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

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journal homepage: www.elsevier.com/locate/survophthal

Major review

Paraneoplastic and non-paraneoplastic retinopathy and optic neuropathy: Evaluation and management Ehsan Rahimy, MDa, David Sarraf, MDa,b,* a b

Jules Stein Eye Institute, UCLA, Los Angeles, California, USA Greater LA VA Healthcare Center, Los Angeles, California, USA

article info

abstract

Article history:

Paraneoplastic syndromes involving the visual system are a heterogeneous group of

Received 29 June 2012

disorders occurring in the setting of systemic malignancy. Timely recognition of one of

Received in revised form

these entities can facilitate early detection and treatment of an unsuspected, underlying

27 August 2012

malignancy, sometimes months before it would have otherwise presented, and gives the

Accepted 4 December 2012

patient an increased chance at survival. We outline the clinical features, pathogenesis, and treatment strategies for the retinal- and optic nerveebased paraneoplastic syndromes: cancer-associated retinopathy; melanoma-associated retinopathy; paraneoplastic vitelli-

Keywords:

form maculopathy; bilateral diffuse uveal melanocytic proliferation; paraneoplastic

paraneoplastic

optic neuropathy; and polyneuropathy, organomegaly, endocrinopathy, monoclonal

cancer-associated retinopathy

gammopathy, and skin changes syndrome. Distinguishing these disorders from their non-

melanoma-associated retinopathy

paraneoplastic counterparts (e.g., autoimmune-related retinopathy and optic neuropathy,

vitelliform maculopathy

and acute zonal occult outer retinopathy) and determining appropriate systemic evalua-

bilateral diffuse uveal melanocytic

tion for the responsible tumor can be challenging. In addition, we discuss the utility and

proliferation

interpretation of autoantibody testing.

optic neuropathy

Published by Elsevier Inc.

POEMS syndrome autoimmune-related retinopathy and optic neuropathy anti-retinal antibody autoantibody testing

1.

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

* Corresponding author: David Sarraf, MD, Retinal Disorders and Ophthalmic Genetics Division, Jules Stein Eye Institute, UCLA, Los Angeles, CA 90024. E-mail address: [email protected] (D. Sarraf). 0039-6257/$ e see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.survophthal.2012.09.001

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Fig. 1 e Proposed pathophysiologic mechanisms underlying the intraocular 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 crossreact 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., autoimmunerelated 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.

2.

Paraneoplastic retinopathies

2.1.

Cancer-associated retinopathy

2.1.1.

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 than doubled. The primary tumor accounting for the vast majority is small-cell lung carcinoma,48 followed by gynecologic (ovarian, endometrial, and cervical)4,70,140,185,207,230,246,251,255,264 and breast17,68,182 malignancies. Less commonly reported solid tumor associations prostate,173 include non-small-cell lung,248,253 124,229,274,293 166 95 thymus, thyroid, pancreatic, colon,113 and 173 cancers. Hematological malignancies (leukemia, bladder lymphoma, myeloma) have also been linked to CAR.2,212,278 The average age of symptom onset in patients with CAR is 65 years.2,48 Historically, there has been no known sex predilection, although these demographics may be changing after Adamus2 recently reported a 2:1 female-to-male ratio. Visual loss is painless, develops over weeks to months, and precedes the diagnosis of underlying malignancy in nearly half of patients.19,48,115,247 Symptomatic complaints reflect both rod and cone photoreceptor dysfunction. Manifestations of conerelated compromise include photosensitivity, photopsias, glare, severely reduced central vision, and impaired color perception. Rod dysfunction may present as nyctalopia, impaired dark adaptation, ring scotoma, or other peripheral visual field loss. A lesser-known variant of CAR, termed cancer-associated cone dysfunction, characteristically affects only cones.41,53,75,114,215 Of note, recent evidence suggests photosensitivity may not be as characteristic for CAR as previously thought. In a case series by Ohguro et al,206 photosensitivity was documented in only 2 of 18 patients. Fundus examination in CAR varies from unremarkable early on to findings of optic nerve pallor, attenuated retinal arterioles, and retinal pigment epithelial (RPE) thinning and mottling later in the disease course. Retinal pigment dispersion is typically absent or sparse.101 A subtle vitritis may be present, which may coincide with an anterior uveitis, and there may also be retinal vasculitis with or without cystoid macular edema (CME).17,48,109,140,206,208,212,230,272 Rare presentations of CAR with associated choroidal neovascularization229 and in combination with BDUMP246 have also been described. Ancillary studies, especially anti-retinal antibody testing and electroretinogram (ERG), are helpful in establishing the diagnosis of CAR, as well as in the evaluation of any

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paraneoplastic retinopathy. Identification of circulating antiretinal antibodies in patient sera is usually confirmed by either Western blot or enzyme-linked immunosorbent assay (ELISA) of a patient’s serum against normal retina extract. Immunohistochemical techniques localizing antibodies in patient sera to the photoreceptor layer of donor retinal sections can be performed. The most sensitive and specific antibody for CAR, when one is detected, is against the 23-kDa retinal antigen, recoverin. Additional cases of CAR have demonstrated antibodies against the 46-kDa antigen, aenolase. Weleber et al288 noted a more rapid onset and visual decline, often prior to the cancer diagnosis, in cases of antirecoverin CAR. In contrast, anti-enolase CAR tended to have a more subacute presentation with less severe course, often in patients with a known history of malignancy. The ERG in CAR classically depicts global retinal dysfunction, with severely reduced, if not extinguished, scotopic and photopic a- and b-waves.144,173,251 This reduction in amplitude is seen early on in the disease course, even while funduscopic exam may be entirely normal. An electronegative ERG, more typical of MAR, has also been described in three individuals with CAR.17,91,140 Visual field deficits can manifest as generalized depression, or central, paracentral, arcuate, or ring scotomas.206 While fluorescein angiography (FA) is unremarkable in the vast majority of CAR patients, it is nonetheless useful to obtain for ruling out other posterior segment pathology. Isolated cases have documented perivascular leakage and CME on FA.17,109,140,171,208,230,272 Optical coherence tomography (OCT) typically reveals severe macular atrophy, often associated with thinning of the photoreceptor layer,166,215 loss of the inner segment/outer segment (IS/OS) junction,109 and loss of the inner highly reflective layer.185,255 Lima et al157 advocated the additional use of fundus autofluorescence together with high-definition spectral domain OCT to aid in the diagnosis of this entity and monitoring for progression. In their report, four patients with autoimmunerelated retinopathy (two with small-cell lung cancer) displayed a hyperautofluorescent ring in the parafoveal region on fundus autofluorescence, and the corresponding OCT over this region demonstrated loss of the IS/OS junction and thinning of the outer nuclear layer. The increased zone of autofluorescence is suggestive of compromised RPE function due to increased metabolic demand, and may be a precursor to cell apoptosis and further visual compromise.157 Finally, systemic evaluation in cases of suspected CAR may reveal elevated levels of cerebrospinal fluid (CSF) protein and lymphocytosis.19

