Management of Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP)-A Case Report.

Background and Objectives: This study reports a case of a 62-year-old patient experiencing a significant decline in vision over the past three months. The initial best-corrected visual acuity (BCVA) of 20/20 in both eyes diminished to 20/200 in the right eye (RE) and counting fingers (CF) in the left eye (LE) within this timeframe. The patient was diagnosed with stage 4 ovarian cancer just one month before the significant vision deterioration. Materials and Methods: A thorough ophthalmologic examination revealed a notable progression of cataracts and the presence of subretinal fluid on the posterior pole, accompanied by choroidal thickening. The right eye exhibited multifocal, orange-pigmented, and elevated choroidal lesions, while the left eye's fundus examination was impeded by dense cataracts. Optical coherence tomography (OCT) revealed bilateral choroidal thickening with overlying folds and subretinal fluid, and ultrasound imaging of the choroidal lesions indicated moderate homogenous internal reflectivity. Results: The patient received a diagnosis of BDUMP (bilateral diffuse uveal melanocytic proliferation), a paraneoplastic syndrome marked by simultaneous, bilateral, painless vision loss and the rapid onset of bilateral cataracts with serous retinal detachments. Despite cataract extraction, the expected visual recovery was not achieved (RE: CF; LE: 2/200, respectively). Plasmapheresis showed some success in stabilizing vision loss attributed to serous retinal detachments. Conclusions: BDUMP necessitates addressing the underlying malignancy for effective treatment. Left untreated, it can lead to near blindness within a year. The prognosis remains grim, with an average survival time ranging from 12 to 15.7 months from the time of diagnosis. Considering this case report, it is crucial to establish effective management plans and further investigate potential treatment methods and predictive markers centered around BDUMP. Collaboration between healthcare professionals and researchers is crucial in addressing the complexities of BDUMP, as the timely diagnosis and treatment of the disease remains a top priority.

Ocular Paraneoplastic Syndromes: A Critical Review of Diffuse Uveal Melanocytic Proliferation and Autoimmune Retinopathy.

Background: Dozens of paraneoplastic syndromes affect the visual system ranging from conjunctival pemphigoid to encephalopathy of the occipital cortex. The most profiled ocular syndromes are bilateral diffuse uveal melanocytic proliferation (BDUMP) and the autoimmune retinopathies.Purpose: To review the critical features of these 2 entities then concentrate on advancements in treatment made within the last 10 years.Study Design: Literature review with structured data abstraction.Results: Major insights into pathogenesis have been wanting. Plasmapheresis appears to improve vision in a substantial proportion of patients with BDUMP. The number of clinical variables that influence visual outcome in paraneoplastic retinopathies combined with the variety of local and systemic treatment options makes interpretation of clinical effectiveness difficult.Conclusions: The rarity of these disorders makes randomized clinical trials unlikely. It may be time for a clinical professional organization to use a modified Delphi method to establish a consensus algorithm for the diagnosis and management of retinal paraneoplastic syndromes to augment clinical communications and clinical trials.

Neuro-ophthalmic manifestations of cancer: a narrative review.

BACKGROUND AND OBJECTIVE: Neuro-ophthalmic manifestations of cancer are vast and early recognition of a serious ocular condition due to either cancer or its therapy is important for both vision preservation as well as providing valuable treatment and prognostic information regarding the underlying malignancy. This review focuses on direct and indirect effects of cancer on the eye and its adnexa, hematologic malignancy, complications of traditional and novel oncologic therapies, and paraneoplastic syndromes as they relate to the eye as these disorders can lead to potentially devastating or irreversible vision loss. METHODS: PubMed was searched primarily for the following topics: optic nerve infiltration, primary vitreoretinal lymphoma (PVRL), ocular paraneoplastic disorders, and ophthalmic complications of cancer therapeutics. Literature was selected based on historical significance and landmark studies (e.g., Cross et al. series of paraneoplastic optic neuritis patients; Chan's textbook on primary intraocular lymphoma) as well as publications published after 2000. References from select studies were additionally included. Given the sparsity of literature on many subjects, most publications were included during this time frame in our review. KEY CONTENT AND FINDINGS: There are several ophthalmic entities that the oncologist should be aware of including leukemic optic nerve infiltration, PVRL, paraneoplastic syndromes as they related to the eye, and adverse effects of therapeutics. Unfortunately, given the rarity of some of these entities [e.g., paraneoplastic optic neuropathy (PON), cancer-associated retinopathy (CAR)], diagnosis can be difficult and treatment options are often limited. CONCLUSIONS: Oncologists can develop a set of basic ophthalmology examination skills that will help to triage and manage patient eye complaints. In certain instances, oncologists have the potential to avert devastating vision loss with early recognition of neuro-ophthalmic complications.

