International Journal of Neuroscience
ISSN: 0020-7454 (Print) 1543-5245 (Online) Journal homepage: https://www.tandfonline.com/loi/ines20
Isolated Optic Neuritis after Pembrolizumab Administration for Non-Small-Cell Lung Carcinoma Olga E. Makri, Foteinos-Ioannis Dimitrakopoulos, Foteini Tsapardoni, Iasonas Tsekouras, Andreas A. Argyriou, Haralabos Kalofonos & Constantine D. Georgakopoulos To cite this article: Olga E. Makri, Foteinos-Ioannis Dimitrakopoulos, Foteini Tsapardoni, Iasonas Tsekouras, Andreas A. Argyriou, Haralabos Kalofonos & Constantine D. Georgakopoulos (2020): Isolated Optic Neuritis after Pembrolizumab Administration for Non-Small-Cell Lung Carcinoma, International Journal of Neuroscience, DOI: 10.1080/00207454.2020.1831489 To link to this article: https://doi.org/10.1080/00207454.2020.1831489
Accepted author version posted online: 30 Sep 2020.
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Running head: Pembrolizumab-induced isolated optic neuritis
Isolated Optic Neuritis after Pembrolizumab Administration for Non-Small-Cell Lung Carcinoma Olga E. Makri, MD, PhD1, Foteinos-Ioannis Dimitrakopoulos, MD, PhD2, Foteini Tsapardoni, MD1, Iasonas Tsekouras, MD1, Andreas A. Argyriou, MD, PhD3, Haralabos Kalofonos, MD, PhD2, Constantine D. Georgakopoulos, MD, PhD1 1
Department of Ophthalmology, Medical School, University of Patras, Patras, Greece
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Division of Oncology, Department of Medicine, Medical School, University of Patras, Patras, Greece “Saint Andrew's” State General Hospital of Patras, Tsertidou 1 Str, 26335, Patras, Greece.
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*Corresponding author: Constantine D. Georgakopoulos, MD, PhD, Associate Professor of Ophthalmology, Department of Ophthalmology, University of Patras, Medical School, 265 04, Patras, Greece Tel.: +30 2610 999286, Fax: +30 2610 993994. E-mail: [email protected]
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ABSTRACT
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Purpose: To report a case of isolated optic neuritis associated with pembrolizumab immunotherapy for metastatic nonsmall cell lung carcinoma.
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Case presentation: A 76-year-old man, with a history of metastatic non-small cell lung carcinoma, presented with vision loss in his left eye for the past week. He had been treated with pembrolizumab for the underlying disease for 2 months. On presentation, best corrected visual acuity was 20/30 in the right eye and 20/200 in the left eye. Fundoscopy revealed optic nerve edema in the left eye. Visual fields examination in right eye revealed an enlarged blind spot and an extended defect in the inferior nasal quadrant. In the left eye a partial superior arcuate defect and an extended defect in the inferior hemisphere was observed. The mean deviation was -12.15dB in the right eye and -13.70dB in left eye. Pembrolizumab was withheld and corticosteroids were administered for a total of nine weeks, first intravenously and then slowly tapered orally, resulting in resolution of optic neuritis, restoration of visual acuity and in relative improvement in the visual field defects after 3 months. Calculated Naranjo Nomogram score was 7, indicating a ‘‘highly probable’’ correlation. Conclusions: Optic neuritis is a relatively rare immune-related adverse event after exposure to checkpoint inhibitors cancer immunotherapy. Prompt discontinuation of the offending agent and early initiation of corticosteroid therapy is the mainstay of the treatment. KEYWORDS: Optic neuritis, anti-PD-1 antibody, immune checkpoint inhibitors (ICIs), metastatic non-small cell lung carcinoma, immune-related adverse effects, pembrolizumab INTRODUCTION Immune checkpoint inhibitors (ICIs) have revolutionized the management of patients with metastatic non-small cell lung carcinoma (NSCLC), renal carcinoma and melanoma (1). They are monoclonal antibodies that act by targeting cell surface receptors implicated in the immune checkpoints, such as
the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death-1 receptor (PD-1) as well as its ligand (PD-L1) (2). Through inhibition of these checkpoints, an upregulation of cytotoxic T cell activity promotes tumor cell death (1, 2). Currently, the clinically available ICIs are the CTLA-4 inhibitor ipilimumab, the PD-1 inhibitors nivolumab and pembrolizumab, as well as the PD-L1 inhibitors durvalumab, cemiplimab, avelumab and atezolizumab (1, 2). Although ICIs may result in markedly improved survival rates and durable remissions of cancer patients, they have occasionally been associated with severe or even lifethreatening immune-related adverse events (IRAEs) from various tissues or organs, as a result of loss of self-tolerance (3). Consensus guidelines recommend temporarily withholding ICIs until adequate clinical improvement for grade 1-2 toxicities and immediate cessation of ICIs in the case of grade 3 and 4 toxicity. Steroid pulse therapy should be commenced promptly (4). Ocular adverse events associated with ICIs therapy are rarely encountered (5). We herein describe in detail a case of isolated optic neuritis associated with pembrolizumab administration.
