Ophthalmological and Neurological Findings in Patients with Idiopathic Uveitis Associated with Retinal Vasculitis and the Relation with the HLA DR15 Allele.

PURPOSE: In 15 patients with idiopathic uveitis associated with retinal vasculitis, HLA DRB1 gene testing was performed to detect a possible association. 11 patients tested positive and 4 negative for the HLA DRB1 × 15 allele. The presence of the HLA DRB1 × 15 haplotype might be associated with a higher susceptibility to develop Multiple Sclerosis (MS). METHODS: In this case series, we describe the ophthalmological and neurological findings in 10 HLA DR15-positive patients and 4 HLA DR15-negative patients that had neurological workup, including Magnetic Resonance Imaging (MRI) of the brain. RESULTS: All patients had granulomatous ocular inflammation with either panuveitis or intermediate uveitis. MRI of the brain showed white matter lesions in 13 patients (9/10 and 4/4 respectively) of which 4 patients were eventually diagnosed with MS (3/10 and 1/4 respectively). CONCLUSION: Although the majority of tested patients was carrying at least one HLA DRB1-15 allele, there was no difference in ophthalmological and neurological findings in both groups.

A rare presentation of a common carotid artery occlusion.

Background: A common carotid artery occlusion (CCAO) is very rare and the clinical features of CCAO have rarely been described. Since the blood supply of the eye and orbit is derived from the internal carotid artery, a CCAO may present with various ophthalmological symptoms, ranging from incidental findings to complete visual loss but also other neuro-ophthalmological abnormalities. Case report: A 61-year-old woman presented with acute monocular vision loss and an elevation deficit of the right eye. Fluorescein angiography showed delayed filling of both the retinal and choroidal vasculature, without occlusion/embolisms of the retinal arteries. Vascular imaging showed a right CCAO. Conclusion: CCAO has a variable presentation. In patients with acute unilateral visual loss a CCAO should be considered, especially when ocular motility deficits are present. Fluorescein angiography examination can aid in the localization and diagnosis of the vascular insult. Urgent referral for a systemic work-up is essential.

VOGT-KOYANAGI-HARADA DISEASE-LIKE UVEITIS IN A PATIENT WITH ADVANCED MELANOMA TREATED BY SEQUENTIAL ADMINISTRATION OF NIVOLUMAB AND DABRAFENIB/TRAMETINIB THERAPY.

PURPOSE: To describe a case of bilateral Vogt-Koyanagi-Harada (VKH)-like uveitis during treatment with dabrafenib and trametinib and three months after discontinuation of nivolumab for malignant melanoma, and discuss the possible (synergistic) role(s) of mitogen-activated protein kinase (MAPK) inhibitors and immune checkpoint inhibitors in its pathophysiology. METHODS: Retrospective case report with fluorescein angiography and optical coherence tomography. RESULTS: A 55-year old patient with metastatic melanoma presented with a complaint of gradually worsening blurry vision in the right eye during treatment with dabrafenib and trametinib, three months after discontinuation of nivolumab. Based on the clinical examination, optical coherence tomography and fluorescein angiography findings, and a thorough laboratory work-up, he was diagnosed with a bilateral VKH-like uveitis without extraocular manifestations. The uveitis responded well to oral corticosteroids. CONCLUSION: Vogt-Koyanagi-Harada-like uveitis is a rare adverse effect of MAPK inhibitors and immune checkpoint inhibitors. Similar pathogenetic mechanisms including a drug-induced autoimmunity targeted against benign and malignant melanocytes may underlie MAPK inhibitor-induced and immune checkpoint inhibitors-induced VKH-like uveitis. In our report, the patient developed a VKH-like uveitis during MAPK inhibition therapy, four months after discontinuation of nivolumab. It is difficult to delineate whether MAPK inhibition alone was responsible for this adverse effect, or whether, on the contrary, potentiation occurred as a result of immune modulation by previous treatment with an immune checkpoint inhibitor. Further cases are needed to further clarify this latter hypothesis.

