Melanoma-associated Retinopathy Research Articles

Case Report: Longitudinal Evaluation and Treatment of a Melanoma-Associated Retinopathy Patient.

Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome associated with cutaneous metastatic melanoma in which patients develop vision deficits that include reduced night vision, poor contrast sensitivity, and photopsia. MAR is caused by autoantibodies targeting TRPM1, an ion channel found in melanocytes and retinal ON-bipolar cells (ON-BCs). The visual symptoms arise when TRPM1 autoantibodies enter ON-BCs and block the function of TRPM1, thus detection of TRPM1 autoantibodies in patient serum is a key criterion in diagnosing MAR. Electroretinograms are used to measure the impact of TRPM1 autoantibodies on ON-BC function and represent another important diagnostic tool for MAR. To date, MAR case reports have included one or both diagnostic components, but only for a single time point in the course of a patient's disease. Here, we report a case of MAR supported by longitudinal analysis of serum autoantibody detection, visual function, ocular inflammation, vascular integrity, and response to slow-release intraocular corticosteroids. Integrating these data with the patient's oncological and ophthalmological records reveals novel insights regarding MAR pathogenesis, progression, and treatment, which may inform new research and expand our collective understanding of the disease. In brief, we find TRPM1 autoantibodies can disrupt vision even when serum levels are barely detectable by western blot and immunohistochemistry; intraocular dexamethasone treatment alleviates MAR visual symptoms despite high levels of circulating TRPM1 autoantibodies, implicating antibody access to the retina as a key factor in MAR pathogenesis. Elevated inflammatory cytokine levels in the patient's eyes may be responsible for the observed damage to the blood-retinal barrier and subsequent entry of autoantibodies into the retina.

Paraneoplastic syndromes in patients with melanoma.

Paraneoplastic syndromes are a group of rare clinical conditions characterized by a diverse array of systemic manifestations that arise in association with malignant tumours, often due to the production of bioactive substances by the tumour or an autoimmune response to the tumour. Melanoma, a malignant skin neoplasm originating from melanocytes, has been associated with various paraneoplastic syndromes. This paper provides an overview of the key paraneoplastic syndromes observed in patients with melanoma. Paraneoplastic syndromes in melanoma can manifest with neurological, dermatological, endocrine, haematological, and rheumatological symptoms, among others. Melanoma-associated retinopathy was the most reported paraneoplastic syndrome; this entity is characterized by a spectrum of retinal abnormalities. Paraneoplastic neurological syndromes, such as paraneoplastic encephalitis and paraneoplastic cerebellar degeneration, are among the most frequently reported. The pathophysiology of paraneoplastic syndromes often involves the production of autoantibodies against neuronal or tumour antigens, immune-mediated reactions, or the release of cytokines and growth factors from the tumour. Management strategies for paraneoplastic syndromes associated with melanoma primarily focus on treating the underlying malignancy, which may lead to resolution or improvement of the paraneoplastic manifestations. Immune-modulating therapies, including corticosteroids, intravenous immunoglobulins, and plasmapheresis, may be considered in selected cases to ameliorate symptoms and suppress the autoimmune response. In conclusion, paraneoplastic syndromes in patients with melanoma are a complex and diverse group of clinical entities with a broad range of presentations. Further research is needed to enhance our understanding of the mechanisms and therapeutic options for paraneoplastic syndromes associated with melanoma.

Review of Autoimmune Retinopathy and Its Association with Melanoma and Other Malignancies

