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Infections, Immunodeficiency, and Complications of Immunomodulatory Therapies in Neuroimmunology

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Neuroimmunology

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Abstract

In the presentation of neurological syndromes, such as encephalopathy/encephalitis, meningitis, and/or myelopathy/myelitis, the differential diagnosis is often broad, including infectious, inflammatory, autoimmune, vascular, and neoplastic etiologies. There are numerous inflammatory and autoimmune etiologies alone; however, evaluating for an underlying infection and/or immunodeficiency becomes a critical aspect to the workup. Furthermore, patients on immunotherapy for the treatment of underlying autoimmune or inflammatory diseases are at increased risk for opportunistic infections as well as other neurological complications. This chapter will focus on the relationship of viral infections and dysregulation of the immune system as triggers of autoimmunity, in addition to common infectious and immunomodulatory complications seen in patients treated with various forms of disease-modifying therapies.

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References

  1. Hynson JL, Kornberg AJ, Coleman LT, Shield L, Harvey AS, Kean MJ. Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children. Neurology. 2001;56(10):1308–12.

    Article  CAS  PubMed  Google Scholar 

  2. Kipps A, Dick G, Moodie JW. Measles and the central nervous system. Lancet. 1983;2(8364):1406–10.

    Article  CAS  PubMed  Google Scholar 

  3. Karussis D, Petrou P. The spectrum of post-vaccination inflammatory CNS demyelinating syndromes. Autoimmun Rev. 2014;13(3):215–24.

    Article  PubMed  Google Scholar 

  4. Ercolini AM, Miller SD. The role of infections in autoimmune disease. Clin Exp Immunol. 2009;155(1):1–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fujinami RS, Oldstone MB, Wroblewska Z, Frankel ME, Koprowski H. Molecular mimicry in virus infection: crossreaction of measles virus phosphoprotein or of herpes simplex virus protein with human intermediate filaments. Proc Natl Acad Sci U S A. 1983;80(8):2346–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cusick MF, Libbey JE, Fujinami RS. Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol. 2012;42(1):102–11.

    Article  CAS  PubMed  Google Scholar 

  7. Kirvan CA, Swedo SE, Heuser JS, Cunningham MW. Mimicry and autoantibody-mediated neuronal cell signaling in Sydenham chorea. Nat Med. 2003;9(7):914–20.

    Article  CAS  PubMed  Google Scholar 

  8. Ang CW, Jacobs BC, Laman JD. The Guillain-Barré syndrome: a true case of molecular mimicry. Trends Immunol. 2004;25(2):61–6.

    Article  CAS  PubMed  Google Scholar 

  9. Mameli G, Cocco E, Frau J, Marrosu MG, Sechi LA. Epstein Barr Virus and Mycobacterium avium subsp. paratuberculosis peptides are recognized in sera and cerebrospinal fluid of MS patients. Sci Rep. 2016;6:22401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Husby G, van de Rijn I, Zabriskie JB, Abdin ZH, Williams RC. Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J Exp Med. 1976;144(4):1094–110.

    Article  CAS  PubMed  Google Scholar 

  11. Hoffman KL, Hornig M, Yaddanapudi K, Jabado O, Lipkin WI. A murine model for neuropsychiatric disorders associated with group a beta-hemolytic streptococcal infection. J Neurosci. 2004;24(7):1780–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bronze MS, Dale JB. Epitopes of streptococcal m proteins that evoke antibodies that cross-react with human brain. J Immunol. 1993;151(5):2820–8.

    Article  CAS  PubMed  Google Scholar 

  13. Fujinami RS, von Herrath MG, Christen U, Whitton JL. Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev. 2006;19(1):80–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pearson JA, Wong FS, Wen L. The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes. J Autoimmun. 2016;66:76–88.

    Article  CAS  PubMed  Google Scholar 

  15. Armangue T, Titulaer MJ, Málaga I, Bataller L, Gabilondo I, Graus F, et al. Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr. 2013;162(4):850–6.e2.

