Neuro-ophthalmic Complications of Immune Checkpoint Inhibitors: A Systematic Review

Figures & data

Figure 1 PRISMA chart for screening process, PRISMA figure adapted from Liberati A, Altman D, Tezlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10). Creative Commons.

Table 3 Summary of Cases – Neuromuscular

Author Year Ref	Age M/F	Cancer Type	ICI Name	Cycles and Duration Before Symptoms	Neuro-Ophthalmic Diagnosis	Concomitant Myositis, CK Levels (IU/L)	Ophthalmic Presentation	Treatment	ICI Continued/Held/Terminated	Neuro-Ophthalmic Outcome	Follow-up Period (Months)
Algaeed 2018^Citation51	73M	Melanoma	Pembrolizumab	NR cycles: then 3 weeks	MG	N	OS: ptosis	IVIg 2 g/kg daily, prednisone 60 mg daily, plasmapheresis 5 exchanges	NR	Improvement	5 weeks
Alnahhas 2016^Citation52	84M	Melanoma	Pembrolizumab	2 cycles: then 2 months	MG	N	OU: ptosis, ophthalmoplegia	Prednisone 60 mg daily, pyridostigmine 60 mg TID, and IVIg 0.4 g/kg/day for 5 days	Terminated	Death (hypercapnic respiratory failure)	3 days
Becquart 2019^Citation63	75F	Melanoma	Nivolumab	3 cycles (6 weeks)	MG	N	OU: diplopia, ptosis	Prostigmine 3 mg daily	Continued	Improvement, continued prostigmine	21
Chang 2017^Citation74	75M	Transitional cell carcinoma of bladder and ureter	Nivolumab	2 doses: then 3 weeks	MG	N	OU: diplopia, ptosis	Pyridostigmine 90 mg QID, and IVIg 0.4 g/kg daily over 5 days	Terminated	Improvement in 6 days, death (unknown cause) 10 days	10 days
Chen 2017^Citation85	57M	NSCLC	Nivolumab and ipilimumab	1 cycle ipilimumab, 2 cycles nivolumab: then 2 weeks	MG	Y, 2682	OD: ptosis	IV prednisolone 2 mg/kg daily for 5 days followed by 1 mg/kg daily for 2 days, po pyridostigmine 60 mg TID	Terminated	Improvement, death (pneumonia) 1 week	1 week
Chen 2017^Citation92	65M	NSCLC	Nivolumab	3 cycles: then 5 days	MG	Y, CK NR	OU: ptosis	Methylprednisolone 1 mg/kg daily and pyridostigmine 60 mg po BID	Terminated	Death (hypercapnic respiratory failure)	3 weeks
Cooper 2017^Citation93	68F	NSCLC	Nivolumab	5 cycles: then 1 month	MG exacerbation	N	OU: diplopia, ophthalmoplegia	Pyridostigmine and prednisone at 60 mg daily, 5 exchanges of plasmapheresis	Terminated	Minimal improvement, hospice care	18 days
Crusz 2018^Citation94	78M	Melanoma	Pembrolizumab	2 doses: then 6 days	MG	Y, 1109	OD: ptosis	IVIg, pyridostigmine, later mycophenolate + PLEX, later rituximab 1 g infusion	Terminated	Resolution	4
Dhenin 2019^Citation95	79F	Lung adenocarcinoma	Pembrolizumab	6 doses (22 weeks), then 3 months	MG	N	OU: ptosis	Pyridostigmine 60 mg, five times daily, IV methylprednisolone 80 mg daily	Completed	Resolution	3
Earl 2017^Citation96	74M	Melanoma	Pembrolizumab	2 doses: then 12 days	MG exacerbation	N	OD: impaired adduction, OU: ptosis, ophthalmoplegia	IVIg 2 g/kg total, prednisone 80 mg daily, mycophenolate 1500 mg BID, pyridostigmine 120 mg TID, plasmapheresis	Terminated	Minimal improvement, death (unknown cause)	NR
Fazel 2019^Citation53	78F	Melanoma	Ipilimumab and nivolumab	1 cycle: then 5 days	MG	Y (systemic myositis), CK NR	OU: diplopia, ptosis	IV methylprednisolone 1000 mg daily for 3 days, IVIg 2 g/kg daily for 2 days	Continued	Worsened, hospice care	8 days
Fellner 2018^Citation54	68M	Melanoma	Pembrolizumab	2 doses (5 weeks): then 2 weeks	MG	N	OS: ptosis, esophoria	Prednisone 10 mg daily then taper	Held	Resolution	6 weeks
Fukasawa 2017^Citation55	69F	Lung adenocarcinoma	Nivolumab	3 cycles: then 1 week	MG	N	OU: diplopia, OS: impaired adduction	Methylprednisolone 1 g for 3 days followed by 1 mg/kg daily	NR	Improvement, continued steroids	36 days
Gonzalez 2017^Citation56	71F	Uterine carcinosarcoma	Pembrolizumab	4 doses	MG	N	OU: diplopia, ptosis, OS: impaired abduction	po pyridostigmine up to 60 mg TID, prednisone 20 mg daily	Held	Resolution (3 weeks), death (cancer progression) 5 months	5