Síndromes paraneoplásicos en oftalmología / Paraneoplastic syndromes in ophthalmology

Los síndromes paraneoplásicos consisten en la afectación de órganos y tejidos alejados de un tumor primario, y que no son consecuencia directa de la invasión tumoral ni de sus metástasis. Se sabe que en su fisiopatología desempeñan un papel importante la autoinmunidad y la síntesis de autoanticuerpos debido a un proceso de mimetismo molecular. Los síndromes paraneoplásicos de afectación oftalmológica son una enfermedad poco frecuente, pero es importante reconocerlos clínicamente debido a que en algunas ocasiones los síntomas derivados preceden al diagnóstico de la neoplasia de base. El tumor más frecuentemente relacionado con esta enfermedad es el carcinoma microcítico pulmonar, pero también existe relación con otras etiologías tumorales como el timoma, los tumores ginecológicos o el neuroblastoma en niños. Los síndromes paraneoplásicos de afectación oftalmológica pueden dividirse entre los que afectan a la vía visual aferente, como la retinopatía asociada al cáncer, la retinopatía asociada al melanoma o la neuropatía óptica paraneoplásica; o a la vía visual eferente, como las pupilas tónicas bilaterales, la miastenia gravis, el síndrome de Lambert-Eaton o la degeneración cerebelosa paraneoplásica. Cada vez se conocen más autoanticuerpos relacionados y su positividad es de ayuda en la práctica clínica, pero la negatividad no excluye el diagnóstico. Aunque su evolución y pronóstico va ligado al de la enfermedad causal, en algunos casos el tratamiento específico, habitualmente mediante terapia inmunosupresora puede ayudar a mejorar la calidad de vida de estos pacientes (AU)

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 (AU)

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.

[Paraneoplastic ophthalmopathies]. / Ophtalmies paranéoplasiques.

Ocular paraneoplastic syndromes are rare conditions that can affect any part of the eye at any age. Thus, every ophthalmologist should be familiar with their management, as some of them may reveal severe, life-threatening conditions. These consist overwhelmingly of neuro-ophthalmological manifestations, affecting the optic nerve (paraneoplastic optic neuritis), retina (paraneoplastic retinopathy) or neurological pathways generating eye movements (saccadic intrusion, oculomotor palsy, nystagmus...); occasionally, they involve the anterior segment, orbit or uveal tract. As some of these manifestations appear to be quite common and non-specific, any systemic or especially neurologic comorbidities should increase suspicion. Treatment relies first on oncologic management, and then often more targeted therapy for the associated immune involvement.

Non-paraneoplastic autoimmune retinopathy that developed in fellow eye 10 years after onset in first eye: a case report.

BACKGROUND: Evidence-based criteria for the treatment of autoimmune retinopathy (AIR) have not been established. The pathology and clinical features of each antibody causing AIR, and its long-term course are still undetermined. We report our findings in a case of non-paraneoplastic AIR (npAIR) that developed in the fellow eye 10 years after the onset in the first eye. CASE PRESENTATION: Our patient had photophobia in both eyes and a rapidly progressing visual field defect in his right eye at the initial examination. He was diagnosed with non-paraneoplastic AIR based on the clinical findings and immunoblot analyses for anti-retinal antibodies, and he was treated with steroids. Ten years later, a visual field defect developed in the fellow eye, and a diagnosis of npAIR was made. Immunoblot analyses were positive for anti-α-enolase antibodies. He was treated with steroids, immunosuppressants, and plasma exchange. However, the response to the treatment was poor and both eyes eventually became blind. CONCLUSIONS: As best we know, this is the first case report of npAIR that developed in the fellow eye over 10 years after the development in the first eye. Long-term follow-up and a search for tumor lesions are necessary in cases of npAIR. Further understanding of the long-term course of AIR can contribute to an understanding of the pathology and treatment of npAIR.

Improvement of reduced electroretinographic responses in thymoma-associated retinopathy: a case report and literature review.

