Optic neuropathy due to immune checkpoint inhibitors

Key points at a glance

Immune checkpoint inhibitors (ICIs) are immunotherapy drugs for malignant tumors and can cause autoimmune optic neuropathy.
The incidence of neuro-ophthalmic immune-related adverse events (irAEs) after ICI treatment is up to 0.46%, and overall ocular irAEs are reported to be 1–3%.
Main symptoms include vision loss, visual field defects, and color vision changes, often accompanied by optic disc edema.
First-line treatment is steroid pulse or half-pulse therapy, and with appropriate treatment, approximately 70% or more recover visual function.
Whether to discontinue or continue ICI should be decided on a case-by-case basis by a multidisciplinary team including ophthalmology and oncology.
It is important to differentiate from metastatic, radiation-induced, and paraneoplastic optic neuropathy; currently, it is a diagnosis of exclusion.

1. What is Optic Neuropathy Due to Immune Checkpoint Inhibitors?

Immune checkpoint inhibitors (ICIs) are a class of drugs that block the “immune checkpoint pathways” used by cancer cells to evade immune attack, thereby reactivating the patient’s own immune system to attack tumors. On the other hand, they can cause immune-related adverse events (irAEs) in which normal tissues throughout the body are attacked due to overactivation of the immune system, and the optic nerve can also be a target.

Types of Immune Checkpoint Inhibitors

ICIs are classified into four classes based on their target. The main drugs currently approved by the FDA are as follows:

Class	Main Approved Drugs (Year of Approval)
CTLA-4 inhibitor	Ipilimumab (2011), Tremelimumab (2022)
PD-1 inhibitors	Pembrolizumab (2014), Nivolumab (2014), Cemiplimab (2018)
PD-L1 inhibitors	Atezolizumab (2016), Avelumab (2017), Durvalumab (2017)
LAG-3 inhibitors	Relatlimab (2022)

Incidence and Epidemiology

Incidence of neuro-ophthalmic irAE: Neuro-ophthalmic irAEs after ICI treatment occur in up to 0.46% of patients.
Overall ocular irAE: Ocular irAEs occur in 1–3% of patients, mainly presenting as ocular surface disease or anterior uveitis¹⁾.
Posterior segment inflammation: Accounts for approximately 5–20% of ocular irAEs; retinal, choroidal, and optic nerve lesions are more severe and carry a higher risk of vision loss¹⁾.
Primary disease: Cutaneous melanoma is the most common indication, and in systematic reviews of ICI-related optic neuropathy, malignant melanoma is the most frequent (57% male, 43% female, mean age 60 years).
Medications used: In a 2021 report of 31 cases, pembrolizumab was the most commonly used ICI, followed by ipilimumab plus nivolumab combination therapy.

Q How often does optic neuropathy occur due to immune checkpoint inhibitors?

The incidence of neuro-ophthalmic irAE after ICI treatment is reported to be up to 0.46%. Overall ocular irAEs occur in 1–3%, of which posterior segment inflammation (including optic neuropathy) accounts for 5–20%¹⁾. Optic neuropathy is considered a more severe ocular irAE.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

The time from initiation of ICI to onset varies depending on the case and drug, ranging from several weeks to several months.

Decreased visual acuity: Occurs unilaterally or bilaterally.
Blurred vision: Often described as hazy vision.
Visual field defects: Present as scotomas or horizontal visual field loss.
Color vision changes: Altered perception of colors.
Discomfort with eye movement: Reported in some cases.

Clinical Findings (Findings Confirmed by Physician Examination)

Optic disc edema: Observed in 5 out of 7 cases, either unilateral or bilateral. This is the most common finding.
RAPD (Relative Afferent Pupillary Defect): Present unilaterally or bilaterally with asymmetry.
Pale optic disc: Accompanied by optic nerve pallor in some cases.
Retrobulbar optic neuritis pattern: Inflammation may occur in the retrobulbar region even when the optic disc appears normal.
Concurrent anterior uveitis: Some cases present with anterior chamber cells and posterior synechiae.
MRI findings: Contrast enhancement of the optic nerve was confirmed in 2 out of 4 cases, and increased cerebrospinal fluid signal has also been reported.

Characteristic clinical features reported for each drug are shown below.

Atezolizumab: Findings similar to arteritic AION (optic disc swelling + RAPD + delayed choroidal and retinal artery filling).
Pembrolizumab: May spread to the contralateral eye after unilateral onset.
Ipilimumab: May present with bilateral optic disc edema and anterior chamber inflammation.
Durvalumab: Unilateral grade 4 papilledema and inferior horizontal visual field defect.
Nivolumab: Bilateral papillitis with intermediate uveitis and acute anterior ischemic optic neuropathy.
Cemiplimab: Bilateral optic neuropathy and visual field defects.

3. Causes and Risk Factors

The direct cause of optic neuropathy due to ICIs is that ICIs release immune checkpoints, triggering unintended autoimmune reactions that damage the optic nerve.