Hasegawa 2017^Citation57	76F	NSCLC	Nivolumab	2 doses: then 26 days	MG	Y, 6566	OU: diplopia, OS: ptosis	IVIg, PLEX 3 sessions, prednisolone 10 mg daily	Terminated	Improvement	85 days
Hibino 2018^Citation58	83M	Lung squamous cell carcinoma	Pembrolizumab	2 cycles (on day 38 of treatment)	MG	Y, 4361	OU, ptosis, ophthalmoplegia, diplopia	po pyridostigmine 60 mg TID for 7 days	NR	Improvement	3
Huh 2017^Citation59	34F	Thymic squamous cell carcinoma	Pembrolizumab	4 cycles	MG	Y, 2125	OU: ptosis, ophthalmoplegia	IVIg for 5 days, IV methylprednisolone 1 g daily for 3 days, prednisolone 1 mg/kg daily, then 5 cycles of plasmapheresis	Terminated	Improvement, ptosis resolved, ophthalmoplegia persisted	6
Johnson 2015^Citation60	69F	Melanoma	Ipilimumab	3 doses: then several days	MG	N	OU: diplopia, ptosis	Pyridostigmine 30 mg TID, then IV methylprednisolone 2 mg/kg and plasmapheresis, then 40 mg prednisone daily	NR	Improvement	3
Kim 2019^Citation61	76M	NSCLC	Nivolumab	4 doses: then 3 days	MG	Y, 2934	OD: ptosis, diplopia	IV methylprednisolone 1 mg/kg daily for 32 days, pyridostigmine 30 mg TID for 6 days and was increased to 60 mg TID, tapered to po prednisolone 40 mg BID	Completed	Improvement	8
Konstantina 2019^Citation62	30F	Type B3 thymoma	Pembrolizumab	1 dose: then 3 days	Myasthenic crisis	Y, CK NR	Unilateral ptosis, diplopia	Corticosteroids and pyridostigmine 400 mg/kg for 5 days, then rituximab 375/m^2 for 3 weeks	Terminated	Death (septic shock)	54 days
Lara 2019^Citation64	63F	NSCLC-adenocarcinoma	Pembrolizumab	2 cycles	MG	N	OU: ptosis, EOM palsies	IVIg, high-dose corticosteroid therapy, and pyridostigmine	Terminated	Improvement	NR
Lau 2016^Citation65	75M	Melanoma	Pembrolizumab	5 weeks	MG	N	OS: ptosis	IV methylprednisolone 1 g daily for 5 days, IVIg 0.5 g/kg daily for 4 days, discharged with prednisone 60 mg daily	Held	Resolution	4
Liao 2014^Citation66	70F	Melanoma	Ipilimumab	2 cycles: then 1 week	MG	Y, 1200	OU: ptosis	Plasmapheresis daily for 3 days, 125 mg IV methylprednisolone daily	Terminated	Improvement	2 weeks
Liu 2019^Citation67	73M	Melanoma	Pembrolizumab	2 doses: then <1 week	MG	N	OU: ptosis	IVIg 2 g/kg daily for 5 days, and IV methylprednisolone 1 g daily for 3 days	Terminated	Improvement	6 weeks
Loochtan 2015^Citation68	70M	SCLC	Ipilimumab	Day 16	MG	N	OU: diplopia, ptosis	Prednisone 1 mg/kg daily, followed by 3 sessions of plasmapheresis, prednisone 90 mg daily	Terminated	Death (septic shock, cardiac, ulcers)	22 days
Maeda 2016^Citation69	79M	Melanoma	Nivolumab	3 doses: day 106	MG exacerbation	Y, 1627	OU: diplopia	None	Held	Resolution (timing NR)	9
Mancano 2018^Citation70	76F	NSCLC	Nivolumab	2 doses: day 26	Myasthenic crisis	Y, 6566	OS: ptosis	IVIg for 2 days, then immunoadsorption plasmapheresis therapy and IVIg for 5 days, prednisolone 10 mg daily	NR	Improvement	65 days
March 2017^Citation71	63M	NSCLC	Pembrolizumab	1 dose: then 2 weeks	MG	Y, 10,386	OD: ptosis, blurry vision, periorbital edema with mild erythema	Pyridostigmine 120 mg q6 h and prednisone 60 mg daily, methylprednisolone 1 g daily for 9 days, 5 IVIg treatments, 4 plasmapheresis rounds	Terminated	Death (respiratory failure)	12 days
Mitsune 2018^Citation72	62M	Neuroendocrine carcinoma of trachea	Nivolumab	2 cycles: day 25	MG exacerbation	Y, 14,229	OU: diplopia, ptosis	IV methylprednisolone 2 mg/kg daily	Terminated	Resolution	60 days
Mohn 2019^Citation73	82M	Melanoma	Nivolumab	1 dose: then 8 weeks	MG	Y, 2000	OU: ptosis, ophthalmoplegia	IV methylprednisolone 1000mg daily for 5 days, then IVIg	Terminated	Improvement, death (blood loss) at 8 weeks	8 weeks
Mohn 2019^Citation73	87F	Melanoma	Nivolumab	1 dose: then 4 weeks	MG	Y, CK NR	OU: ptosis	Prednisolone 100mg daily	Terminated	Death (cause unknown)	12 days
Montes 2018^Citation75	74M	Melanoma	Ipilimumab	3 doses: then 1 day	MG	N	OU: diplopia, OD: ophthalmoplegia	High-dose corticosteroids and pyridostigmine	Terminated	Improvement, diplopia persisted, continued steroids	1
