Research progress of tumor immunotherapy-associated optic nerve adverse events, prevention and treatment_Chinese Journal of Ocular Fundus Diseases

Authors：

Zhang Luyin ,  Jiang Libin

Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China;

Corresponding author：

Jiang Libin, Email: jlbjlb@sina.com

Keywords：

Immunotherapy; Immune checkpoint inhibitors; Immune-related adverse events; Optic neuropathy; Review

DOI：

10.3760/cma.j.cn511434-20221216-00663

Video：

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Abstract Full text Figures/Tables Video References Cited by

Tumor immunotherapy includes immune checkpoint inhibitor (ICI), tumor vaccines, and adoptive cell therapy. Immunotherapy, as the main systemic treatment for advanced malignant tumors, kills tumor cells by activating the immune system and prolongs the survival of patients. However, excessive immune responses can cause immune-related adverse events (irAE), causing damage to systemic tissues. ICI are the main tumor immunotherapy drugs that cause optic nerve irAE. The most common optic nerve irAE are optic neuritis, only a few patients appeared arteritic anterior ischemic optic neuropathy. Sudden painless loss of bilateral vision is the most common clinical manifestation. In severe cases, the vision decrease to no light perception. Early diagnosis and early adequate glucocorticoid treatment can improve the symptoms. Therefore, neuro-ophthalmologists and oncologists should know the clinical characteristics of optic nerve irAE, in order to diagnose and treat early and improve the prognosis.

Citation： Zhang Luyin, Jiang Libin. Research progress of tumor immunotherapy-associated optic nerve adverse events, prevention and treatment. Chinese Journal of Ocular Fundus Diseases, 2023, 39(10): 857-861. doi: 10.3760/cma.j.cn511434-20221216-00663 Copy

