Acute visual loss after ipilimumab treatment for metastatic melanoma
© The Author(s). 2016
Received: 24 March 2016
Accepted: 29 September 2016
Published: 18 October 2016
Ipilimumab, a humanized CLTA-4 antibody is a standard therapy in the treatment of advanced melanoma. While ipilimumab provides an overall survival benefit to patients, it can be associated with immune related adverse events (IrAEs).
Here we describe a patient treated with ipilimumab who experienced known IrAEs, including hypophysitis, as well as a profound vision loss due to optic neuritis. There are rare reports of optic neuritis occurring as an adverse event associated with ipilimumab treatment. Furthermore, the patient experienced multiple complications from high dose steroids used to manage his IrAEs.
This case highlights the need for recognition of atypical immune mediated processes associated with newer checkpoint inhibitor therapies including ipilimumab.
KeywordsMelanoma Ipilimumab Immune Side effects Optic neuritis Checkpoint inhibitors
Until recently, there were limited treatment options for patients with advanced stage melanoma. In 2011, the United States Food and Drug Association approved two new treatments for advanced, unresectable melanoma - the antagonist cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody, ipilimumab, and the targeted BRAF inhibitor, vemurafenib. These new medications have demonstrated significant benefits in overall survival [1–3]. Since then, additional therapies have been approved for the treatment of advanced stage melanoma, both targeted therapies [4–8] and immunotherapies, including the newly FDA approved antagonist programmed cell death protein 1 (PD-1) antibodies, pembrolizumab and nivolumab [9–12]. Immuno-oncology is a growing field in the treatment of not only melanoma, but also other solid tumors, such as non-small cell lung and renal cell cancer . These new treatments demonstrate improved and durable responses, but have unique, immune-related side effects which require prompt recognition and management distinct from traditional cytotoxic chemotherapies.
Ipilimumab is a human monoclonal antibody directed against CTLA-4. In the normal immune system, CTLA-4 downregulates activation of T-cells in hosts by interaction with a co-receptor on the antigen presenting cell. Antagonism of CTLA-4 with ipilimumab therefore blocks co-receptor interaction leading to activation of the innate immune system, stimulating an immune response against melanoma tumor cells . It is well understood that treatment with ipilimumab can result in a number of immune related adverse events (IrAEs), felt to be the result of cross-reactive tissue damage by activated T-cells [15, 16]. Most IrAEs generally respond and resolve with steroid treatment for several weeks or longer. However, there are cases of IrAEs refractory to steroids that require additional immunosuppressive interventions, including intravenous immunoglobulin (IVIG) and Infliximab [17–19]. The most common immune-related side effects from treatment with ipilimumab include: colitis - causing diarrhea, endocrinopathies - such as hypophysitis and hypothyroidism, hepatitis, and dermatitis [20–25].
Ophthalmologic complications from ipilimumab therapy are rare, occurring in less than 1 % of patients, but generally manifest as uveitis [26–28] with symptoms of blurred vision, decreased visual acuity, dry eyes, pain, and photophobia [28, 29]. An association of colitis with uveitis in patients has been reported . Thyroid like orbitopathy [16, 30–33] and ocular inflammation involving choroid and retina [34–36] have also been reported. Optic neuritis, which involves inflammation of the optic nerve is associated with a number of conditions including multiple sclerosis and autoimmune disorders. Several biologic agents, (especially tumor necrosis factor (TNF)-alpha inhibitors like infliximab, etanercept, and adalimumab) have been associated with optic neuritis . Optic neuritis was recently described in association with ipilimumab treatment [33, 37]. We report here a patient who demonstrated multiple immune-related adverse events including panhypopituitarism and optic neuritis, resulting in monocular blindness, after undergoing treatment with ipilimumab. Moreover, treatment of the immune-related side effects with high dose steroids induced a catatonic depression requiring electroconvulsive therapy (ECT).
