Neuro-ophthalmic complications of immune checkpoint inhibitors

Key Points at a Glance

Key Points of This Disease

• The incidence of neuro-ophthalmic complications from immune checkpoint inhibitors (ICIs) is approximately 0.46%, which is rare but can lead to severe visual impairment.
• The five main manifestations are optic neuropathy, orbital inflammatory disease, thyroid eye disease (TED), giant cell arteritis (GCA), and myasthenia gravis (MG).
• ICI-related optic neuritis may present atypically, with only 10% of patients experiencing painful vision loss.
• Decisions to continue, interrupt, or discontinue ICI are based on CTCAE grade classification, but 62% of patients discontinue ICI due to neuro-ophthalmic complications.
• Steroids are the mainstay of treatment for ocular irAEs caused by ICI, but MG and giant cell arteritis require urgent and rapid management.
• Ocular immune privilege (blood-retinal barrier) limits ICI penetration into the eye, but its disruption can allow inflammation to spread.

1. What are neuro-ophthalmic complications of immune checkpoint inhibitors?

Immune checkpoint inhibitors (ICIs) are monoclonal antibody drugs for malignant tumors that activate the immune system to target cancer cells. Side effects mainly manifest as the onset or reactivation of autoimmune diseases due to excessive immune activation, collectively termed immune-related adverse events (irAEs).

Neuro-ophthalmic complications have been reported with an incidence of 0.46% in a review of 109 patients, making them a rare category among ocular irAEs caused by ICIs. The most commonly associated ICI is pembrolizumab (32% of cases), and the most frequent treatment indication was cutaneous melanoma (44%). The overall incidence of ocular irAEs is 1–3%, but posterior segment inflammation accounts for only about 5–20% of ocular cases, yet it is more severe and carries a higher risk of visual impairment ¹⁾.

Currently, nine ICIs are approved, classified into three target molecules (CTLA-4, PD-1/PD-L1, and LAG-3).

A list of approved ICIs is shown below.

Drug Class	Generic Name	Approval Year
CTLA-4 inhibitor	Ipilimumab / Tremelimumab	2011 / 2022
PD-1 inhibitor	Pembrolizumab / Nivolumab / Cemiplimab	2014 / 2014 / 2018
PD-L1 inhibitor	Atezolizumab / Avelumab / Durvalumab	2016 / 2017 / 2017
LAG-3 inhibitor	Relatlimab	2022

Neurological ophthalmic manifestations may also be due to the underlying malignancy or other treatments, making differential diagnosis important.

Q How often do neuro-ophthalmic complications occur with immune checkpoint inhibitors?

A

In a review of 109 patients, the incidence after ICI therapy was reported as 0.46%. The most commonly associated ICI is pembrolizumab (32%), and among indicated diseases, melanoma (44%) is the most frequent. Since neuro-ophthalmic complications are rare, detailed characterization of risk factors is challenging.

2. Main symptoms and clinical findings

Subjective symptoms

Subjective symptoms of neuro-ophthalmic complications due to ICIs vary depending on the affected anatomical site.

• Decreased visual acuity: Unilateral or bilateral. Prominent in optic neuropathy and giant cell arteritis.
• Diplopia: Associated with ocular muscle palsy due to orbital inflammation, myasthenia gravis, or giant cell arteritis.
• Ptosis: Main symptom of myasthenia gravis. Characterized by variability.
• Proptosis: Seen in orbital inflammation and thyroid eye disease.
• Ocular pain: Prominent in orbital inflammation. Ocular movement pain occurs in only 10% of ICI-related optic neuritis.
• Temporal headache and jaw claudication: Characteristic symptoms of giant cell arteritis.

Clinical Findings (5 Major Neuro-Ophthalmic Manifestations)

Neuro-ophthalmic complications from ICIs are classified into five major manifestations.

Optic Neuropathy

Reported as optic neuritis or non-arteritic anterior ischemic optic neuropathy (NAION). Most cases of immune checkpoint inhibitor-associated optic neuritis are related to ipilimumab.

Atypical presentation: In a retrospective review of 11 patients, only 10% had painful vision loss, 67% had color vision abnormalities, 36% were unilateral, and 40% had abnormal MRI findings.