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2.	Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors[J]. Nat Rev Dis Primers, 2020, 6(1): 38. DOI: 10.1038/s41572-020-0160-6.
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5.	Gerdes LA, Held K, Beltrán E, et al. CTLA4 as immunological checkpoint in the development of multiple sclerosis[J]. Ann Neurol, 2016, 80(2): 294-300. DOI: 10.1002/ana.24715.
6.	Narumi Y, Yoshida R, Minami Y, et al. Neuromyelitis optica spectrum disorder secondary to treatment with anti-PD-1 antibody nivolumab: the first report[J]. BMC Cancer, 2018, 18(1): 95. DOI: 10.1186/s12885-018-3997-2.
7.	Yshii LM, Hohlfeld R, Liblau RS. Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives[J]. Nat Rev Neurol, 2017, 13(12): 755-763. DOI: 10.1038/nrneurol.2017.144.
8.	Mukharesh L, Chwalisz BK. Neuro-ophthalmic complications of immune-checkpoint inhibitors[J]. Semin Ophthalmol, 2021, 36(4): 241-249. DOI: 10.1080/08820538.2021.1890796.
9.	Francis JH, Jaben K, Santomasso BD, et al. Immune checkpoint inhibitor-associated optic neuritis[J]. Ophthalmology, 2020, 127(11): 1585-1589. DOI: 10.1016/j.ophtha.2020.05.003.
10.	Nasralla S, Abboud H. Is neuromyelitis optica without AQP4-IgG a T-cell mediated disease? insights from checkpoint inhibitor immune-related adverse events[J/OL]. Mult Scler Relat Disord, 2020, 46: 102451[2020-08-15]. https://pubmed.ncbi.nlm.nih.gov/32835902/. DOI: 10.1016/j.msard.2020.102451.
11.	Khimani K, Patel SP, Whyte A, et al. Case report: neuromyelitis optica after treatment of uveal melanoma with Nivolumab and Ipilimumab[J/OL]. Front Oncol, 2022, 12: 806501[2022-03-23]. https://pubmed.ncbi.nlm.nih.gov/35402220/. DOI: 10.3389/fonc.2022.806501.
12.	Teodorescu R, Liu H, Sadun AA. Pembrolizumab-associated optic neuritis with an unusual manifestation of monocular optic disc edema[J/OL]. J Neuroophthalmol, 2023, 2023: E1(2022-12-16)[2023-01-04]. https://pubmed.ncbi.nlm.nih.gov/36728538/. DOI:10.1097/wno.0000000000001798. [published online ahead of print.
13.	Wilson MA, Guld K, Galetta S, et al. Acute visual loss after ipilimumab treatment for metastatic melanoma[J]. J Immunother Cancer, 2016, 4: 66. DOI: 10.1186/s40425-016-0170-9.
14.	Berry EC, Mullany S, Quinlivan A, et al. Eosinophilic vasculitis and arteritic anterior ischemic optic neuropathy associated with anti-PD-L1 therapy[J]. J Immunother, 2022, 45(1): 51-55. DOI: 10.1097/cji.0000000000000394.
15.	Ahluwalia A, Kohli AA. Photopsias in the setting of Nivolumab therapy[J/OL]. J Neuroophthalmol, 2021, 41(1): e25-e26[2021-03-01]. https://pubmed.ncbi.nlm.nih.gov/32108668/. DOI: 10.1097/wno.0000000000000909.
16.	Sun MM, Seleme N, Chen JJ, et al. Neuro-ophthalmic complications in patients treated with CTLA-4 and PD-1/PD-L1 checkpoint blockade[J]. J Neuroophthalmol, 2021, 41(4): 519-530. DOI: 10.1097/wno.0000000000001148.
17.	Yu CW, Yau M, Mezey N, et al. Neuro-ophthalmic complications of immune checkpoint inhibitors: a systematic review[J]. Eye Brain, 2020, 12: 139-167. DOI: 10.2147/eb.S277760.
18.	Navarro-Perea C, Garcia-Gonzalez J, Perez-Blazquez E. Case report: bilateral uveitis and papillitis secondary to treatment with pembrolizumab[J]. Indian J Ophthalmol, 2019, 67(12): 2075-2077. DOI: 10.4103/ijo.IJO_1161_19.
19.	Kawakado K, Tamura T, Nakanishi M, et al. Retrobulbar optic neuritis induced by Pembrolizumab in a patient with lung adenocarcinoma[J]. Intern Med, 2021, 60(24): 3941-3945. DOI: 10.2169/internalmedicine.7425-21.
20.	Weiss D, Cantré D, Zettl UK, et al. Lethal form of a late-onset aquaporin-4 antibody-positive NMOSD related to the immune checkpoint inhibitor nivolumab[J]. J Neurol, 2022, 269(5): 2778-2780. DOI: 10.1007/s00415-021-10913-y.
21.	Makri OE, Dimitrakopoulos FI, Tsapardoni F, et al. Isolated optic neuritis after Pembrolizumab administration for non-small-cell lung carcinoma[J]. Int J Neurosci, 2022, 132(7): 643-648. DOI: 10.1080/00207454.2020.1831489.