    Article  CAS  PubMed  Google Scholar 

  16. Leypoldt F, Titulaer MJ, Aguilar E, Walther J, Bönstrup M, Havemeister S, et al. Herpes simplex virus-1 encephalitis can trigger anti-NMDA receptor encephalitis: case report. Neurology. 2013;81(18):1637–9.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Armangue T, Leypoldt F, Málaga I, Raspall-Chaure M, Marti I, Nichter C, et al. Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol. 2014;75(2):317–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Armangue T, Spatola M, Vlagea A, Mattozzi S, Cárceles-Cordon M, Martinez-Heras E, et al. Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol. 2018;17(9):760–72.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Linnoila JJ, Binnicker MJ, Majed M, Klein CJ, McKeon A. CSF herpes virus and autoantibody profiles in the evaluation of encephalitis. Neurol Neuroimmunol Neuroinflamm. 2016;3(4):e245.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Höftberger R, Armangue T, Leypoldt F, Graus F, Dalmau J. Clinical neuropathology practice guide 4-2013: post-herpes simplex encephalitis: N-methyl-D-aspartate receptor antibodies are part of the problem. Clin Neuropathol. 2013;32(4):251–4.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Schäbitz WR, Rogalewski A, Hagemeister C, Bien CG. VZV brainstem encephalitis triggers NMDA receptor immunoreaction. Neurology. 2014;83(24):2309–11.

    Article  PubMed  Google Scholar 

  22. Salovin A, Glanzman J, Roslin K, Armangue T, Lynch DR, Panzer JA. Anti-NMDA receptor encephalitis and nonencephalitic HSV-1 infection. Neurol Neuroimmunol Neuroinflamm. 2018;5(4):e458.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Jolles S. The variable in common variable immunodeficiency: a disease of complex phenotypes. J Allergy Clin Immunol Pract. 2013;1(6):545–56; quiz 57.

    Article  PubMed  Google Scholar 

  24. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93(3):190–7.

    Article  CAS  PubMed  Google Scholar 

  25. Schubert RD, Wilson MR. A tale of two approaches: how metagenomics and proteomics are shaping the future of encephalitis diagnostics. Curr Opin Neurol. 2015;28(3):283–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wilson MR, Naccache SN, Samayoa E, Biagtan M, Bashir H, Yu G, et al. Actionable diagnosis of neuroleptospirosis by next-generation sequencing. N Engl J Med. 2014;370(25):2408–17.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Quan PL, Wagner TA, Briese T, Torgerson TR, Hornig M, Tashmukhamedova A, et al. Astrovirus encephalitis in boy with X-linked agammaglobulinemia. Emerg Infect Dis. 2010;16(6):918–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Naccache SN, Peggs KS, Mattes FM, Phadke R, Garson JA, Grant P, et al. Diagnosis of neuroinvasive astrovirus infection in an immunocompromised adult with encephalitis by unbiased next-generation sequencing. Clin Infect Dis. 2015;60(6):919–23.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, et al. International Consensus Document (ICON): common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4(1):38–59.

    Article  PubMed  Google Scholar 

  30. Boursiquot JN, Gérard L, Malphettes M, Fieschi C, Galicier L, Boutboul D, et al. Granulomatous disease in CVID: retrospective analysis of clinical characteristics and treatment efficacy in a cohort of 59 patients. J Clin Immunol. 2013;33(1):84–95.

    Article  CAS  PubMed  Google Scholar 

  31. Morimoto Y, Routes JM. Granulomatous disease in common variable immunodeficiency. Curr Allergy Asthma Rep. 2005;5(5):370–5.

    Article  CAS  PubMed  Google Scholar 

  32. Ardeniz O, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Clin Immunol. 2009;133(2):198–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Arnold DF, Wiggins J, Cunningham-Rundles C, Misbah SA, Chapel HM. Granulomatous disease: distinguishing primary antibody disease from sarcoidosis. Clin Immunol. 2008;128(1):18–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Misbah SA, Spickett GP, Esiri MM, Hughes JT, Matthews WB, Thompson RA, et al. Recurrent intra-cranial granulomata presenting as space-occupying lesions in a patient with common variable immunodeficiency. Postgrad Med J. 1992;68(799):359–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nguyen JT, Green A, Wilson MR, DeRisi JL, Gundling K. Neurologic complications of common variable immunodeficiency. J Clin Immunol. 2016;36(8):793–800.

    Article  CAS  PubMed  Google Scholar 

  36. Major EO, Yousry TA, Clifford DB. Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned. Lancet Neurol. 2018;17(5):467–80.