Nakatani 2018^Citation50	73F	Lung squamous cell carcinoma	Nivolumab	25 doses: at 51 weeks	Lambert–Eaton Myasthenic Syndrome	N	OU: photophobia, ptosis	po prednisolone 20 mg daily for 7 days, pyridostigmine and ambenonium, 3,4-DAP	Restarted then terminated	Improvement	16
Nguyen 2017^Citation76	81M	Melanoma	Pembrolizumab	3 cycles: then 2 weeks	MG	N	OU: ptosis	Prednisolone 25 mg daily then taper	Continued	Resolution	6
Nguyen 2017^Citation76	86F	Melanoma	Pembrolizumab	2 cycles	MG	N	OU: ptosis	IV methylprednisolone 500 mg daily for 5 days, then po prednisolone taper	Continued	Improvement	3
Onda 2019^Citation77	73M	Lung adenocarcinoma	Pembrolizumab	Day 23	MG	Y, 7311	OU: diplopia, ptosis, ophthalmoplegia	Prednisolone total 20 mg, methylprednisolone 1g daily for 3 days	NR	Resolution	4
Phua 2020^Citation78	66M	Lung adenocarcinoma	Durvalumab	5 doses: then 3 days	MG	Y, 499	OU: diplopia, ptosis	Prednisone 60 mg daily, pyridostigmine 120 mg TID, mycophenolate mofetil 1 g BID, IVIg 2 g/kg	Terminated	Improvement	2
Polat 2016^Citation79	65M	NSCLC	Nivolumab	3 doses: then 3 days	MG	N	OU: blurry vision, diplopia, ptosis	Pyridostigmine 45 mg q6 h for 6 weeks	Completed	Resolution (6 weeks)	4
Sciacca 2016^Citation80	81M	NSCLC	Nivolumab	3 cycles	MG	N	OU: blurry vision, diplopia, ptosis	Prednisone 50 mg daily for 4 weeks	Terminated	Resolution (4 weeks)	1
So 2019^Citation81	55F	Melanoma	Nivolumab	2 doses: then 1 day	Myasthenic crisis	Y, CK NR	OU: ptosis, ophthalmoplegia	IVIg 0.5 g/kg daily for 5 days, 4 cycles of steroid pulse, 2 cycles of PLEX	Terminated	Improvement	6
Takai 2020^Citation82	77M	Bladder cancer	Pembrolizumab	1 dose: then 20 days	MG	Y, 8574	OU: diplopia, ptosis	Prednisone 80 mg daily, IVIg at 0.4 g/kg daily for 5 days	Terminated	Death (cardiac arrest)	13 days
Tan 2017^Citation83	45M	NSCLC	Nivolumab	1 dose: then 2 weeks	MG	Y, CK NR	OU: ptosis, ophthalmoplegia	Pyridostigmine, methylprednisolone 1 g daily for 3 days, and IVIg 400 mg/kg daily for 5 days	Held for 5 months	Improvement	5
Tedbirt 2019^Citation84	77M	Melanoma	Pembrolizumab and nivolumab	4 doses	MG	N	OU: ptosis, visual disorders (unspecified)	IVIg 0.4 g/kg daily for 5 days, pyridostigmine 360 mg daily, prednisone 60 mg daily	Held for 5 months	Recurrence of myasthenic syndrome, improvement	29
Thakolwiboon 2019^Citation86	87M	Urothelial carcinoma	Atezolizumab	2 doses	MG	Y, 1542	OU: diplopia, ptosis	Prednisone 60 mg daily for 1 week, IVIg 0.4 g/kg daily, low-dose pyridostigmine	Terminated	Death (cardiac arrest)	10 days
Tozuka 2018^Citation87	82M	Pulmonary pleomorphic carcinoma	Pembrolizumab	3 cycles: then 44 days	MG with agranulocytosis	N	OU: diplopia	Pyridostigmine 60 mg TID	Terminated	NR	NR
Veccia 2020^Citation88	65M	Lung squamous cell carcinoma	Nivolumab	2 doses: day 27	MG	Y, 3844	OU: diplopia, OD: ptosis	IVIg 0.4 mg/kg daily for 5 days, pyridostigmine 60 mg daily for 1 week, IV dexamethasone 8 mg BID, prednisone 1 mg/kg daily	Terminated	Worsened, death	7 weeks
Werner 2019^Citation89	62M	Melanoma	Nivolumab and ipilimumab	2 doses: then 1 week	MG	N	OD: ptosis	Pyridostigmine 300 mg daily, prednisone 20 mg daily	Held for 6 weeks	Resolution (6 weeks)	2
Wilson 2018^Citation91	57M	Lung adenocarcinoma	Pembrolizumab	4 weeks	MG	N	OU: ptosis, ophthalmoplegia	Corticosteroids and pyridostigmine 400 mg/kg daily for 5 days, followed by rituximab 375 mg/m^2 for 3 weeks	Terminated	Resolution, death (cancer progression)	6
Wilson 2018^Citation91	62F	Melanoma	Nivolumab and ipilimumab	4 weeks	MG	N	OU: ptosis	Pyridostigmine and corticosteroids	Terminated	Resolution	12
Xing 2020^Citation90	66M	Lung adenocarcinoma	Sintilimab	2 doses: then 4 days	Myasthenic crisis	Y, 11,919	OU: ptosis, ophthalmoplegia	Pyridostigmine bromide 120 mg BIG, IV methylprednisolone 2 mg/kg daily, IVIg 400 mg/kg daily for 5 days, PLEX	Terminated	Improvement	3