Autoimmune Retinopathy (AIR) is an immune-mediated degenerative retinal disorder affecting retinal cell function leading to progressive vision loss. This review aims to quantify documented AIR cases in the literature; and elucidate common visual symptoms, AIR and cancer diagnosis chronology and autoantibodies’ role in AIR pathophysiology. A literature search extracted 58 Melanoma-Associated Retinopathy (MAR) and 76 Cancer-Associated Retinopathy (CAR) cases; CAR primarily consisted of lung, endometrial, ovarian and breast cancer. The majority of MAR cases presented with a melanoma diagnosis preceding onset of AIR symptoms, while the majority of CAR cases presented with AIR symptoms preceding the diagnosis of malignancy. MAR patients experienced nyctalopia and photopsias while CAR patients experienced vision loss, photopsias and nyctalopia. Anti-recoverin is the most well-established antibody implicated in AIR pathogenicity. However, autoantibodies to α-enolase, aldolase A and C, transducin-α, carbonic anhydrase II, arrestin, GAPDH and Transient Receptor Potential cation channel, subfamily M, member 1 (TRPM1) are also key components of retinal degeneration. AIR is likely caused by antibodies-targeting retinal antigens aberrantly expressed in cancer cells-penetrating the blood-retinal barrier and cross-reacting with retinal cell antigens, inducing retinal pathology. It may be appropriate to include AIR vision panel screening as standard of care for individuals with personal/family history or signs/symptoms of retinopathy or cancers for early detection and intervention.

Cancer-Associated Retinopathy (CAR) And Melanoma-Associated Retinopathy (MAR)

Cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR) are rare paraneoplastic syndromes in which antibodies are directed against retinal antigens, independent of primary tumor or metastasis, that can cause vision loss. The fact that these antigens differ according to different types of cancer causes the developing retinopathy and accordingly the symptoms to be heterogeneous and causing difficulties in diagnosis and treatment. The literature on this subject is limited with few reported case reports and case series. The lack of controlled clinical studies also makes it difficult for clinicians to manage these cases. Paraneoplastic syndromes are important because they can diagnose undiagnosed malignancies or indicate recurrence of treated malignancies. The appearance of the symptoms of CAR and MAR is of great importance for the prognosis of cancer, as it may precede cancer findings. In addition, with early diagnosis, irreversible retinal damage will be minimal. In this review, the pathophysiology, clinical findings and treatments of CAR and MAR are emphasized.

Vogt-Koyanagi-Harada-like Syndrome and Electronegative Electroretinogram after Nivolumab Therapy for Metastatic Cutaneous Melanoma: A Case Report

Background: Vogt-Koyanagi-Harada-like (VKH) syndrome or electronegative electroretinograms (ERG) have both been described before or after immunotherapy for metastatic cutaneous melanoma, but they have not been described occurring together. Objective: The objective of this study is to describe a case of VKH-like syndrome occurring simultaneously with an electronegative ERG after nivolumab therapy for metastatic cutaneous melanoma. Methods: Case report of a patient with ocular findings after nivolumab therapy for metastatic melanoma was reported. Multimodal imaging, including color fundus photography, optical coherence tomography (OCT), and both full-field and multifocal ERGs were used to describe the findings. Literature review was conducted with PubMed. Results: We reported a case of a patient with nivolumab-treated melanoma presenting with presumed VKH-like syndrome with panuveitis, choroidal depigmentation, and cutaneous vitiligo, as well as melanoma-associated retinopathy (MAR)-like electronegative ERG findings. Nivolumab was stopped and corticosteroid therapy was initiated. Although the patient’s visual acuity remained severely limited, her inflammation resolved, and the areas of choroidal depigmentation slowly decreased over years of subsequent follow-up. Conclusion: Vision loss accompanied by simultaneous VKH-like findings with choroidal vitiligo and a MAR-like electronegative ERG may develop after nivolumab therapy. The uveitic and vitiligo may improve with immunosuppressive therapy, but the vision loss and ERG findings may persist.