PURPOSE: To report a patient with thymoma-associated retinopathy presenting as having a good visual prognosis. METHODS: Case report and literature review. CASE REPORT: A 42-year-old female patient was referred to our hospital for complaints of sudden visual-field defects bilaterally. Decimal corrected visual acuity (VA) was 1.5 and 1.2 in the right (RE) and left eyes (LE), respectively. Fundus autofluorescence revealed hyper-autofluorescence from the posterior pole to mid-peripheral retina in both eyes. Full-field electroretinography (ERG) amplitudes were reduced to 20-50% and 30-50% of our controls for the scotopic and photopic conditions, respectively. A systemic examination revealed the presence of thymoma, and the patient underwent thymectomy and immunosuppression therapies. Immunohistochemical analysis using the patient's serum showed immunolabeling on the photoreceptor inner segment and outer plexiform layer in the monkey retina. Two years later, VA remained at 1.5 and 1.2 in RE and LE. ERG amplitudes improved to 30-60% of the controls for the scotopic conditions. However, photopic ERG showed no remarkable change. CONCLUSIONS: To our knowledge, improvement of reduced rod-mediated ERG responses has not been described in seven previously reported patients with thymoma-associated retinopathy. The good visual prognosis of our patient may be associated with well-timed intervention.

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.

Heterogeneity of cultured melanocyte elongation and proliferation factor in bilateral diffuse uveal melanocytic proliferation.

A patient with bilateral diffuse uveal melanocytic proliferation (BDUMP) associated with endometrial cancer was treated with plasmapheresis, but failed therapy with progressive serous retinal detachment. We collected plasma before and after plasmapheresis therapy. Our goal was to determine if the cultured melanocyte elongation and proliferation (CMEP) factor and hepatocyte growth factor (HGF) was present in the IgG enriched fraction and understand why our patient failed plasmapheresis therapy. Melanocytes were cultured for 3-5 days in the presence of control medium, unfractionated pre-plasmapheresis BDUMP medium, IgG enriched or IgG depleted BDUMP medium, or unfractionated post-plasmapheresis BDUMP medium. Subretinal fluid was collected from patients with BDUMP and control retinal detachments and analyzed by electropheresis with immunoblotting. Medium with unfractionated BDUMP plasma stimulated melanocyte growth 1.4-1.5 fold compared to control medium on days 3-5 (p < 0.001 for all). Both IgG enriched and IgG depleted BDUMP medium mildly increased melanocyte growth 1.3 fold (p < 0.05 for enriched, p < 0.01 for depleted) compared to control. In comparison, unfractionated BDUMP medium caused a 1.7-fold increase in melanocyte growth, which was significantly more than the enriched (p < 0.01) and depleted (p < 0.05) fractions. Pre-plasmapheresis and post-plasmapheresis unfractionated BDUMP medium equally stimulated melanocyte growth 1.7-fold (p < 0.05) compared to control. HGF was present in IgG depleted, pre-plasmapheresis, and post-plasmapheresis samples, but absent in the IgG enriched fraction. There was no enrichment of IgG in the subretinal fluid from eyes with BDUMP. In conclusion, CMEP factor is not concentrated in the IgG enriched plasma fraction in our patient who failed plasmapheresis therapy. HGF levels have no correlation with melanocyte growth. Because plasmapheresis preferentially removes immunoglobulins from the plasma, our patient responded poorly to plasmapheresis treatment with worsening retinal detachment.

[Paraneoplastic Syndromes in Ophthalmology (French version of the article)]. / Syndromes paranéoplasiques en ophtalmologie.

Paraneoplastic syndromes involving the visual system are a heterogeneous group of disorders occurring in the setting of systemic malignancy. Although these syndromes are rare, the clinical manifestations can herald an unsuspected, underlying malignancy. The associated antibodies and histopathology of each syndrome are presented to help in the understanding of these autoimmune phenomena. Outlined in this review article are diagnostic features useful in differentiating cancer-associated retinopathy, melanoma-associated retinopathy, paraneoplastic polymorphous vitelliform maculopathy, bilateral diffuse uveal melanocytic proliferation and paraneoplastic neurologic syndromes such as optic neuropathy, opsoclonus-myoclonus, Lambert-Eaton myasthenia and paraneoplastic cerebellar degeneration.

Unilateral cancer-associated retinopathy: diagnosis, serology and treatment.