Diagnostic Tests and Workup of Patient’s Vision Loss
Time after initial ipilimumab treatment
Five and a half months
Prednisone 40 mg with taper to 20 mg
Methyprednisolone IV 1 gram x 3 days, then prednisone 40 mg
Methyprednisolone IV 1 gram x 5 days, then prednisone 100 mg daily, tapered to 80 mg daily
IV 1 gram daily x 10 days, then prednisone 100 mg daily, mycophenolate mofetil 1000 mg BID
Mycophenolate mofetil 1000 mg BID, slow prednisone taper
Left Eye -No light perception Vision; Left afferent pupillary defect; Optic nerve swelling; retinal whitening
Right Eye- visual acuity 20/50; decreased color vision; visual field
disc swelling; Left eye
- vision remained no
Right Eye - subjective
reduced optic disc
Right Eye- declined
Right Eye - visual acuity 20/20; resolved optic disc swelling; Left Eye -no light perception; atrophic optic nerve
Magnetic Resonance Imaging
Unremarkable; No metastases
Circumferential enhancement of intraorbital optic nerves, right > > left
Negative for brain metastases
Protein (normal 15-45)
Glucose (normal 40-70)
Fungal Cx neg; AFB stain neg; Crytpo Ag neg; HSV PCR neg; RPR neg; Lyme neg; CMV neg; VZV; neg; Bartonella neg
Negative for malignancy
Negative for malignancy
Negative for malignancy
Fifteen months after the initiation of ipilimumab, he was clinically stable on mycophenolate mofetil and a slow prednisone taper; his ophthalmologic examination was notable for visual acuities of 20/20 in the right eye, and no light perception in the left eye; the right optic disc swelling had resolved, and the left optic nerve remained atrophic. He was again intolerant of further steroid taper with recurrent right eye blurred vision prompting hospital re-admission and another course of intravenous methylprednisolone 250 mg every 6 h. During this stay, he received five treatments with plasmapheresis. A lumbar puncture performed during this hospital stay was negative for malignancy or infection and he was discharged on mycophenolate mofetil 1000 mg twice daily and prednisone 80 mg daily (Table 1). At this time, his metastatic melanoma was slowly progressing with increasing lymphadenopathy and his visual acuity ranged from 20/20 to 20/40 in the right eye, and no light perception in the left eye. He also experienced several adverse effects from high dose steroids, including catatonic depression, severe deconditioning, and steroid myopathy.
Seventeen months after initiation of ipilimumab, the patient experienced increased fatigue, lightheadedness, and multiple falls at home. Head imaging demonstrated multiple hemorrhagic brain metastases. Anticoagulation was stopped and an inferior vena cava filter was placed. Four days later the patient was found to be obtunded. Comfort measures were initiated and the patient passed away shortly afterward.
With the increased use of checkpoint inhibitors, antagonist CTLA-4 and PD-1 and PDL-1 antibodies, and the growing field of immuno-oncology, the recognition and treatment of immune-related side effects is crucial. This case highlights several issues: a patient can develop multiple IrAEs, IrAEs can develop while on steroid treatment, IrAEs can be delayed in onset, steroid therapy alone may not be sufficient to effect and maintain control of IrAEs, and the treatments required for management of IrAEs (ie steroids, immunosuppressive therapy) may have significant adverse effects. Most importantly, we highlight a rare complication of optic neuropathy.
Initially, the patient’s left eye vision loss was thought to be vascular in nature, given a new pulmonary embolus, the acute onset of his vision loss, and the retinal findings of optic disc swelling and retinal whitening in the setting of ongoing treatment with high dose prednisone for previously diagnosed hypophysitis. The possibility of an ocular IrAE was discussed from the outset but the presentation was not determined to be concordant. Although it is possible that a vascular mechanism as the result of drug effect is still possible, and there are rare reports of vascular related issues, there is nothing definitive to suggest this. Shortly thereafter, the second eye then became affected in a fashion more typical of an inflammatory optic neuritis.
Importantly, these new and different visual complaints in the right eye occurred despite full anti-coagulation and prednisone therapy. The initial MRI of the brain and orbits was unrevealing and the clinical findings in the right eye were distinct from those previously identified in the left eye. However, repeat MRI imaging of the orbits revealed bilateral subtle circumferential perineural optic nerve enhancement suggestive of optic nerve inflammation. This feature, in conjunction with the noninfectious inflammatory CSF, supported the diagnosis of atypical optic neuritis from an immune-mediated process. High dose steroid therapy stabilized the right eye vision but the left eye vision never improved after initial presentation, again supporting a probable vascular cause for the left eye visual loss. This may or may not have been secondary to an inflammatory/immune-mediated process (ie, local thrombosis related to inflammation/vasculitis). Given intolerance of even small tapering of steroids, mycophenolate mofetil was selected due to its use in the treatment of other inflammatory/immune-mediated optic neuropathies as well as for its possible penetration into the CNS.
The patient’s visual loss in the right eye was not consistent with an ischemic optic neuropathy as optic nerve ischemia causes permanent visual impairment and is not steroid dependent. Infectious or parainfectious optic neuropathies, although possible in this immunosuppressed patient, were also felt to be unlikely due to an extensive laboratory work up which was unremarkable. This included negative cytomegalovirus (CMV), varicella zoster virus (VZV), rapid plasma reagin (RPR), lyme and bartonella titers. The patient never developed findings suspicious for retinal metastases or paraneoplastic retinopathy. Finally, acute demyelinating optic neuritis was considered in the differential given the enhancement of the optic nerve seen on MRI. However, during a follow up of approximately one and half years no additional or new neurological complaints developed and multiple MRI scans during this period were normal with no demyelinating lesions noted. Neuromyelitis optica (NMO) antibodies were not ordered.