Paraneoplastic syndromes in ophthalmology

Paraneoplastic syndromes consist on systemic manifestations associated with certain cancers which are not a direct consequence of tumor invasion or its metastases. It is known that autoimmunity and autoantibody synthesis play an important role in its pathophysiology due to a process of molecular mimicry. Paraneoplastic syndromes in ophthalmology are rare, but it is important to recognize them clinically because in some cases symptoms preceded the diagnosis of an underlying neoplasia. Most frequently involved cancer is small cell lung carcinoma, but there is also a relationship with other tumor etiologies such as thymoma, gynecological tumors or neuroblastoma in children. Paraneoplastic syndromes with ocular involvement can be divided into those that affect the afferent visual pathway, such as cancer-associated retinopathy, melanoma-associated retinopathy, or paraneoplastic optic neuropathy; and the ones that affect the efferent visual pathway, such as bilateral tonic pupils, Myasthenia Gravis, Lambert-Eaton syndrome or paraneoplastic cerebellar degeneration. The presence of autoantibodies is helpful in clinical practice but negativity does not exclude this diagnosis. Although evolution and prognosis is linked to primary disease, in some cases specific treatment, usually immunosuppressive therapy, can help improving patients quality of life.

Autoimmune retinopathy with associated anti-retinal antibodies as a potential immune-related adverse event associated with immunotherapy in patients with advanced cutaneous melanoma: case series and systematic review

ObjectiveTo demonstrate the spectrum of autoimmune retinopathy (AIR) associated with immunotherapy for advanced cutaneous melanoma.Methods and analysisRetrospective chart review on patients with advanced cutaneous melanoma who developed AIR after initiating...

Broad locations of antigenic regions for anti-TRPM1 autoantibodies in paraneoplastic retinopathy with retinal ON bipolar cell dysfunction

PurposeCancer-associated retinal ON bipolar cell dysfunction (CARBD), which includes melanoma-associated retinopathy (MAR), has been reported to be caused by autoantibodies against the molecules expressed in ON bipolar cells, including TRPM1. The purpose of this study was to determine the antigenic regions of the autoantibodies against TRPM1 in the sera of CARBD patients, in whom we previously detected anti-TRPM1 autoantibodies. MethodsThe antigenic regions against TRPM1 in the sera of eight CARBD patients were examined by Western blots using HEK293T cells transfected with the plasmids expressing FLAG-tagged TRPM1 fragments. The clinical course of these patients was also documented. ResultsThe clinical course differed among the patients. The electroretinograms (ERGs) and symptoms were improved in three patients, deteriorated in one patient, remained unchanged for a long time in one patient, and were not followable in three patients. Seven of the eight sera possessed multiple antigenic regions: two sera contained at least four antigen recognition regions, and three sera had at least three regions. The antigen regions were spread over the entire TRPM1 protein: five sera in the N-terminal intracellular domain, six sera in the transmembrane-containing region, and six sera in the C-terminal intracellular domain. No significant relationship was observed between the location of the antigen epitope and the patients’ clinical course. ConclusionsThe antigenic regions of anti-TRPM1 autoantibodies in CARBD patients were present not only in the N-terminal intracellular domain, which was reported in an earlier report, but also in the transmembrane-containing region and in the C-terminal intracellular domain. In addition, the antigenic regions for TRPM1 were found to vary among the CARBD patients examined, and most of the sera had multiple antigenic regions.

Off-Label Use of 0.19 mg Fluocinolone Acetonide Intravitreal Implant: A Systematic Review.

Corticosteroids are used in a variety of ophthalmological diseases. One challenge faced by ophthalmologists is to deliver corticosteroids to the posterior segment of the eye with efficacy and safety. Sustained-release corticosteroid implants may be the answer to this problem. The 0.19 mg fluocinolone acetonide (FAc) implant (Iluvien®) releases FAc for 36 months, and it is approved for the treatment of diabetic macular edema (DME) and noninfectious uveitis. We decided to do a systematic review to acknowledge in which other diseases FAc implant is being used off-label. A literature search was performed in the following three electronic databases: PubMed, Scopus, and Web of Science (from January 1st, 2000, to September 20th, 2020), using the following query: (“Fluocinolone Acetonide” OR Iluvien®) AND (“eye” OR “ocular” OR “intravitreal).” A total of 11 papers were included, and the use of FAc implant was analyzed in the following diseases: radiation-induced maculopathy (RM); paraneoplastic visual syndromes (melanoma-associated retinopathy (MAR) and cancer-associated retinopathy (CAR)); Sjogren's syndrome-related keratopathy; retinal vein occlusion (RVO); cystoid macular edema (CME); diabetic retinal neurodegeneration (DRN); and retinitis pigmentosa (RP). FAc implant may be a potential treatment for these diseases; however, the level of scientific evidence of the included studies in this review is limited. Further studies with larger cohorts and longer follow-ups are needed to validate this data.