Abbreviations: NSCLC, non-squamous cell lung cancer; OU, both eyes; OD, right eye; OS, left eye; IV, intravenous; po, per os; IVIg, intravenous immunoglobulin; NR, not reported; PLEX, plasma exchange; BID, twice daily; TID, three times daily; QID, four times daily; MG, myasthenia gravis.

Table 4 Summary of Cases— Orbit

Author Year Ref	Age M/F	Cancer Type	ICI Name	Cycles and Duration Before Symptoms	Neuro-Ophthalmic Diagnosis	For Myositis: EOMs Normal or Abnormal Size	Ophthalmic Presentation	Treatment	ICI Continued/Held/Terminated	Neuro-Ophthalmic Outcome	Follow-up Period (Months)
Borodic 2011^Citation100	51F	Melanoma	Ipilimumab	2 infusions	TED^a		OU: diplopia, proptosis	Cantholysis, corticosteroids	NR	Resolution	NR
Campredon 2018^Citation101	61M	NSCLC	Nivolumab	3 infusions	TED		OU: ptosis, conjunctival injection with chemosis, proptosis, ophthalmoplegia	IV methylprednisolone 1 g for 2 weeks, 500 mg for 4 weeks, and 250 mg for 5 weeks	Terminated	Improvement of chemosis, ptosis and ophthalmoplegia unchanged, death (massive hemoptysis)	13 weeks
McElnea 2014^Citation104	68F	Melanoma	Ipilimumab	3 cycles (4 doses each): then 5 weeks	TED		OU: ophthalmoplegia	IV methylprednisolone 1 g for 5 days and po prednisolone 60 mg daily for 1 week then taper	Terminated	Improvement	6 weeks
Min 2011^Citation105	51F	Melanoma	Ipilimumab	4 doses (8 weeks)	TED^a		OU: eye pain, proptosis, conjunctival injection, periorbital edema	IV methylprednisolone 250 mg q6h for 12 doses, prednisone 100 mg BID then taper	NR	Improvement	12
Park 2018^Citation107	52M	Merkel cell carcinoma	Pembrolizumab	3 doses (6 weeks)	TED^a (euthyroid)		OU: diplopia, proptosis	Prednisone daily, ocular lubricants and po atenolol, Fresnel prisms (diplopia)	Terminated	Improvement	3
Rhea 2018^Citation106	83M	Melanoma	Ipilimumab and pembrolizumab	1 infusion of ipilimumab: then 3 days; 1 infusion of pembrolizumab: then 1 day	TED^a		OU: diplopia, blurry vision, proptosis, chemosis	Prednisone 60 mg daily	Continued	Resolution then recurrence	10
Ricciuti 2017^Citation102	63F	Non-squamous non-small-cell lung cancer	Nivolumab	6 cycles: then 7 months	TED		OU: diplopia, blurry vision, ophthalmoplegia, exophthalmos	High-dose steroids	Held for 6 months	Resolution	6
Sabini 2018^Citation108	70M	Lung adenocarcinoma	Tremelimumab and durvalumab	1 month	TED^a		OU: diplopia, exophthalmos, ophthalmoplegia	Prednisone 25 mg daily then taper	Terminated	Persistent bilateral orbitopathy with primary gaze diplopia and ophthalmoplegia	6
Sagiv 2019^Citation103	42M	Renal cell carcinoma	Nivolumab	4 doses (2 months)	TED		OU: diplopia, eyelid retraction	NR	Continued	Resolution	24
Sagiv 2019^Citation103	51M	Melanoma	Tremelimumab	6 months	TED^a		OU: diplopia, periocular swelling and erythema, exophthalmos.	Methylprednisolone 125 mg daily then taper	Continued	Resolution	3
Bitton 2019^Citation109	80M	NSCLC	Pembrolizumab	2 infusions: then 1 day	Orbital myositis	NR	OU: ptosis, ophthalmoplegia OD ophthalmoplegia OS	Systemic corticosteroid 1 mg/kg daily, IVIg 2 g/kg daily, methotrexate 15 mg per week	Terminated	Resolution	6
Haddox 2017^Citation111	78M	Melanoma	Pembrolizumab	2 cycles: then 2 weeks	Orbital myositis	NA	OU: ptosis, ophthalmoplegia	Prednisone 1 mg/kg, after 1 week: PLEX	Terminated	Worsened, death (respiratory failure)	3 days
Henderson 2015^Citation112	55M	Melanoma	Ipilimumab	3 cycles	Orbital myositis	Abnormal size	OU: burning, injection, FB sensation, photophobia, diplopia, chemosis, ophthalmoplegia, ptosis, periorbital edema	Prednisone	Terminated	Improvement with persistent abduction deficit OS and binocular diplopia	NR
Kamo 2019^Citation113	78M	Renal, pelvis, and ureter cancer	Pembrolizumab	NR	Orbital myositis	Abnormal size	OU: ophthalmoplegia, ptosis	IV methylprednisolone, PLEX	Terminated	Improvement, death (cancer progression)	NR
Kamo 2019^Citation113	72F	Lung cancer	Pembrolizumab	NR	Orbital myositis	Abnormal size	OU: ophthalmoplegia, OD: ptosis	Prednisone 0.5 mg/kg daily then taper	NR	Resolution	NR
Liewluck 2018^Citation114	78M	Melanoma	Pembrolizumab	2 cycles (28 days)	Orbital myositis	Normal size (assumed)	OU: diplopia, proptosis	Prednisone, PLEX	Terminated	Death (respiratory failure)	NR
Liewluck 2018^Citation114	68M	Gastroesophageal adenocarcinoma	Pembrolizumab	2 cycles (30 days)	Orbital myositis	Abnormal size	OU: diplopia, proptosis	IV methylprednisolone, prednisone, and PLEX	Terminated	Resolution	NR
Liewluck 2018^Citation114	55M	Non-Hodgkin's lymphoma	Pembrolizumab	4 cycles (72 days)	Orbital myositis	NR	OU: diplopia	Prednisone	Terminated	Resolution	NR
Nardin 2018^Citation115	68M	Melanoma	Ipilimumab	51 cycles (3 years)	Orbital myositis	Abnormal size	OU: diplopia, eyelid swelling and retraction, proptosis, ophthalmoplegia, OD: retro-orbital pain, redness	IV methylprednisolone 500 mg weekly for 3 months, then prednisone 1 mg/kg daily	Terminated	Resolution	10
Nasr 2018^Citation116	79M	Gastric adenocarcinoma	Pembrolizumab	2 doses: then 2 weeks	Orbital myositis	Abnormal size	OU: ptosis, ophthalmoplegia	IV prednisone 1 mg/kg daily, IVIg 2 mg/kg for 4 days, pyridostigmine 10 mg daily	Terminated	No improvement, death (cause NR)	NR
Patel 2016^Citation110	39M	Melanoma	Ipilimumab	4 cycles: then 4 days	Orbital myositis	Abnormal size	OU: blurry vision, diplopia	Prednisone up to 125 mg daily, later IV steroids	NR	Resolution	3
Pushkarevskaya 2017^Citation117	60F	Melanoma	Ipilimumab	2 cycles (4 doses each): then 2 months	Orbital myositis	Abnormal size	OU: ptosis, ophthalmoplegia	IV methylprednisolone, mycophenolate mofetil 3 g daily, IVIg 2 g/kg monthly	Terminated	Improvement with minor difficulties with distant vision	11
Pushkarevskaya 2017^Citation117	60F	Melanoma	Ipilimumab	2 cycles: then 2 weeks	Orbital myositis	Abnormal size	OU: ophthalmoplegia, blurry vision, diplopia	Prednisolone up to 160 mg daily, then mycophenolate mofetil 3g daily	Continued	Resolution	3
Sagiv 2019^Citation103	73M	Bladder urothelial carcinoma	Nivolumab and ipilimumab	3 doses	Orbital myositis	NR	OU: diplopia, periocular pain, ophthalmoplegia, exophthalmos, conjunctival injection, eyelid edema and erythema	Methylprednisolone 1g daily for 3 days, 80mg prednisone BID then tapered to 60 mg daily	Continued	Resolution (2 weeks), death (cancer progression, 1 months)	1
Valenti-Azcarate 2020^Citation118	66M	NSCLC	Nivolumab and Ipilimumab	2 cycles (4 weeks)	Orbital myositis	NR (MRI showed “inflammation” did not specify which muscle)	OU: diplopia	IV prednisolone 2 mg/kg daily	Continued	Improvement, death (cancer progression)	2
Williams 2020^Citation119	69M	Prostate adenocarcinoma	Nivolumab and Ipilimumab	2 cycles	Orbital myositis	Normal size	OS: ptosis	IV methylprednisolone 1 g daily, plasmapheresis, IVIg 4 cycles, and mycophenolate mofetil	Terminated	Resolution (6 months), death (cancer progression)	12
Hassanzadeh 2017^Citation120	64F	Melanoma	Ipilimumab	NR	Orbital apex syndrome		OD: vision loss, right RAPD, proptosis, ptosis, ophthalmoplegia	IV methylprednisolone 1 g daily for 7 days, then taper prednisone 1mg/kg	Terminated	Persistent esotropia on prednisone 10 mg daily	6
Voskens 2013^Citation22	65M	Melanoma	Ipilimumab	1 dose: then 18 weeks	Tolosa–Hunt Syndrome		Unilateral headache, OU: diplopia, OD: pain, epiphora, mydriasis, ptosis, paresis of oculomotor nerve	IV methylprednisolone, oral dexamethasone, local radiotherapy (10⨰3 Gy)	Terminated	Improvement of pain and paresis, visual disturbance persisted	NR