It is noteworthy that the visual symptoms developed while on steroid therapy and 4 months after the last dose of CTLA-4 blockade. Given treatment with ipilimumab accompanied by the well described immune related adverse event of hypophysitis, it is reasonable to conclude that the optic nerve involvement was also an immune-related adverse event attributable to ipilimumab. Kaehler et. al. reported a characteristic pattern of immune-mediated side effects related to ipilimumab use, with some manifestations [29, 38] occurring weeks following treatment.
The immune mediated mechanism of action of these side effects is unique to checkpoint blockade and, unlike other drug-mediated side effects, is a T-lymphocyte (T cell) mediated process. Moreover, it is thought that there is loss of recognition of self-antigens and decreased self-tolerance [39, 40], which then results in an autoimmune response. Histologically, tissues affected by immune responses (both antitumor and adverse events) after ipilimumab treatment demonstrate a T-cell infiltrate , however multiple types of infiltrates have been observed – neutrophilic, lymphocytic, and mixed neutrophilic and lymphocytic infiltrates [26, 29]. The recommended therapy for IrAEs involves suppression of T-cell function, with steroids or other immunosuppressive agents, which interestingly does not interfere with the anti-tumor effect of ipilimumab . This patient’s visual loss was severe in one eye and recurred multiple times in the other eye requiring many courses of steroids, plasmapheresis, IVIG, and mycophenylate mofetil.
This patient with metastatic melanoma developed hypophysitis related to treatment with ipilimumab, and subsequently developed acute left vision loss and waxing and waning vision loss of the right eye consistent with an inflammatory optic neuritis attributed to CTLA-4 blockade. This case emphasizes a rare and refractory IrAE. The recognition of immune-related adverse events is not limited to oncologists, but extends to physicians in other subspecialties that will be involved in the care of patients receiving immune modulating therapies.
Cytotoxic T-lymphocyte antigen 4
Food and drug administration
Follicle stimulating hormone
Immune related adverse events
Inferior vena cava
Magnetic resonance angiogram
Magnetic resonance imaging
Magnetic resonance venography
Programmed death 1
Tumor necrosis factor
Thyroid stimulating hormone
This research was funded in part by a NCI Cancer Center Research Training Program Grant T32 CA009615 (PI: Dr. John Maris) (MAW).
Availability of data and materials
MW, KG, SG, RW, JK, MT, SM, LS, and LF participated in the care of the patient. MW, KG, and LF drafted the manuscript. SG, RW, JK, MT, SM, and LS helped to revise the manuscript. All authors read and approved the final manuscript.
MW: BMS – advisory board; SM: BMS – Speaker’s bureau; LF: BMS– research support. The remaining authors’ declare no conflict of interest at this time.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Ethical approval and consent to participate
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.View ArticlePubMedPubMed CentralGoogle Scholar
- Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.View ArticlePubMedPubMed CentralGoogle Scholar
- Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.View ArticlePubMedGoogle Scholar
- Falchook GS, Lewis KD, Infante JR, et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:782–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694–703.View ArticlePubMedPubMed CentralGoogle Scholar
- Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107–14.View ArticlePubMedGoogle Scholar
- Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–65.View ArticlePubMedGoogle Scholar
- Kim KB, Kefford R, Pavlick AC, et al. Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 2013;31:482–9.View ArticlePubMedGoogle Scholar
- Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013;369:134–44.View ArticlePubMedPubMed CentralGoogle Scholar
- Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014;384:1109–17.View ArticlePubMedGoogle Scholar
- Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.View ArticlePubMedGoogle Scholar
- Weber JS, D’Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16:375–84.View ArticlePubMedGoogle Scholar
- Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.View ArticlePubMedPubMed CentralGoogle Scholar
- Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol. 2001;19:565–94.View ArticlePubMedGoogle Scholar