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CASE PRESENTATION
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A 76-year-old Caucasian male presented to the Emergency Department complaining of reduced vision in his left eye (OS) over the past week. Patient did not mention headache or other symptoms. The patient had been diagnosed with ΝSCLC with hypermetabolic mediastinal and subclavicular lymph nodes a year ago. In addition, his medical history included coronary artery disease, which had been treated with bypass graft surgery a decade ago, paroxysmal atrial fibrillation and hyperuricemia. For these reasons, he was under treatment with clopidogrel, allopurinol, metoprolol, furosemide, ezetimibe/simvastatin. Ophthalmic history included uncomplicated cataract surgery in both eyes.
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The patient had initially been managed for NSCLC with the concurrent administration of carboplatin/gemcitabine (weekly) combined with radiotherapy. Due to the progression of the disease and taking into account the overexpression of PD-L1, pembrolizumab was chosen as a second line treatment. Pembrolizumab was administered 4 months after the completion of chemotherapy/radiotherapy. More specifically, patient had received 3 cycles of intravenous pembrolizumab (200mg q3weeks). The last cycle had been administered 9 days before visual disturbances occurred, meaning that the total time from the initiation of pembrolizumab therapy to the onset of the ocular symptoms was 72 days.
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On ophthalmic examination, patient’s best corrected visual acuity (BCVA) was 20/30 in the right eye (OD) and 20/200 in OS. A mild relative afferent pupillary defect was detected in OS. Ocular motility was normal, without painful eye movements. Slit lamp examination of the anterior segment and intraocular pressure were normal. In dilated fundus examination, the optic disc in OD appeared normal while the optic disc in OS was edematous and hyperemic with mild vascular congestion (Figure 1A, 1B). Peripapillary atrophy was present in both eyes. Fluoroscein angiography revealed staining due to the peripapillary atrophy in both eyes and dye leakage from the optic disc in OS (Figure 2A, 2B).We did not observe any leakage along the vessels. A half-disc diameter, round, well defined lesioncomprising of peripheral hyperfluorescence and central hypofluorescence was also noticed along the superior temporal arcade in the posterior pole. This lesion corresponded to an area of subretinal fluid accumulation and retinal pigment epithelium abnormalities in optical coherence tomography (OCT). The OCT in OD demonstrated general reduction of the retinal nerve fiber layer (RNFL) thickness, which was attributed to the peripapillary atrophy (Figure 2C). In the OS the OCT confirmed the overall increased thickness of the RNFL (Figure 2D). Examination of visual fields (24-2 SITA Standard, Humphrey perimetry) in OD revealed an enlarged blind spot and an extended defect in the inferior nasal quadrant (Figure 1E). In OS, a partial superior
arcuate defect and an extended defect was observed in the inferior hemisphere (Figure 1F). The mean deviation (MD) was -12.15dB in OD and -13.70dB in OS. Blood counts, general biochemistry, and C-reactive protein were essentially normal. Erythrocyte sedimentation rate was 15mm/h. Neurological examination was normal and a brain magnetic resonance imaging with gadolinium enhancement was negative for metastatic lesions or recent infarcts. No orbital pathology was detected. The patient refused to undergo lumbar puncture and hence cerebrospinal fluid analysis (CSF) is lacking. Onconeuronal and antineuropil antibodies were not assessed, because optic neuritis of paraneoplastic origin does not fit the clinical presentation of our case as it is typically characterized by gradual visual loss, bilateral involvement and poor visual prognosis (6).
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Consequently, the presenting optic neuritis was considered as a highly probable (score 7) pembrolizumab-related adverse event, according to the Naranjo nomogram (7) and discontinuation of the drug was decided. The patient received, as inpatient, 1gr intravenous methylprednisolone for 3 consecutive days, resulting in BCVA improvement to 20/25 in OD and 20/40 in OS. He was then discharged with a regimen of oral prednisolone (0.5mg/Kg/day). Three weeks after presentation, BCVA improved to 20/22 in OD and 20/33 in OS. Fundoscopy revealed resolution of optic disc edema in OS with some residual hyperemia in the inferior nasal quadrant of the optic nerve head (Figure 1C). In perimetry the defects persisted but indices exhibited subtle improvement. The MD was -10.28dB in OD and -13.44dB in OS. The RNFL thickness in OS decreased. At that time tapering of prednisone by 5mg per week was initiated. At 2 months follow-up, while patient was under treatment with 10mg/day prednisolone, BCVA was 20/25 in OD and 20/22 in OS. The prednisone dosage was finally decreased to 5mg/day for one week and then discontinued. Three months after the onset of symptoms and while the patient had been off steroid treatment for 3 weeks, BCVA was 20/28 in OD and 20/25 in OS. Fundoscopy was normal in both eyes (Figure 1D). Perimetry revealed a relative improvement of the visual field defects. The MD was -8.57dB in OD and -9.64dB in OS (Figure 1E, 1F). Re-challenge with pembrolizumab was omitted throughout.