Type of ICI and risk: CTLA-4 inhibitors release suppression of T cell activation and are prone to inducing autoimmune diseases. PD-1/PD-L1 inhibitors inhibit peripheral immune tolerance, preventing tumor immune escape while inducing autoimmunity. LAG-3 inhibitors inhibit the mechanism limiting activated T cell proliferation and are increasingly used in combination with other ICIs.
ICI combination therapy: Combination therapy such as ipilimumab + nivolumab increases the risk of irAE compared to monotherapy¹⁾.
Host genetic predisposition: HLA type may predispose to autoimmune events¹⁾.
Breakdown of ocular immune privilege: Pre-existing disruption of the blood-retinal barrier (BRB) (e.g., diabetic eye disease) may be a risk factor¹⁾.
Primary disease: Cutaneous melanoma is the most common, with reports also in non-small cell lung cancer, Hodgkin lymphoma, renal cell carcinoma, prostate cancer, and head and neck squamous cell carcinoma.

Q Which types of immune checkpoint inhibitors are more likely to cause optic neuropathy?

PD-1 inhibitors (e.g., pembrolizumab) are the most commonly used drugs and have many case reports, but optic neuropathy has also been reported with CTLA-4 inhibitors (ipilimumab) and PD-L1 inhibitors (atezolizumab, durvalumab). In particular, the combination of ipilimumab and nivolumab increases the risk of irAE ¹⁾.

4. Diagnosis and Examination Methods

There are no established biomarkers for ICI-related optic neuropathy, and at present it is a diagnosis of exclusion.

Ophthalmic Examination

A complete ophthalmic evaluation including visual acuity testing, visual field testing, color vision testing, pupillary response (checking for RAPD), and fundus examination is recommended. The following additional tests are useful ¹⁾:

OCT (Optical Coherence Tomography): Evaluation of the peripapillary retinal nerve fiber layer (pRNFL).
Fundus photography and fundus autofluorescence: Morphological evaluation of the optic disc.
Fluorescein angiography (FA): Evaluation of vascular filling dynamics. ICGA (indocyanine green angiography) may also be performed as needed.
B-scan ultrasonography: Evaluation of the posterior segment of the eye.

Neuroimaging

Head and orbital MRI (with and without contrast) is essential. It is performed to differentiate metastatic, radiation-induced, and paraneoplastic optic neuropathies. Contrast enhancement of the optic nerve has been confirmed in 2 out of 4 cases, and small vessel ischemic changes have also been reported.

Ancillary Tests

HLA testing and anti-retinal autoantibody testing may aid in clinical diagnosis ¹⁾.

Differential Diagnosis

Metastatic lesions (especially melanoma)
Radiation-induced optic neuropathy
Paraneoplastic optic neuropathy
Infectious causes (especially caution due to immunosuppression)
Thromboembolic events

Severity Grading

Severity is assessed using the 4-grade scale of the Common Terminology Criteria for Adverse Events (CTCAE) version 5 from the U.S. Department of Health and Human Services. Grade determination directly influences treatment decisions (see “Standard Treatment” section).

5. Standard Treatment

Steroid Therapy (Japanese Standard)

The first-line treatment for optic neuropathy is steroid pulse or half-pulse therapy. After 1 to 3 courses, switch to oral steroids. With appropriate treatment, approximately 70% or more of patients achieve visual function recovery.

Grade-Specific Management Guidelines (SITC Recommendations)

Grade	Criteria	Management
Grade 1	Mild visual impairment	Usually no need for steroids or ICI discontinuation
Grade 2	Affects daily life	Consider temporarily holding ICI and starting systemic steroids; consider resuming ICI after improvement
Grade 3	Marked vision loss	Consider holding ICI; if no improvement in 4–6 weeks, consider discontinuing + systemic steroids
Grade 4	Visual acuity 20/200 or worse	Usually discontinue ICI + administer systemic steroids

Representative treatment examples

Atezolizumab-related: Methylprednisolone IV → prednisolone oral taper, ICI discontinued.
Pembrolizumab-related (recurrent case): Methylprednisolone IV + plasma exchange + immunoglobulin therapy + mycophenolate mofetil → 6-month steroid taper.
Ipilimumab-related (with anterior chamber inflammation): Prednisolone eye drops + atropine eye drops, ICI continued.
Cemiplimab-related: ICI held, methylprednisolone IV up to 1 g/day × 1–7 days → oral taper over several months with significant improvement.

Decision to discontinue or continue ICI

The decision to continue or discontinue ICI therapy should be made on a case-by-case basis by a multidisciplinary team including ophthalmology and oncology, weighing the risks and benefits.

Q If ICI-related optic neuropathy is diagnosed, must ICI therapy always be discontinued?

ICI discontinuation is not mandatory; the decision is based on the severity grade and the patient’s underlying disease status. For grade 1, ICI can usually be continued; for grade 2, resumption after temporary interruption may be considered. There are reports of improvement with steroid eye drops alone while continuing ICI. The final decision is made by a multidisciplinary team including ophthalmology and oncology.