Relation between ocular paraneoplastic syndromes and Immune Checkpoint Inhibitors (ICI): review of literature.

PURPOSE: To describe different ocular paraneoplastic syndromes in patients treated with Immune Checkpoint Inhibitors (ICI), its relation with different types of ICI and different types of tumors, and its implications for treatment. METHODS: A comprehensive review of the literature was performed. RESULTS: Patients treated with ICI can present with different ocular paraneoplastic syndromes, such as Carcinoma Associated Retinopathy (CAR), Melanoma Associated Retinopathy (MAR) and paraneoplastic Acute Exudative Polymorphous Vitelliform Maculopathy (pAEPVM). In literature, the different types of paraneoplastic retinopathy are mostly related to different types of primary tumors, with MAR and pAEPVM seen in melanoma, and CAR in carcinoma. Visual prognosis is limited in MAR and CAR. CONCLUSION: Paraneoplastic disorders result from an antitumor immune response against a shared autoantigen between the tumor and ocular tissue. ICI enhance the antitumor immune response, which can lead to increased cross-reaction against ocular structures and unmasking of a predisposed paraneoplastic syndrome. Different types of primary tumors are related to different cross-reactive antibodies. Therefore, the different types of paraneoplastic syndromes are related to different types of primary tumors and are probably unrelated to the type of ICI. ICI-related paraneoplastic syndromes often lead to an ethical dilemma. Continuation of ICI treatment can lead to irreversible visual loss in MAR and CAR. In these cases overall survival must be weighed against quality of life. In pAEPVM however, the vitelliform lesions can disappear with tumor control, which may involve continuation of ICI.

Relapse of Birdshot Uveitis after Stopping Immunosuppressive Treatment and Starting Immune Checkpoint Inhibitors for Lung Cancer.

A 56-year-old Caucasian woman with birdshot uveitis had to stop immunosuppressive treatment with adalimumab due to metastatic squamous lung carcinoma. She was subsequently treated with chemotherapy and pembrolizumab, an immune checkpoint inhibitor (ICI). After stopping adalimumab and starting pembrolizumab, the patient had an inflammatory relapse of birdshot uveitis with macular oedema. Birdshot uveitis is triggered by an unknown antigen presented on the HLA-A29 molecule which activates cytotoxic T-cells. Although immunosuppressive therapy effectively stabilizes birdshot uveitis, it might induce a higher risk of developing cancer. Treatment with ICIs, on the other hand, might exacerbate birdshot uveitis by increasing anti-tumoural immune reaction and inducing off-target autoimmunity.

Iris pigment epithelial (IPE) cysts secondary to Hodgkin's lymphoma: A case report.

Purpose: To describe a unique case of a white male who presented with reduced visual acuity, growing bilateral iris pigment epithelial (IPE) cysts and granulomatous panuveitis, probably related to Hodgkin's lymphoma. Observations: The granulomatous panuveitis was reactive to corticosteroids, but the IPE cysts were not. After extensive work-up, the patient was diagnosed with Hodgkin's lymphoma (HL) mixed cellularity type with cervical and mediastinal lymph node involvement. After starting chemotherapy, the IPE cysts shrank. Conclusions and importance: To our knowledge, IPE cysts have not been described in HL before. Therefore, this case can contribute to our knowledge of the relation between IPE cysts and hematological malignancy.

Brentuximab vedotin induced uveitis.