PURPOSE: To report a case of unilateral cancer-associated retinopathy (CAR) with clinical, serological and electroretinogram (ERG) normalization after aggressive cancer treatment combined with steroids and rituximab. METHODS: Work-up included extensive clinical and electrophysiological testing. Also, serological work-up for antiretinal antibodies and oncological screening was organized. RESULTS: A 45-year-old female presented with progressive photopsias, photophobia and relative central scotoma in the right eye since 6 weeks prior. BCVA was 1.0 in both eyes. Biomicroscopy, IOP and fundus exam were unremarkable. Also, colour vision, autofluorescence imaging, OCT and EOG were normal. Visual fields showed decreased central sensitivity in the right eye. ERG showed a unilateral, electronegative combined and ON-bipolar response. A diagnosis of CAR was suspected. After a diagnosis of an adenocarcinoma of the right ovary, radical ovariectomy and hysterectomy were performed, followed by adjuvant chemotherapy. A whole-body PET scan revealed no metastasis. Treatment with rituximab monoclonal antibodies in combination with corticosteroids was initiated. The patient tested positive for serum autoantibodies against TRPM1, a transient receptor potential cation channel expressed in ON-bipolar cells. During treatment, there was progressive improvement in symptoms and the ERG normalized. Serology confirmed complete clearance of autoantibodies. CONCLUSIONS: Although rare, unilateral CAR does occur and in cases with high clinical suspicion an oncological work-up is mandatory. Aggressive cancer treatment combined with steroids and rituximab can lead to normalization of the clinical and ERG phenotype, with clearing of antiretinal antibodies.

Bilateral diffuse uveal melanocytic proliferation: a management dilemma.

A female patient suffered from gradual decline of vision for few months. She presented with bilateral multiple pigmented choroidal tumours, associated with overlying retinal changes. The clinical presentation suggested bilateral diffuse uveal melanocytic proliferation (BDUMP) syndrome, which is a paraneoplastic disease, although there was no evidence of any concurrent malignancy. The periodic systemic surveillance that was undertaken for the following 4 years failed to reveal any occult cancer. Nevertheless, there has been relentless progressive deterioration in vision as a consequence of BDUMP syndrome. The management of the declining vision in BDUMP syndrome is challenging and controversial.

[Bilateral diffuse uveal melanocytic proliferation in a patient with metastatic breast cancer]. / Bilaterale diffuse uveale melanozytäre Proliferation bei metastasierendem Mammakarzinom.

A 64-year-old female patient with a history of metastatic breast cancer presented with bilateral deterioration of visual acuity over a period of several weeks. Examination revealed patchy fundus pigmentation, serous retinal detachment and cataract in both eyes. After diagnosis of a bilateral diffuse uveal melanocytic proliferation (BDUMP) and due to disease progression, a course of plasmapheresis three times a week over a period of 2 weeks was initiated. Apart from the occurrence of peripheral edemas the therapy was well-tolerated by the patient. Treatment success could not be evaluated because the patient died a short time later. This is the first reported case of BDUMP due to breast cancer.

Autoimmune retinopathy and antiretinal antibodies: a review.

PURPOSE: To review the current state for diagnosis and management of autoimmune retinopathy. METHODS: A review of the literature was performed, encompassing autoimmune retinopathy including paraneoplastic retinopathy (cancer-associated retinopathy, melanoma-associated retinopathy, and bilateral diffuse uveal melanocytic proliferation) and non-paraneoplastic autoimmune retinopathy. Based on this review, current principles and techniques for diagnosis and the treatments reported for autoimmune retinopathy are discussed with the aim to clarify some of the confusion that exists regarding this complex entity. RESULTS: Autoimmune retinopathy encompasses a spectrum of retinal degeneration phenotypes. The clinical features, fundus characteristics, and electroretinogram findings for paraneoplastic and non-paraneoplastic retinopathy are reviewed. The different antiretinal antibodies reported in these entities are described. The diagnostic approaches for detecting these antiretinal antibodies and their limitations are covered. The treatments reported for autoimmune retinopathy and their outcomes are reviewed. CONCLUSION: Among the myriad of antiretinal antibodies reported, challenges persist in determining which antibodies are pathogenic and which are benign and what factors cause antiretinal antibodies to become pathologic. There also remain difficulties in the detection and accurate measurement of antiretinal antibodies, and the response to therapeutic intervention in autoimmune retinopathy is variable.

Autoimmune retinopathy.

