This case series describes 2 patients who developed ophthalmologic events after treatment with the programmed death 1 axis inhibitor, atezolizumab.
Key Points
Question
Is there an association between cancer immunotherapy and acute macular neuroretinopathy with diffuse retinal venulitis?
Findings
This study describes 2 patients receiving the programmed death ligand 1 inhibitor atezolizumab who experienced acute macular neuroretinopathy and diffuse retinal venulitis.
Meaning
Cancer immunotherapies targeting the programmed death ligand 1 axis may be associated with retinal vascular changes involving microvasculature and large retinal vessels.
Abstract
Importance
Checkpoint inhibition in cancer immunotherapy related to T-cell–driven mechanisms of action associated with acute macular neuroretinopathy (AMN) and diffuse retinal venulitis, an adverse event not previously described, is reported here.
Objective
To describe 2 patients who developed ophthalmologic events after treatment with the programmed death 1 axis inhibitor, atezolizumab.
Design, Setting, and Participants
Retrospective review of 2 patients treated with atezolizumab for metastatic breast cancer and colon cancer, respectively, who presented with AMN and diffuse retinal venulitis conducted at 2 tertiary medical centers.
Main Outcomes and Measures
Multimodal imaging including near infrared, optical coherence tomography, and fluorescein angiography were used to characterize retinal vascular abnormalities.
Results
Based on optical coherence tomography and multimodal imaging findings, the clinical diagnosis of AMN associated with diffuse retinal venulitis was made in these 2 patients receiving atezolizumab.
Conclusions and Relevance
While only 2 cases of patients receiving the programmed death ligand 1 inhibitor atezolizumab who experienced AMN and diffuse retinal venulitis are described here, these findings suggest that patients receiving programmed death 1 axis inhibitor therapies may need to be monitored for unexpected immune-related ocular toxicity including abnormalities of the microvasculature and large retinal vessels. Further studies might investigate the potential mechanisms of retinal vascular changes associated with these therapies.
Introduction
Immune-checkpoint inhibitors targeting the programmed death 1 (PD-1) axis block tumor immune system recognition.1 Many anti–PD-1 pathway toxicities derive from their immune-based mechanism of action,2 and virtually any organ or system may be affected. Ocular toxicities have been reported, including uveitis,3 uveal effusion,4 retinitis, retinal detachment, vitritis, and choroidopathy.5
Acute macular neuroretinopathy (AMN) is a rare condition characterized by wedge-shaped intraretinal lesions pointing to the fovea, affecting the outer retina.6,7 Ischemic insult to the outer retinal capillary network has been implicated as the underlying mechanism.7 Here, from more than 6000 patients (as of January 2016) enrolled in randomized clinical trials who received the programmed death ligand 1 (PD-L1) inhibitor atezolizumab, we present 2 patients who experienced AMN with diffuse retinal venulitis.
Case 1
A woman in her early 30s with metastatic triple negative breast cancer presented for ophthalmologic evaluation after receiving atezolizumab. Twelve days after the first infusion (1200 mg intravenously), she developed fever, fatigue, myalgia, and arthralgia. On day 15, she reported blotchy vision and a peanut-shaped scotoma in the left eye. On day 18, she began oral antibiotics for presumptive urinary tract infection, and the fever abated. Blood and urine cultures subsequently returned negative. Antinuclear antibody was positive at 1:1280 at follow-up.
Ophthalmic evaluation on day 19 showed best-corrected visual acuity of 20/25 OD and 20/80 OS. Pupillary response and color vision were normal. Slitlamp examination results were normal; signs of anterior chamber inflammation and vitritis were absent. No macular lesions were readily appreciated on fundoscopic examination, which was remarkable for mild diffuse perivenous sheathing (eFigure 1 in the Supplement).
Near-infrared imaging (Figure 1A and B) showed distinct dark wedge-shaped macular lesions corresponding to the areas of outer nuclear layer hyperreflectivity and ellipsoid zone disruption on optical coherence tomography (OCT). Spectral-domain OCT (Figure 1C and D) revealed bilateral hyperreflective band-shaped lesions involving the middle layers of the neurosensory retina, most marked at the level of the outer plexiform layer and the outer nuclear layer. Disruption of the ellipsoid zone at the level of the photoreceptors’ outer segments and retinal pigment epithelium junction was also noted. Angiography (eFigure 2A and B in the Supplement) and microperimetry (eFigure 2C and D in the Supplement) confirmed parafoveal scotomas corresponding to the areas of abnormal retinal architecture. Based on OCT and multimodal imaging findings, the diagnosis of AMN associated with mild peripheral retinal venulitis was confirmed.