2.1.2.

Pathogenesis

Molecular mimicry is the generally accepted pathogenic mechanism driving CAR.15,48 By this process, tumor cells expressing antigenic epitopes with retinal photoreceptors elicit an immune response that cross-reacts with the retina, disrupting normal signal transmission. In 1983, Keltner et al128 demonstrated the presence of anti-retinal antibodies in the serum of a patient with CAR who was responsive to steroid therapy, suggesting an autoimmune basis for the disease process. This antibody was later identified as the 23-kDa CAR antigen, or recoverin, by Thirkill et al,276,277 a finding subsequently confirmed by Polans et al.222e224 To date, over 18

retinal antigens have been implicated in CAR, with the most commonly identified ones being recoverin and a-enolase (46-kDa). Recoverin is a calcium-binding protein located within retinal photoreceptor cells. Via a calcium-dependent process, it regulates phosphorylation of rhodopsin during visual transduction. The human recoverin gene has been mapped to chromosome 17p13.1, a region containing a number of other oncogenic loci, notably p53.174,175,191 McGinnis et al174 postulated that a single mutational event inactivating a copy of the p53 tumor suppressor gene may be sufficient to increase expression of the adjacent recoverin gene by tumor cells. Indeed, aberrant expression of recoverin or recoverin-like peptides has been previously detected in tumor tissue obtained from CAR patients with small-cell lung carcinoma.28,172,224,294 Maeda et al164 separately measured recoverin expression in 21 of 31 tumor cell lines. This extraocular expression of the protein has been shown to be both highly antigenic and uveogenic in a rat model, in which immunization of animals with purified recoverin led to increased antibody titers, photoreceptor degeneration, vitreous cells, perivasculitis, and retinal lesions.11 A separate rat model of CAR, whereby intravitreal injections of anti-recoverin antibodies recapitulated many features of the disease, has provided valuable insight into the potential mechanism of immune-mediated photoreceptor destruction.9,165,203 Antirecoverin antibodies have been shown to incorporate into photoreceptors where they likely block the function of endogenous recoverin. This results in unregulated rhodopsin phosphorylation, leading to increased intracellular calcium levels, which triggers activation of a caspasedependent apoptotic cascade, and ultimately, photoreceptor death.9,10,13,165,203 These findings are supported by postmortem histopathologic analyses of patients with CAR revealing patchy loss of photoreceptors in conjunction with immunohistochemical staining of antibodies localizing to the outer plexiform layer, the outer nuclear layer, and the inner and outer segments of most photoreceptors.238 By injecting anti-recoverin antibodies into the rat vitreous cavity, the blooderetinal barrier, which normally protects retinal antigens from immune surveillance, is bypassed. Autoantibodies, however, do indeed cross the blooderetinal barrier into the intraocular fluid, as evidenced by Ohguro et al,202 who detected anti-recoverin antibody within the aqueous humor of a patient with CAR. How these autoantibodies cross the blooderetinal barrier to access their intra-retinal targets in CAR remains poorly understood. Of note, intravenously administered anti-recoverin antibodies in a murine model could not pass through the blooderetinal barrier and did not induce apoptotic cell death.138 Likely, secondary factors facilitate the actions of the primary autoantibodies. Tumorderived vascular endothelial growth factor (VEGF) and placental growth factor have been postulated to induce significant retinal vascular remodeling via the VEGF receptor 1. The resulting ablation of pericytes and breakdown of the blooderetinal barrier would lead to increased vascular leakage and antibody access to the intra-retinal space.42,43 Although recoverin is the most frequently implicated antigen in CAR, other immunogenic factors may also be at play. In a recent cohort reported by Adamus and colleagues,2

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only 65% of patients with CAR had detectable serum antiretinal autoantibodies that, when present, were not always directed against a well-characterized antigen. Antibodies to recoverin were present in only 10% of those patients.2 They also identified targets such as a-enolase (46-kDa) and transducin-a (40-kDa) in 30% and 17% of patients, respectively.2 Antibodies to retinal a-enolase appear to target the ganglion cell and inner retinal layers, whereas those of transducina localize to the outer and inner segments of photoreceptors, as well as the cytoplasm of ganglion cells. This variation in immunogenic profile, they argue, accounts for the phenotypic diversity of the clinical manifestations of CAR.7 Specifically, they propose that different retinal autoantigens can be used as biomarkers for different subtypes of CAR: 1) anti-recoverin phenotype typically presents with equal and severe loss of the rod and cone system that may rapidly progress to blindness with widespread panretinal degeneration and even an extinguished ERG, while being associated with cancer in almost all cases; 2) anti-enolase retinopathy presents with isolated cone dysfunction with or without optic atrophy (due to ganglion cell loss) that is typically more indolent (or stable) without severe vision loss, and is associated with an underlying cancer in only 40% of cases; and 3) anti-transducin-a retinopathy that presents as a primary rod degeneration that is mildly progressive and is associated with cancer only about 25% of the time.2,7,288 Numerous other potential CAR antigens continue to be described, including arrestin (48-kDa),182 carbonic anhydrase II (CAII, 30-kDa),2,97 tubby-like protein 1 (TULP1, 78-kDa),137 interphotoreceptor retinoid-binding protein (IRBP, 145kDa),229 heat shock cognate protein 70 (hsc-70, 70-kDa),204 and photoreceptor cell-specific nuclear receptor (PNR, 41-kDa).67 It is clear that CAR is an immunologically heterogeneous condition associated with numerous anti-retinal autoantibodies. The clinical utility of such antigenic targets, however, needs to be better defined.