Normalization of electroretinogram and symptom resolution of melanoma-associated retinopathy with negative autoantibodies after treatment with programmed death-1 (PD-1) inhibitors for metastatic melanoma

Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome that involves the production of autoantibodies which can cross-react with retinal epitopes leading to visual symptoms. Autoantibodies can target intracellular proteins, and only a few are directed against membrane proteins. This discrepancy in autoantibody–protein target can translate into different immune responses (T-cell mediated vs B-cell mediated). Historically, treatment of MAR has focused on surgical reduction or immunosuppressive medication, mainly glucocorticoids. However, tumor resection is not relevant in metastatic melanoma in which MAR is mostly encountered. Moreover, the use of glucocorticoids can reduce the efficacy of immunotherapy. We report the first case to our knowledge with subjective resolution of visual symptoms and objective evidence of normalization of electroretinogram of MAR with undetectable autoantibodies after administration of programmed death-1 (PD-1) inhibitor (pembrolizumab) without the use of surgical reduction or systemic immunosuppression. This case highlights the potential improvement and resolution of negative autoantibody MAR with the use of PD-1 inhibitors and emphasizes the importance of multidisciplinary approach and team discussion to avoid interventions that can decrease immunotherapy-mediated anti-tumor effect.

Ocular Paraneoplastic Syndromes.

Ocular-involving paraneoplastic syndromes present a wide variety of clinical symptoms. Understanding the background pathophysiological and immunopathological factors can help make a more refined differential diagnosis consistent with the signs and symptoms presented by patients. There are two main pathophysiology arms: (1) autoimmune pathomechanism, which is presented with cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), cancer-associated cone dysfunction (CACD), paraneoplastic vitelliform maculopathy (PVM), and paraneoplastic optic neuritis (PON), and (2) ectopic peptides, which is often caused by tumor-expressed growth factors (T-exGF) and presented with bilateral diffuse uveal melanocytic proliferation (BDUMP). Meticulous systematic analysis of patient symptoms is a critical diagnostic step, complemented by multimodal imaging, which includes fundus photography, optical coherent tomography, fundus autofluorescence, fundus fluorescein angiography, electrophysiological examination, and sometimes fundus indocyjanin green angiography if prescribed by the clinician. Assessment of the presence of circulating antibodies is required for diagnosis. Antiretinal autoantibodies are highly associated with visual paraneoplastic syndromes and may guide diagnosis by classifying clinical manifestations in addition to monitoring treatment.

Correction: Identification and characterization of novel TRPM1 autoantibodies from serum of patients with melanoma-associated retinopathy.

[This corrects the article DOI: 10.1371/journal.pone.0231750.].

Identification and characterization of novel TRPM1 autoantibodies from serum of patients with melanoma-associated retinopathy.

Melanoma-associated retinopathy (MAR) is a rare paraneoplastic retinal disorder usually occurring in the context of metastatic melanoma. Patients present with night blindness, photopsias and a constriction of the visual field. MAR is an auto-immune disorder characterized by the production of autoantibodies targeting retinal proteins, especially autoantibodies reacting to the cation channel TRPM1 produced in melanocytes and ON-bipolar cells. TRPM1 has at least three different isoforms which vary in the N-terminal region of the protein. In this study, we report the case of three new MAR patients presenting different anti-TRPM1 autoantibodies reacting to the three isoforms of TRPM1 with variable binding affinity. Two sera recognized all isoforms of TRPM1, while one recognized only the two longest isoforms upon immunolocalization studies on overexpressing cells. Similarly, the former two sera reacted with all TRPM1 isoforms on western blot, but an immunoprecipitation enrichment step was necessary to detect all isoforms with the latter serum. In contrast, all sera labelled ON-bipolar cells on Tprm1+/+ but not on Trpm1-/- mouse retina as shown by co-immunolocalization. This confirms that the MAR sera specifically detect TRPM1. Most likely, the anti-TRPM1 autoantibodies of different patients vary in affinity and concentration. In addition, the binding of autoantibodies to TRPM1 may be conformation-dependent, with epitopes being inaccessible in some constructs (truncated polypeptides versus full-length TRPM1) or applications (western blotting versus immunohistochemistry). Therefore, we propose that a combination of different methods should be used to test for the presence of anti-TRPM1 autoantibodies in the sera of MAR patients.