    Article  CAS  PubMed  Google Scholar 

  37. Miskin DP, Koralnik IJ. Novel syndromes associated with JC virus infection of neurons and meningeal cells: no longer a gray area. Curr Opin Neurol. 2015;28(3):288–94.

    Article  PubMed  PubMed Central  Google Scholar 

  38. O’Connor PW, Goodman A, Willmer-Hulme AJ, Libonati MA, Metz L, Murray RS, et al. Randomized multicenter trial of natalizumab in acute MS relapses: clinical and MRI effects. Neurology. 2004;62(11):2038–43.

    Article  PubMed  CAS  Google Scholar 

  39. Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354(9):924–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Borchardt J, Berger JR. Re-evaluating the incidence of natalizumab-associated progressive multifocal leukoencephalopathy. Mult Scler Relat Disord. 2016;8:145–50.

    Article  PubMed  Google Scholar 

  41. Berger JR, Fox RJ. Reassessing the risk of natalizumab-associated PML. J Neurovirol. 2016;22(4):533–5.

    Article  CAS  PubMed  Google Scholar 

  42. Zhovtis Ryerson L, Frohman TC, Foley J, Kister I, Weinstock-Guttman B, Tornatore C, et al. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016;87(8):885–9.

    Article  CAS  PubMed  Google Scholar 

  43. Longbrake EE, Ramsbottom MJ, Cantoni C, Ghezzi L, Cross AH, Piccio L. Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients. Mult Scler. 2016;22(8):1061–70.

    Article  CAS  PubMed  Google Scholar 

  44. Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, et al. PML diagnostic criteria: consensus statement from the AAN neuroinfectious disease section. Neurology. 2013;80(15):1430–8.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Cree BA, Lamb S, Morgan K, Chen A, Waubant E, Genain C. An open label study of the effects of rituximab in neuromyelitis optica. Neurology. 2005;64(7):1270–2.

    Article  CAS  PubMed  Google Scholar 

  46. Barmettler S, Ong M, Farmer JR, Choi H, Walter J. Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open. 2018;1(7):e184169.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Roberts DM, Jones RB, Smith RM, Alberici F, Kumaratne DS, Burns S, et al. Rituximab-associated hypogammaglobulinemia: incidence, predictors and outcomes in patients with multi-system autoimmune disease. J Autoimmun. 2015;57:60–5.

    Article  CAS  PubMed  Google Scholar 

  48. Barmettler S, Price C. Continuing IGG replacement therapy for hypogammaglobulinemia after rituximab--for how long? J Allergy Clin Immunol. 2015;136(5):1407–9.

    Article  PubMed  Google Scholar 

  49. Tallantyre EC, Whittam DH, Jolles S, Paling D, Constantinesecu C, Robertson NP, et al. Secondary antibody deficiency: a complication of anti-CD20 therapy for neuroinflammation. J Neurol. 2018;265(5):1115–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tuohy O, Costelloe L, Hill-Cawthorne G, Bjornson I, Harding K, Robertson N, et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry. 2015;86(2):208–15.

    Article  PubMed  Google Scholar 

  51. Devonshire V, Phillips R, Wass H, Da Roza G, Senior P. Monitoring and management of autoimmunity in multiple sclerosis patients treated with alemtuzumab: practical recommendations. J Neurol. 2018;265(11):2494–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, et al. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of camms223 clinical trial. Neurology. 2012;78(14):1069–78.

    Article  CAS  PubMed  Google Scholar 

  53. Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K. Interpreting lymphocyte reconstitution data from the pivotal phase 3 trials of alemtuzumab. JAMA Neurol. 2017;74(8):961–9.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Marrie RA, Reider N, Cohen J, Stuve O, Sorensen PS, Cutter G, et al. A systematic review of the incidence and prevalence of autoimmune disease in multiple sclerosis. Mult Scler. 2015;21(3):282–93.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Demko S, Summers J, Keegan P, Pazdur R. FDA drug approval summary: alemtuzumab as single-agent treatment for B-cell chronic lymphocytic leukemia. Oncologist. 2008;13(2):167–74.

    Article  CAS  PubMed  Google Scholar 

  56. Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4(12):1721–8.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Fellner A, Makranz C, Lotem M, Bokstein F, Taliansky A, Rosenberg S, et al. Neurologic complications of immune checkpoint inhibitors. J Neuro-Oncol. 2018;137(3):601–9.