22.	Yeh OL, Francis CE. Ipilimumab-associated bilateral optic neuropathy[J]. J Neuroophthalmol, 2015, 35(2): 144-147. DOI: 10.1097/wno.0000000000000217.
23.	Toosy AT, Mason DF, Miller DH. Optic neuritis[J]. Lancet Neurol, 2014, 13(1): 83-99. DOI: 10.1016/s1474-4422(13)70259-x.
24.	Pucar D, Boustani AM, Bronen RA, et al. Superior pituitary border analysis in immunotherapy-induced hypophysitis[J]. Clin Nucl Med, 2018, 43(4): 284-286. DOI: 10.1097/rlu.0000000000001981.
25.	Kartal Ö, Ataş E. Bilateral optic neuritis secondary to Nivolumab therapy: a case report[J]. Medicina (Kaunas), 2018, 54(5): 82. DOI: 10.3390/medicina54050082.
26.	Marraffa F, Dybala A, Grassi S, et al. Retrobulbar optic neuritis secondary to Nivolumab therapy for metastatic melanoma in a 71-year-old patient affected by multiple sclerosis[J]. Ital J Dermatol Venerol, 2022, 157(5): 454-455. DOI: 10.23736/s2784-8671.22.07204-8.
27.	Cohen DA, Bhatti MT, Pulido JS, et al. Collapsin response-mediator protein 5-associated retinitis, vitritis, and optic disc edema[J]. Ophthalmology, 2020, 127(2): 221-229. DOI: 10.1016/j.ophtha.2019.09.012.
28.	Oliveira MCB, de Brito MH, Simabukuro MM. Central nervous system demyelination associated with immune checkpoint inhibitors: review of the literature[J/OL]. Front Neurol, 2020, 11: 538695[2020-12-11]. https://pubmed.ncbi.nlm.nih.gov/33362680/. DOI: 10.3389/fneur.2020.538695.
29.	Rahimy E, Sarraf D. Paraneoplastic and non-paraneoplastic retinopathy and optic neuropathy: evaluation and management[J]. Surv Ophthalmol, 2013, 58(5): 430-458. DOI: 10.1016/j.survophthal.2012.09.001.
30.	Cross SA, Salomao DR, Parisi JE, et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG[J]. Ann Neurol, 2003, 54(1): 38-50. DOI: 10.1002/ana.10587.
31.	Damek DM. Paraneoplastic retinopathy/optic neuropathy[J]. Curr Treat Options Neurol, 2005, 7(1): 57-67. DOI: 10.1007/s11940-005-0007-1.
32.	Graus F, Vogrig A, Muñiz-Castrillo S, et al. Updated diagnostic criteria for paraneoplastic neurologic syndromes[J/OL]. Neurol Neuroimmunol Neuroinflamm, 2021, 8(4): e1014[2021-05-18]. https://pubmed.ncbi.nlm.nih.gov/34006622/. DOI: 10.1212/nxi.0000000000001014.
33.	Song S, Chang D, Li H, et al. Association of optic nerve sheath lesion and brain or meningeal metastasis caused by lung cancer[J]. Thorac Cancer, 2022, 13(15): 2164-2169. DOI: 10.1111/1759-7714.14538.
34.	Achrol AS, Rennert RC, Anders C, et al. Brain metastases[J]. Nat Rev Dis Primers, 2019, 5(1): 5. DOI: 10.1038/s41572-018-0055-y.
35.	中国中西医结合学会检验医学专业委员会. 流式细胞术检测脑脊液肿瘤细胞的专家共识[J]. 中华检验医学杂志, 2021, 44(8): 679-689. DOI: 10.3760/cma.j.cn114452-20200927-00747.Chinese Association of Integrated Traditional and Western Medicine Laboratory Medicine Professional Committee. Consensus of experts on the detection of tumor cells in cerebrospinal fluid by flow cytometry[J]. Chin J Lab Med, 2021, 44(8): 679-689. DOI: 10.3760/cma.j.cn114452-20200927-00747.
36.	Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2017, 28(Suppl): S119-142. DOI: 10.1093/annonc/mdx225.
37.	中国抗癌协会肿瘤支持治疗专业委员会, 中国抗癌协会肿瘤临床化疗专业委员会. 免疫检查点抑制剂相关神经不良反应诊治中国专家共识(2022版)[J]. 中华肿瘤杂志, 2022, 44(9): 935-941. DOI: 10.3760/cma.j.cn112152-20220213-00098.Professional Committee of Tumor Supportive Therapy of Chinese Anti-Cancer Association, Professional Committee of Tumor Clinical Chemotherapy of Chinese Anti-Cancer Association. Chinese expert consensus on diagnosis and treatment of neurologic immune-related adverse events associated with immune checkpoint inhibitors (2022 edition)[J]. Chin J Oncol, 2022, 44(9): 935-941. DOI: 10.3760/cma.j.cn112152-20220213-00098.
38.	Kumar P, Saini S, Prabhakar BS. Cancer immunotherapy with check point inhibitor can cause autoimmune adverse events due to loss of Treg homeostasis[J]. Semin Cancer Biol, 2020, 64: 29-35. DOI: 10.1016/j.semcancer.2019.01.006.

1. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice[J]. Nat Rev Immunol, 2020, 20(11): 651-668. DOI: 10.1038/s41577-020-0306-5.
2. Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors[J]. Nat Rev Dis Primers, 2020, 6(1): 38. DOI: 10.1038/s41572-020-0160-6.
3. Friedman CF, Proverbs-Singh TA, Postow MA. Treatment of the immune-related adverse effects of immune checkpoint inhibitors: a review[J]. JAMA Oncol, 2016, 2(10): 1346-1353. DOI: 10.1001/jamaoncol.2016.1051.
4. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined Nivolumab and Ipilimumab in advanced melanoma[J]. N Engl J Med, 2019, 381(16): 1535-1546. DOI: 10.1056/NEJMoa1910836.
5. Gerdes LA, Held K, Beltrán E, et al. CTLA4 as immunological checkpoint in the development of multiple sclerosis[J]. Ann Neurol, 2016, 80(2): 294-300. DOI: 10.1002/ana.24715.
6. Narumi Y, Yoshida R, Minami Y, et al. Neuromyelitis optica spectrum disorder secondary to treatment with anti-PD-1 antibody nivolumab: the first report[J]. BMC Cancer, 2018, 18(1): 95. DOI: 10.1186/s12885-018-3997-2.
7. Yshii LM, Hohlfeld R, Liblau RS. Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives[J]. Nat Rev Neurol, 2017, 13(12): 755-763. DOI: 10.1038/nrneurol.2017.144.
8. Mukharesh L, Chwalisz BK. Neuro-ophthalmic complications of immune-checkpoint inhibitors[J]. Semin Ophthalmol, 2021, 36(4): 241-249. DOI: 10.1080/08820538.2021.1890796.
9. Francis JH, Jaben K, Santomasso BD, et al. Immune checkpoint inhibitor-associated optic neuritis[J]. Ophthalmology, 2020, 127(11): 1585-1589. DOI: 10.1016/j.ophtha.2020.05.003.
10. Nasralla S, Abboud H. Is neuromyelitis optica without AQP4-IgG a T-cell mediated disease? insights from checkpoint inhibitor immune-related adverse events[J/OL]. Mult Scler Relat Disord, 2020, 46: 102451[2020-08-15]. https://pubmed.ncbi.nlm.nih.gov/32835902/. DOI: 10.1016/j.msard.2020.102451.
11. Khimani K, Patel SP, Whyte A, et al. Case report: neuromyelitis optica after treatment of uveal melanoma with Nivolumab and Ipilimumab[J/OL]. Front Oncol, 2022, 12: 806501[2022-03-23]. https://pubmed.ncbi.nlm.nih.gov/35402220/. DOI: 10.3389/fonc.2022.806501.
12. Teodorescu R, Liu H, Sadun AA. Pembrolizumab-associated optic neuritis with an unusual manifestation of monocular optic disc edema[J/OL]. J Neuroophthalmol, 2023, 2023: E1(2022-12-16)[2023-01-04]. https://pubmed.ncbi.nlm.nih.gov/36728538/. DOI:10.1097/wno.0000000000001798. [published online ahead of print.
13. Wilson MA, Guld K, Galetta S, et al. Acute visual loss after ipilimumab treatment for metastatic melanoma[J]. J Immunother Cancer, 2016, 4: 66. DOI: 10.1186/s40425-016-0170-9.
14. Berry EC, Mullany S, Quinlivan A, et al. Eosinophilic vasculitis and arteritic anterior ischemic optic neuropathy associated with anti-PD-L1 therapy[J]. J Immunother, 2022, 45(1): 51-55. DOI: 10.1097/cji.0000000000000394.
15. Ahluwalia A, Kohli AA. Photopsias in the setting of Nivolumab therapy[J/OL]. J Neuroophthalmol, 2021, 41(1): e25-e26[2021-03-01]. https://pubmed.ncbi.nlm.nih.gov/32108668/. DOI: 10.1097/wno.0000000000000909.
16. Sun MM, Seleme N, Chen JJ, et al. Neuro-ophthalmic complications in patients treated with CTLA-4 and PD-1/PD-L1 checkpoint blockade[J]. J Neuroophthalmol, 2021, 41(4): 519-530. DOI: 10.1097/wno.0000000000001148.
17. Yu CW, Yau M, Mezey N, et al. Neuro-ophthalmic complications of immune checkpoint inhibitors: a systematic review[J]. Eye Brain, 2020, 12: 139-167. DOI: 10.2147/eb.S277760.
18. Navarro-Perea C, Garcia-Gonzalez J, Perez-Blazquez E. Case report: bilateral uveitis and papillitis secondary to treatment with pembrolizumab[J]. Indian J Ophthalmol, 2019, 67(12): 2075-2077. DOI: 10.4103/ijo.IJO_1161_19.
19. Kawakado K, Tamura T, Nakanishi M, et al. Retrobulbar optic neuritis induced by Pembrolizumab in a patient with lung adenocarcinoma[J]. Intern Med, 2021, 60(24): 3941-3945. DOI: 10.2169/internalmedicine.7425-21.
20. Weiss D, Cantré D, Zettl UK, et al. Lethal form of a late-onset aquaporin-4 antibody-positive NMOSD related to the immune checkpoint inhibitor nivolumab[J]. J Neurol, 2022, 269(5): 2778-2780. DOI: 10.1007/s00415-021-10913-y.