Note: ^aAssociated with Graves’ disease.

Abbreviations: NSCLC, non-squamous cell lung cancer; OU, both eyes; OD, right eye; OS, left eye; IV, intravenous; po, per os; IVIg, intravenous immunoglobulin; NR, not reported; PLEX, plasma exchange; BID, twice daily; TID, three times daily; QID, four times daily; TED, thyroid-like eye disease.

Table 5 Summary of Cases— Giant Cell Arteritis

Author Year Ref	Age M/F	Cancer Type	ICI Name	Cycles and Duration Before Symptoms	Neuro-Ophthalmic Diagnosis	Ophthalmic Presentation	Treatment	ICI Continued/Held/Terminated	Outcome and Follow-up Period	Follow-up Period (Months)
Betrains 2020^Citation121	72F	Melanoma	Nivolumab	30 cycles	GCA	Blurry vision, proximal myalgia, frontal headache, temporal artery tenderness, jaw claudication	Prednisolone 1 mg/kg then taper	Held	Resolution (timeline NR)	12
Chow 2020^Citation122	69M	Pleural mesothelioma	Nivolumab and ipilimumab	5 months (weekly treatment)	GCA	1st visit: blurry vision, fatigue, myalgia; 2nd visit: diplopia, scalp tenderness, jaw claudication; 3rd visit: transient amaurosis fugax	High dose prednisolone	Terminated at 8 months	Resolution (4 days)	10
Goldstein 2014^Citation123	62M	Melanoma	Ipilimumab	5 cycles: then 1 week	GCA	Transient diplopia, amaurosis fugax, occipital headache, scalp tenderness, jaw claudication, proximal myalgia	Prednisone 60 mg daily	Completed	Resolution (2 days)	6
Hid Cadena 2018^Citation124	70M	Melanoma	Nivolumab or ipilimumab (clinical trial), then another ICI	9 months	GCA	Scalp tenderness, jaw claudication, proximal myalgia, no visual complaints	Prednisolone 60 mg daily then taper	Terminated, then started on another ICI	Persistence of low-grade symptoms	13
Micaily 2017^Citation125	88F	NSCLC	Pembrolizumab	1 dose: then 1 week	GCA	OS: sudden onset blindness	High dose prednisone	Held	Resolution (timeline NR)	NR

