Advertisement

Newer Immunotherapies for the Treatment of Acute Neuromuscular Disease in the Critical Care Unit

  • Alok Patel
  • Fiona Lynch
  • Starane A. ShepherdEmail author
Critical Care Neurology (H Hinson, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Critical Care Neurology

Opinion statement

Purpose of review

In this review, we discuss current treatment options for commonly encountered neuromuscular disorders in intensive care units. We will discuss epidemiology, pathophysiology, and acute and chronic treatment options for myasthenia gravis, Guillain-Barré syndrome, West Nile virus, Botulism, and amyotrophic lateral sclerosis.

Recent findings

Eculizumab is the newest immunomodulator therapy approved by the Food and Drug Administration in treatment of myasthenia gravis, shown to improve long-term functional outcomes. Edaravone is the newest therapy in management of amyotrophic lateral sclerosis, shown to slow functional deterioration. Efgartigimod showed great promise in a phase 2 safety and efficacy trial in the treatment of stable generalized myasthenia gravis. Eculizumab was found to be safe in a small phase 2 trial for use in Guillain-Barré syndrome.

Summary

Currently, therapies such as plasma exchange, intravenous immunoglobulins, and steroids remain the mainstay of treatment in the ICU for many neuromuscular disorders. While there are some newer immunotherapies available, few have been studied in the acute setting. However, with the advent of new immunotherapies and biologics, changes in these approaches may be on the horizon.

Keywords

Myasthenia gravis Myasthenic crisis Eculizumab Immunotherapy Guillain-Barre syndrome Efgartigimod Botulism 

Notes

Compliance with Ethical Standards

Conflict of Interest

Dr. Patel declares that he has no conflict of interest.

Dr. Lynch declares that she has no conflict of interest.

Dr. Shepherd declares that he has no conflict of interest.

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.