6. Pathophysiology and Detailed Mechanisms of Onset

Basic Mechanism of Action of ICIs

CTLA-4: A receptor on T lymphocytes that suppresses T cell activation (immune checkpoint) by binding to B7. CTLA-4 inhibitors release this control and hyperactivate T cells.
PD-1: An inhibitory receptor on T lymphocytes. Interaction with PD-L1 mediates peripheral immune tolerance. Tumors upregulate this pathway to evade immunity, but PD-1 inhibitors block it.
LAG-3: A co-inhibitory receptor on activated CD4+/CD8+ T cells. It binds to MHC class II and suppresses cytokine/granzyme production and proliferation.

Ocular Immune Privilege and ICIs

The eye has ocular immune privilege due to anatomical barriers such as the blood-retinal barrier (BRB) and sparse ocular lymphatics. The normal BRB prevents peripheral T cells from entering the vitreous and choroidal space ¹⁾. CTLA-2α, PD-L1, and PD-L2 on RPE cells, and PD-L1 expression on retinal Müller glia and microglia, convert T cells into regulatory T cells (Tregs), minimizing T cell-mediated inflammation ¹⁾. ICIs target these defense mechanisms, potentially leading to immune attack on the eye.

Three Types of ICI-Induced Posterior Segment Adverse Reactions

Haliyur et al. (2025) classified the mechanisms of ICI-related posterior segment inflammation into the following three types ¹⁾.

Type 1a

Cross-reaction of antitumor T cells: Cross-reaction with melanin-containing cells induces VKH-like panuveitis.

Frequency: 5–14% of ICI-related ocular adverse reactions in melanoma patients are VKH-like reactions.

Type 1b

Auto-reactivity to eye-specific self-peptides: Involves HLA predisposition (e.g., HLA-DR4) in susceptible individuals.

Phenotypes: Granulomatous uveitis, multifocal geographic chorioretinitis, Birdshot-like chorioretinitis, MEWDS, etc.

Type 2

Nonspecific vasculitis: Nonspecific inflammation induced by ICI causes retinal vasculitis and vascular occlusion.

Mechanism: Lymphoplasmacytic infiltration with predominant CD4+ T cells and upregulation of cell adhesion molecules. More common with anti-PD-1 therapy.

Type 3

Autoantibody-mediated inflammation: CTLA-4 inhibition → Treg suppression + B cell activation. PD-1 inhibition → memory T cell activation → B cell clonal expansion.

Outcome: Progression to autoimmune retinopathy (AIR), CAR, MAR.

Q Why do immune checkpoint inhibitors cause inflammation in the eye?

The eye normally has “immune privilege” due to the blood-retinal barrier (BRB), but ICIs target defense mechanisms such as PD-L1, making it easier for immune T cells to enter the eye ¹⁾. Furthermore, multiple mechanisms—including cross-reaction of antitumor T cells with ocular tissues (Type 1a), reaction to self-antigens in genetically predisposed individuals (Type 1b), nonspecific vasculitis (Type 2), and autoantibody-mediated inflammation (Type 3)—can damage ocular tissues including the optic nerve.

7. Latest Research and Future Perspectives (Reports at Research Stage)

Potential of Rituximab

Rituximab (CD-20 monoclonal antibody) is attracting attention as an immune countermeasure against steroid-resistant irAEs. Significant improvement has been reported in 7 cases of steroid-resistant immune-related cutaneous adverse events, and another study showed improvement of irCAE by 2 or more grades in all patients. It is also being investigated in combination with plasma exchange for treatment-resistant neurological irAEs (autoimmune encephalitis, myasthenia gravis). However, direct evidence for optic neuropathy is still lacking and remains controversial.

Treatment Optimization Based on Type 3 Classification

Haliyur et al. (2025) stated that the type 3 classification framework for ICI-related posterior segment inflammation (see “Pathophysiology” section) is expected to improve prognosis prediction and treatment decision-making¹⁾. In Type 1a/1b and Type 3, HLA and anti-retinal autoantibody testing may support clinical diagnosis. Future mechanistic laboratory studies are expected to develop targeted treatment strategies that control ocular inflammation while avoiding ICI discontinuation.

Development of OirAE Biomarkers

Currently, there are no biomarkers for OirAE, and diagnosis relies on exclusion. The development of biomarkers is considered an important future task. With the expansion of indications for FDA-approved ICIs, an increase in the number of posterior segment irAE cases is predicted, and the need for long-term follow-up has also been indicated¹⁾.

8. References

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.
Pietris J, Santhosh S, Ferdinando Cirocco G, Lam A, Bacchi S, Tan Y, et al. Immune Checkpoint Inhibitors and Optic Neuropathy: A Systematic Review. Semin Ophthalmol. 2023;38(6):547-558. PMID: 36683270.
Ostroumova OD, Chikh EV, Rebrova EV, Ryazanova AY, Panteleeva LR, Arzhimatova GS, et al. [Drug-induced uveitis]. Vestn Oftalmol. 2021;137(1):94-101. PMID: 33610156.

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