21. Makri OE, Dimitrakopoulos FI, Tsapardoni F, et al. Isolated optic neuritis after Pembrolizumab administration for non-small-cell lung carcinoma[J]. Int J Neurosci, 2022, 132(7): 643-648. DOI: 10.1080/00207454.2020.1831489.
22. Yeh OL, Francis CE. Ipilimumab-associated bilateral optic neuropathy[J]. J Neuroophthalmol, 2015, 35(2): 144-147. DOI: 10.1097/wno.0000000000000217.
23. Toosy AT, Mason DF, Miller DH. Optic neuritis[J]. Lancet Neurol, 2014, 13(1): 83-99. DOI: 10.1016/s1474-4422(13)70259-x.
24. Pucar D, Boustani AM, Bronen RA, et al. Superior pituitary border analysis in immunotherapy-induced hypophysitis[J]. Clin Nucl Med, 2018, 43(4): 284-286. DOI: 10.1097/rlu.0000000000001981.
25. Kartal Ö, Ataş E. Bilateral optic neuritis secondary to Nivolumab therapy: a case report[J]. Medicina (Kaunas), 2018, 54(5): 82. DOI: 10.3390/medicina54050082.
26. Marraffa F, Dybala A, Grassi S, et al. Retrobulbar optic neuritis secondary to Nivolumab therapy for metastatic melanoma in a 71-year-old patient affected by multiple sclerosis[J]. Ital J Dermatol Venerol, 2022, 157(5): 454-455. DOI: 10.23736/s2784-8671.22.07204-8.
27. Cohen DA, Bhatti MT, Pulido JS, et al. Collapsin response-mediator protein 5-associated retinitis, vitritis, and optic disc edema[J]. Ophthalmology, 2020, 127(2): 221-229. DOI: 10.1016/j.ophtha.2019.09.012.
28. Oliveira MCB, de Brito MH, Simabukuro MM. Central nervous system demyelination associated with immune checkpoint inhibitors: review of the literature[J/OL]. Front Neurol, 2020, 11: 538695[2020-12-11]. https://pubmed.ncbi.nlm.nih.gov/33362680/. DOI: 10.3389/fneur.2020.538695.
29. Rahimy E, Sarraf D. Paraneoplastic and non-paraneoplastic retinopathy and optic neuropathy: evaluation and management[J]. Surv Ophthalmol, 2013, 58(5): 430-458. DOI: 10.1016/j.survophthal.2012.09.001.
30. Cross SA, Salomao DR, Parisi JE, et al. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG[J]. Ann Neurol, 2003, 54(1): 38-50. DOI: 10.1002/ana.10587.
31. Damek DM. Paraneoplastic retinopathy/optic neuropathy[J]. Curr Treat Options Neurol, 2005, 7(1): 57-67. DOI: 10.1007/s11940-005-0007-1.
32. Graus F, Vogrig A, Muñiz-Castrillo S, et al. Updated diagnostic criteria for paraneoplastic neurologic syndromes[J/OL]. Neurol Neuroimmunol Neuroinflamm, 2021, 8(4): e1014[2021-05-18]. https://pubmed.ncbi.nlm.nih.gov/34006622/. DOI: 10.1212/nxi.0000000000001014.
33. Song S, Chang D, Li H, et al. Association of optic nerve sheath lesion and brain or meningeal metastasis caused by lung cancer[J]. Thorac Cancer, 2022, 13(15): 2164-2169. DOI: 10.1111/1759-7714.14538.
34. Achrol AS, Rennert RC, Anders C, et al. Brain metastases[J]. Nat Rev Dis Primers, 2019, 5(1): 5. DOI: 10.1038/s41572-018-0055-y.
35. 中国中西医结合学会检验医学专业委员会. 流式细胞术检测脑脊液肿瘤细胞的专家共识[J]. 中华检验医学杂志, 2021, 44(8): 679-689. DOI: 10.3760/cma.j.cn114452-20200927-00747.Chinese Association of Integrated Traditional and Western Medicine Laboratory Medicine Professional Committee. Consensus of experts on the detection of tumor cells in cerebrospinal fluid by flow cytometry[J]. Chin J Lab Med, 2021, 44(8): 679-689. DOI: 10.3760/cma.j.cn114452-20200927-00747.
36. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2017, 28(Suppl): S119-142. DOI: 10.1093/annonc/mdx225.
37. 中国抗癌协会肿瘤支持治疗专业委员会, 中国抗癌协会肿瘤临床化疗专业委员会. 免疫检查点抑制剂相关神经不良反应诊治中国专家共识(2022版)[J]. 中华肿瘤杂志, 2022, 44(9): 935-941. DOI: 10.3760/cma.j.cn112152-20220213-00098.Professional Committee of Tumor Supportive Therapy of Chinese Anti-Cancer Association, Professional Committee of Tumor Clinical Chemotherapy of Chinese Anti-Cancer Association. Chinese expert consensus on diagnosis and treatment of neurologic immune-related adverse events associated with immune checkpoint inhibitors (2022 edition)[J]. Chin J Oncol, 2022, 44(9): 935-941. DOI: 10.3760/cma.j.cn112152-20220213-00098.
38. Kumar P, Saini S, Prabhakar BS. Cancer immunotherapy with check point inhibitor can cause autoimmune adverse events due to loss of Treg homeostasis[J]. Semin Cancer Biol, 2020, 64: 29-35. DOI: 10.1016/j.semcancer.2019.01.006.

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Research progress of tumor immunotherapy-associated optic nerve adverse events, prevention and treatment

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