Onset timing: Use of multiple ICIs is a risk factor for early onset (median 4 cycles). The latest onset was at 95 cycles.

Orbital Inflammatory Disease

Inflammation of the orbit, orbital apex, and cavernous sinus. Primarily associated with anti-CTLA-4 inhibitors (ipilimumab)²⁾.

Onset: Appears after the first infusion to several cycles later (2 days to 2 months)²⁾. Usually bilateral, and may be accompanied by malaise, fever, systemic myositis, and myocarditis²⁾.

Imaging findings: Gadolinium enhancement on MRI. Ranges from mass lesions to enlargement of extraocular muscles²⁾.

Thyroid Eye Disease and Giant Cell Arteritis

Thyroid eye disease (TED): Antibody-mediated. Activation of orbital fibroblasts leads to hypertrophy of extraocular muscles, sparing the tendon insertions. The inferior rectus and medial rectus are affected early. Occurs independently of thyroid hormone status. Association with CTLA-4 +49A/G polymorphism has been suggested.

Giant cell arteritis (GCA): Vasculitis of large vessels. Main symptoms include temporal artery tenderness, jaw claudication, and visual impairment. There are cases confirmed by biopsy.

Myasthenia gravis

Autoimmune disease of the neuromuscular junction. The prevalence of ICI-associated generalized MG is approximately 0.24%, with a strong association with PD-1 inhibitors.

Ocular symptoms: Ptosis 75%, diplopia 42%. Cogan’s lid twitch and pseudoretraction of the eyelid may be observed.

Onset: Median time to symptom onset is 29 days. Onset may occur up to 3 months after the last ICI dose.

Q How does ICI-associated optic neuritis differ from typical optic neuritis?

A

Typical optic neuritis presents with painful vision loss, eye movement pain, and color vision abnormalities, but ICI-associated optic neuritis shows atypical presentations: only 10% have painful vision loss, 36% are unilateral, and 40% have MRI abnormalities. It is most commonly associated with ipilimumab.

3. Causes and Risk Factors

Mechanism of Immune Checkpoint Inhibition

The mechanism of action of ICIs causes overactivation of the immune system, forming the basis of irAEs.

• CTLA-4 pathway: The “priming phase” in lymph nodes. It binds to B7 with higher affinity than CD28, suppressing T cell activation. CTLA-4 inhibitors (ipilimumab) release this suppression.
• PD-1/PD-L1 pathway: The “effector phase” in peripheral tissues. It releases the suppression of activated T cells.
• LAG-3 pathway: Expressed on the surface of effector T cells and regulatory T cells. Involved in regulating the T cell-APC pathway.

Risk Factors

• Combination of multiple ICIs: Risk factor for early onset (median onset at the 4th cycle).
• Genetic predisposition: Host HLA type may contribute to susceptibility to irAE¹⁾.
• CTLA-4 +49A/G polymorphism: Meta-analysis has shown an association with TED.
• Disruption of the blood-retinal barrier (BRB): When the BRB is compromised, such as in diabetic eye disease, T cells can more easily infiltrate the eye¹⁾.

Ocular immune privilege is maintained by the blood-retinal barrier (BRB), the scarcity of intraocular lymphatics, PD-L1/PD-L2 on RPE cells, and PD-L1 expression on Müller cells. When immune checkpoint inhibitors (ICIs) inhibit these suppressive mechanisms, intraocular inflammation increases ¹⁾.

Precautions before starting ICI

It is standardly recommended to perform thyroid function tests as a baseline before starting ICI. The frequency of thyroid disease with hormonal abnormalities is high, and this can lead to early detection of TED onset.

4. Diagnosis and Examination Methods

CTCAE Grade Classification

The ocular toxicity grade classification according to CTCAE version 5 published by the U.S. Department of Health and Human Services is used to determine treatment strategies.