2.1.3.

Management

Given CAR’s propensity to precede the discovery of malignancy, maintaining a high index of suspicion is of utmost importance in making a timely diagnosis. Jacobson et al115 previously proposed a clinical triad of photosensitivity, ring scotomata, and attenuated arteriole caliber. A simpler variation, offered by Sobrin,A advocates consideration for CAR in cases of unexplained vision loss and visual field deficits in the setting of a near normal examination. The detection of antiretinal antibodies, especially against recoverin, further justifies pursuit of an occult malignancy (see section IV, Systemic Evaluation in the Patient Without Known Malignancy). Although no effective treatment for CAR exists, long-term immunosuppression remains the mainstay of therapy. Treatment of the underlying malignancy alone with surgery, chemotherapy, and radiation therapy does not improve vision; thus, intervention must be targeted at the ocular disorder.48,135,260 Despite aggressive immunosuppressive therapy, the visual prognosis is poor, and rapid, relentless visual loss often occurs. Some benefit is obtained from combinations of systemic corticosteroids,128,255,273 plasmapheresis,195 and intravenous

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immunoglobulin (IVIg)95 that presumably decrease circulating autoantibody titers and their resultant destruction of photoreceptors. Keltner et al131 reported a case of steroidresponsive CAR in a patient whose circulating antibody levels diminished in association with improved visual function. Likewise, Murphy et al195 observed a decline in antiretinal antibody (60-kDa) titers from 1:2,000 to 1:200 in a patient after treatment with oral corticosteroids in combination with plasmapheresis. Visual acuity improved from counting fingers to 20/200 in the right eye (OD), and from 20/40 to 20/25 in the left eye (OS). Steroid-sparing immunomodulatory therapy (IMT) shows some promising results. Ferreyra et al72 reported improvement of visual acuity and visual fields in six out of six patients treated for CAR with IMT. The caveat was that all patients were also on systemic corticosteroids, and no patients received the same IMT regimen, which consisted of azathioprine, cyclosporine, or mycophenolate mofetil, either alone or in combination. Unfortunately, toxicity limits the use of many of these agents. Monoclonal antibodies targeting B-cell lymphocytes offer a new avenue for future therapy. Espandar et al71 first reported on the successful use of alemtuzumab (anti-CD52, panlymphocytic marker) to treat several bouts of CAR exacerbation over an 8-year period. Previous treatment with steroids, plasmapheresis, and cyclosporine had failed, but a dramatic improvement in symptoms, visual acuity, and visual fields occurred after each infusion of alemtuzumab. Mahdi et al166 described a patient who responded to rituximab (anti-CD20, B-cell marker) after showing no response to either prednisone or IVIg. There has been concern that using IMT to reduce the antibody response may increase cancer mortality; however, this has not yet been observed.E Ohguro et al203 suggested a role for inhibiting antirecoverin-mediated photoreceptor apoptosis via pharmacologic reduction of intracellular calcium levels. In a rat model of CAR, use of the calcium channel blocker nilvadipine led to recovery of ERG function. Adamus et al13 found that use of the calcium channel blocker nifedipine inhibited the entry of calcium into rat retinal cells and protected them from undergoing apoptosis. How these findings translate to clinical practice remains to be seen, but in a patient treated with a systemic calcium channel blocker, visual loss still progressed to light perception OD and no light perception OS.185 Periocular steroid injections have been met with mixed results. A murine model of CAR treated with subconjunctival triamcinolone showed a trend toward improved survival of outer nuclear layer cell bodies, but ERG amplitudes were not significantly improved.163 Ferreyra et al72 noted a positive response to sub-Tenon methylprednisolone (40e60 mg) injections in four of their CAR patients without significant complications. Responses to treatment consisted of improvement in visual acuity and/or expansion of visual field by at least 25%. Notably, a patient was maintained on bilateral sub-Tenon steroid injections every 2 months as an alternative to systemic immunomodulation with azathioprine and mycophenolate mofetil, which she was unable to tolerate. Huynh et al109 reported a CAR patient presenting with diffuse retinal vasculitis and CME on FA refractory to various systemic interventions, including intravenous methylprednisolone, oral prednisone, mycophenolate mofetil, and IVIg,

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who then received five bilateral intravitreal corticosteroid injections over 2.5 years, resulting in stable visual function until the time of death. They suggested a causal relationship between the injections and resulting visual improvement. Although they acknowledge the initial improvement may have been attributed at least in part to resolution of CME, they note that visual improvement from subsequent injections occurred in the absence of cystic changes on OCT. The authors attributed this positive response to suppressed photoreceptor inflammation, as suggested by restoration of the IS/OS junction and the highly reflective layer on follow-up OCT imaging. Local injections may be an attractive option in select cases of CAR, notably in patients refractory to systemic therapy or intolerant to their associated side effects. Additionally, it remains to be determined whether blockage of VEGF receptor 1 can augment CAR therapy by inhibiting the retinal penetration of autoantibodies.42

2.2.

Melanoma-associated retinopathy

2.2.1.