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DISCUSSION
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Pembrolizumab is a humanized IgG4 kappa monoclonal antibody (8), which binds and blocks the PD-1 on CD8+ T cells. This results in increased cytotoxic T-cell activity that promotes tumor cell death while carries a risk of stirring up autoimmunity (9). Blockade of checkpoints such as PD-1 may activate T-cell responses against intrinsic molecules which act as self-antigens in certain tissues where these checkpoints are expressed. Potential mechanisms triggering autoimmunity include epitope spreading or cross reactivity to microbiome-derived products (10). Pembrolizumab has been approved for various metastatic cancer types, including NSCLC (8, 9). Itis administered intravenously until the occurrence of disease regression or unacceptable toxicity (8). With anti-PD1 and anti-PD-L1 antibodies, IRAEs have been reported to affect up to 70% of patients. Neurological complications account for 1-5% of all IRAEs, while less than 1% concern ocular IRAEs (11, 12). Ocular complications with ICIs usually include dry eye disease, peripheral ulcerative keratitis and uveitis, Vogt Koyanagi Harada-like disease and choroidal neovascularization (12). Treatment-related ocular toxicity has more commonly been encountered with anti-CTLA-4 antibodies. More precisely, literature contains a report of bilateral optic neuritis in combination with hypophysitis and another case of bilateral optic neuropathy, both attributed to ipilimumab toxicity (13,14). Recently, optic nerve toxicity has been reported with anti-PD-1 antibodies. Nivolumab combined with a peptide vaccine has been implicated in the development of optic neuritis during treatment (15). Optic neuritis has also been associated with anti-PD-L1 treatment (16). Finally, immunotherapy with durvalumab was complicated by unilateral optic neuropathy in a patient treated for metastatic prostate cancer (17).
To date, pembrolizumab has been linked to severe uveitis complicated by hypotony, uveitis with papillitis, choroidal effusion with exudative retinal detachment (-18-20), as well as a case of bird shot-like chorioretinopathy (21). Typically, IRAEs with pembrolizumab, including the neuroopthalmological ones, present 2-12 weeks after commencing treatment (8). In consistency with the latter timeframe, we present a case of isolated optic disc involvement, highly probable induced by PD-1 blockade therapy 10 weeks after its first infusion. Apart from the obvious temporal association between optic neuritis and pembrolizumab initiation, the exclusion of other possible causes responsible for the inflammatory process within the optic nerve, in combination with the prompt improvement of visual acuity and resolution of optic disc edema after cessation of treatment support the etiological relationship between the presenting ocular pathology and the drug. Moreover, our patient’s response to corticosteroids suggests that pembrolizumab-related optic neuritis can be managed as a case of typical optic neuritis with concurrent discontinuation of the offending agent. Unfortunately, analysis of CSF is not available in our case to most likely show albuminocytologic dissociation in keeping with an immune-driven inflammatory reaction.
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Nonetheless, the aforementioned adverse event was rated as grade 4, as it resulted in a visual acuity of 20/200 (4). Adhering to the recommendations for the management of grade 4 ICIs-related toxicities, pembrolizumab was indefinitely discontinued and for ethical reasons was not reintroduced after recovery of optic neuritis.
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To conclude, immune-related complications of ICIs, involving the eye, are rare, but potentially severe. Fortunately, they are often reversible and responsive to steroid treatment. Our report highlights an uncommon cause of inflammatory optic neuritis that may be more frequently encountered with the increasing exposure of cancer patients to PD-1 blockade therapy. On clinical grounds, high clinical suspicion is essential in patients treated with ICIs who develop abrupt visual disturbances, for prompt recognition and management.
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Funding details
Disclosure of interest
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No funding source had a role in the preparation of this paper or in the decision to submit it for publication.
