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Immunotherapeutics for Autoimmune Encephalopathies and Dementias

  • DEMENTIA (E MCDADE, SECTION EDITOR)
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Opinion statement

The timely implementation of immunotherapy is key to successful treatment of autoimmune encephalopathies or dementias (from here on will be referred to as autoimmune encephalopathies). There are different levels of diagnostic certainty which should guide the immunological treatment of autoimmune encephalopathies. There is a high level of diagnostic certainty for patients who have classic limbic encephalitis and have a neural antibody detected in serum or CSF (such as potassium channel complex antibody). For these patients, initiating high-dose corticosteroids or IVIg is indicated, with plasma exchange, rituximab or cyclophosphamide used as second-line therapy if first-line therapy proves only partially beneficial. There is a lower level of diagnostic certainty in patients with non-limbic atypical phenotypes (though rapidly progressive) when no neural antibody is detected in serum and CSF. A trial of corticosteroids or IVIg (or both sequentially) may be undertaken in these patients, but if no objective improvements occur, further immunotherapy is unlikely to be beneficial. Antiepileptic treatment also plays a critical role in those who have seizures as well as cognitive symptoms. Evaluation for and treatment of any underlying cancer is another component for those patients with a paraneoplastic cause of encephalitis. An individualized maintenance regimen needs to be designed for patients who do improve with immunotherapy. Individual factors that need to be considered when formulating a program of maintenance treatment include disease severity, antibody specificity and proclivity for disease relapse. Azathioprine and mycophenolate mofetil are frequently used for the purpose of remission maintenance, and should permit gradual withdrawal of steroids, IVIg or more toxic immunosuppressants. The duration of maintenance therapy is uncertain, but this author typically recommends 3–5 years of relapse-free maintenance treatment before discontinuing immunotherapy altogether.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Flanagan EP, McKeon A, Lennon VA, et al. Autoimmune dementia: clinical course and predictors of immunotherapy response. Mayo Clin Proc. 2010;85:881–97. This article describes the spectrum of autoimmune encephalopathies seen at Mayo Clinic. As well as clinical descriptions, serological findings, and predictors of immunotherapy response are discussed.

    Article  PubMed  Google Scholar 

  2. McKeon A, Lennon VA, Pittock SJ. Immunotherapy-responsive dementias and encephalopathies. Continuum (Minneap Minn). 2010;16:80–101. This describes in detail the evaluation of patients with suspected autoimmune encephalopathy.

    Article  Google Scholar 

  3. Geschwind MD, Tan KM, Lennon VA, et al. Voltage-gated potassium channel autoimmunity mimicking creutzfeldt-jakob disease. Arch Neurol. 2008;65:1341–6.

    Article  PubMed  Google Scholar 

  4. Castillo P, Woodruff B, Caselli R, et al. Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol. 2006;63:197–202.

    Article  PubMed  Google Scholar 

  5. McKeon A, Pittock SJ, Lennon VA. CSF complements serum for evaluating paraneoplastic antibodies and NMO-IgG. Neurology. 2011;76:1108–10.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  7. Vernino S, O'Neill BP, Marks RS, et al. Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neuro Oncol. 2004;6:55–62.

    Article  PubMed  Google Scholar 

  8. Vincent A, Buckley C, Schott JM, et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain. 2004;127:701–12.

    Article  PubMed  Google Scholar 

  9. Lai M, Huijbers MG, Lancaster E, et al. Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 2010;9:776–85.

    Article  PubMed  CAS  Google Scholar 

  10. McKeon A, Lennon VA, Pittock SJ. Immunotherapy-responsive dementias and encephalopathies. Continuum Lifelong Learn Neurol. 2010;16:80–101.

    Article  Google Scholar 

  11. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12:157–65. This is an important detailed study of the benefits of immunotherapy for NMDA R encephalitis. The authors describe 1st ine and 2nd line therapy.

    Article  PubMed  CAS  Google Scholar 

  12. Quek AM, Britton JW, McKeon A et al. Autoimmune Epilepsy: Clinical Characteristics and Response to Immunotherapy. Arch Neurol. 2012.

  13. Oakley RH, Cidlowski JA. Cellular processing of the glucocorticoid receptor gene and protein: new mechanisms for generating tissue-specific actions of glucocorticoids. J Biol Chem. 2011;286:3177–84.

