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Journal of Neuro-Oncology

, Volume 137, Issue 3, pp 601–609 | Cite as

Neurologic complications of immune checkpoint inhibitors

  • Avi FellnerEmail author
  • Chen Makranz
  • Michal Lotem
  • Felix Bokstein
  • Alisa Taliansky
  • Shai Rosenberg
  • Deborah T. Blumenthal
  • Jacob Mandel
  • Suzana Fichman
  • Elena Kogan
  • Israel Steiner
  • Tali Siegal
  • Alexander Lossos
  • Shlomit Yust-Katz
Clinical Study

Abstract

Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days–19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.

Keywords

Immune checkpoint inhibitors Neurological complications PD-1 CTLA-4 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This case study received an approval from the Head of Institutional Review Board (Helsinki Committee) of Rabin Medical Center, Petah Tikva, Israel. This study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

Israeli regulations do not require consent for case report or case series, provided that they are anonymous. This manuscript is a retrospective study, does not contain clinical studies and the data in this case series do not disclose the identities of the patients.

References

  1. 1.
    Bellmunt J, Powles T, Vogelzang NJ (2017) A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: the future is now. Cancer Treat Rev 54:58–67CrossRefPubMedGoogle Scholar
  2. 2.
    Cuzzubbo S, Javeri F, Tissier M, Roumi A, Barlog C, Doridam J et al (2017) Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur J Cancer 73:1–8CrossRefPubMedGoogle Scholar
  3. 3.
    Sinnadurai M, McDonald KL (2017) Immune checkpoint inhibition and its relationship with hypermutation phenotype as a potential treatment for Glioblastoma. J Neurooncol 132:359–372CrossRefPubMedGoogle Scholar
  4. 4.
    Swaika A, Hammond WA, Joseph RW (2015) Current state of anti-PD-L1 and anti-PD1 agents in cancer therapy. Mol Immunol 67(2 Pt A):4–17CrossRefPubMedGoogle Scholar
  5. 5.
    Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P, Chandra AB (2017) Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitors. Front Pharmacol 8:49.  https://doi.org/10.3389/fphar.2017.00049 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hottinger AF (2016) Neurologic complications of immune checkpoint inhibitors. Curr Opin Neurol 29(6):806–812CrossRefPubMedGoogle Scholar
  7. 7.
    Larkin J, Chmielowski B, Lao CD, Hodi FS, Sharfman W, Weber J et al (2017) Neurologic serious adverse events associated with nivolumab plus ipilimumab or nivolmab alone in advanced melanoma, including a case series of encephalitis. Oncologist 22(6):709–718CrossRefPubMedGoogle Scholar
  8. 8.
    Liao B, Shroff S, Kamiya-Matsuoka C, Tummala S (2014) Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. Neuro-Oncology 16(4):589–593CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Nguyen BH, Kuo J, Budiman A, Christie H, Ali S (2017) Two cases of clinical myasthenia gravis associated with pembrolizumab use in responding melanoma patients. Melanoma Res 27(2):152–154CrossRefPubMedGoogle Scholar
  10. 10.
    Wick W, Hertenstein A, Platten M (2016) Neurological sequelae of cancer immunotherapies and targeted therapies. Lancet Oncol 17(12):e529–e541CrossRefPubMedGoogle Scholar
  11. 11.
    Zimmer L, Goldinger SM, Hofmann L, Loquai C, Ugurel S, Thomas I et al (2016) Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy. Eur J Cancer 60:210–225CrossRefPubMedGoogle Scholar
  12. 12.
    Kao JC, Liao B, Markovic SN, Klein CJ, Naddaf E, Staff NP et al (2017) Neurological complications associated with anti-programmed death 1 (PD-1) antibodies. JAMA Neurol 74(10):1216–1222CrossRefPubMedGoogle Scholar
  13. 13.
    Gonzales NL, Puwanant A, Lu A, Marks SM, Zivkovic SA (2017) Myasthenia triggered by immune checkpoint inhibitors: new case and literature review. Neuromuscul Disord 27(3):266–268CrossRefGoogle Scholar
  14. 14.