REFERENCES
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The authors report no conflict of interest
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1. Hui E. Immune checkpoint inhibitors. J Cell Biol. 2019;218:740-741 2. Wilky BA. Immune Checkpoint Inhibitors: The Linchpins of Modern Immunotherapy Immunol Rev. 2019;290:6-23 3. Teufel A, Zhan T, Härtel N, Bornschein J, Ebert MP, Schulte N. Management of immune related adverse events induced by immune checkpoint inhibition. Cancer Lett. 2019;456:80-87 4. Brahmer JR, Lacchetti C, Schneider BJ, et al. National Comprehensive Cancer Network. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714-1768
5. Bitton K, Michot JM, Barreau E, et al. Prevalence and Clinical Patterns of Ocular Complications Associated With Anti-PD-1/PD-L1 Anticancer Immunotherapy. Am J Ophthalmol. 2019; 202:109117 6. Xu Q, Du W, Zhou H, Zhang X, Liu H, Song H, Wang X, Wei S. Distinct clinical characteristics of paraneoplastic optic neuropathy. Br J Ophthalmol. 2019; 103:797-801 7. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30:239-245 8. Keytruda Summary of product characteristics. Available at https://www.ema.europa.eu/en/documents/product-information/keytruda-epar-product-information_ en.pdf. Accessed at March 11, 2020
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9. Turnis ME, Andrews LP, Vignali DA. Inhibitory receptors as targets for cancer immunotherapy. Eur J Immunol. 2015; 45:1892-905
cr
10. June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy. Nat Med. 2017;23:540–547.
us
11. Della Vittoria Scarpati G, Fusciello C, Perri F, Sabbatino F, Ferrone S, Carlomagno C, et al. Ipilimumab in the treatment of metastatic melanoma: management of adverse events. OncoTargets Ther. 2014;7:203-9
an
12. Antoun J, Titah C, Cochereau I. Ocular and orbital side-effects of checkpoint inhibitors: a review article. Curr Opin Oncol. 2016;28:288-94
M
13. Wilson MA, Guld K, Galetta S, Walsh RD, Kharlip J, Tamhankar M, et al. Acute visual loss after ipilimumab treatment for metastatic melanoma. J Immunother Cancer. 2016;4:66
pt ed
14. Yeh OL, Francis CE. Ipilimumab-associated bilateral optic neuropathy. J Neuroophthalmol. 2015;35:144-7
ce
15. Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013;31:4311-8
Ac
16. Mori S, Kurimoto T, Ueda K, Enomoto H, Sakamoto M, Keshi Y, Yamada Y, Nakamura M. Optic Neuritis Possibly Induced by Anti-PD-L1 Antibody Treatment in a Patient with Non-Small Cell Lung Carcinoma. Case Rep Ophthalmol. 2018 Jul 20;9:348-356 17. Noble CW, Gangaputra SS, Thompson IA, et al. Ocular Adverse Events following Use of Immune Checkpoint Inhibitors for Metastatic Malignancies [published online ahead of print, 2019 Apr 23]. Ocul Immunol Inflamm. 2019;1-6 18. Abu Samra K, Valdes-Navarro M, Lee S, Swan R, Foster CS, Anesi SD. A case of bilateral uveitis and papillitis in a patient treated with pembrolizumab. Eur J Ophthalmol. 2016 Apr 12;26:e46-8 19. Basilious A, Lloyd JC. Posterior subcapsular cataracts and hypotony secondary to severe pembrolizumab induced uveitis: Case report. Can J Ophthalmol. 2016;51:e4-6
20. Telfah M, Whittaker TJ, C Doolittle G. Vision loss with pembrolizumab treatment: A report of two cases. J Oncol Pharm Pract. 2019;25:1540-1546
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21. Acaba-Berrocal LA, et al. Birdshot-like chorioretinopathy associated with pembrolizumab treatment. JAMA Ophthalmol 2018; 136: 1205-1207
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Figure 1 Color fundus photographs (A-D). Fundoscopy in the right eye showed a normal optic disk while peripapillary atrophy was present (A).Fundoscopy of the left eye at baseline examination (B) revealed an hyperemic optic disc with edema and mild vascular congestion. Three weeks later partial resolution of disc edema with residual inferonasal hyperemia was noted in the left eye (C). Three months after pembrolizumab discontinuation and steroid administration complete recovery of the optic disc edema was observed in the left eye (D).
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Changes in visual fields before and after pembrolizumab discontinuation and steroid therapy (E-F). Automated visual fields initially demonstrated enlargement of the blind spot and an inferonasal defect in the right eye. Comparison of visual fields on presentation and 3 months later, exhibits a subtle constriction of the defect (E). In the left eye, baseline automated perimetry showed severe inferior loss and mild central depression along with a superior arcuate defect. Relative recovery of the defects at 3 months following steroid treatment and an overall improvement of indices were recorded (F).
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Figure 2 Fluoroscein angiography in the right eye revealed staining due to the peripapillary atrophy (A). In the left eye (B) dye leakage from the optic disc is observed as well as staining due to the peripapillary atrophy. A half-disc diameter, round, well defined lesion with peripheral hyperfluorescence and central hypofluorescence is also noted superotemporally in the posterior pole. No leakage along the vessels is observed in both eyes.
Optical coherence tomography in the right eye (C) demonstrated general reduction of the retinal nerve fiber layer thickness, which was attributed to the peripapillary atrophy. In the left eye increased thickness of the retinal nerve fiber layer is observed (D).