Paraneoplastic causes of vision loss

AbstractParaneoplastic occular disorders are clinical syndromes resulting from nonmetastatic systemic effects of underlying cancers. While not fully elucidated the underlying mechanism is presumed to be a cross reaction of the immune reaction to the underlying cancer that attaches normal host tissue. This cross reaction can happen in a variety of occular tissues resulting in dysfunction of the retina, optic nerve and tear film and extraocular muscles. (1‐3). The lists of cancers and associated antibodies is constantly growing but, in many cases, the clinical phenotype is very similar. Cancer associated retinopathy (CAR) for example is associated with several antibodies including anti‐recoverin, anti‐alpha enolase, anti‐transducin, and anti‐carbonic anhydrase(2, 3). Each of these antibodies have been associated with a distinct cancer including skin, genital and small cell lung cancer (SCLC). CAR causes a slowly progressive asymmetric vision loss due to damage to retinal ganglion cells and bipolar cells which can result in optic nerve pallor. Melanoma associated retinopathy (MAR), similarly can present with nyctalopia, photopsia’s and loss of peripheral vision. The antibodies associated with MAR; anti‐transducin, anti‐rhodopsin and anti‐arrestin typically attack the on bipolar system. As with CAR the visual dysfunction can predate the discovery of the cancer. Conversely, autoimmune related retinopathy and optic neuropathy occurs without an underlying cancer and is associated with anti‐GAD and anti‐ anti‐collapsin‐responsive mediator protein‐5 (CRMP‐5) antibodies(2). In all three cases electroretinograms are key to making the diagnosis as the objective clinical examination can be normal. Electroretinograms are key to distinguishing retinal dysfunction which can cause an optic neuropathy from a paraneoplastic optic neuropathy (PON). The classical antibody in PON is. CRMP‐5 is associated with SCLC and thymoma and can produce optic disc edema with subsequent atrophy. The treatment and management of occular paraneoplastic disorders requires appropriate investigations to look for an underlying cancer. Knowing the specific antibody associated with the disorder can be helpful in this regard and in some cases a panel of antibody tests is appropriate in the right clinical context(4). Treatment of the underlying cancer can, in some cases, can lead to a resolution of the clinical symptoms. Symptom control can also be accomplished using immunosuppression with steroids or IVIG and in some cases plasmapheresis has been useful(4, 5).References Grewal DS, Fishman GA, Jampol LM. Autoimmune retinopathy and antiretinal antibodies: a review. Retina. 2014;34(5):827–45. Bataller L, Dalmau J. Neuro‐ophthalmology and paraneoplastic syndromes. Current opinion in neurology. 2004;17(1):3–8. Rahimy E, Sarraf D. Paraneoplastic and non‐paraneoplastic retinopathy and optic neuropathy: evaluation and management. Survey of ophthalmology. 2013;58(5):430–58. Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010;85(9):838–54. Damek DM. Paraneoplastic Retinopathy/Optic Neuropathy. Current treatment options in neurology. 2005;7(1):57–67.

Melanoma-associated retinopathy.