Figure 1. Case 1: Initial Presentation.
On initial presentation, near-infrared (nIR) imaging (A and B) and optical coherence tomography (OCT) (C and D) of the right (A and C) and left (B and D) eyes show dark gray wedge-shaped parafoveal lesions on nIR associated with outer retinal hyperreflectivity on OCT.
Atezolizumab treatment was interrupted. Best-corrected visual acuity improved to 20/20 OD and 20/16 OS with complete resolution of visual symptoms. Interestingly, the wedge-shaped lesions became more prominent on examination and persisted on near-infrared imaging (Figure 2A and B); however OCT (Figure 2C and D) showed improvement of outer retinal architecture with residual granularity of the ellipsoid band and vascular sheathing resolved spontaneously (eFigure 3 in the Supplement). Humphrey visual field 10-2 showed persistent parafoveal scotoma. The patient was discontinued from the study on day 41 owing to cancer progression.
Figure 2. Case 1: 3 Weeks After Presentation.
Three weeks after interruption of atezolizumab, near-infrared (nIR) imaging (A and B) and optical coherence tomography (OCT) (C and D) of the right (A and C) and left (B and D) eyes show persistent dark gray wedge-shaped parafoveal lesions on nIR but improved hyperreflectivity on OCT.
Case 2
A man in his mid 30s with metastatic adenocarcinoma of the colon presented for ophthalmologic evaluation after receiving atezolizumab combined with oral indoleamine 2,3-dioxygenase inhibitor GDC-0919.8 The patient presented with fever after receiving first cycle of atezolizumab and GCD-0919 (days 14 and 15 postdose, respectively) and was treated empirically with antibiotics. That evening, he became confused, was admitted to the intensive care unit for sepsis, and received broad spectrum antimicrobials and high-dose intravenous steroids. In less than 12 hours, his general condition had improved and he reported appearance of visual symptoms, describing “reddish crescents” in both eyes.
Ophthalmologic evaluation on day 18 showed best-corrected visual acuity of 20/20 OU. Slitlamp examination results were unremarkable; anterior chamber inflammation and vitritis were absent. Fundoscopic examination (eFigure 4 in the Supplement) revealed diffuse frosted branch angiitis extending to the periphery with multiple vascular occlusions and preretinal hemorrhage in both eyes.
Near-infrared imaging (eFigure 5A and B in the Supplement) showed distinct dark wedge-shaped macular lesions corresponding to the abnormal areas on OCT. Cross-sectional OCT (eFigure 5C and D in the Supplement) revealed hyperreflective band-shaped lesions at the level of the outer plexiform layer and outer nuclear layer and disruption of the ellipsoid zone. Acute macular neuroretinopathy with diffuse retinal venulitis was diagnosed. Fluorescein angiography (Figure 3) revealed patchy choroidal filling with diffuse midperipheral branch vein occlusions and venous sheathing. Treatment with GDC-0919 and atezolizumab was interrupted.
Figure 3. Case 2: Initial Presentation.
On initial presentation, fluorescein angiography (FA) of the right (A and C) and left (B and D) eyes shows on early to mid phase (A and B) patchy choroidal filling with diffuse scattered retinal branch vein occlusions and on late phase (C and D) shows diffuse venous sheathing and staining.
Brain magnetic resonance imaging showed increased T2-weighted signal in the caudate heads and anterior lentiform nuclei, which were likely metabolic or immune-mediated in origin. Infection was ruled out and antimicrobial agents stopped. Antinuclear antibody was positive at 1:320 at baseline and day 18 (speckled), and double-stranded DNA antibody was negative.
The patient was discharged and instructed to take oral steroids (prednisone, 40 mg daily). GDC-0919 and atezolizumab were not restarted, and he was removed from the study. Oral steroids were continued for 5 weeks and then tapered. Brain abnormalities resolved in about 4 weeks, and the ocular venulitis and choroidal perfusion improved in about 10 weeks. The patient experienced slow visual improvement but died of progressive cancer about 5 months after the onset of visual symptoms.