ISSN: 0020-7454 (Print) 1543-5245 (Online) Journal homepage: https://www.tandfonline.com/loi/ines20
Isolated Optic Neuritis after Pembrolizumab Administration for Non-Small-Cell Lung Carcinoma Olga E. Makri, Foteinos-Ioannis Dimitrakopoulos, Foteini Tsapardoni, Iasonas Tsekouras, Andreas A. Argyriou, Haralabos Kalofonos & Constantine D. Georgakopoulos To cite this article: Olga E. Makri, Foteinos-Ioannis Dimitrakopoulos, Foteini Tsapardoni, Iasonas Tsekouras, Andreas A. Argyriou, Haralabos Kalofonos & Constantine D. Georgakopoulos (2020): Isolated Optic Neuritis after Pembrolizumab Administration for Non-Small-Cell Lung Carcinoma, International Journal of Neuroscience, DOI: 10.1080/00207454.2020.1831489 To link to this article: https://doi.org/10.1080/00207454.2020.1831489
Accepted author version posted online: 30 Sep 2020.
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Article views: 1
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Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ines20
Running head: Pembrolizumab-induced isolated optic neuritis
Isolated Optic Neuritis after Pembrolizumab Administration for Non-Small-Cell Lung Carcinoma Olga E. Makri, MD, PhD1, Foteinos-Ioannis Dimitrakopoulos, MD, PhD2, Foteini Tsapardoni, MD1, Iasonas Tsekouras, MD1, Andreas A. Argyriou, MD, PhD3, Haralabos Kalofonos, MD, PhD2, Constantine D. Georgakopoulos, MD, PhD1 1
Department of Ophthalmology, Medical School, University of Patras, Patras, Greece
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Division of Oncology, Department of Medicine, Medical School, University of Patras, Patras, Greece “Saint Andrew's” State General Hospital of Patras, Tsertidou 1 Str, 26335, Patras, Greece.
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*Corresponding author: Constantine D. Georgakopoulos, MD, PhD, Associate Professor of Ophthalmology, Department of Ophthalmology, University of Patras, Medical School, 265 04, Patras, Greece Tel.: +30 2610 999286, Fax: +30 2610 993994. E-mail: [email protected]
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ABSTRACT
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Purpose: To report a case of isolated optic neuritis associated with pembrolizumab immunotherapy for metastatic nonsmall cell lung carcinoma.
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Case presentation: A 76-year-old man, with a history of metastatic non-small cell lung carcinoma, presented with vision loss in his left eye for the past week. He had been treated with pembrolizumab for the underlying disease for 2 months. On presentation, best corrected visual acuity was 20/30 in the right eye and 20/200 in the left eye. Fundoscopy revealed optic nerve edema in the left eye. Visual fields examination in right eye revealed an enlarged blind spot and an extended defect in the inferior nasal quadrant. In the left eye a partial superior arcuate defect and an extended defect in the inferior hemisphere was observed. The mean deviation was -12.15dB in the right eye and -13.70dB in left eye. Pembrolizumab was withheld and corticosteroids were administered for a total of nine weeks, first intravenously and then slowly tapered orally, resulting in resolution of optic neuritis, restoration of visual acuity and in relative improvement in the visual field defects after 3 months. Calculated Naranjo Nomogram score was 7, indicating a ‘‘highly probable’’ correlation. Conclusions: Optic neuritis is a relatively rare immune-related adverse event after exposure to checkpoint inhibitors cancer immunotherapy. Prompt discontinuation of the offending agent and early initiation of corticosteroid therapy is the mainstay of the treatment. KEYWORDS: Optic neuritis, anti-PD-1 antibody, immune checkpoint inhibitors (ICIs), metastatic non-small cell lung carcinoma, immune-related adverse effects, pembrolizumab INTRODUCTION Immune checkpoint inhibitors (ICIs) have revolutionized the management of patients with metastatic non-small cell lung carcinoma (NSCLC), renal carcinoma and melanoma (1). They are monoclonal antibodies that act by targeting cell surface receptors implicated in the immune checkpoints, such as
the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death-1 receptor (PD-1) as well as its ligand (PD-L1) (2). Through inhibition of these checkpoints, an upregulation of cytotoxic T cell activity promotes tumor cell death (1, 2). Currently, the clinically available ICIs are the CTLA-4 inhibitor ipilimumab, the PD-1 inhibitors nivolumab and pembrolizumab, as well as the PD-L1 inhibitors durvalumab, cemiplimab, avelumab and atezolizumab (1, 2). Although ICIs may result in markedly improved survival rates and durable remissions of cancer patients, they have occasionally been associated with severe or even lifethreatening immune-related adverse events (IRAEs) from various tissues or organs, as a result of loss of self-tolerance (3). Consensus guidelines recommend temporarily withholding ICIs until adequate clinical improvement for grade 1-2 toxicities and immediate cessation of ICIs in the case of grade 3 and 4 toxicity. Steroid pulse therapy should be commenced promptly (4). Ocular adverse events associated with ICIs therapy are rarely encountered (5). We herein describe in detail a case of isolated optic neuritis associated with pembrolizumab administration.