Melanoma-associated retinopathy (MAR) is a rare paraneoplastic autoimmune manifestation of cutaneous malignant melanoma. Patients classically present with acute onset night blindness, positive visual phenomena and visual field defects, and typically have significantly reduced quality of life as a result. Early recognition of MAR is of prognostic significance as it can precede the diagnosis of primary or metastatic malignant melanoma, and early treatment can lower the risk of irreversible immunological damage to the retinal cells with improved visual outcomes. The focus of our review article is therefore to raise awareness of MAR and present the latest evidence relating to the investigation and management of this condition.

Typical electronegative electroretinography and nyctalopia as a presenting feature of systemic malignant melanoma.

We report a unique case of a female who presented with unilateral disk edema, melanoma-associated retinopathy symptoms, and suggestive electroretinography findings preceding a diagnosis of metastatic melanoma of the pelvis. A 63-year-old female presented with complaints of seeing shimmering lights and nyctalopia, and underwent an extensive ophthalmological and electrophysiological examination. Best-corrected visual acuity was 20/20 in both eyes. Visual fields showed relative central scotomata and concentric narrowing. Slit-lamp and fundus examinations were normal. Rod-specific electroretinography responses were severely reduced, with electronegative maximal combined rod–cone responses and delayed cone responses with normal amplitude. Melanoma-associated retinopathy was suspected. Extensive systemic and internal evaluation revealed occult metastatic melanoma of the pelvis of unknown primary site.

TRPM1 Autoantibodies in Melanoma Patients Without Self-Reported Visual Symptoms.

PurposeMelanoma-associated retinopathy (MAR) is a paraneoplastic syndrome associated with cutaneous malignant melanoma (CMM). Visual symptoms include night blindness, photopsia, and reduced-contrast sensitivity. An abnormal ERG b-wave and the presence of anti-bipolar cell autoantibodies, including autoantibodies reacting with the ON-bipolar cell TRPM1 channel, help to confirm the diagnosis. The goal of this study was to determine if CMM patients without visual symptoms also express anti-TRPM1 autoantibodies.MethodsSerum samples from 15 CMM patients were tested using three assays: immunofluorescent labeling of TRPM1-transfected HEK cells, immunofluorescent labeling of retinal sections from wild-type and TRPM1 knockout mice, and immunoblot detection of a bacterially produced recombinant TRPM1 peptide.ResultsSerum specimens from 5 of the 15 CMM patients without declared visual symptoms were positive for anti-TRPM1 autoantibodies in at least one of the three assays. One of 50 control sera from patients not known to have cancer was also weakly reactive with the TRPM1 peptide.ConclusionsAutoantibodies against TRPM1 are present in CMM patient sera without self-reported visual symptoms. Most patients had advanced (stage III and IV) disease and were undergoing aggressive treatments, including immunotherapy. It is unknown if immunotherapy affects the expression of TRPM1 autoantibodies. The presence of TRPM1 autoantibodies may predispose patients for MAR.

Abstract B032: PhIP-seq assessment of the serum antibody repertoire before and after immune-related adverse events in four melanoma patients treated with checkpoint blockade immunotherapy