References

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

  1. 1.
    Lacomis D, Petrella JT, Giuliani MJ. Causes of neuromuscular weakness in the intensive care unit: a study of ninety-two patients. Muscle Nerve. 1998;21(5):610–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Crespo V, James ML. Neuromuscular disease in the neurointensive care unit. Anesthesiol Clin. 2016;34(3):601–19.PubMedCrossRefGoogle Scholar
  3. 3.
    Heatwole C. et al. Plasma Exchange versus Intravenous Immunoglobulin for Myasthenia Gravis Crisis: An Acute Hospital Cost Comparison Study. 2011;13(2):85–94.Google Scholar
  4. 4.
    Guptill JT, Runken MC, Eaddy M, Lunacsek O, Fuldeore RM. Treatment patterns and costs of chronic inflammatory demyelinating polyneuropathy: a claims database analysis. Am Health Drug Benefits. 2019;12(3):127–35.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Peres J, et al. Rituximab in generalized myasthenia gravis: clinical, quality of life and cost–utility analysis. Porto Biomedical Journal. 2017;2(3):81–5.CrossRefGoogle Scholar
  6. 6.
    Bonifati DM, Angelini C. Long-term cyclosporine treatment in a group of severe myasthenia gravis patients. J Neurol. 1997;244(9):542–7.80.PubMedCrossRefGoogle Scholar
  7. 7.
    Stone K. The most expensive prescription drugs in the world 2018 [updated 12/30/2018]. Available from: https://www.thebalance.com/the-8-most-expensive-prescription-drugs-in-the-world-2663232.
  8. 8.
  9. 9.
  10. 10.
    • Burakgazi AZ. Immunoglobulin treatment in neuromuscular medicine. J Clin Neuromuscul Dis. 2019;20(4):182–93 Provides details on IVIg therapy in NMD.PubMedCrossRefGoogle Scholar
  11. 11.
    • Osman C, et al. Plasma exchange in neurological disease. Pract Neurol. 2019:practneurol-201 Provides details on plasma exchange in NMD.Google Scholar
  12. 12.
    Szczeklik W, Wawrzycka K, Włudarczyk A, Sega A, Nowak I, Seczyńska B, et al. Complications in patients treated with plasmapheresis in the intensive care unit. Anaesthesiol Intensive Ther. 2013;45(1):7–13.PubMedCrossRefGoogle Scholar
  13. 13.
    Lindberg C, Andersen O, Lefvert AK. Treatment of myasthenia gravis with methylprednisolone pulse: a double blind study. Acta Neurol Scand. 1998;97(6):370–3.PubMedCrossRefGoogle Scholar
  14. 14.
    Sathasivam S. Steroids and immunosuppressant drugs in myasthenia gravis. Nat Clin Pract Neurol. 2008;4(6):317–27.PubMedCrossRefGoogle Scholar
  15. 15.
    Fonseca V, Havard CW. Long term treatment of myasthenia gravis with azathioprine. Postgrad Med J. 1990;66(772):102–5.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    A randomised clinical trial comparing prednisone and azathioprine in myasthenia gravis. Results of the second interim analysis. Myasthenia Gravis Clinical Study Group. J Neurol Neurosurg Psychiatry. 1993;56(11):1157–63.Google Scholar
  17. 17.
    Palace J, Newsom-Davis J, Lecky B. A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Myasthenia Gravis Study Group. Neurology. 1998;50(6):1778–83.PubMedCrossRefGoogle Scholar
  18. 18.
    Perez MC, Buot WL, Mercado-Danguilan C, Bagabaldo ZG, Renales LD. Stable remissions in myasthenia gravis. Neurology. 1981;31(1):32–7.PubMedCrossRefGoogle Scholar
  19. 19.
    De Feo LG, et al. Use of intravenous pulsed cyclophosphamide in severe, generalized myasthenia gravis. Muscle Nerve. 2002;26(1):31–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Drachman DB, et al. Rebooting the immune system with high-dose cyclophosphamide for treatment of refractory myasthenia gravis. Ann N Y Acad Sci. 2008;1132(1):305–14.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Cerny T, et al. Mechanism of action of rituximab. Anti-Cancer Drugs. 2002;13(Suppl 2):S3–10.PubMedCrossRefGoogle Scholar
  22. 22.
    Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000;47(2–3):119–25.PubMedCrossRefGoogle Scholar
  23. 23.
    Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. 1995;17(6):584–91.PubMedCrossRefGoogle Scholar
  24. 24.
    Ciafaloni E, et al. Retrospective analysis of the use of cyclosporine in myasthenia gravis. Neurology. 2000;55(3):448–50.PubMedCrossRefGoogle Scholar
  25. 25.
    Ponseti JM, Gamez J, Azem J, López-Cano M, Vilallonga R, Armengol M. Tacrolimus for myasthenia gravis: a clinical study of 212 patients. Ann N Y Acad Sci. 2008;1132:254–63.PubMedCrossRefGoogle Scholar
  26. 26.
    Carr AS, et al. A systematic review of population based epidemiological studies in myasthenia gravis. BMC Neurol. 2010;10:46.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    • Wijdicks EF. Management of acute neuromuscular disorders. Handb Clin Neurol. 2017;140:229–37 Provides comprehensive summary of NMD management in ICU.PubMedCrossRefGoogle Scholar
