On this episode of Evidence Based Retina, Rishi Singh, MD, sits down with Lindsay Klofas Kozek, MD, PHD, Director of Resident Academics at Harvard Ophthalmology and Director of the Eye Trauma Service at Mass Eye and Ear, to discuss a case of immune-related ocular adverse effects related to programmed cell death protein 1 (PD-1) inhibitors.
Exam findings and initial workup
A 67-year-old woman came to the emergency room with sudden blurry vision in both eyes at distance and near that started 2 days prior. She also noted flashes in both eyes. The patient's vision was count fingers at 5 feet in both eyes. In situations like this, the patient is triaged for an immediate evaluation due to suspicion of an underlying systemic issue or possible bilateral retinal detachment.
Her anterior segment exam showed only trace mixed cells in the anterior chamber, mostly pigmented, which appeared after dilation. Fundus exam revealed multifocal serous detachments in the posterior pole bilaterally.
Figures 1 and 2: Magnified views of ultra-widefield fundus imaging OD and OS, respectively, of the patient at presentation demonstrated multiple areas of serous detachments in the posterior pole bilaterally and well-preserved optic nerves.
Figure 1: Courtesy of Lindsay Klofas Kozek, MD, PhD.
Figure 2: Courtesy of Lindsay Klofas Kozek, MD, PhD.
Fundus autofluorescence (FAF) showed mottled hyperautofluorescence in the juxtapapillary region and throughout the macula in both eyes. Optical coherence tomography (OCT) showed subretinal fluid, with bacillary layer detachments (BALADs), and undulations of the retinal pigment epithelium (RPE) and choroid in the right eye, with similar findings in the left eye.
Figures 3 and 4: FAF imaging OD and OS, respectively, highlighting mottled hyperautofluorescence in the juxtapapillary region OU and clearer borders for the multifocal serous detachments.
Figure 3: Courtesy of Lindsay Klofas Kozek, MD, PhD.
Figure 4: Courtesy of Lindsay Klofas Kozek, MD, PhD.
Figures 5 and 6: OCT imaging OD and OS, respectively, demonstrating subretinal fluid, with bacillary layer detachments (BALADs), and undulations of the RPE and choroid OD, with similar findings in the left eye and no cells that can be appreciated in the vitreous.
Figure 5: Courtesy of Lindsay Klofas Kozek, MD, PhD.
Figure 6: Courtesy of Lindsay Klofas Kozek, MD, PhD.
Given a presentation like this, differential diagnosis includes:
- Sympathetic ophthalmia
- Vogt-Koyanagi-Harada (VKH) disease
- Lupus
- Sarcoid
- Posterior scleritis
- Masquerade syndromes (oncologic manifestations)
- Infectious causes (Lyme, toxoplasmosis, tuberculosis)
- Hypertension
- Uveal effusion syndrome
Fluorescein angiography (FA) showed patchy filling of the choroid early on, followed by pinpoint hyperfluorescence, pooling in the areas of detachment, and staining of the disc in the late frames.
Figures 7, 8, 9, and 10: FA at 25 seconds and 8:45 minutes OD and 43 seconds and 11:52 minutes OS, respectively. There was patchy filling of the choroid early but no leakage, pinpoint hyperfluorescence, and pooling in the areas of detachment later on in both eyes.
Figure 7: Courtesy of Lindsay Klofas Kozek, MD, PhD.
Figure 8: Courtesy of Lindsay Klofas Kozek, MD, PhD.
Figure 9: Courtesy of Lindsay Klofas Kozek, MD, PhD.
Figure 10: Courtesy of Lindsay Klofas Kozek, MD, PhD.
The patient's initial lab workup for infectious causes was negative. She had mildly elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and lysozyme levels, which led Dr. Kozek to consider an inflammatory component.
Diagnosis and management
A complex medical history emerged: the patient had been diagnosed with metastatic melanoma 2 months before presenting. Importantly, she was 2 days away from her second cycle of immune checkpoint therapy with nivolumab and ipilimumab.
The thought process was that this was a VKH-like disease secondary to immune checkpoint inhibitors. More cases of VKH-like syndrome have been reported with these inhibitors, especially PD-1 inhibitors, as their use becomes more common.
Immunopathology of VKH involves a T-cell-mediated autoimmune response against melanocyte-related antigens. The condition initially presents as granulomatous choroiditis with secondary exudative retinal detachment, along with optic disc hyperemia and swelling. Without proper treatment, it can later extend to the anterior segment.1
Immune-related adverse effects (irAEs) can cause inflammatory side effects, and up to 7% of patients on these therapies have reported adverse effects affecting the eyes.2 Current American Society of Clinical Oncology (ASCO) recommendations suggest pausing therapy for a class three event (3+ AC cell or any intermediate/posterior uveitis) and stopping for a class four event (vision worse than 20/200).3
The patient was initially treated with systemic steroids (prednisone 60mg tapered over the week). Her vision improved rapidly to 20/30 just weeks after starting steroids. Patients with basilar layer detachments associated with VKH tend to have worse presenting visual acuity but respond rapidly to steroids.
Figures 11 and 12: OCT imaging OD and OS, respectively, 2 months after being treated with systemic steroids and switching from ipi/nivo to nivo alone, and then recently starting nivo/relatlimab.
Figure 11: Courtesy of Lindsay Klofas Kozek, MD, PhD.
Figure 12: Courtesy of Lindsay Klofas Kozek, MD, PhD.
She had a recurrence a few months later, developing vitiligo (consistent with VKH) and later cystoid macular edema (CME) and anterior chamber cell, which required topical steroids, a sub-Tenon's triamcinolone injection, and ultimately an Ozurdex implant.
Figures 13 and 14: OCT imaging OD and OS, respectively, demonstrating CME due to a recurrence.
Figure 13: Courtesy of Lindsay Klofas Kozek, MD, PhD.
Figure 14: Courtesy of Lindsay Klofas Kozek, MD, PhD.
About a year and a half after the initial presentation, she had a classic "sunset glow" fundus appearance that can occur with VKH.1 Her vision was 20/50 in the right eye and 20/25 in the left eye.
Co-management with oncology allowed her to continue her chemotherapy.
Figures 15 and 16: Ultra-widefield fundus imaging OD and OS, respectively, 1.5 years after presentation, highlighting a sunset glow appearance associated with VKH.
Figure 15: Courtesy of Lindsay Klofas Kozek, MD, PhD.
Figure 16: Courtesy of Lindsay Klofas Kozek, MD, PhD.