Abstract Phage immunoprecipitation sequencing (PhIP-seq) is a technique to profile the epitope specificities of an antibody repertoire by phage display of a peptide library followed by immunoprecipitation and next-generation sequencing (1). We have developed phage libraries corresponding to all 36-mer peptides in the human proteome (approximately 413,000 peptides), as well as libraries of peptides found in viruses, bacteria, and toxins. Here, in a pilot study to understand if PhIP-seq might be used to identify predictive biomarkers for immune-related adverse events (irAE) in the context of checkpoint blockade immunotherapy, we applied the human proteome library to probe the self-directed IgG response in sera from four melanoma patients receiving checkpoint blockade who experienced irAE. In total, 16 serum samples acquired at the pre-treatment, post-treatment / pre-irAE, or post-irAE timepoints were assayed from these patients. We additionally analyzed samples from six melanoma patients who received vaccines targeting the MART-1 and NY-ESO-1 antigens. Using a stringent confidence threshold, we identified a median 31 self-directed antibody specificities (hits) at the pre-immunotherapy timepoint in these cancer patients and 41.5 hits post-therapy, compared to a median 6.5 hits in healthy donors. Patients receiving combination checkpoint blockade showed more hits than those treated with monotherapy. For a patient who received combination nivolumab and ipilimumab and developed a hepatic irAE, a cluster of 25 hits (of 161 total) was detected uniquely in a sample taken within two months subsequent to the adverse event. This cluster included a peptide from the C-Reactive Protein (CRP) gene and other genes expressed in the liver (EHBP1, VSTM2L), or across tissues (SAFB2), but also included genes with low expression in the liver (SPTBN4, DMBT1, IQGAP3, SPTBN4). In a patient who received ipilimumab and nivolumab and developed myalgia, hits against targets associated with autoimmune disease were found including NUMA1 (connective tissue autoimmunity), TRPM1 (melanoma-associated retinopathy), as well as three epitopes in the Mediator Of DNA Damage Checkpoint 1 (MDC1) gene. Finally, for three patients receiving a peptide vaccine targeting MART-1 and NY-ESO-1 with adjuvant poly-ICLC and montanide, we detected an IgG response against NY-ESO-1, but not MART-1, in each patient. No response to either protein was observed in three patients receiving a dendritic cell vaccine against the same antigens.Our small study suggests that PhIP-seq readily detects changes in the epitope specificities of the serum antibody repertoire in the course of immunotherapy. A key limitation of PhIP-seq is that the method can only detect antibodies with specificities for linear (as opposed to conformational) epitopes. Nevertheless, the assay’s low cost (approximately $30 per sample), small sample size requirement (1 µL serum), and ability to work with dried blood spot samples may make it an attractive technology to discover serological predictors of irAE in larger cohorts.

Immunopathogenesis of ophthalmological paraneoplastic syndromes: Recent findings

The aim of this study was to summarize the current knowledge of paraneoplastic syndromes involving eyes. The main interest was the immunopathogenesis of the abovementioned entities. A web search was conducted using Medline, Web of Science and Scopus engines. Key words concerning ocular paraneoplastic syndromes (OPS) such as: "ocular paraneoplastic syndrome", "cancer-associated retinopathy", "cancer-associated cone dysfunction", "melanoma-associated retinopathy", "bilateral diffuse uveal melanocytic proliferation", and "paraneoplastic optic neuritis" were combined with "immunology", "immune response", "antibodies", or "autoantibodies". Numerous papers were found as a result of "ocular paraneoplastic syndrome" search and many of them matched the chosen criteria. We focused on the most recent papers - published in the last 5 years - and eventually, 92 items were found. Only several papers from each detailed category fulfilled both OPS and immunologic criteria. Site-specific paraneoplastic syndromes still remain a difficult clinical challenge. The immunopathogenesis of some of them seems to be more complex than previously thought.

ISCEV extended protocol for the photopic On\u2013Off ERG

The International Society for Clinical Electrophysiology of Vision (ISCEV) standard for full-field electroretinography (ERG) describes a minimum procedure, but encourages more extensive testing. This ISCEV extended protocol describes an extension to the ERG standard, namely the photopic On–Off ERG, and outlines common clinical applications. A light stimulus duration of 150–200 ms is used in the presence of a rod-suppressing background to elicit cone-driven On- and Off-system ERG components. The On-response occurs after the stimulus onset and has a negative a-wave and positive b-wave. The Off d-wave is a positive component evoked by stimulus offset. Common diagnoses that may benefit from additional photopic On–Off ERG testing include retinal dystrophies and retinal disorders that cause dysfunction at a level that is post-phototransduction or post-receptoral. On–Off ERGs assess the relative involvement of On- and Off-systems and may be of use in the diagnosis of disorders such as complete and incomplete congenital stationary night blindness (complete and incomplete CSNB), melanoma-associated retinopathy, and some forms of autoimmune retinopathy. The photopic On–Off ERGs may also be useful in X-linked retinoschisis, Batten disease, Duchenne muscular dystrophy, spinocerebellar degeneration, quinine toxicity, and other retinal disorders.