PURPOSE: To report a case of bilateral Vogt-Koyanagi-Harada (VKH)-like granulomatous pan uveitis secondary to brentuximab vedotin (BV) administration to treat for classical Hodgkin lymphoma (CHL). OBSERVATIONS: A case of bilateral pan uveitis is described, following administration of BV, with features of VKH-like uveitis: presence of inflammatory cells in the anterior and posterior segment, multiple small serous detachments around the optic disc and retinal pigment epithelium (RPE) folds confirmed by optical coherence tomography (OCT) as well as hypocyanesent dark dots, disc hyperfluorescence and fuzzy vascular patterns seen on indocyanine green and fluorescein angiography. There were no systemic features of VKH disease. Further etiological investigation showed no clear infectious or inflammatory cause. The uveitis responded well to treatment with corticosteroids and cessation of BV. A relapse occurred a few months later when BV treatment was reinitiated, suggesting a probable adverse event to this drug, according to the Naranjo algorithm. CONCLUSIONS: We hypothesize that administration of BV can induce a VKH-like uveitis, caused by loss of function of protective CD30+ cells present in the uveal tract, possibly aggravated by collateral damage to surrounding CD30-cells and melanocytes, leading to a uveal immune reaction. It is therefore important for the clinicians using BV to be aware of this adverse event. Growing experience with immunotherapy will provide more clinical insights in these complex immune mechanisms in the future.

THE ROLE OF CHECKPOINT INHIBITORS IN PARANEOPLASTIC ACUTE EXUDATIVE POLYMORPHOUS VITELLIFORM MACULOPATHY: REPORT OF TWO CASES.

PURPOSE: To report on two cases with paraneoplastic acute exudative polymorphous vitelliform maculopathy within one month after the initiation of nivolumab. METHODS: Case report. RESULTS: Two patients with metastatic mucosal melanoma were diagnosed with acute exudative polymorphous vitelliform maculopathy within one month after the initiation of the checkpoint inhibitor nivolumab. Both cases showed a neurosensory retinal detachment and subretinal hyperautofluorescent material, which persisted after discontinuation of nivolumab and treatment with local and/or systemic corticosteroids. In one case, nivolumab was introduced again in a later stage in combination with surgical reduction of the tumor, eventually leading to resolution of the subretinal lipofuscin-rich fluid. CONCLUSION: The development of paraneoplastic acute exudative polymorphous vitelliform maculopathy in melanoma patients can be triggered by treatment with nivolumab. However, achieving tumor control, which may involve continuation of nivolumab, could be the key to success.

Occurrence of Macular Neovascularization after Retinal Pigment Epithelium-Choroid Translocation Surgery to Treat Complicated Age-Related Macular Degeneration: Incidence, Management, and Outcome.

INTRODUCTION: This study investigates the incidence, clinical characteristics, and treatment response of macular neovascularization (MNV) occurring after retinal pigment epithelium (RPE) and choroid graft translocation surgery (RPE-choroid TS). METHODS: Retrospective analysis of 36 eyes of 36 consecutive patients who underwent RPE-choroid TS. Longer term follow-up of graft survival focusing on the occurrence of MNV was performed using multimodal imaging. RESULTS: Indications for RPE-choroid TS included complications of neovascular age-related macular degeneration in 34 patients and drusenoid pigment epithelial detachment in 2 patients. With a mean follow-up of 30 months, 8 patients out of 36 developed signs of MNV. Of these 8 patients, 4 presented with a drop in visual acuity (VA) due to centrally located type 3 MNV. Early diagnosis and treatment prevented significant functional consequences. Four patients developed type 2 MNV at the border of the graft, which did not tend to affect the VA. CONCLUSION: We report a high incidence of MNV after RPE-choroid TS. Early diagnosis and treatment may preserve function in these patients. The type of MNV and location can be used to guide the management.

Bilateral Corneal Perforation in a Patient Under Anti-PD1 Therapy.

ABSTRACT: Immune checkpoint inhibition has improved the clinical outcomes for numerous patients with cancer. However, the downside is a whole new spectrum of immune-related adverse events. We report a 68-year-old man with a history of nonsmall cell lung cancer presenting with a spontaneous corneal perforation in the right eye after 22 cycles of pembrolizumab. In addition, a chronic central nonhealing epithelial defect developed after performing a penetrating keratoplasty. Treatment with autologous serum drops resulted in complete healing of the corneal ulcer, where other conventional therapies had no effect. One month after reinitiating pembrolizumab therapy, our patient presented again with a corneal perforation in the fellow eye. This case describes relapsing sterile ulcerations associated with pembrolizumab use and presents an unexpected cure.