    Article  PubMed  CAS  Google Scholar 

  14. Byyny RL. Withdrawal from glucocorticoid therapy. N Engl J Med. 1976;295:30–2.

    Article  PubMed  CAS  Google Scholar 

  15. Green H, Paul M, Vidal L, Leibovici L. Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials. Mayo Clin Proc. 2007;82:1052–9.

    Article  PubMed  CAS  Google Scholar 

  16. Sangiolo D, Storer B, Nash R, et al. Toxicity and efficacy of daily dapsone as Pneumocystis jiroveci prophylaxis after hematopoietic stem cell transplantation: a case-control study. Biol Blood Marrow Transplant. 2005;11:521–9.

    Article  PubMed  CAS  Google Scholar 

  17. Tomonari A, Takahashi S, Ooi J, et al. No occurrence of Pneumocystis jiroveci (carinii) pneumonia in 120 adults undergoing myeloablative unrelated cord blood transplantation. Transpl Infect Dis. 2008;10:303–7.

    Article  PubMed  CAS  Google Scholar 

  18. Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res. 2010;62:1515–26.

    Article  Google Scholar 

  19. Richards RN. Short-term corticosteroids and avascular necrosis: medical and legal realities. Cutis. 2007;80:343–8.

    PubMed  Google Scholar 

  20. Dubovsky AN, Arvikar S, Stern TA, Axelrod L. The neuropsychiatric complications of glucocorticoid use: steroid psychosis revisited. Psychosomatics. 2012;53:103–15.

    Article  PubMed  CAS  Google Scholar 

  21. Abu-Shakra M. Safety of vaccination of patients with systemic lupus erythematosus. Lupus. 2009;18:1205–8.

    Article  PubMed  CAS  Google Scholar 

  22. Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med. 2012;367:2015–25.

    Article  PubMed  CAS  Google Scholar 

  23. Burks AW, Sampson HA, Buckley RH. Anaphylactic reactions after gamma globulin administration in patients with hypogammaglobulinemia. Detection of IgE antibodies to IgA. N Engl J Med. 1986;314:560–4.

    Article  PubMed  CAS  Google Scholar 

  24. Ford LT, Berg JD. Thiopurine S-methyltransferase (TPMT) assessment prior to starting thiopurine drug treatment; a pharmacogenomic test whose time has come. J Clin Pathol. 2010;63:288–95.

    Article  PubMed  CAS  Google Scholar 

  25. Costanzi C, Matiello M, Lucchinetti CF, et al. Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. Neurology. 2011;77:659–66.

    Article  PubMed  CAS  Google Scholar 

  26. Sanderson J, Ansari A, Marinaki T, Duley J. Thiopurine methyltransferase: should it be measured before commencing thiopurine drug therapy? Ann Clin Biochem. 2004;41:294–302.

    Article  PubMed  CAS  Google Scholar 

  27. Kandiel A, Fraser AG, Korelitz BI, et al. Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine. Gut. 2005;54:1121–5.

    Article  PubMed  CAS  Google Scholar 

  28. Witte AS, Cornblath DR, Schatz NJ, Lisak RP. Monitoring azathioprine therapy in myasthenia gravis. Neurology. 1986;36:1533–4.

    Article  PubMed  CAS  Google Scholar 

  29. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000;47:85–118.

    Article  PubMed  CAS  Google Scholar 

  30. Jacob A, Matiello M, Weinshenker BG, et al. Treatment of neuromyelitis optica with mycophenolate mofetil: retrospective analysis of 24 patients. Arch Neurol. 2009;66:1128–33.

    Article  PubMed  Google Scholar 

  31. Jacob A, Weinshenker BG, Violich I, et al. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol. 2008;65:1443–8.

    Article  PubMed  Google Scholar 

  32. Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies. Arthritis Rheum. 2012;64:3043–51.

    Article  PubMed  CAS  Google Scholar 

  33. McKeon A, Pittock, SJ. Individualized Rituximab Treatment for Neuromyelitis Optica Spectrum Disorders JAMA Neurol. 2013

  34. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235–42.

    Article  PubMed  CAS  Google Scholar 

  35. Gourley MF, Austin 3rd HA, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med. 1996;125:549–57.

    Article  PubMed  CAS  Google Scholar 

  36. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349:36–44.