Abbreviations: NSCLC, non-squamous cell lung cancer; OS, left eye; IV, intravenous; GCA, giant cell arteritis.

Table 1 Summary of Observational Studies or Clinical Trials

Author Year Ref	Purpose	Cancer Type		ICI Name	Diagnosis	Prevalence
Camacho 2009^Citation21	Phase I and II study on safety of tremelimumab	Metastatic melanoma		Tremelimumab	Thyroid-like eye disease	1 of 28 patients in phase I
Voskens 2013^Citation22	Retrospective chart review on prevalence of IRAEs for ipilimumab	Metastatic melanoma		Ipilimumab	Tolosa–Hunt Syndrome	1 of 752
Weber 2013^Citation31	Phase I study evaluating safety and IRAEs of nivolumab with peptide vaccine in ipilimumab—refractory or —naïve melanoma	Unresectable stage III or IV melanoma		Nivolumab	Optic neuritis	1 of 90
Hodi 2014^Citation32	Phase I study on safety of bevacizumab plus ipilimumab inpatients with metastatic melanoma	Metastatic melanoma		Ipilimumab + bevacizumab	Giant cell arteritis	1 of 46
Balar 2017^Citation33	Phase II Study (KEYNOTE-052) evaluating safety of pembrolizumab in cisplatin-ineligible patients with urothelial cancer	Advanced urothelial cancer		Pembrolizumab	Eyelid ptosis	1 of 370
Diehl 2017^Citation34	Retrospective chart review on relationship between absolute lymphocyte counts and risk of IRAEs	Lung cancer, melanoma, RCC, urothelial, HNSCC, Merkel cell carcinoma, and colon cancer		Nivolumab or pembrolizumab	Optic neuritis	1 of 167
Suzuki 2017^Citation35	Safety databases based on postmarketing surveys in Japan investigating clinical features of myasthenia gravis induced by ICIs compared to idiopathic myasthenia gravis	Melanoma, NSCLC, and colon cancer		Nivolumab or ipilimumab	Myasthenia gravis with myositis and myocarditis	12 of 10,277, including 4 with concurrent myositis
Omuro 2018^Citation36	Phase I study (CheckMate 143) evaluating safety and IRAEs of nivolumab ± ipilimumab for glioblastoma	Glioblastoma		Nivolumab ± ipilimumab	Optic neuritis	2 of 40
Touat 2018^Citation37	Retrospective chart review on myositis for all ICIs, multicenter	Melanoma, NSCLC, breast cancer, and renal cell cancer		Nivolumab, pembrolizumab, durvalumab, or ipilimumab	Myocarditis and myositis	10 cases of myositis
Kao 2017^Citation38	Retrospective cohort study on prevalence of neurological complications in all patients receiving anti-PD-1 therapy at one centre	Malignant melanoma and other solid-organ tumors		Pembrolizumab or nivolumab	Necrotizing myopathy, bilateral internuclear ophthalmoplegia	1 of 347 necrotizing myopathy, 1 of 347 bilateral internuclear ophthalmoplegia
Kaur 2019^Citation23	Retrospective chart review on IRAEs at one centre for all ICIs	Melanoma, NSCLC, renal cell carcinoma, bladder cancer, clear cell sarcoma, Hodgkin’s lymphoma, gastric adenocarcinoma, and squamous cell cancer	Pembrolizumab, nivolumab, ipilimumab, or combination therapy with nivolumab and ipilimumab		Optic neuritis	1 of 220
Mancone 2018^Citation24	Retrospective chart review on prevalence of neurologic IRAEs at one centre	Squamous cell lung carcinoma	Nivolumab		Oculomotor nerve palsy	1 of 526
Johnson 2019^Citation25	Disproportionality analysis using pharmacovigilance database to compare neurologic IRAEs in patients receiving ICI vs control	Lung cancer, melanoma, and other cancers	Nivolumab, pembrolizumab, atezolizumab, other anti-PD-1/PD-L1, anti CTLA-4 drugs, or combination of drugs		Myasthenia gravis	228 of 48,653
Kim 2019^Citation26	Retrospective chart review on ophthalmic IRAEs at one centre	Metastatic cutaneous melanoma, uveal melanoma, NSCLC	Nivolumab ± ipilimumab		Optic neuritis	1 of 1474
Moreira 2019^Citation27	Retrospective chart review on autoimmune neurological IRAEs at one centre for all ICIs	Metastatic skin cancers	Ipilimumab, tremelimumab, nivolumab, or pembrolizumab		All neurologic complications including myositis, myasthenia gravis (ocular involvement unknown)	38 cases of autoimmune neurological disorders
Safa 2019^Citation28	Retrospective chart review on myasthenia gravis at one center for all ICIs	Metastatic melanoma and other cancers	Nivolumab, pembrolizumab, ipilimumab, or other ICIs		Myasthenia gravis	63 of 5898, including 24 with concurrent myositis
Seki 2019^Citation29	Retrospective cohort study on inflammatory myopathy associated with PD-1 inhibitors	NSCLC and other cancers	Nivolumab or pembrolizumab		Myositis with ocular involvement	Of 19 cases of inflammatory myopathy, 13 had diplopia and 15 had ptosis
Williams 2019^Citation30	Retrospective chart review of patients receiving ICIs to evaluate corticosteroid use in management of IRAEs at one centre	Melanoma, lung cancer, RCC, HNSCC, and other cancers	Nivolumab, ipilimumab, or pembrolizumab		Optic neuritis	3 of 103