Insights into multiple sclerosis-associated uveitis: a scoping review.

PURPOSE: This paper is a scoping review of research on multiple sclerosis (MS)-associated uveitis to determine its epidemiology, pathophysiology, clinical features and treatment. METHODS: A comprehensive search of the medical databases MEDLINE (PubMed), EMBASE, Web of Science and Cochrane was carried out on 25 November 2019, to identify papers published between 1980 and 2019 that focus on patients with MS-associated uveitis. RESULTS: Based on large cohort studies (n ≥ 1000), the prevalence of uveitis in patients with MS is estimated to be 0.53-1.34% (mean = 0.83%), and MS is diagnosed in 0.52-3.20% (mean = 1.30%) of patients with uveitis. The condition is most frequent among middle-aged women. Patients usually complain of floaters and/or blurred vision, with bilateral intermediate uveitis (with retinal vasculitis) as the most frequent ophthalmological finding. Both MS and intermediate uveitis are associated with HLA-DRB1*15:01 and IL-2RA gene polymorphism rs2104286 A > G, suggesting a common genetic background. T cells, and possibly B cells, play an important role in both autoimmune disorders. Multiple sclerosis (MS)-related uveitis is classically treated as non-infectious uveitis, with corticosteroids as the first treatment step. Other treatments include immunosuppressants, cryotherapy, laser photocoagulation and vitrectomy. These treatment options have a limited, if any, effect on the course of MS and can be complicated by side-effects. As treatment strategies for MS have increased in the last decade, it would be interesting to evaluate the efficacy of these new treatments during the course of uveitis. Moreover, the correlation between retinal periphlebitis and MS could be established more accurately with the recently developed techniques of wide-field fluorescein angiography in a large cohort of MS patients. CONCLUSION: MS-associated uveitis is a rare, highly discussed pathology about which much is still unknown. Large epidemiological studies and extrapolation of new MS treatments to this condition are warranted.

Acute bilateral serous retinal detachments with spontaneous resolution in a 6-year-old boy.

A healthy 6-year-old boy presented with acute bilateral vision loss, multiple serous retinal detachments between the vascular arcades and a thickened choroid. Spontaneous resolution occurred over several weeks. We hypothesize that the clinical constellation in our patient is suggestive of acute exudative polymorphous vitelliform maculopathy (AEPVM) or might be an atypical presentation of Vogt-Koyanagi-Harada (VKH) disease. We propose that it was caused by an autoimmune-mediated activation of inflammatory cells at the level of the choroid, induced by an unknown trigger.

Autologous full-thickness RPE-choroid graft to treat high-risk drusenoid pigment epithelial detachment without CNV.

Objective: To report on the survival of a retinal pigment epithelium (RPE)-choroid graft translocated to treat a patient with drusenoid pigment epithelial detachment (DPED). Methods: We describe a patient with bilateral high-risk DPED where one eye was treated with RPE-choroid translocation surgery and followed up for more than two years. Results: The RPE-choroid graft surgery was straightforward and the fully perfused graft was able to support stable vision of 0.5 Snellen acuity for more than two years despite the development of a choroidal neovessel at the edge of the graft. The vision in the fellow eye dropped from 0.5 to 0.2 Snellen in the same period. Conclusion: RPE-choroid translocation may slow the progression of DPED to atrophy but it can also transform dry age-related macular degeneration (AMD) into neovascular AMD.

Co-occurrence of bilateral nodular anterior scleritis and large-vessel arteritis in a patient with TINU syndrome.