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CASE PRESENTATION
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A 76-year-old Caucasian male presented to the Emergency Department complaining of reduced vision in his left eye (OS) over the past week. Patient did not mention headache or other symptoms. The patient had been diagnosed with ΝSCLC with hypermetabolic mediastinal and subclavicular lymph nodes a year ago. In addition, his medical history included coronary artery disease, which had been treated with bypass graft surgery a decade ago, paroxysmal atrial fibrillation and hyperuricemia. For these reasons, he was under treatment with clopidogrel, allopurinol, metoprolol, furosemide, ezetimibe/simvastatin. Ophthalmic history included uncomplicated cataract surgery in both eyes.
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The patient had initially been managed for NSCLC with the concurrent administration of carboplatin/gemcitabine (weekly) combined with radiotherapy. Due to the progression of the disease and taking into account the overexpression of PD-L1, pembrolizumab was chosen as a second line treatment. Pembrolizumab was administered 4 months after the completion of chemotherapy/radiotherapy. More specifically, patient had received 3 cycles of intravenous pembrolizumab (200mg q3weeks). The last cycle had been administered 9 days before visual disturbances occurred, meaning that the total time from the initiation of pembrolizumab therapy to the onset of the ocular symptoms was 72 days.
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On ophthalmic examination, patient’s best corrected visual acuity (BCVA) was 20/30 in the right eye (OD) and 20/200 in OS. A mild relative afferent pupillary defect was detected in OS. Ocular motility was normal, without painful eye movements. Slit lamp examination of the anterior segment and intraocular pressure were normal. In dilated fundus examination, the optic disc in OD appeared normal while the optic disc in OS was edematous and hyperemic with mild vascular congestion (Figure 1A, 1B). Peripapillary atrophy was present in both eyes. Fluoroscein angiography revealed staining due to the peripapillary atrophy in both eyes and dye leakage from the optic disc in OS (Figure 2A, 2B).We did not observe any leakage along the vessels. A half-disc diameter, round, well defined lesioncomprising of peripheral hyperfluorescence and central hypofluorescence was also noticed along the superior temporal arcade in the posterior pole. This lesion corresponded to an area of subretinal fluid accumulation and retinal pigment epithelium abnormalities in optical coherence tomography (OCT). The OCT in OD demonstrated general reduction of the retinal nerve fiber layer (RNFL) thickness, which was attributed to the peripapillary atrophy (Figure 2C). In the OS the OCT confirmed the overall increased thickness of the RNFL (Figure 2D). Examination of visual fields (24-2 SITA Standard, Humphrey perimetry) in OD revealed an enlarged blind spot and an extended defect in the inferior nasal quadrant (Figure 1E). In OS, a partial superior
arcuate defect and an extended defect was observed in the inferior hemisphere (Figure 1F). The mean deviation (MD) was -12.15dB in OD and -13.70dB in OS. Blood counts, general biochemistry, and C-reactive protein were essentially normal. Erythrocyte sedimentation rate was 15mm/h. Neurological examination was normal and a brain magnetic resonance imaging with gadolinium enhancement was negative for metastatic lesions or recent infarcts. No orbital pathology was detected. The patient refused to undergo lumbar puncture and hence cerebrospinal fluid analysis (CSF) is lacking. Onconeuronal and antineuropil antibodies were not assessed, because optic neuritis of paraneoplastic origin does not fit the clinical presentation of our case as it is typically characterized by gradual visual loss, bilateral involvement and poor visual prognosis (6).
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Consequently, the presenting optic neuritis was considered as a highly probable (score 7) pembrolizumab-related adverse event, according to the Naranjo nomogram (7) and discontinuation of the drug was decided. The patient received, as inpatient, 1gr intravenous methylprednisolone for 3 consecutive days, resulting in BCVA improvement to 20/25 in OD and 20/40 in OS. He was then discharged with a regimen of oral prednisolone (0.5mg/Kg/day). Three weeks after presentation, BCVA improved to 20/22 in OD and 20/33 in OS. Fundoscopy revealed resolution of optic disc edema in OS with some residual hyperemia in the inferior nasal quadrant of the optic nerve head (Figure 1C). In perimetry the defects persisted but indices exhibited subtle improvement. The MD was -10.28dB in OD and -13.44dB in OS. The RNFL thickness in OS decreased. At that time tapering of prednisone by 5mg per week was initiated. At 2 months follow-up, while patient was under treatment with 10mg/day prednisolone, BCVA was 20/25 in OD and 20/22 in OS. The prednisone dosage was finally decreased to 5mg/day for one week and then discontinued. Three months after the onset of symptoms and while the patient had been off steroid treatment for 3 weeks, BCVA was 20/28 in OD and 20/25 in OS. Fundoscopy was normal in both eyes (Figure 1D). Perimetry revealed a relative improvement of the visual field defects. The MD was -8.57dB in OD and -9.64dB in OS (Figure 1E, 1F). Re-challenge with pembrolizumab was omitted throughout.