Clinical presentation

The first report of MAR came from Berson and Lessell29 in 1988, describing a 69-year-old man who developed acute night blindness and hallucinations of shimmering lights 3 years after resection of a cutaneous malignant melanoma. A previous report by Ripps et al236 of a patient who presented with signs and symptoms consistent with MAR attributed the findings to a toxic effect of vincristine, which was part of the individual’s melanoma chemotherapy regimen. By 2001, Keltner et al132 had collected 62 cases, 11 new and 51 previously published. Unlike CAR, which frequently precedes the discovery of systemic malignancy, patients presenting with MAR are far more likely to have a known history of melanoma. In the over 70 reported cases to date, MAR often heralded the presence of non-ocular metastasis.132 All but two cases of MAR had been associated with cutaneous melanomas until Lu et al159 also implicated choroidal and ciliary body melanomas, and even choroidal nevi. Machida et al162 recently presented a patient with MAR-like signs and symptoms who showed no signs of a malignant tumor after skin survey by a dermatologist and whole-body computerized tomography (CT) and positron emission tomography (PET) scans. An intranasal melanoma was discovered 5 months later. This was the first reported case of mucosal melanoma being associated with MAR. Another case of MAR preceded a diagnosis of primary intestinal melanoma by 3 months.231 These occurrences, although rare, highlight the importance of investigating preferential sites of mucosal melanoma (nasal cavity, paranasal sinuses, oropharynx, intestinal tract, vagina, urinary tract) when the primary lesion cannot be identified. Keltner et al132 found a latent period averaging 3.6 years (range, 2 months to 19 years) from diagnosis of the primary neoplasm to the onset of MAR. Affected individuals often present in their 50s, with males being preferentially affected over females by a ratio of 4.7:1, far exceeding the 5:4 sexual predilection of malignant cutaneous melanoma in the United States.49,132 Clinical features of MAR typically reflect rodmediated dysfunction, with patients experiencing sudden onset of bilateral shimmering photopsias and nyctalopia.

Visual loss is painless and typically not as pronounced as in CAR, with 82% (28 of 34 patients) maintaining a visual acuity of 20/60 or better at the time of presentation in Keltner et al’s132 review. A small minority do suffer from central visual deficits, as demonstrated by the remaining six patients who presented with visual acuities of 20/200 or worse in one or both eyes.132 Initial fundus examination, as is the case with CAR, is often normal. In more advanced cases, there may be optic disk pallor, retinal vessel attenuation, and areas of RPE atrophy.132,159 Retinal pigment dispersion is absent to minimal in MAR, a potentially helpful distinction from other causes of pigmentary retinal degenerations such as retinitis pigmentosa (RP). Although less common, there may be a vitreous cellular reaction117,126,132,139,178,226 with vasculitis193,233 and CME. Work-up, in the form of serologies, visual function tests, and various imaging modalities, increases diagnostic confidence. Western blot or ELISA to detect the presence of serum anti-retinal antibodies, or less conventional immunohistochemical staining of donor retina (especially bipolar cells), is confirmatory for MAR. Visual field testing most commonly reveals generalized constriction, but arcuate defects, central, and paracentral scotomas are also described.132 OCT may demonstrate normal retinal architecture and thickness in the early stages of disease, but progressive thinning of the inner retina around the paramacular region can be a later finding.162 The ERG pattern in MAR is classically electronegative, resembling that seen in congenital stationary night blindness (CSNB), central retinal artery occlusion, and juvenile x-linked retinoschisis. A preserved dark-adapted a-wave, indicating normal photoreceptor function, is followed by a markedly attenuated b-wave, reflecting either bipolar cell dysfunction or disruption of synaptic transmission between photoreceptors and the bipolar cells.132

2.2.2.

Pathogenesis

Historically, anti-bipolar cell antibodies have been considered the defining marker of MAR. It is postulated that these autoantibodies directed against the postsynaptic receptors of the depolarizing, or ON, bipolar cells disrupt neural transmission with associated rod photoreceptors, resulting in the predominantly rod-related visual compromise.16 The hyperpolarizing, or OFF, bipolar cells are believed to be spared. Lie et al156 demonstrated that a single intravitreal injection of sera from MAR patients suppresses the photopic and scotopic b-waves in a monkey model. Bipolar cells subserving the ON pathway were preferentially affected in their study. Efforts to elucidate a specific bipolar cell antigen in MAR have revealed a number of photoreceptor proteins, but none specific to the ON bipolar cells. For example, antibodies against a 35-kDa Muller cell protein,76 a 22-kDa neuronal antigen found in both the retina and optic nerve,129 and a novel membrane-associated 33-kDa protein205 have all been described in MAR. Because visual phototransduction proteins are known to be produced by melanoma cells, it should come as no surprise that autoantibodies against transducin-a,2 transducin-b,225 arrestin,27 and rhodopsin98 are found in MAR patients. The wide diversity of retinal antigens encountered is likely indicative of the immunologic heterogeneity of this disorder.

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More recently, however, Kondo et al146 and Dhingra et al62 independently identified autoantibodies in the sera of four patients with MAR directed against the transient receptor potential cation channel, subfamily M, member 1 (TRPM1), which is specifically expressed in retinal ON bipolar cells. Also known as melastatin 1 (MLSN1), TRPM1 was recently identified as the cation channel that mediates the light response in ON bipolar cells.145,188,258 Interestingly, mutations in TRPM1 have been linked to human CSNB,196,282 and Trpm1 knock-out mice have displayed electronegative ERG patterns.258 These results are an encouraging step towards identifying a MARspecific antigen, but await further confirmation. Conversely, Keltner et al132 reported that although they were able to label retinal bipolar cells with patients’ sera via immunohistochemistry, they could not identify any MARspecific retinal antigens by Western blot technique. Likewise, Milam et al178 were unable to detect a specific antigen responsible for the immunostaining of rod bipolar cells by MAR sera using Western blotting techniques. They hypothesized that this absence may have been secondary to amino group modification by paraformaldehyde fixation, denaturation by sodium dodecyl sulfate, or the MAR-specific antigen being veiled by a nonspecifically stained component it comigrates with.178 Furthermore, the MAR-specific antigen may not even be a protein, but may be a ganglioside, proteoglycan, lipid, carbohydrate, or a combination of these. Histopathological analysis of postmortem retinas from MAR patients has revealed a variety of findings, ranging from unremarkable to widespread retinal degeneration. Okel et al210 initially observed considerable disruption of macular anatomy, with extensive destruction of photoreceptor elements. This was followed by Gittinger and Smith,90 who noted a marked reduction in the density of bipolar neurons in the inner nuclear layer, with preservation of the photoreceptor cell neurons in the outer nuclear layer. Finally, Keltner et al132 found normal retinal architecture by light microscopy, even in the presence of a strong antibody reaction to various retinal layers as detected by indirect immunohistochemistry. The variability of retinal pathology observed may be representative of the different stages of disease from which specimens were obtained.