- Bosch X, Saiz A, Ramos-Casals M, Group BS. Monoclonal antibody therapy-associated neurological disorders. Nat Rev Neurol. 2011;7:165–72.View ArticlePubMedGoogle Scholar
- Min L, Vaidya A, Becker C. Thyroid autoimmunity and ophthalmopathy related to melanoma biological therapy. Eur J Endocrinol. 2011;164:303–7.View ArticlePubMedGoogle Scholar
- Akhtari M, Waller EK, Jaye DL, et al. Neutropenia in a patient treated with ipilimumab (anti-CTLA-4 antibody). J Immunother. 2009;32:322–4.View ArticlePubMedGoogle Scholar
- Johnston RL, Lutzky J, Chodhry A, Barkin JS. Cytotoxic T-lymphocyte-associated antigen 4 antibody-induced colitis and its management with infliximab. Dig Dis Sci. 2009;54:2538–40.View ArticlePubMedGoogle Scholar
- Minor DR, Chin K, Kashani-Sabet M. Infliximab in the treatment of anti-CTLA4 antibody (ipilimumab) induced immune-related colitis. Cancer Biother Radiopharm. 2009;24:321–5.View ArticlePubMedGoogle Scholar
- Blansfield JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005;28:593–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Dillard T, Yedinak CG, Alumkal J, Fleseriu M. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes. Pituitary. 2010;13:29–38.View ArticlePubMedGoogle Scholar
- Graziani G, Tentori L, Navarra P. Ipilimumab: a novel immunostimulatory monoclonal antibody for the treatment of cancer. Pharmacol Res. 2012;65:9–22.View ArticlePubMedGoogle Scholar
- Prieto PA, Yang JC, Sherry RM, et al. CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res. 2012;18:2039–47.View ArticlePubMedPubMed CentralGoogle Scholar
- Weber J. Ipilimumab: controversies in its development, utility and autoimmune adverse events. Cancer Immunol Immunother. 2009;58:823–30.View ArticlePubMedGoogle Scholar
- Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155–64.View ArticlePubMedGoogle Scholar
- Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24:2283–9.View ArticlePubMedPubMed CentralGoogle Scholar
- Maker AV, Phan GQ, Attia P, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;12:1005–16.View ArticlePubMedPubMed CentralGoogle Scholar
- Robinson MR, Chan CC, Yang JC, et al. Cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma: a new cause of uveitis. J Immunother. 2004;27:478–9.View ArticlePubMedGoogle Scholar
- Kaehler KC, Piel S, Livingstone E, et al. Update on immunologic therapy with anti-CTLA-4 antibodies in melanoma: identification of clinical and biological response patterns, immune-related adverse events, and their management. Semin Oncol. 2010;37:485–98.View ArticlePubMedGoogle Scholar
- Lecouflet M, Verschoore M, Giard C, et al. Orbital myositis associated with ipilimumab. Ann Dermatol Venereol. 2013;140:448–51.View ArticlePubMedGoogle Scholar
- McElnea E, Ni Mhealoid A, Moran S, et al. Thyroid-like ophthalmopathy in a euthyroid patient receiving Ipilimumab. Orbit. 2014;33:424–7.View ArticlePubMedGoogle Scholar
- Papavasileiou E, Prasad S, Freitag SK, et al. Ipilimumab-induced ocular and orbital inflammation-a case series and review of the literature. Ocul Immunol Inflamm. 2016;24:140–6.PubMedGoogle Scholar
- Sheldon CA, Kharlip J, Tamhankar MA. Inflammatory Orbitopathy Associated with Ipilimumab. Ophthal Plast Reconstr Surg 2015. PMID:26068559. [Epub ahead of print].
- Audemard A, de Raucourt S, Miocque S, et al. Melanoma-associated retinopathy treated with ipilimumab therapy. Dermatology. 2013;227:146–9.View ArticlePubMedGoogle Scholar
- Crosson JN, Laird PW, Debiec M, et al. Vogt-Koyanagi-Harada-like syndrome after CTLA-4 inhibition with ipilimumab for metastatic melanoma. J Immunother. 2015;38:80–4.View ArticlePubMedPubMed CentralGoogle Scholar
- Mantopoulos D, Kendra KL, Letson AD, Cebulla CM. Bilateral choroidopathy and serous retinal detachments during ipilimumab treatment for cutaneous melanoma. JAMA Ophthalmol. 2015;133:965–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Yeh OL, Francis CE. Ipilimumab-associated bilateral optic neuropathy. J Neuroophthalmol. 2015;35:144–7.PubMedGoogle Scholar
- Kahler KC, Hauschild A. Treatment and side effect management of CTLA-4 antibody therapy in metastatic melanoma. J Dtsch Dermatol Ges. 2011;9:277–86.PubMedGoogle Scholar
- Sanderson K, Scotland R, Lee P, et al. Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma. J Clin Oncol. 2005;23:741–50.View ArticlePubMedGoogle Scholar
- Weber J. Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events. Oncologist. 2007;12:864–72.View ArticlePubMedGoogle Scholar