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DISCUSSION
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Pembrolizumab is a humanized IgG4 kappa monoclonal antibody (8), which binds and blocks the PD-1 on CD8+ T cells. This results in increased cytotoxic T-cell activity that promotes tumor cell death while carries a risk of stirring up autoimmunity (9). Blockade of checkpoints such as PD-1 may activate T-cell responses against intrinsic molecules which act as self-antigens in certain tissues where these checkpoints are expressed. Potential mechanisms triggering autoimmunity include epitope spreading or cross reactivity to microbiome-derived products (10). Pembrolizumab has been approved for various metastatic cancer types, including NSCLC (8, 9). Itis administered intravenously until the occurrence of disease regression or unacceptable toxicity (8). With anti-PD1 and anti-PD-L1 antibodies, IRAEs have been reported to affect up to 70% of patients. Neurological complications account for 1-5% of all IRAEs, while less than 1% concern ocular IRAEs (11, 12). Ocular complications with ICIs usually include dry eye disease, peripheral ulcerative keratitis and uveitis, Vogt Koyanagi Harada-like disease and choroidal neovascularization (12). Treatment-related ocular toxicity has more commonly been encountered with anti-CTLA-4 antibodies. More precisely, literature contains a report of bilateral optic neuritis in combination with hypophysitis and another case of bilateral optic neuropathy, both attributed to ipilimumab toxicity (13,14). Recently, optic nerve toxicity has been reported with anti-PD-1 antibodies. Nivolumab combined with a peptide vaccine has been implicated in the development of optic neuritis during treatment (15). Optic neuritis has also been associated with anti-PD-L1 treatment (16). Finally, immunotherapy with durvalumab was complicated by unilateral optic neuropathy in a patient treated for metastatic prostate cancer (17).
To date, pembrolizumab has been linked to severe uveitis complicated by hypotony, uveitis with papillitis, choroidal effusion with exudative retinal detachment (-18-20), as well as a case of bird shot-like chorioretinopathy (21). Typically, IRAEs with pembrolizumab, including the neuroopthalmological ones, present 2-12 weeks after commencing treatment (8). In consistency with the latter timeframe, we present a case of isolated optic disc involvement, highly probable induced by PD-1 blockade therapy 10 weeks after its first infusion. Apart from the obvious temporal association between optic neuritis and pembrolizumab initiation, the exclusion of other possible causes responsible for the inflammatory process within the optic nerve, in combination with the prompt improvement of visual acuity and resolution of optic disc edema after cessation of treatment support the etiological relationship between the presenting ocular pathology and the drug. Moreover, our patient’s response to corticosteroids suggests that pembrolizumab-related optic neuritis can be managed as a case of typical optic neuritis with concurrent discontinuation of the offending agent. Unfortunately, analysis of CSF is not available in our case to most likely show albuminocytologic dissociation in keeping with an immune-driven inflammatory reaction.
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Nonetheless, the aforementioned adverse event was rated as grade 4, as it resulted in a visual acuity of 20/200 (4). Adhering to the recommendations for the management of grade 4 ICIs-related toxicities, pembrolizumab was indefinitely discontinued and for ethical reasons was not reintroduced after recovery of optic neuritis.
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To conclude, immune-related complications of ICIs, involving the eye, are rare, but potentially severe. Fortunately, they are often reversible and responsive to steroid treatment. Our report highlights an uncommon cause of inflammatory optic neuritis that may be more frequently encountered with the increasing exposure of cancer patients to PD-1 blockade therapy. On clinical grounds, high clinical suspicion is essential in patients treated with ICIs who develop abrupt visual disturbances, for prompt recognition and management.
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Disclosure of interest
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No funding source had a role in the preparation of this paper or in the decision to submit it for publication.