Abbreviations: IRAEs, immune-related adverse effects; ICI, immune checkpoint inhibitors; PD-1, programmed death-1 receptor; NSCLC, non-squamous cell lung cancer; RCC, renal cell carcinoma; HNSCC, head and neck squamous cell carcinoma.

Table 2 Summary of Cases—Optic Neuritis or Neuroretinitis

Author Year Ref	Age M/F	Cancer Type	ICI Name	Cycles and Duration Before Symptoms	Neuro-Ophthalmic Diagnosis	Ophthalmic Presentation	Treatment	ICI Continued/Held/Terminated	Neuro-Ophthalmic Outcome	Follow-up Period (Months)
Boisseau 2017^Citation42	27F	Renal cell carcinoma	Ipilimumab	5 cycles: then 5 weeks	Optic neuritis	OU: vision loss and optic disc edema	IV methylprednisolone 1 g daily for 3 days then po steroid taper, PLEX 10 sessions	Held	Resolution (1 month)	6
Francis 2020^Citation43	61F	Melanoma	Ipilimumab	3 cycles	Optic neuritis	OU: vision loss and optic disc edema	Prednisone 80 mg with taper, topical prednisolone, timolol/dorzolamide	Terminated	Cecocentral detect OD	33
Francis 2020^Citation43	71M	NSCLC	Pembrolizumab	3 cycles	Optic neuritis	OU: vision loss and optic disc edema/pallor	IV methylprednisolone 1 g daily for 5 days, prednisone 80 mg with taper	Terminated	Disc pallor with resolved edema, thinning OU	7
Francis 2020^Citation43	58M	Small-cell lung carcinoma	Ipilimumab and nivolumab	4 cycles	Optic neuritis	OU: vision loss	IV methylprednisolone 1 gx5 days and 5 PLEX, prednisone 50 mg with taper over 6 months	Terminated	Pink OD, 4+ pallor OS	6
Hahn 2015^Citation48	44M	Melanoma	Ipilimumab	3 infusions then 2 months	Neuroretinitis	OD metamorphopsia, OS scotoma, OU: eye pain, redness, photophobia, optic disc edema	Prednisone 80 mg, gtts: prednisolone 1%, brimonidine 0.2%, timolol 0.5% TID OU	Terminated	Resolution (2 months)	2
Kartal 2018^Citation45	9M	Glioblastoma multiforme	Nivolumab	2 cycles: then 2 days	Optic neuritis	OU: decreased vision, optic disc edema	IV corticosteroids 1 g daily for 5 days	Terminated	Improvement	1 week
Kaur 2019^Citation23	27F	Melanoma	Ipilimumab	4 cycles	Optic neuritis	NR	Corticosteroids	Continued	Improvement	NR
Kim 2019^Citation26	61F	Melanoma	Ipilimumab and nivolumab	4 cycles of combination, 1 cycle of nivolumab monotherapy	Optic neuritis	OU: decreased VF, optic disc edema	IVIg and infliximab	Terminated	Death (cancer progression)	18
Mori 2018^Citation46	64M	NSCLC	Atezolizumab	NR cycles: then 12 months	Optic neuritis	OS: sudden vision loss, optic disc edema, venous congestion without bleeding	IV methylprednisolone 1 g for 3 days followed by 30 mg po prednisolone administration	NR	Resolution (24 months)	24
Noble 2019^Citation11	65M	Prostate cancer	Durvalumab	NR	Optic neuritis	OS: inferior scotoma with central sparing, EOM discomfort, optic disc edema	IV corticosteroid bolus	Continued	Improvement	NR
Samanci 2019^Citation47	53M	Lung adenocarcinoma	Atezolizumab	1 cycle: then 20 days	Optic neuritis	OU: blurry vision, optic disc edema	IV methylprednisolone 2 mg/kg followed by po methylprednisolone	Terminated	Resolution (1 month)	1
Sun 2008^Citation39	72M	Bladder cancer	Ipilimumab	1 dose: then 3 weeks	Optic neuritis	OU: vision loss, optic disc edema	IV dexamethasone 20 mg, then IV methylprednisolone 250 mg q6 h, later prednisone 100 mg daily then taper	Terminated	Improvement	24 weeks
Sun 2020^Citation40	43M	Melanoma	Pembrolizumab	NR	Optic neuritis	NR	NR	NR	NR	NR
Wilson 2016^Citation41	53M	Melanoma	Ipilimumab	3 cycles: 4 months after start	Optic neuritis	OS: no light perception, optic disc edema, retinal whitening	Prednisone, methylprednisolone, mycophenolate mofetil with prednisone, plasmapheresis	Held	Resolution (15 months)	17
Yeh 2015^Citation44	67M	Melanoma	Ipilimumab	3 infusion: then 3 weeks	Optic neuritis	OU: left VF vision loss, photopsia, blurry vision, optic disc edema; OD reduced color vision	gtts: prednisolone and atropine OU	Terminated	Normal visual acuity, persistent VF defects	6

Abbreviations: NSCLC, non-squamous cell lung cancer; OU, both eyes; OD, right eye; OS, left eye; IV, intravenous; po, per os; IVIg, intravenous immunoglobulin; NR, not reported; PLEX, plasma exchange; BID, twice daily; TID, three times daily; QID, four times daily.