Discussion
The prescribing information for some agents targeting PD-1/PD-L1 report ocular toxicity including inflammatory events. Papillitis and uveitis are associated with pembrolizumab, and retinitis was reported in a patient with ocular metastases treated with pembrolizumab.9,10
The 2 patients reported here received atezolizumab for metastatic cancer and each presented with fever and flulike symptoms approximately 2 weeks after the first dose of immunotherapy, and the antinuclear antibody was elevated during the illness. Notably, fever and flulike symptoms have been reported in patients receiving atezolizumab.11 Antinuclear antibody was elevated during the illness in both patients. Antinuclear antibody has good sensitivity but poor specificity for autoimmune disease. Evaluation of antinuclear antibody in future cases, including absolute values and change from baseline, is required to better understand the predictive and diagnostic value of this test for ocular immune-related adverse events.12
Ischemia involving the outer capillary network located at the border of the inner nuclear layer is thought to lead to AMN.7 This would explain early changes in the outer plexiform layer, which have been typically described in AMN, with OCT showing photoreceptors’ changes later in disease evolution. The localized band-shaped hyperreflectivity on OCT at the level of the outer plexiform layer and outer nuclear layer may indicate intracellular edema of the photoreceptor cell bodies and axons.7 The nature of the dark wedge-shaped lesions on fundus examination or near-infrared imaging is still debatable, but it correlates with OCT abnormalities at the level of the outer retinal layers.7 The association of retinal changes in these patients with PD-L1–specific immune checkpoint blockade suggests that a T-cell–mediated response could also contribute to the pathogenesis of AMN. The diffuse vascular sheathing described here has not been previously associated with AMN, suggesting that more widespread vascular involvement can also occur with anti-PD-L1 therapy.
Conclusions
In conclusion, these cases illustrate the occurrence of AMN associated with diffuse retinal venulitis in 2 patients receiving atezolizumab, an ocular toxicity not previously reported with agents targeting the PD-1 axis. Because these drugs are associated with immune-related adverse events, these cases generate hypotheses about the potential underlying pathophysiology of AMN. While based on only 2 patients, these findings suggest patients receiving these agents may require prompt evaluation by an ophthalmologist if they experience visual symptoms and be closely monitored thereafter. Whether interruption of cancer immunotherapy should be considered in the management of potential immune-related ocular toxicity should be determined based on the risks and benefits of interrupting immunotherapy.
eFigure 1. Case 1: On initial presentation, wide-field fundus photographs of the right (A) and left (B) eyes show perivenous sheathing in the macular area and throughout the fundus through the retinal periphery.
eFigure 2. Case 1: On initial presentation, indocyanine-green angiography (A, B) of the right (left panels) and left (right panels) eyes shows a macular wedge-shaped area of hypocyanenscence corresponding to lesions on near infra-red imaging. Microperimetry sensitivity maps (C, D) of the right and left eyes shows decreased focal retinal sensitivity in the corresponding macular regions with anatomical changes at baseline visit.
eFigure 3. Case 1: Three weeks after interruption of atezolizumab, wide-field fundus photographs of the right (A) and left (B) eyes show resolution of perivenous sheathing.
eFigure 4. Case 2: On initial presentation, wide field color fundus photographs of the right (A) and left (B) eyes show frosted branch angiitis throughout the fundus extending to the retinal periphery, with multiple vascular occlusions and a few dots of pre-retinal hemorrhage.
eFigure 5. Case 2: On initial presentation, near infra-red imaging (A, B) in right (left panels) and left (right panels) eyes shows distinct dark grey wedge-shaped macular lesions, which correspond on optical coherence tomography (C, D) to hyperreflective band-shaped lesions at the level of the outer plexiform layer and outer nuclear layer, with disruption of the ellipsoid zone.
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Associated Data
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Supplementary Materials
eFigure 1. Case 1: On initial presentation, wide-field fundus photographs of the right (A) and left (B) eyes show perivenous sheathing in the macular area and throughout the fundus through the retinal periphery.
eFigure 2. Case 1: On initial presentation, indocyanine-green angiography (A, B) of the right (left panels) and left (right panels) eyes shows a macular wedge-shaped area of hypocyanenscence corresponding to lesions on near infra-red imaging. Microperimetry sensitivity maps (C, D) of the right and left eyes shows decreased focal retinal sensitivity in the corresponding macular regions with anatomical changes at baseline visit.
eFigure 3. Case 1: Three weeks after interruption of atezolizumab, wide-field fundus photographs of the right (A) and left (B) eyes show resolution of perivenous sheathing.
eFigure 4. Case 2: On initial presentation, wide field color fundus photographs of the right (A) and left (B) eyes show frosted branch angiitis throughout the fundus extending to the retinal periphery, with multiple vascular occlusions and a few dots of pre-retinal hemorrhage.
eFigure 5. Case 2: On initial presentation, near infra-red imaging (A, B) in right (left panels) and left (right panels) eyes shows distinct dark grey wedge-shaped macular lesions, which correspond on optical coherence tomography (C, D) to hyperreflective band-shaped lesions at the level of the outer plexiform layer and outer nuclear layer, with disruption of the ellipsoid zone.