    Article  PubMed  CAS  Google Scholar 

  37. Allopurinol and cytotoxic drugs. Interaction in relation to bone marrow depression. Boston Collaborative Drug Surveillance Program. JAMA. 1974;227:1036–1040

  38. Park MC, Park YB, Jung SY, et al. Risk of ovarian failure and pregnancy outcome in patients with lupus nephritis treated with intravenous cyclophosphamide pulse therapy. Lupus. 2004;13:569–74.

    Article  PubMed  CAS  Google Scholar 

  39. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies. Neurology. 1998;50:652–7.

    Article  PubMed  CAS  Google Scholar 

  40. Pittock SJ, Lucchinetti CF, Lennon VA. Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments. Ann Neurol. 2003;53:580–7.

    Article  PubMed  CAS  Google Scholar 

  41. Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic opsoclonus and breast cancer. Ann Neurol. 1991;29:241–51.

    Article  PubMed  CAS  Google Scholar 

  42. Chan KH, Vernino S, Lennon VA. ANNA-3 anti-neuronal nuclear antibody: marker of lung cancer-related autoimmunity. Ann Neurol. 2001;50:301–11.

    Article  PubMed  CAS  Google Scholar 

  43. Vernino S, Lennon VA. New Purkinje cell antibody (PCA-2): marker of lung cancer-related neurological autoimmunity. Ann Neurol. 2000;47:297–305.

    Article  PubMed  CAS  Google Scholar 

  44. Pittock SJ, Lucchinetti CF, Parisi JE, et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol. 2005;58:96–107.

    Article  PubMed  Google Scholar 

  45. Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol. 2001;49:146–54.

    Article  PubMed  CAS  Google Scholar 

  46. Dalmau J, Graus F, Villarejo A, et al. Clinical analysis of anti-Ma2-associated encephalitis. Brain. 2004;127:1831–44.

    Article  PubMed  Google Scholar 

  47. Dalmau J, Gultekin SH, Voltz R, et al. Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders. Brain. 1999;122(Pt 1):27–39.

    Article  PubMed  Google Scholar 

  48. Graus F, Vincent A, Pozo-Rosich P, et al. Anti-glial nuclear antibody: marker of lung cancer-related paraneoplastic neurological syndromes. J Neuroimmunol. 2005;165:166–71.

    Article  PubMed  CAS  Google Scholar 

  49. Klein CJ, Lennon VA, Aston PA, et al. Insights from LGI1 and CASPR2 potassium channel complex autoantibody subtyping. JAMA Neurol. 2013;70:229–34.

    Article  PubMed  Google Scholar 

  50. Dalmau J, Tuzun E, Wu HY, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61:25–36.

    Article  PubMed  CAS  Google Scholar 

  51. Lancaster E, Lai M, Peng X, et al. Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 2010;9:67–76.

    Article  PubMed  CAS  Google Scholar 

  52. Boronat A, Sabater L, Saiz A, et al. GABA(B) receptor antibodies in limbic encephalitis and anti-GAD-associated neurologic disorders. Neurology. 2011;76:795–800.

    Article  PubMed  CAS  Google Scholar 

  53. Lai M, Hughes EG, Peng X, et al. AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol. 2009;65:424–34.

    Article  PubMed  CAS  Google Scholar 

  54. McKeon A, Lennon VA, Lachance DH, et al. Ganglionic acetylcholine receptor autoantibody: oncological, neurological, and serological accompaniments. Arch Neurol. 2009;66:735–41.

    Article  PubMed  Google Scholar 

  55. Lancaster E, Martinez-Hernandez E, Titulaer MJ, et al. Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology. 2011;77:1698–701.

    Article  PubMed  CAS  Google Scholar 

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Conflict of Interest

Andrew McKeon has received grant support from the Guthy Jackson Charitable Foundation.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. College of Medicine, Mayo Clinic, 200 1st ST SW, Rochester, MN, 55905, USA

    Andrew McKeon MD

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Correspondence to Andrew McKeon MD.

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McKeon, A. Immunotherapeutics for Autoimmune Encephalopathies and Dementias. Curr Treat Options Neurol 15, 723–737 (2013). https://doi.org/10.1007/s11940-013-0251-8

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