PURPOSE: To provide a detailed review of current clinical guidelines for the diagnosis, work-up and treatment of autoimmune retinopathy and to preview briefly possible future therapies. DESIGN: Perspective based on literature review and clinical expertise. METHODS: Interpretation of current literature, relying on the authors' clinical experience. RESULTS: Autoimmune retinopathy is a rare immunologic disease characterized by the presence of circulating antiretinal antibodies along with electroretinographic and visual field abnormalities. An ophthalmic examination can be normal or show minimal findings. The diagnosis of autoimmune retinopathy is made difficult by diagnostic criteria that are both limited and nonstandardized. Currently, the diagnosis is made based on the demonstration of serum antiretinal antibodies and the presence of clinical manifestations (including abnormal electroretinographic findings). The mere presence of these antibodies is not diagnostic. Lack of an accepted gold standard for antiretinal antibodies detection and poor interlaboratory concordance make the diagnosis challenging. There are anecdotal reports of immunosuppressive therapy in autoimmune retinopathy; however, the response to treatment is variable, with more favorable results achieved in paraneoplastic retinopathy, particularly cancer-associated retinopathy, with a combination of chemotherapy and immunosuppression. Whether an earlier attempt to treat nonparaneoplastic autoimmune retinopathy would be more beneficial is unknown. Early treatment attempts are limited by lack of sensitive and specific assays and definitive clinical criteria. CONCLUSIONS: Little is known about the clinical course, prognosis and treatment of autoimmune retinopathy. Additional studies should examine the specificity and pathogenicity of antiretinal antibodies and screen for biomarkers, and they should be conducted concurrently with studies seeking to identify appropriate treatment.

[Clinical characteristics of paraneoplastic retinopathy and optic neuropathy].

OBJECTIVE: To analyze the clinical characteristics of paraneoplastic retinopathy and optic neuropathy(PRON). METHODS: Case series study. Eight patients were enrolled from October 2006 to March 2012 visited in ophthalmology department, the People Liberation Army General Hospital. The patients were underwent a series of examinations, including fundus photography, visual electrophysiology, fundus fluorescein angiography, optic coherent tomography,fundus autofluorescent imaging, perimetry, ultrasonography, magnetic resonance imaging, spinal tap and cerebrospinal fluid test, paraneoplastic syndrome (PNS) antibody test. The patients were followed up in outpatient department and(or) by phone. The clinical manifestation,entity types, and treatment were analyzed. RESULTS: Of the eight patients, there were cancer associated retinopathy(CAR) 3 cases, bilateral diffuse uveal melanocytic proliferation (BDUMP) 2 cases and paraneoplastic optic neuropathy(PON) 3 cases. Five patients were detected the PNS antibodies and revealed three patients with positive results. As for the primary malignancy,four of the eight patients were lung carcinoma,others included invasive thymoma, kidney cancer, acute lymphocytic leukemia and cervical cancer, each for one case. All the patients complained vision blurring or progressive visual decrease. Other complaints included dark shadow in two patients, shimmering, dazzling, double vision and eye pain, each in one patient. One patient complained progressive decreased vision in both eyes prior to the diagnosis of lung cancer. Of the 16 eyes of the eight patients, there were six patients with no light perception vision, five from light perception to 0.05, and other five with no less than 0.4 vision, in the end of the follow up. Five patients were treated with steroid with unsatisfactory efficacy. CONCLUSIONS: Each entity of PRON has its own clinical characteristics. PRON especially BDUMP may be a pre-metastatic disease.

Paraneoplastic and non-paraneoplastic retinopathy and optic neuropathy: evaluation and management.

Paraneoplastic syndromes involving the visual system are a heterogeneous group of disorders occurring in the setting of systemic malignancy. Timely recognition of one of these entities can facilitate early detection and treatment of an unsuspected, underlying malignancy, sometimes months before it would have otherwise presented, and gives the patient an increased chance at survival. We outline the clinical features, pathogenesis, and treatment strategies for the retinal- and optic nerve-based paraneoplastic syndromes: cancer-associated retinopathy; melanoma-associated retinopathy; paraneoplastic vitelliform maculopathy; bilateral diffuse uveal melanocytic proliferation; paraneoplastic optic neuropathy; and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome. Distinguishing these disorders from their non-paraneoplastic counterparts (e.g., autoimmune-related retinopathy and optic neuropathy, and acute zonal occult outer retinopathy) and determining appropriate systemic evaluation for the responsible tumor can be challenging. In addition, we discuss the utility and interpretation of autoantibody testing.