  28. 28.
    Nicolle MW. Myasthenia gravis and Lambert-Eaton myasthenic syndrome. Continuum (Minneap Minn). 2016;22(6, Muscle and Neuromuscular Junction Disorders):1978–2005.Google Scholar
  29. 29.
    Koneczny I, Cossins J, Vincent A. The role of muscle-specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. J Anat. 2014;224(1):29–35.PubMedCrossRefGoogle Scholar
  30. 30.
    •• Beecher G, Putko BN, Wagner AN, Siddiqi ZA. Therapies directed against B-cells and downstream effectors in generalized autoimmune myasthenia gravis: current status. Drugs. 2019;79(4):353–64 Provides additional details on ritixumab and its mechanism for immunomodulation.PubMedCrossRefGoogle Scholar
  31. 31.
    Berrih-Aknin S. Cortactin: a new target in autoimmune myositis and myasthenia gravis. Autoimmun Rev. 2014;13(10):1001–2.PubMedCrossRefGoogle Scholar
  32. 32.
    Binks S, Vincent A, Palace J. Myasthenia gravis: a clinical-immunological update. J Neurol. 2016;263(4):826–34.PubMedCrossRefGoogle Scholar
  33. 33.
    Zhang B, Shen C, Bealmear B, Ragheb S, Xiong WC, Lewis RA, et al. Autoantibodies to Agrin in myasthenia gravis patients. PLoS One. 2014;9(3):e91816.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Thomas CE, Mayer SA, Gungor Y, Swarup R, Webster EA, Chang I, et al. Myasthenic crisis: clinical features, mortality, complications, and risk factors for prolonged intubation. Neurology. 1997;48(5):1253–60.PubMedCrossRefGoogle Scholar
  35. 35.
    Gajdos P, Chevret S, Toyka KV. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. 2012;12:Cd002277.PubMedGoogle Scholar
  36. 36.
    Bril V, et al. IVIG and PLEX in the treatment of myasthenia gravis. Ann N Y Acad Sci. 2012;1275(1):1–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Dhawan PS, Goodman BP, Harper CM, Bosch PE, Hoffman-Snyder CR, Wellik KE, et al. IVIG versus PLEX in the treatment of worsening myasthenia gravis: what is the evidence?: a critically appraised topic. Neurologist. 2015;19(5):145–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Skeie GO, Apostolski S, Evoli A, Gilhus NE, Illa I, Harms L, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol. 2010;17(7):893–902.PubMedCrossRefGoogle Scholar
  39. 39.
    Dhillon S. Eculizumab: a review in generalized myasthenia gravis. Drugs. 2018;78(3):367–76.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    •• Howard JF Jr, et al. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017;16(12):976–86 Landmark trial which resulted in approval of eculizumab in treatment of MG.CrossRefGoogle Scholar
  41. 41.
    Edmundson C, Guidon AC. Eculizumab: a complementary addition to existing long-term therapies for myasthenia gravis. Muscle Nerve. 2019.Google Scholar
  42. 42.
    •• Howard JF, et al. Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis. Neurology. 2019;92(23):e2661–73 Landmark phase 2 study which showed safety and efficacy of using efgartigimod in MG.PubMedCrossRefGoogle Scholar
  43. 43.
    Yuki N, Hartung H-P. Guillain–Barré syndrome. N Engl J Med. 2012;366(24):2294–304.PubMedCrossRefGoogle Scholar
  44. 44.
    McGrogan A, Madle GC, Seaman HE, de Vries CS. The epidemiology of Guillain-Barré syndrome worldwide. Neuroepidemiology. 2009;32(2):150–63.PubMedCrossRefGoogle Scholar
  45. 45.
    Sejvar JJ, Baughman AL, Wise M, Morgan OW. Population incidence of Guillain-Barré syndrome: a systematic review and meta-analysis. Neuroepidemiology. 2011;36(2):123–33.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Wu X, et al. Predictors for mechanical ventilation and short-term prognosis in patients with Guillain-Barré syndrome. Crit Care. 2015;19(1).Google Scholar
  47. 47.
    Harms M. Inpatient management of Guillain-Barré syndrome. Neurohospitalist. 2011;1(2):78–84.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Hughes RAC, et al. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2016;10.Google Scholar
  49. 49.
    Lawn ND, et al. Anticipating mechanical ventilation in Guillain-Barré syndrome. 2001;58(6):893.Google Scholar
  50. 50.
    Kannan Kanikannan MA, Durga P, Venigalla NK, Kandadai RM, Jabeen SA, Borgohain R. Simple bedside predictors of mechanical ventilation in patients with Guillain-Barre syndrome. J Crit Care. 2014;29(2):219–23.PubMedCrossRefGoogle Scholar
  51. 51.
    Willison HJ, Goodyear CS. Glycolipid antigens and autoantibodies in autoimmune neuropathies. Trends Immunol. 2013;34(9):453–9.PubMedCrossRefGoogle Scholar
  52. 52.