    Article  CAS  Google Scholar 

  58. Touat M, Talmasov D, Ricard D, Psimaras D. Neurological toxicities associated with immune-checkpoint inhibitors. Curr Opin Neurol. 2017;30(6):659–68.

    Article  CAS  PubMed  Google Scholar 

  59. Williams TJ, Benavides DR, Patrice KA, Dalmau JO, de Ávila AL, Le DT, et al. Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer. JAMA Neurol. 2016;73(8):928–33.

    Article  PubMed  Google Scholar 

  60. Gettings EJ, Hackett CT, Scott TF. Severe relapse in a multiple sclerosis patient associated with ipilimumab treatment of melanoma. Mult Scler. 2015;21(5):670.

    Article  PubMed  Google Scholar 

  61. Gerdes LA, Held K, Beltrán E, Berking C, Prinz JC, Junker A, et al. CTLA4 as immunological checkpoint in the development of multiple sclerosis. Ann Neurol. 2016;80(2):294–300.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Maurice C, Schneider R, Kiehl TR, Bavi P, Roehrl MH, Mason WP, et al. Subacute CNS demyelination after treatment with nivolumab for melanoma. Cancer Immunol Res. 2015;3(12):1299–302.

    Article  CAS  PubMed  Google Scholar 

  63. Lau KH, Kumar A, Yang IH, Nowak RJ. Exacerbation of myasthenia gravis in a patient with melanoma treated with pembrolizumab. Muscle Nerve. 2016;54(1):157–61.

    Article  PubMed  Google Scholar 

  64. Zhu J, Li Y. Myasthenia gravis exacerbation associated with pembrolizumab. Muscle Nerve. 2016;54(3):506–7.

    Article  PubMed  Google Scholar 

  65. Phadke SD, Ghabour R, Swick BL, Swenson A, Milhem M, Zakharia Y. Pembrolizumab therapy triggering an exacerbation of preexisting autoimmune disease: a report of 2 patient cases. J Investig Med High Impact Case Rep. 2016;4(4):2324709616674316.

    PubMed  PubMed Central  Google Scholar 

  66. Suzuki S, Ishikawa N, Konoeda F, Seki N, Fukushima S, Takahashi K, et al. Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology. 2017;89(11):1127–34.

    Article  CAS  PubMed  Google Scholar 

  67. Shirai T, Sano T, Kamijo F, Saito N, Miyake T, Kodaira M, et al. Acetylcholine receptor binding antibody-associated myasthenia gravis and rhabdomyolysis induced by nivolumab in a patient with melanoma. Jpn J Clin Oncol. 2016;46(1):86–8.

    Article  PubMed  Google Scholar 

  68. Johnson DB, Saranga-Perry V, Lavin PJ, Burnette WB, Clark SW, Uskavitch DR, et al. Myasthenia gravis induced by ipilimumab in patients with metastatic melanoma. J Clin Oncol. 2015;33(33):e122–4.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology, Section of Neuroimmunology, Neuro-Infectious Diseases Group, University of Colorado School of Medicine, Aurora, CO, USA

    Amanda L. Piquet

  2. Department of Neurology, Medicine (Infectious Diseases), and Epidemiology, Neuro-Infectious Diseases Group, University of Colorado School of Medicine, Aurora, CO, USA

    Daniel M. Pastula

  3. Departments of Medicine, Neurology, and Immunology & Microbiology, Neuro-Infectious Diseases Group, University of Colorado School of Medicine, Rocky Mountain Regional VA Medical Center, Aurora, CO, USA

    J. David Beckham

  4. Department of Medicine and Immunology-Microbiology, Department of Neurology, Neuro-Infectious Diseases Group, University of Colorado School of Medicine, University of Colorado Hospital and Rocky Mountain Regional VA Medical Center, Aurora, CO, USA

    Kenneth L. Tyler

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Correspondence to Amanda L. Piquet .

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  1. University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Amanda L. Piquet

  2. University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Enrique Alvarez

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Piquet, A.L., Pastula, D.M., Beckham, J.D., Tyler, K.L. (2021). Infections, Immunodeficiency, and Complications of Immunomodulatory Therapies in Neuroimmunology. In: Piquet, A.L., Alvarez, E. (eds) Neuroimmunology. Springer, Cham. https://doi.org/10.1007/978-3-030-61883-4_25

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