    Chang E, Sabichi AL, Sada YH (2017) Myasthenia gravis after nivolumab therapy for squamous cell carcinoma of the bladder. J Immunother 40(3):114–116CrossRefPubMedGoogle Scholar
  15. 15.
    Lau KH, Kumar A, Yang IH, Nowak RJ (2016) Exacerbation of myasthenia gravis in a patient with melanoma treated with pembrolizumab. Muscle Nerve 54(1):157–161CrossRefPubMedGoogle Scholar
  16. 16.
    Kimura T, Fukushima S, Miyashita A, Aoi J, Jinnin M, Kosaka T et al (2016) Myasthenic crisis and polymyositis induced by one dose of nivolumab. Cancer Sci 107(7):1055–1058CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Makarious D, Horwood K, Coward JIG (2017) Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors. Eur J Cancer 82:128–136CrossRefPubMedGoogle Scholar
  18. 18.
    Suzuki S, Ishikawa N, Konoeda F, Seki N, Fukushima S, Takahashi K et al (2017) Nivolumab-related myasthenia gravis with myositis and myocarditis in Japan. Neurology 89(11):1127–1134CrossRefPubMedGoogle Scholar
  19. 19.
    Papadopoulos KP, Romero RS, Gonzales G, Dix JE, Lowy I, Fury M (2017) Anti-Hu-associated autoimmune limbic encephalitis in a patient with PD-1 inhibitor-responsive myxoid chondrosarcoma. Oncologist 22:1–3CrossRefGoogle Scholar
  20. 20.
    Richard K, Weslow J, Porcella SL, Nanjappa S (2017) A case report of steroid responsive nivolumab-induced encephalitis. Cancer Control 24(5):1–3CrossRefGoogle Scholar
  21. 21.
    Brown MP, Hissaria P, Hsieh AH, Kneebone C, Vallat W (2017) Autoimmune limbic encephalitis with anti-contactin-associated protein-like 2 antibody secondary to pembrolizumab therapy. J Neuroimmunol 305:16–18CrossRefPubMedGoogle Scholar
  22. 22.
    Behling J, Kaes J, Munzel T, Grabbe S, Loquai C (2017) New-onset third-degree atrioventricular block because of autoimmune-induced myositis under treatment with anti-programmed cell death-1 (nivolumab) for metastatic melanoma. Melanoma Res 27(2):155–158CrossRefPubMedGoogle Scholar
  23. 23.
    De Velasco G, Je Y, Bosse D, Awad MM, Ott PA, Moreira RB et al (2017) Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-L1 inhibitors in cancer patients. Cancer Immunol Res 5(4):312–318CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Williams TJ, Benavides DR, Patrice KA, Dalmau JO, de Avila AL, Le DT et al (2016) Association of autoimmune encephalitis with combined immune checkpoint inhibitor treatment for metastatic cancer. JAMA Neurol 73(8):928–933CrossRefPubMedGoogle Scholar
  26. 26.
    Yshii LM, Gebauer CM, Pignolet B, Maure E, Queriault C, Pierau M et al (2016) CTLA4 blockade elicits paraneoplastic neurological disease in a mouse model. Brain 139(11):2923–2934CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Avi Fellner
    • 1
    • 2
    Email author
  • Chen Makranz
    • 3
  • Michal Lotem
    • 4
  • Felix Bokstein
    • 2
    • 5
  • Alisa Taliansky
    • 6
  • Shai Rosenberg
    • 3
  • Deborah T. Blumenthal
    • 2
    • 5
  • Jacob Mandel
    • 7
  • Suzana Fichman
    • 2
    • 8
  • Elena Kogan
    • 1
    • 2
  • Israel Steiner
    • 1
    • 2
  • Tali Siegal
    • 1
    • 9
  • Alexander Lossos
    • 3
  • Shlomit Yust-Katz
    • 1
    • 2
    • 9
  1. 1.Department of Neurology, Rabin Medical CenterBeilinson HospitalPetah TikvaIsrael
  2. 2.Sackler Faculty of MedicineTel Aviv UniversityTel-AvivIsrael
  3. 3.Department of Oncology, Leslie and Michael Gaffin Center for Neuro-OncologyHadassah-Hebrew University Medical CenterJerusalemIsrael
  4. 4.Sharett Institute of OncologyHadassah-Hebrew University Medical CenterJerusalemIsrael
  5. 5.Neuro-Oncology ServiceTel-Aviv Sourasky Medical CenterTel-AvivIsrael
  6. 6.Oncology InstituteSheba Medical CenterRamat-GanIsrael
  7. 7.Department of NeurologyBaylor College of MedicineHoustonUSA
  8. 8.Department of Pathology, Rabin Medical CenterBeilinson HospitalPetah TikvaIsrael
  9. 9.Neuro-Oncology UnitDavidoff Cancer Center at Rabin Medical CenterPetah TikvaIsrael

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