplex virus encephalitis and paraneoplastic encephalitis - a clinico-pathological study. Ann Pathol. May 2000;20(3):249-52. [Medline].

  8. Foster AR, Caplan JP. Paraneoplastic limbic encephalitis. Psychosomatics. Mar-Apr 2009;50(2):108-13. [Medline].

  9. Maddison P, Lang B. Paraneoplastic neurological autoimmunity and survival in small-cell lung cancer. J Neuroimmunol. Sep 15 2008;201-202:159-62. [Medline].

  10. Shavit YB, Graus F, Probst A, et al. Epilepsia partialis continua: a new manifestation of anti-Hu-associated paraneoplastic encephalomyelitis. Ann Neurol. Feb 1999;45(2):255-8. [Medline].

  11. Saiz A, Blanco Y, Sabater L, González F, Bataller L, Casamitjana R, et al. Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. Oct 2008;131:2553-63. [Medline].

  12. Mihara M, Sugase S, Konaka K, et al. The "pulvinar sign" in a case of paraneoplastic limbic encephalitis associated with non-Hodgkin's lymphoma. J Neurol Neurosurg Psychiatry. Jun 2005;76(6):882-4. [Medline].

  13. Wingerchuk DM, Noseworthy JH, Kimmel DW. Paraneoplastic encephalomyelitis and seminoma: importance of testicular ultrasonography. Neurology. Nov 1998;51(5):1504-7. [Medline].

  14. Honnorat J, Antoine JC. Paraneoplastic neurological syndromes. Orphanet J Rare Dis. May 4 2007;2:22. [Medline].

  15. Dropcho EJ. Paraneoplastic Diseases of the Nervous System. Curr Treat Options Neurol. Nov 1999;1(5):417-427. [Medline].

  16. Keime-Guibert F, Graus F, Broet P, et al. Clinical outcome of patients with anti-Hu-associated encephalomyelitis after treatment of the tumor. Neurology. Nov 10 1999;53(8):1719-23. [Medline].

  17. 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. Apr 2000;68(4):479-82. [Medline].

  18. Shams'ili S, de Beukelaar J, Gratama JW, Hooijkaas H, van den Bent M, van 't Veer M, et al. An uncontrolled trial of rituximab for antibody associated paraneoplastic neurological syndromes. J Neurol. Jan 2006;253(1):16-20. [Medline].

  19. Ances BM, Vitaliani R, Taylor RA, et al. Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain. Aug 2005;128(Pt 8):1764-77. [Medline].

  20. Bakheit AM, Kennedy PG, Behan PO. Paraneoplastic limbic encephalitis: clinico-pathological correlations. J Neurol Neurosurg Psychiatry. Dec 1990;53(12):1084-8. [Medline].

  21. Compta Y, Valldeoriola F, Urra X, Gómez-Ansón B, Rami L, Tolosa E, et al. Isolated frontal disequilibrium as presenting form of anti-Hu paraneoplastic encephalomyelitis. Mov Disord. Apr 15 2007;22(5):736-8. [Medline].

  22. Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain. Aug 2004;127(Pt 8):1831-44. [Medline].

  23. de Beukelaar JW, Sillevis Smitt PA. Managing paraneoplastic neurological disorders. Oncologist. Mar 2006;11(3):292-305.

  24. de Beukelaar JW, Sillevis Smitt PA, Hop WC, Kraan J, Hooijkaas H, Verjans GM, et al. Imbalances in circulating lymphocyte subsets in Hu antibody associated paraneoplastic neurological syndromes. Eur J Neurol. Dec 2007;14(12):1383-91. [Medline].

  25. de Graaf M, de Beukelaar J, Bergsma J, Kraan J, van den Bent M, Klimek M, et al. B and T cell imbalances in CSF of patients with Hu-antibody associated PNS. J Neuroimmunol. Mar 2008;195(1-2):164-70. [Medline].

  26. Gultekin SH, Rosenfeld MR, Voltz R, et al. Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients. Brain. Jul 2000;123 ( Pt 7):1481-94. [Medline].

  27. Inuzuka T. Autoantibodies in paraneoplastic neurological syndrome. Am J Med Sci. Apr 2000;319(4):217-26. [Medline].

  28. Provenzale JM, Barboriak DP, Coleman RE. Limbic encephalitis: comparison of FDG PET and MR imaging findings. AJR Am J Roentgenol. Jun 1998;170(6):1659-60. [Medline].

  29. Sabater L, Gomez-Choco M, Saiz A, Graus F. BR serine/threonine kinase 2: a new autoantigen in paraneoplastic limbic encephalitis. J Neuroimmunol. Dec 30 2005;170(1-2):186-90. [Medline].

  30. Scaravilli F, An SF, Groves M, Thom M. The neuropathology of paraneoplastic syndromes. Brain Pathol. Apr 1999;9(2):251-60. [Medline].

  31. Tani T, Tanaka K, Idezuka J, Nishizawa M. Regulatory T cells in paraneoplastic neurological syndromes. J Neuroimmunol. May 30 2008;196(1-2):166-9. [Medline].

  32. Vincent A. Antibodies associated with paraneoplastic neurological disorders. Neurol Sci. May 2005;26 Suppl 1:S3-4. [Medline].

  33. Vincent A, Buckley C, Schott JM, et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain. Mar 2004;127(Pt 3):701-12. [Medline].

  34. Voltz R, Gultekin SH, Rosenfeld MR, et al. A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med. Jun 10 1999;340(23):1788-95. [Medline].

 
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Paraneoplastic encephalomyelitis.
Paraneoplastic encephalomyelitis.
Mesial temporal hyperintensity demonstrated on T2-weighted (left) and fluid-attenuated inversion recovery (FLAIR, right) MRI.
 
 
 
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