Grade	Visual acuity / Symptoms	Management guidance
1	Mild / Asymptomatic (clinically detectable)	Usually no steroids needed; ICI can be continued
2	Moderate, ADL impairment, visual acuity 20/40 or better	Temporarily hold ICI, consider systemic steroids
3	Visual acuity less than 20/40 to 20/200 or better	Discontinue ICI, discontinue if no improvement, plus systemic steroids
4	Visual acuity 20/200 or worse	ICI discontinuation + systemic steroids

Examinations by disease

• Optic neuropathy: Visual acuity test, color vision test, RAPD confirmation, MRI (check for optic nerve enhancement).
• Orbital inflammation: MRI with gadolinium enhancement, extraocular muscle enlargement.
• Thyroid eye disease: CT/MRI/ultrasound shows tendon-sparing extraocular muscle enlargement; thyroid function tests.
• General posterior segment inflammation: OCT, fundus photography + FAF, B-scan ultrasound, fluorescein angiography (FA) ± ICGA¹⁾.
• Giant cell arteritis: Definitive diagnosis by temporal artery biopsy.
• Differential diagnosis: It is important to differentiate from underlying malignant tumors, infectious diseases, and thromboembolic events¹⁾.

5. Standard Treatment

Currently, there are no formal treatment recommendations for ICI-related neuro-ophthalmic complications. Risk-benefit analysis should be performed on a case-by-case basis, referring to the grade-based management guidelines from the Society for Immunotherapy of Cancer (SITC). In the literature, 62% of patients discontinued ICI due to neuro-ophthalmic complications.

Points to note when deciding on treatment

Ocular side effects rarely occur alone and are often accompanied by systemic irAEs. The decision to discontinue or continue ICI should be made in collaboration between the ophthalmologist and the treating oncologist, taking into account alternative cancer treatments and the patient’s long-term prognosis.

Treatment by disease

Optic neuritis

• Rapid tapering after high-dose steroid administration.
• In the largest review (11 patients), 10 received ICI discontinuation plus steroid therapy. Among 16 eyes with poor initial visual acuity, 12 improved, 2 stabilized, and 2 worsened.
• For non-arteritic anterior ischemic optic neuropathy, consider managing cardiovascular risk factors and antiplatelet therapy.

Orbital inflammatory disease

• Systemic steroids are the mainstay.
• For refractory cases, add IVIG, methotrexate, plasma exchange, or mycophenolate mofetil.
• Orbital inflammation due to anti-PD-1/PD-L1 inhibitors also responds well to steroids²⁾.

Thyroid eye disease (TED)

• Stepwise selection based on symptom severity: NSAIDs → systemic steroids → immunosuppressants → teprotumumab (IGF-1R antibody).
• For ICI-related TED, carefully evaluate the risk-benefit of NSAIDs considering the risk of renal impairment.

Giant cell arteritis (GCA)

• Start high-dose steroids immediately when GCA is suspected. To prevent irreversible progression of visual impairment, treatment should generally be initiated even before biopsy confirmation.

Myasthenia gravis (MG)

• Combination of acetylcholinesterase inhibitors (pyridostigmine) and immunosuppressive therapy.
• In a report of 65 patients from a single institution, steroids were used in 94%, pyridostigmine in 51%, plasma exchange in 48%, and IVIG in 44%. Many cases were severe: 96% were hospitalized, and 19% required invasive mechanical ventilation.

Ocular inflammation may persist after ICI discontinuation, requiring long-term monitoring ¹⁾. If the same drug or same class is resumed, close follow-up is necessary ¹⁾.

Q If neuro-ophthalmic complications occur, must ICI be discontinued?

A

According to grade-based management, continuation is possible for grade 1, while interruption or discontinuation is considered for grade 2 or higher. In the literature, 62% of patients discontinued ICI, but the final decision requires a risk-benefit analysis including alternative cancer treatments and the patient’s long-term prognosis.

6. Pathophysiology and Detailed Mechanism of Onset

Immune Checkpoints and Ocular Immune Privilege

The eye is an immune-privileged site and is protected from excessive immune responses by the following mechanisms¹⁾.

• Blood-retinal barrier (BRB): Limits the influx of inflammatory cells into the eye.
• Scarcity of intraocular lymphatics: Limited contact with immune cells.
• PD-L1/PD-L2 expression on RPE and Müller cells: Minimizes intraocular T cell activation¹⁾.