2.2.3.

Management

Treatment for MAR has been largely ineffective, with successes limited to individual cases. Overall visual prognosis is guarded, and although vision is traditionally thought to remain stable, some cases progressively deteriorate despite treatment with combinations of steroids, plasma exchange, and IVIg.117,132,233,242,283 Treatment is directed at decreasing the melanoma tumor burden with cytoreductive surgery to resect metastases, followed by systemic immunotherapy.132 Seven of Keltner et al’s132 62 patients experienced some type of improvement after these various interventions. Of these, four had undergone cytoreductive surgery, either alone, or in combination with IVIg. Highlighting the importance of adjuvant immunotherapy is a case described by Subhadra et al,270 in which a patient’s visual function continued to deteriorate despite surgical resection of tumor metastases and chemotherapy. Once IVIg was instituted, best-corrected visual acuity and visual fields, but not the ERG, steadily improved over the

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ensuing year. Yamamoto et al295 observed full recovery of both ERG function and visual fields in a patient with MAR secondary to a cutaneous melanoma treated with cytoreductive surgery and monthly local injections of interferon-b. This appears to be the first case where treatment of MAR resulted in recovery of ERG function. There has been speculation that the autoimmune response underlying the development of MAR is actually protective to the patient, helping to eradicate melanoma cells, prevent tumor spread, and prolong survival.47 Such reports advise caution prior to blunting the immune response with IMT as a treatment for the retinopathy; however, Keltner and colleagues found no difference in survival rates between MAR patients, treated or untreated, and those without MAR.E Pfohler et al218 also reported that anti-retinal antibodies are not always associated with prolonged survival in melanoma patients. As with CAR, the benefit of adjuvant local therapy in MAR has been difficult to assess secondary to the scarcity of reports. Handler et al96 treated a patient with MAR with three cycles of the oral alkylating chemotherapeutic temozolomide, an off-label treatment for metastatic melanoma. In addition, their patient had two bilateral periocular injections of triamcinolone acetonide 40 mg 3 months apart. Visual acuity remained stable at 20/25 in both eyes, and visual field function improved, with a reduction in the size and density of scotomata. Ultimately, a supplemental role may exist for peri- or intraocular corticosteroid injections, especially in cases with associated vitritis, vasculitis, or CME.

2.3.

Paraneoplastic vitelliform maculopathy

2.3.1.

Clinical presentation

A growing number of reports have documented retinopathies of presumed paraneoplastic origin with concurrent vitelliform fundus lesions. To our knowledge, 23 cases of PVM, albeit under different designations, have been reported in the literature (Table 1).14,20,33,35,69,93,120,122,136,147,148,200,214,265,271,301 All but two carried a known diagnosis of malignancy. Until recently, all known cases were associated with either choroidal or cutaneous melanomas, leading many authors to speculate these may be atypical variants of MAR; however, three recent reports demonstrated similar findings in patients with non-melanoma malignancies. The first was in a patient with primary carcinomas of the breast and lung without evidence of systemic melanoma, although the authors entertained the possibility of a simultaneous regressed cutaneous melanoma or undetectable visceral melanoma.93 The second patient had a history of clear cell sarcoma of the right big toe previously in remission, but onset of visual impairment consistent with PVM coincided with detection of metastatic clear cell carcinoma to the lung.271 The third occurrence was in a patient with newly diagnosed metastatic lung adenocarcinoma.14 In patients with a known history of malignancy, diagnosis and treatment of the primary tumor was often remote from onset of PVM. In one case, an eye with a choroidal melanoma had been enucleated 23 years prior to the onset of visual complaints in the remaining eye.301 The presence of PVM appears to correlate with systemic disease burden, as all

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Table 1 e Clinical characteristics of patients with paraneoplastic vitelliform maculopathy (PVM) Patient Age/ No. Sex

Author, Year

Ref Known No. Malignancy at Time of Diagnosis

Metastases

Yes (brain metastases noted several months later) Yes (mediastinal)

Decreased vision, nyctalopia

OD: 20/400, OS: CF @3ft

Bilateral

Nyctalopia, shimmering lights

20/25

Bilateral

Yes (liver metastases noted 13 months later) Yes (ovarian, lymph nodes)

Blurred vision, nyctalopia

OD: 20/100

Yes (“widespread melanoma” noted 5 months later)

Halos around lights, mild eye pain, difficulty with light-dark adaptation

OD: 20/20

Yes (peritoneal cavity, omental metastases noted 1 month later) Yes (lymph nodes)

Difficulty with light-dark adaptation

20/20

Acute onset bilateral vision loss

OD: 20/125, OS: 20/50

1

47F

Borkowski et al, 2001

35

Yes

Cutaneous melanoma (face)

2

57M

Borkowski et al, 2001

35

Yes

Cutaneous melanoma (scalp)

3

69F

Zacks et al, 2001

301

Yes

Choroidal melanoma OS s/p enucleation

4

33F

Palmowski et al, 2002

214

Yes

Cutaneous melanoma

5

41F

Jampol et al, 2004

120

Yes

Choroidal melanoma OS s/p enucleation

6

41F

Jampol et al, 2004

120

No

7

59M

Sotodeh et al, 2005

265

Yes

e

Cutaneous melanoma (back)