REFERENCES
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The authors report no conflict of interest
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1. Hui E. Immune checkpoint inhibitors. J Cell Biol. 2019;218:740-741 2. Wilky BA. Immune Checkpoint Inhibitors: The Linchpins of Modern Immunotherapy Immunol Rev. 2019;290:6-23 3. Teufel A, Zhan T, Härtel N, Bornschein J, Ebert MP, Schulte N. Management of immune related adverse events induced by immune checkpoint inhibition. Cancer Lett. 2019;456:80-87 4. Brahmer JR, Lacchetti C, Schneider BJ, et al. National Comprehensive Cancer Network. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36:1714-1768
5. Bitton K, Michot JM, Barreau E, et al. Prevalence and Clinical Patterns of Ocular Complications Associated With Anti-PD-1/PD-L1 Anticancer Immunotherapy. Am J Ophthalmol. 2019; 202:109117 6. Xu Q, Du W, Zhou H, Zhang X, Liu H, Song H, Wang X, Wei S. Distinct clinical characteristics of paraneoplastic optic neuropathy. Br J Ophthalmol. 2019; 103:797-801 7. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30:239-245 8. Keytruda Summary of product characteristics. Available at https://www.ema.europa.eu/en/documents/product-information/keytruda-epar-product-information_ en.pdf. Accessed at March 11, 2020
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t
9. Turnis ME, Andrews LP, Vignali DA. Inhibitory receptors as targets for cancer immunotherapy. Eur J Immunol. 2015; 45:1892-905
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10. June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy. Nat Med. 2017;23:540–547.
us
11. Della Vittoria Scarpati G, Fusciello C, Perri F, Sabbatino F, Ferrone S, Carlomagno C, et al. Ipilimumab in the treatment of metastatic melanoma: management of adverse events. OncoTargets Ther. 2014;7:203-9
an
12. Antoun J, Titah C, Cochereau I. Ocular and orbital side-effects of checkpoint inhibitors: a review article. Curr Opin Oncol. 2016;28:288-94
M
13. Wilson MA, Guld K, Galetta S, Walsh RD, Kharlip J, Tamhankar M, et al. Acute visual loss after ipilimumab treatment for metastatic melanoma. J Immunother Cancer. 2016;4:66
pt ed
14. Yeh OL, Francis CE. Ipilimumab-associated bilateral optic neuropathy. J Neuroophthalmol. 2015;35:144-7
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15. Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol. 2013;31:4311-8
Ac
16. Mori S, Kurimoto T, Ueda K, Enomoto H, Sakamoto M, Keshi Y, Yamada Y, Nakamura M. Optic Neuritis Possibly Induced by Anti-PD-L1 Antibody Treatment in a Patient with Non-Small Cell Lung Carcinoma. Case Rep Ophthalmol. 2018 Jul 20;9:348-356 17. Noble CW, Gangaputra SS, Thompson IA, et al. Ocular Adverse Events following Use of Immune Checkpoint Inhibitors for Metastatic Malignancies [published online ahead of print, 2019 Apr 23]. Ocul Immunol Inflamm. 2019;1-6 18. Abu Samra K, Valdes-Navarro M, Lee S, Swan R, Foster CS, Anesi SD. A case of bilateral uveitis and papillitis in a patient treated with pembrolizumab. Eur J Ophthalmol. 2016 Apr 12;26:e46-8 19. Basilious A, Lloyd JC. Posterior subcapsular cataracts and hypotony secondary to severe pembrolizumab induced uveitis: Case report. Can J Ophthalmol. 2016;51:e4-6
20. Telfah M, Whittaker TJ, C Doolittle G. Vision loss with pembrolizumab treatment: A report of two cases. J Oncol Pharm Pract. 2019;25:1540-1546
pt ed
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21. Acaba-Berrocal LA, et al. Birdshot-like chorioretinopathy associated with pembrolizumab treatment. JAMA Ophthalmol 2018; 136: 1205-1207
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Figure 1 Color fundus photographs (A-D). Fundoscopy in the right eye showed a normal optic disk while peripapillary atrophy was present (A).Fundoscopy of the left eye at baseline examination (B) revealed an hyperemic optic disc with edema and mild vascular congestion. Three weeks later partial resolution of disc edema with residual inferonasal hyperemia was noted in the left eye (C). Three months after pembrolizumab discontinuation and steroid administration complete recovery of the optic disc edema was observed in the left eye (D).
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Changes in visual fields before and after pembrolizumab discontinuation and steroid therapy (E-F). Automated visual fields initially demonstrated enlargement of the blind spot and an inferonasal defect in the right eye. Comparison of visual fields on presentation and 3 months later, exhibits a subtle constriction of the defect (E). In the left eye, baseline automated perimetry showed severe inferior loss and mild central depression along with a superior arcuate defect. Relative recovery of the defects at 3 months following steroid treatment and an overall improvement of indices were recorded (F).
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Figure 2 Fluoroscein angiography in the right eye revealed staining due to the peripapillary atrophy (A). In the left eye (B) dye leakage from the optic disc is observed as well as staining due to the peripapillary atrophy. A half-disc diameter, round, well defined lesion with peripheral hyperfluorescence and central hypofluorescence is also noted superotemporally in the posterior pole. No leakage along the vessels is observed in both eyes.
Optical coherence tomography in the right eye (C) demonstrated general reduction of the retinal nerve fiber layer thickness, which was attributed to the peripapillary atrophy. In the left eye increased thickness of the retinal nerve fiber layer is observed (D).
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