Elsevier

Survey of Ophthalmology

Volume 58, Issue 5, September–October 2013, Pages 430-458
Survey of Ophthalmology

Major Review
Paraneoplastic and non-paraneoplastic retinopathy and optic neuropathy: Evaluation and management

https://doi.org/10.1016/j.survophthal.2012.09.001Get rights and content

Abstract

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.

Introduction

Paraneoplastic syndromes are complexes of signs and symptoms in cancer-bearing patients resulting from dysfunction of tissues remote from the site of a malignant neoplasm or its metastases.57, 58 Most of these syndromes occur as a result of ectopic tumor production of a hormone or functional growth factor acting at a distal site (e.g., Cushings syndrome, syndrome of inappropriate antidiuretic hormone secretion, hypercalcemia secondary to parathyroid hormone-related protein, and carcinoid syndrome), whereas others are believed to involve immune-mediated cross-reactivity between tumor antigens and normal host tissues (e.g., Lambert-Eaton myasthenic syndrome, paraneoplastic cerebellar degeneration, and opsoclonus-myoclonus). The true incidence and prevalence of paraneoplastic syndromes remains unknown, but are estimated to occur in as many as 10% of cancer patients.149 Those involving the nervous and visual systems are considerably less common, affecting as little as 0.01% of patients with cancer evaluated at one tertiary care oncology hospital.57, 58 In addition to their infrequency, these conditions can be easily overlooked given their subtle signs, making their detection all the more challenging.

Here, we review the retinal- and optic nerve-based paraneoplastic syndromes: cancer-associated retinopathy (CAR); melanoma-associated retinopathy (MAR); paraneoplastic vitelliform maculopathy (PVM); bilateral diffuse uveal melanocytic proliferation (BDUMP); paraneoplastic optic neuropathy (PON); and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. The proposed pathophysiologic mechanisms underlying each syndrome vary and continue to evolve as we learn more about their complex origins (Fig. 1). Traditionally, molecular mimicry has been purported to underlie the development of the paraneoplastic retinopathies and optic neuropathies. By this mechanism, susceptible individuals mount an immune response to cancer antigens sharing homology with endogenous proteins of the retina and/or optic nerve. The resultant antibodies then inappropriately cross-react with and localize to these tissue sites, where they disrupt normal cellular function, and ultimately cause visual dysfunction. Recent research efforts, however, have revealed that tumor-expressed growth factors may also contribute to the development of these diseases, notably BDUMP and POEMS.

Patients presenting with visual dysfunction of suspected paraneoplastic origin warrant a thorough systemic evaluation for underlying malignancy. We recommend diagnostic modalities, and discuss differentiating these syndromes from their non-paraneoplastic counterparts (e.g., autoimmune-related retinopathy and optic neuropathy [ARRON], and acute zonal occult outer retinopathy [AZOOR]), which are likely more common than the paraneoplastic variety.58, 101 Finally, we explore the utility and interpretation of autoantibody testing, a beneficial adjunct if correlated appropriately within the clinical context.

Section snippets

Clinical Presentation

CAR is considered the most common of the intraocular paraneoplastic syndromes. In 1976, Sawyer et al251 presented the first three patients with retinal degeneration associated with cancer. Although there are no prevalence estimates for CAR, its incidence appears to be on the rise as the result of increased clinical awareness and improved diagnostic surveillance. As evidence, since Chan's48 review in 2003 that examined the 55 known cases of CAR at the time, the number of reported cases has more

Clinical presentation

Though less commonly encountered, the optic nerve may be the primary site of paraneoplastic phenomena. Early case reports by Hoogenraad et al108 and Oohira et al211 histologically confirmed the presence of optic neuropathy without evidence of tumor invasion. In 1992, Malik et al167 were the first to suggest an immunologic basis for this condition, identifying a serum antibody reactive with neuronal and glial cytoplasm in a 63-year-old man with subacute bilateral visual loss followed by

Systemic evaluation in the patient without known malignancy

The presence of a clinically suspected paraneoplastic syndrome in conjunction with autoantibodies, particularly against recoverin or CRMP-5, mandates a thorough systemic evaluation for cancer in collaboration with the primary care provider. In addition to a comprehensive general physical examination, this may also entail dermatologic skin survey, colonoscopy, prostate screening, and/or gynecologic exam as dictated by the individual case.213

Imaging studies, at bare minimum, should include a

Non-paraneoplastic retinopathies

The paraneoplastic syndromes, primarily CAR and MAR, must be differentiated from other mimicking retinal degenerations that may present with similar symptoms and signs: RP, cone dystrophy, AZOOR, and ARRON. Two of these entities, AZOOR and ARRON, warrant careful consideration.

Autoantibody testing

Laboratory techniques for detecting circulating anti-retinal antibodies in patient sera include Western blot, ELISA, and immunohistochemistry, all which have limitations. In order to ensure both accurate and reproducible assays for anti-retinal antibodies, Foorooghian et al77 stressed that rigorous control measures must be instituted. Furthermore, although all three laboratory assays require a scaffolding of protein/tissue on which to detect anti-retinal antibodies, the source of that

Conclusion

The paraneoplastic retinopathies and optic neuropathies are a heterogenous group of disorders with numerous overlapping features. Clinically, these entities remain among the most challenging to diagnose, even for the most experienced ophthalmologist. Patients may present with no known oncologic history, and ophthalmologic exam may offer no strong clues to alert the investigator to the presence of an underlying malignancy, let alone any pathology at all. With no clear diagnostic criteria to

Method of literature search

An electronic search of the literature was performed using Medline and PubMed (up to August 2012). Key search terms were cancer-associated retinopathy, CAR, melanoma-associated retinopathy, MAR, paraneoplastic retinopathy, autoimmune retinopathy, autoimmune-related retinopathy and optic neuropathy, ARRON, acute zonal occult outer retinopathy, AZOOR, paraneoplastic vitelliform maculopathy, paraneoplastic vitelliform retinopathy, bilateral diffuse uveal melanocytic proliferation, BDUMP,

Disclosure

The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article.

Supported by a grant from the Karl Kirchgessner Foundation at the Jules Stein Eye Institute.

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