Symptoms

VA at Laterality Presentation

Disabling glare, 20/20 nyctalopia, metamorphopsia

Macular Lesions

Oval-shaped white lesions at the outer retina or RPE

Autoantibodies (antigen)

ERG

EOG

Yes (retinal bipolar cells)

n/a

Scattered, wellcircumscribed chorioretinal atrophic lesions with diffuse loss of RPE Unilateral Two small serous (monocular) retinal detachments

Yes (retinal bipolar cells)

Abnormal n/a

Died 4 years later

Yes (retinal bipolar cells)

Abnormal n/a

Died 2 years later

Bilateral

Yes (retinal bipolar cells)

Abnormal Normal

Alive 2 years later

n/a

n/a

n/a

Died <1 year later

n/a

n/a

n/a

Died 2 months later

Yes (rod outer segment (ROS) protein)

Abnormal n/a

Multiple wellcircumscribed detachments of the RPE, each containing small, yellow-orange lesions Unilateral Serous elevation (monocular) of retina with yellow spot in the fovea, multiple areas of serous retinal detachment Bilateral Multiple yellow serous detachments

Bilateral

Serous retinal detachments with multiple scattered, nummular, yellowish-orange spots at the level of the RPE

n/a

Course

Died 2 months after brain mets noted

Died 1 year later

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Type

56M

Sotodeh et al, 2005

265

Yes

Choroidal melanoma OD s/p enucleation

Yes (“multiple biopsyproven metastases”)

Acute onset of OS: 20/90 decreased vision, nyctalopia, shimmering colored spots

9

61F

Sotodeh et al, 2005

265

Yes

Cutaneous melanoma (neck)

Acute onset of OD: 20/200 reading OS: 20/125 difficulty, vanishing letters, color dullness

10

62F

200

Yes

11

45M

Nieuwendijk and Hooymans, 2007 Eksandh et al, 2008

69

Yes

12

65M

Javaheri et al, 2008

122

Yes

Choroidal melanoma OD s/p enucleation Choroidal melanoma OS s/p enucleation Mucosal melanoma (small bowel)

Yes (pulmonary metastases noted 1 month later) Yes (liver, lung)

13

58M

Krema et al, 2010

148

Yes

Cutaneous melanoma

14

74M

Bianciotto et al, 2010

33

Yes

Cutaneous melanoma (face, neck)

15

50M

Koreen et al, 2011

147

No

e

Gradual vision loss

Yes (liver, lung)

Fluctuations in visual acuity, nyctalopia Yes (kidneys, Nyctalopia brain, bladder)

Unilateral Numerous small, (monocular) round, curvilinear, yellowish vitelliform lesions arranged in a honeycomb pattern at the level of the RPE with mild serous macular detachment Bilateral Serous retinal detachments with multiple small, round vitelliform lesions

n/a

n/a

n/a

n/a

n/a

Abnormal Died 3 months later

OS: 20/40

Unilateral Multiple yellowish (monocular) areas of serous retinal detachment

Negative

Normal

Normal

OD: 20/160

Unilateral Central serous retinal Yes (bestrophin-1) (monocular) detachment as a “pseudohypopyon” vitelliform lesion Bilateral Multiple, Negative pseudovitelliform lesions varying in size (100e500 microns) at the level of the RPE/ outer retinal junction, coalescing inferiorly, with overlying neurosensory and RPE detachment Bilateral Multiple vitelliform Negative lesions involving the outer retina and RPE

Normal

Abnormal Died 4 months later

20/40

Yes (small bowel metastases noted 2 months later) Yes (liver, lung, brain)

Mild unilateral blurred vision

OD: 20/20, OS: 20/25

Gradual vision loss

OD: 20/70, OS: 20/60

Bilateral

Yes (axillary lymph node, liver metastatic melanoma of unknown primary)

Blurring of central vision

20/40

Bilateral

Serous retinal detachments

Abnormal n/a

Normal

Died 1 year later

Died 2 years later

Died

Abnormal n/a

Yes (interNormal n/a photoreceptor retinoid binding protein (IRBP)) Shallow subretinal fluid Yes (peroxiredoxin Abnormal Abnormal with whitish-yellow 3 (PRDX3)) round lesions in a honeycomb-like pattern at the level of the RPE

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8

Died 3 months later

(continued on next page)

437

Alive 41 months later, with “excellent treatment response” to oral temozolomide

438

Table 1 e (continued ) Patient Age/ No. Sex

Author, Year

Ref Known No. Malignancy at Time of Diagnosis

Type

Metastases

Symptoms

VA at Laterality Presentation

Macular Lesions

58F

West Coast Retina, 2011

B

Yes

Choroidal Yes (lung) melanoma OS s/p plaque brachytherapy

Seeing bubbles

OD: 20/30, OS: 20/40

Bilateral

17

69F

Grunwald et al, 2011

93

Yes

Breast cancer, Yes (liver) Lung cancer

Progressive blurred vision

OD: 20/80, OS: 20/70

Bilateral

18

73M

Khurana et al, 2011

136

Yes

Cutaneous melanoma

Nyctalopia

20/30

Bilateral

19

46M

Suelves et al, 2012

271

Yes

Clear cell Yes (lung) sarcoma (toe)

Acute onset vision loss

20/20

Bilateral

20

80M

Aronow et al, 2012

20

Yes

Cutaneous melanoma

Yes (lungs, liver, spine)

n/a

OD: 20/30, OS: 20/25

Bilateral

21

79M

Al-Dahmash et al, 2012

14

Yes

Cutaneous melanoma (neck)