Table 6 Summary of Cases— Other

Author Year Ref	Age M/F	Cancer Type	ICI Name	Cycles and Duration Before Symptoms	Neuro-Ophthalmic Diagnosis	For Myositis: EOMs Normal or Abnormal Size	Ophthalmic Presentation	Treatment	ICI Continued/Held/Terminated	Neuro-Ophthalmic Outcome	Follow-up Period (Months)
Maller 2018^Citation134	74M	Epithelioid mesothelioma	Ipilimumab and nivolumab	2 ipilimumab and 5 nivolumab infusions: then 10 weeks	Opsoclonus-myoclonus-ataxia syndrome		OU: involuntary and conjugate horizontal eye movements	IV methylprednisolone 1 g daily, IVIg 0.4 g/kg daily for 5 days, prednisone taper	Completed	Resolution	8 weeks
Alnabulsi 2018^Citation130	67M	Melanoma	Ipilimumab and nivolumab	Day 10	Myositis	Normal size	OU: ptosis, ophthalmoplegia	IV methylprednisolone up to 1 g daily IVIg 81 mg for 2 doses, IV infliximab 400 mg for 1 dose	Terminated	No improvement, death (cardiac arrest, multi-organ failure)	NR
Bourgeois-Vionnet 2018^Citation126	79NR	Lung adenocarcinoma	Nivolumab	2 injections: then 1 week	Myositis	Normal size (assumed)	OU: ptosis	IVIg, po corticosteroids 1 mg/kg daily for 6 months	Terminated	Resolution	6
Carrera 2017^Citation131	68M	NSCLC	Tremelimumab and durvalumab	2 doses: then 4 days	Myositis	NR	OU: diplopia, OS: hypertropia, ptosis	60 mg prednisone then taper	Terminated	Resolution (1 month)	6
Diamantopoulos 2017^Citation129	82M	Melanoma	Pembrolizumab	1 infusion: then 15 days	Myositis	NR	OS: ptosis, miosis, OU: diplopia	Prednisolone 75 mg, IVIg 0.3 g/kg daily, plasmapheresis	Terminated	Improvement, death (respiratory failure)	34 days
Hamada 2018^Citation128	83M	Lung adenocarcinoma	Pembrolizumab	2 cycles: then 1 week	Myositis	NR	OD: ptosis	Systemic prednisone 40 mg/day	Terminated	Resolution	2
Hellman 2019^Citation127	83M	Urothelial carcinoma	Pembrolizumab	2 cycles	Myositis	NR	OU: ptosis, ophthalmoplegia	Prednisone 1 mg/kg daily, later IV methylprednisolone	Terminated	Improvement, death (pneumothorax)	33 days
Kang 2018^Citation133	75M	HNSCC	Nivolumab	1 infusion: then 3 weeks	Myositis	Normal size (assumed)	OU: ptosis	IV methylprednisolone 80 mg daily for 3 weeks, then prednisone 100 mg daily, plasmapheresis, a trial of pyridostigmine 60 mg	Terminated	No improvement, death (cardiac arrest)	2
Khoo 2019^Citation132	80F	Urothelial cancer	Atezolizumab	8 weeks	Myositis	Normal size (assumed)	OU: ptosis	IV methylprednisolone 1 g daily for 3 days, IVIg 2 g/kg total dose, po prednisolone slow taper	Terminated	Improvement with residual ptosis	3
Kao 2017^Citation38	Age NR, F	Leiomyosarcoma	Nivolumab	3 cycles	Internuclear ophthalmoplegia		OU: internuclear ophthalmoplegia	Corticosteroid (dose NR) for 1 week	Continued	Improvement	NR
Mancone 2018^Citation24	75M	Lung squamous cell carcinoma	Nivolumab	3 cycles	Oculomotor nerve palsy		OU: diplopia, OD: ptosis	Prednisone taper	Terminated	Resolution	NR

Abbreviations: NSCLC, non-squamous cell lung cancer; HNSCC, head and neck squamous cell carcinoma; OU, both eyes; OD, right eye; OS, left eye; IV, intravenous; po, per os; IVIg, intravenous immunoglobulin; NR, not reported; PLEX, plasma exchange; BID, twice daily; TID, three times daily; QID, four times daily; TED, thyroid-like eye disease.

Table 7 Breakdown of Neuro-ophthalmic Diagnoses. Excludes Pharmacovigilance or Observational Trials That Do Not Include Details of the Patients

Neuro-ophthalmic primary diagnosis	N	% of Total (n=109)
Optic neuritis	14	12.8
Neuroretinitis	1	0.9
Myasthenia gravis^*	49	45.0
Lambert-Eaton myasthenic syndrome gravis^*	1	0.9
Orbital myositis	15	13.8
Thyroid-like eye disease	13	11.9
Giant cell arteritis	4	3.7
General myositis^*	8	7.3
Internuclear ophthalmoplegia	1	0.9
opsoclonus-myoclonus-ataxia syndrome	1	0.9
Oculomotor nerve palsy	1	0.9

Note: ^*With ocular involvement.

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