We present a case of tubulointerstitial nephritis and uveitis (TINU) with nodular anterior scleritis and large-vessel arteritis. A 67-year-old patient was admitted to the hospital with high fever, thoracic pain, and weakness. Bilateral anterior uveitis was seen at that time. Laboratory examination showed acute renal failure. A renal biopsy was performed and showed pathognomonic signs of tubulointerstitial nephritis (TIN). Six months later, she developed ocular inflammation suggestive of nodular scleritis. One year after hospital admission, she presented with large-vessel arteritis. We describe a case of TINU with co-occurrence of scleritis and large-vessel arteritis.

A Bird's-Eye View of Chronic Unilateral Conjunctivitis: Remember about Chlamydia psittaci.

Chlamydia psittaci causes psittacosis in humans, mainly in people in contact with birds in either the setting of occupational or companion bird exposure. Infection is associated with a range of clinical manifestations from asymptomatic infection to severe atypical pneumonia and systemic disease. C. psittaci has also been associated with ocular adnexal lymphoma in human patients. The current paper describes successful doxycycline treatment of a male patient suffering from C. psittaci chronic unilateral conjunctivitis, most probably linked to the visit of a South African wildlife reserve. Increased awareness among general and occupational physicians, ophthalmologists, clinicians, and the public on the potential of C. psittaci to cause ocular infection is needed.

High-resolution optical coherence tomography, autofluorescence, and infrared reflectance imaging in Sjögren reticular dystrophy.

PURPOSE: To describe the phenotype of three cases of Sjögren reticular dystrophy in detail, including high-resolution optical coherence tomography, autofluorescence imaging, and near-infrared reflectance imaging. METHODS: Two unrelated teenagers were independently referred for ophthalmologic evaluation. Both underwent a full ophthalmologic workup, including electrophysiologic and extensive imaging with spectral-domain optical coherence tomography, autofluorescence imaging, and near-infrared reflectance imaging. In addition, mutation screening of ABCA4, PRPH2, and the mitochondrial tRNA gene was performed in Patient 1. Subsequently, the teenage sister of Patient 2 was examined. RESULTS: Strikingly similar phenotypes were present in these three patients. Fundoscopy showed bilateral foveal pigment alterations, and a lobular network of deep retinal, pigmented deposits throughout the posterior pole, tapering toward the midperiphery, with relative sparing of the immediate perifoveal macula and peripapillary area. This network is mildly to moderately hyperautofluorescent on autofluorescence and bright on near-infrared reflectance imaging. Optical coherence tomography showed abnormalities of the retinal pigment epithelium-Bruch membrane complex, photoreceptor outer segments, and photoreceptor inner/outer segment interface. The results of retinal function test were entirely normal. No molecular cause was detected in Patient 1. CONCLUSION: Imaging suggested that the lobular network of deep retinal deposits in Sjögren reticular dystrophy is the result of accumulation of both pigment and lipofuscin between photoreceptors and retinal pigment epithelium, as well as within the retinal pigment epithelium.

Confocal microscopy of corneal crystals in a patient with hereditary tyrosinemia type I, treated with NTBC.

PURPOSE: To describe the confocal microscopic findings in a patient with hereditary tyrosinemia type I (HT-I) treated with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) who developed corneal crystals. METHODS: In this case study, we describe the confocal microscopic findings in a boy, who was diagnosed with HT-I at the age of 4 months. At 16 years of age, he developed painful corneal lesions in both eyes. On slit-lamp examination, whorl-like branching epithelial corneal lesions were found, staining faintly with fluorescein. His NTBC treatment was stopped and reintroduced at a lower dose after 1 month. The lesions clearly regressed, leaving only mild residual epithelial scarring, without fluorescein staining and without pain. Confocal microscopy was performed in the acute painful stage and in the asymptomatic convalescent stage 5 months later. RESULTS: Confocal microscopy confirmed the presence of slender birefringent spiky crystals in the very superficial corneal epithelium. In the asymptomatic convalescent phase, the crystals clearly persisted on confocal microscopy, although they were barely visible on slit-lamp examination. CONCLUSIONS: This is the first in vivo demonstration by confocal microscopy of corneal crystals present in a patient with proven type I tyrosinemia, under NTBC treatment.