OD: 20/50, OS: 20/30

Bilateral

Multifocal serous retinal detachments with yellow-white subretinal fluid

22

60F

Al-Dahmash et al, 2012

14

Yes

Choroidal melanoma OS s/p plaque brachytherapy

Yes Gradual vision (“multiple loss systemic melanoma metastases”) Yes (liver) Gradual vision loss

OD: 20/30, OS: 20/100

Bilateral

Multifocal serous retinal detachments with yellow-white subretinal fluid

Yes (brain, noted 16 months later)

Multifocal, circumscribed, yellow-orange vitelliform lesions with serous retinal detachments Multiple small, round, vitelliform lesions (w500 microns), multiple areas of localized subretinal fluid with debris overlying flat RPE Multiple neurosensory and RPE detachments of varying size (500-5000 microns) with layered fluid-lipid interfaces inferiorly in the larger RPE detachments Multifocal neurosensory detachments, yellow lesions along superior temporal vessels, eventual “pseudohypopyon” formation Multiple nummular, flat, well-demarcated yellow-white lesions

ERG

EOG

Negative

Normal

Normal

n/a

n/a

n/a

n/a

Alive 10 months later

n/a

n/a

n/a

Died 3 years later

n/a

n/a

n/a

Died 6 months later

Yes (carbonic anhydrase II (CAII), and 35-kDa RPE protein) Yes (carbonic anhydrase II (CAII))

Abnormal Abnormal Died 1 month later

Abnormal n/a

Died 7 months later

Yes (68-kDa protein)

Normal

Died 2 months later

n/a

Course

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16

Autoantibodies (antigen)

M ¼ male; F ¼ female; n/a ¼ not available; VA ¼ visual acuity; OD ¼ right eye; OS ¼ left eye; CF ¼ counting fingers; RPE ¼ retinal pigment epithelium; ERG ¼ electroretinopgrahy; EOG ¼ electrooculography. Comments in quotes represent information as provided by source article. Patient number assigned based on chronological appearance in the literature.

23

74M

Al-Dahmash et al, 2012

14

Yes

Lung adenocarcinoma

Yes (bone)

Painless loss of vision

OD: 20/60, OS: 20/60

Bilateral

Multifocal serous retinal detachments with yellow-white subretinal fluid

n/a

n/a

n/a

Alive 2 months later

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reported cases had evidence of metastatic disease. Furthermore, PVM frequently heralded metastatic spread, often discovered within several months of a patient’s initial ophthalmologic evaluation. The average age of onset is 59 years (range, 33e80 years), with an equal sex distribution.14,20,33,35,69,93,120,122,136,147,148,200, 214,265,271,301 The most common presentation is nyctalopia, although some patients experienced blurry vision, metamorphopsia, shimmering photopsias, glare, and halos. Clinically, PVM may more closely resemble other vitelliform retinopathies, such as acute exudative polymorphous vitelliform maculopathy, or the multifocal variant of Best’s disease, than MAR or CAR. Ophthalmoscopy reveals varying degrees of multifocal yellow-orange vitelliform lesions at the level of the subneurosensory retina and RPE (Fig. 2), often accompanied by overlying serous macular detachment, with a tendency of the vitelliform material to gravitate inferiorly and layer out within the areas of subretinal fluid.14,33,69,93,120,122,136,147,148,200, 214,265,271 Involvement is typically bilateral, and although most cases associated with choroidal melanoma were in monocular patients, two treated with plaque brachytherapy alone had bilateral fundus lesions consistent with PVM.14,B FA typically demonstrates blockage of background choroidal fluorescence by the vitelliform lesions with late staining,14,20,93,122,136,148,200,265 although in some cases the lesions displayed a mild early hyperfluorescence.14,120,147, 214,265,271 There is little, if any, leakage of dye into the corresponding subretinal space. Corresponding fundus autofluorescence shows increased fluorescence of the lesions.20,93,214 OCT reveals multiple areas of localized serous neurosensory detachments containing optically dense debris overlying flat RPE.14,93 The advent of high-definition spectral domain OCT has more accurately localized this accumulation of fluid and vitelliform material to the subretinal space, not beneath the RPE as had been previously suggested, although the RPE may demonstrate thickening (Fig. 2).14,93 The absence of focal choroidal thickening on OCT also helps exclude choroidal metastases. Serological testing has identified autoantibodies directed against bipolar cells,35,214,301 rod outer segment protein (ROS, 120-kDa),265 peroxiredoxin 3 (PRDX3, 26kDa),147 bestropin-1 (68-kDa),69 carbonic anhydrase II (CAII, 30kDa),14,20 interphotoreceptor retinoid binding protein (IRBP, 145-kDa),33 and unnamed 35-kDa20 and 68-kDa14 proteins. Meanwhile, ERG and electrooculography (EOG) evaluation has yielded variable results.

2.3.2.

Pathogenesis

The mechanism underlying the formation of the vitelliform lesions in PVM remains poorly understood; individual reports uncovering the presence of certain anti-retinal and anti-RPE antibodies offers some potentially valuable insights, however. Koreen et al147 demonstrated circulating serum antibodies directed against a 26-kDa RPE protein identified as PRDX3, a mitochondrial peroxidase important in protection against cellular oxidative damage (Table 1, Patient 15). Accordingly, they hypothesized an autoimmune-mediated retinal pigment epitheliopathy resulting in the accumulation of unprocessed cellular debris and possibly lipofuscin, which manifests on a macroscopic level by the accumulation of yellowish subretinal deposits.

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Fig. 2 e PVM in a 58-year-old man with history of metastatic cutaneous melanoma to the axillary lymph nodes who presented with mild blurring of vision in the left eye (20/25) and preserved acuity (20/20) in the right eye. Color fundus photography (A, only left eye pictured) was remarkable for bilateral, multiple, subretinal, vitelliform lesions of the macula. Red-free (B) images of the fundus lesions are also presented. Fluorescein angiography (C ) demonstrated predominant blockage of background fluorescence by the material, which appeared to layer and gravitate into the inferior macula. OCT (D) confirmed these infiltrates to be at the level of the RPE without associated serous fluid. Visual field and ERG were essentially normal, autoantibodies to bipolar cells were not detected, and EOG revealed only a mildly decreased Arden ratio to 1.7. The patient developed metastatic spread to his small bowel 2 months later. Reproduced from Krema et al148 with permission from Wolters Kluwer Health Publishing Group Ltd. Photos courtesy of Peter J. Kertes, MD.