    • Chevret S, Hughes RAC, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2017;(2) Provides an overall summary of several previously published articles on use of PLEX in treatment of GBS.Google Scholar
  53. 53.
    •• Misawa S, et al. Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial. Lancet Neurol. 2018;17(6):519–29 Phase 2 trial which showed safety of eculizumab in GBS. Efficacy not established from small study, albeit there was an overall trend towards improvement.PubMedCrossRefGoogle Scholar
  54. 54.
    Marin B, Boumédiene F, Logroscino G, Couratier P, Babron MC, Leutenegger AL, et al. Variation in worldwide incidence of amyotrophic lateral sclerosis: a meta-analysis. Int J Epidemiol. 2017;46(1):57–74.PubMedGoogle Scholar
  55. 55.
    Marin B, Fontana A, Arcuti S, Copetti M, Boumédiene F, Couratier P, et al. Age-specific ALS incidence: a dose-response meta-analysis. Eur J Epidemiol. 2018;33(7):621–34.PubMedCrossRefGoogle Scholar
  56. 56.
    Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377(2):162–72.PubMedCrossRefGoogle Scholar
  57. 57.
    Beard JD, Engel LS, Richardson DB, Gammon MD, Baird C, Umbach DM, et al. Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology. Environ Int. 2016;91:104–15.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Bonafede R, Mariotti R. ALS pathogenesis and therapeutic approaches: the role of mesenchymal stem cells and extracellular vesicles. Front Cell Neurosci. 2017;11:80.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Lucette Lacomblez GB, Leigh PN, Guillet P, Meininger V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet. 1996;347(9013):1425–31.CrossRefGoogle Scholar
  60. 60.
    • Abe K, et al. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(7):505–12 Randomized trial which showed safety and efficacy of Edaravone in ALS.CrossRefGoogle Scholar
  61. 61.
    Abe K, et al. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15(7–8):610–7.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
  63. 63.
    Khalid SI, et al. Immune modulation in the treatment of amyotrophic lateral sclerosis: a review of clinical trials. Front Neurol. 2017;8:486.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Crum-Cianflone NF. Bacterial, fungal, parasitic, and viral myositis. Clin Microbiol Rev. 2008;21(3):473–94.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Robinson-Papp J. Infectious neuropathies. CONTINUUM: Lifelong Learning in Neurology. 2012;18(1):126–38.PubMedGoogle Scholar
  66. 66.
    Hayes EB, Komar N, Nasci RS, Montgomery SP, O’Leary DR, Campbell GL. Epidemiology and transmission dynamics of West Nile virus disease. Emerg Infect Dis. 2005;11(8):1167–73.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Hayes EB, Sejvar JJ, Zaki SR, Lanciotti RS, Bode AV, Campbell GL. Virology, pathology, and clinical manifestations of West Nile virus disease. Emerg Infect Dis. 2005;11(8):1174–9.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Hughes JM, Wilson ME, Sejvar JJ. The long-term outcomes of human West Nile virus infection. Clin Infect Dis. 2007;44(12):1617–24.CrossRefGoogle Scholar
  69. 69.
    Lim SM, Koraka P, Osterhaus AD, Martina BE. West Nile virus: immunity and pathogenesis. Viruses. 2011;3(6):811–28.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Fateh R, et al. Interferon-alpha in a patient with West Nile virus myelitis: a case-report. (P5.114). Neurology. 2015;84(14 Supplement):P5.114.Google Scholar
  71. 71.
    Shimoni Z, et al. The clinical response of West Nile virus neuroinvasive disease to intravenous immunoglobulin therapy. Clin Pract. 2012;2(1):e18–8.CrossRefGoogle Scholar
  72. 72.
    Hart J, et al. West Nile virus neuroinvasive disease: neurological manifestations and prospective longitudinal outcomes. BMC Infect Dis. 2014;14(1):248.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    National Botulism Surveillance Center of Disease Control and Prevention [updated June 6, 2019. Available from: https://www.cdc.gov/botulism/surveillance.html.
  74. 74.
    Dressler D, Adib SF. Botulinum toxin: mechanisms of action. Eur Neurol. 2005;53(1):3–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Botulism in United States, 1899–1996. Handbook for epidemiologists, clinicians, and laboratory workers Center of Disease Control and Prevention; 1998.Google Scholar
  76. 76.
    Simpson LL. Identification of the major steps in botulinum toxin action. Annu Rev Pharmacol Toxicol. 2004;44(1):167–93.PubMedCrossRefGoogle Scholar
  77. 77.
    Robinson RF, Nahata MC. Management of botulism. 2003;37:127–31.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of NeurologyRush University Medical CenterChicagoUSA

Personalised recommendations