ICIs inhibit these suppressive mechanisms, and when the BRB is disrupted, T cells invade the vitreous and choroidal space, triggering inflammation³⁾.

Three categories of ICI-related posterior segment adverse reactions

Haliyur et al. (2025) classified the pathology of ICI-related posterior segment and choroidal adverse reactions into the following three types ¹⁾.

Type 1: T-cell cross-reactivity

Type 1a (cross-reactivity): Molecular mimicry between antitumor T cells and ocular tissues. A typical example is VKH-like panuveitis in melanoma patients.

Type 1b (autoreactivity): Proliferation of ocular-specific autoreactive T cells in predisposed individuals. Includes granulomatous uveitis, multifocal placoid pigment epitheliopathy, and MEWDS-like reactions.

Type 2: Bystander effect

Nonspecific inflammation: Nonspecific inflammation induced by ICI disrupts the blood-retinal barrier, leading to retinal vasculitis and vascular occlusion.

Rather than direct antigen recognition, the essence of this type is ocular tissue damage due to inflammatory “spillover”.

Type 3: Autoantibody-mediated

B cell activation → autoantibody production: Includes exacerbation of paraneoplastic syndromes and reactions similar to cancer-associated retinopathy (CAR) or melanoma-associated retinopathy (MAR).

Multiple mechanisms may coexist in the same patient, and some cases cannot be classified into a single disease type¹⁾.

Q What is the mechanism by which ICIs affect the eye?

A

Three main pathways are postulated: (1) cross-reactivity between antitumor T cells and ocular tissues (Type 1), (2) BRB disruption and retinal vasculitis due to nonspecific inflammation (Type 2), and (3) autoantibody production and paraneoplastic syndromes due to B cell activation (Type 3). The underlying background is that ICIs inhibit the mechanisms that maintain ocular immune privilege (BRB and RPE PD-L1 expression)¹⁾.

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7. Latest Research and Future Perspectives (Reports under Investigation)

For Patients: Please Read Carefully

The following content is currently under research or in clinical trials and is not standard treatment available at general hospitals. It is reference information for experts regarding future medical developments.

Increase in Posterior Segment irAE Cases and Accelerated Research

With the expansion of indications for ICI, an increase in the number of posterior segment irAE cases is expected ¹⁾. Posterior segment and panuveitis are considered grade 3 or 4 irAEs and often require discontinuation or temporary suspension of ICI ¹⁾.

Haliyur et al. (2025) identified future research topics including defining the uveitis spectrum associated with specific drugs, -omics analysis of vitreous samples, the utility of serological tests, the role of genetic/immune/environmental factors, and elucidating the recurrence rate of ocular inflammation after ICI resumption ¹⁾.

Teprotumumab (IGF-1R antibody)

Teprotumumab, an insulin-like growth factor 1 receptor (IGF-1R) antibody recently approved for TED treatment, is also expected to be indicated for ICI-related TED. Since drug interactions and immunological backgrounds differ from typical TED during ICI administration, accumulation of specialized data on efficacy and safety is required.

Standardization of ophthalmic screening

Some opinions recommend regular ophthalmic examinations every 4 to 6 months, but the additional benefit for patients with asymptomatic or grade 1 toxicity is unclear, and optimizing screening frequency remains a challenge. Cases with RPE/Bruch’s membrane damage carry a risk of choroidal neovascularization (CNV) formation, necessitating a framework for long-term monitoring ¹⁾.

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8. References

1. Haliyur R, Elner SG, Sassalos T, Kodati S, Johnson MW. Pathogenic Mechanisms of Immune Checkpoint Inhibitor (ICI)-Associated Retinal and Choroidal Adverse Reactions. Am J Ophthalmol. 2025;272:8-18.
2. Ang T, et al. Orbital inflammation associated with immune checkpoint inhibitors. Surv Ophthalmol. 2024;69:622-631.
3. Tomkins-Netzer O, Niederer R, Greenwood J, et al. Mechanisms of blood-retinal barrier disruption related to intraocular inflammation and malignancy. Prog Retin Eye Res. 2024;99:101245. doi:10.1016/j.preteyeres.2024.101245.