Eksandh et al.69 identified serum anti-RPE autoantibodies against a separate 68-kDa protein, bestrophin-1, in a patient with a history of enucleation for choroidal melanoma who presented with a pseudohypopyon within a serous macular detachment in the remaining eye (Table 1, Patient 11). ERG was within normal limits, whereas EOG showed a pathological Arden ratio of 1.1, similar to what is elicited in Best disease; there was no family history of this and genetic analysis for VMD2 mutation was negative, however, leading the authors to postulate a paraneoplastic etiology for the autoantibodies. Aronow et al20 detected high titers of autoantibodies in a patient with PVM against a 30-kDa protein present in the RPE and retina, determined to be CAII (Table 1, Patient 20). Additionally, they also detected subtle reactivity to an unknown 35-kDa RPE protein. How these contributed to the development of the vitelliform lesions was not clear; although they postulated that by inhibiting the catalytic activity of CAIId which is localized to the outer segment of photoreceptors, inner nuclear layer, and ganglion cell layerdthe intracellular pH levels decrease, with a concurrent rise in intracellular calcium reducing retinal cell viability.8,20 Four other cases had serum autoantibodies that labeled retinal bipolar cells using immunohistochemical techniques

(Table 1, Patients 1e4).35,214,301 Such findings invite further investigation and clarification as to whether PVM falls along the spectrum as a MAR variant or a unique paraneoplastic entity. Adding to the discord are findings from the first histologic report of PVM136 that detailed a patient with bilateral vitelliform macular detachments in the setting of metastatic cutaneous melanoma. Although there was no clinical evidence of choroidal metastasis, postmortem pathologic examination of the eye revealed a flat, pigmented choroidal infiltrate composed of spindle-shaped and epithelioid cells with marked nuclear and cellular pleomorphism. This argues against PVM as a paraneoplastic entity altogether, suggesting instead local metastases with subclinical choroidal involvement. The authors did acknowledge that metastasis may have occurred independently of and well after the development of vitelliform lesions. Aronow et al20 actually described the histopathological correlate to the clinically observed vitelliform lesions. Microscopically, there was focal retinal edema as well as loss of nuclei from the inner retina, likely from bipolar cells. In addition, there was atrophy of the outer nuclear layer and splitting of the outer plexiform layer. In contrast to the previously described case,136 here, there was no evidence of active inflammation or malignant melanoma cells in either enucleated eye.20

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441

Fig. 3 e DUMP in a 55-year-old woman with 2-year history of metastatic small cell lung carcinoma who presented with decreased visual acuity in the left eye (20/40). She was noted to have moderate nuclear sclerotic cataract in that eye. Color fundus photography (A) revealed islands of atrophic RPE separated by a reticular pattern of yellow-orange pigmentation in the left macula. Corresponding fluorescein angiography (B) was remarkable for nummular areas of early hyperfluorescence consistent with RPE atrophy. B-scan ultrasound (C ) revealed extensive choroidal thickening of the affected left eye (arrowheads). OCT of the same eye (D) demonstrated neurosensory detachment over the macula with focal areas of RPE atrophy and hypertrophy. The respective studies in the right eye were all normal. Reproduced from Reddy and Finger232 with permission from BMJ Publishing Group Ltd. Photos courtesy of Shantan Reddy, MD.

2.3.3.

Management

The presence of vitelliform fundus lesions in the appropriate clinical setting should alert the physician to the possibility of PVM. If there is any history of malignancy, a thorough investigation for systemic spread should be undertaken, regardless of how long the patient has been in remission. Treatment with various combinations of palliative surgical resection, radiotherapy, and chemotherapy is aimed at the underlying malignancy. Unfortunately, the identification of PVM is a grim prognostic indicator, with most patients succumbing to metastatic disease from several months up to 4 years after presentation. One patient had a favorable response to treatment with the chemotherapeutic agent temozolomide (Table 1, Patient 15).147 After initial empiric therapy with prednisone produced no subjective or objective improvement, the patient was diagnosed with a metastatic melanoma of unknown origin and treated with temozolomide therapy, with subsequent resolution of subretinal fluid bilaterally and return of visual acuity to baseline levels. The vitelliform lesions, however, not only persisted, but slightly increased in size. The patient demonstrated an excellent treatment response systemically, with normalized CT imaging, and at the time of publication, was alive and doing well.147

2.4.

Bilateral diffuse uveal melanocytic proliferation

2.4.1.

Clinical presentation

In 1966, Machemer161 first described a patient with presumed pancreatic cancer who developed bilateral visual loss, cataracts, and retinal detachments. Barr et al25 later named the disorder BDUMP in 1982, and at least 50 cases have since been described.22,31,40,59,65,111,142,168,177,187,190,198,201,232,246,256,257,262, 281,292,299 BDUMP usually presents with rapid-onset, bilateral, painless vision loss accompanied by various funduscopic findings. Patients are typically in their 50s through 80s with no sex predilection.201 BDUMP often precedes the diagnosis of the systemic malignancy by months to years. Affiliated tumors typically involve the reproductive tract in women (ovarian, uterine, or cervical cancer), whereas men are likely to have an underlying lung, pancreatic, or colon carcinoma.201 Though bilateral by definition, one unilateral case has been reported (Fig. 3).232 Gass et al85 described the five cardinal signs of BDUMP: 1) multiple, subtle, round, orange-red subretinal patches in the fundus; 2) multifocal early hyperfluorescence of these patches on FA; 3) focally elevated pigmented and non-pigmented uveal melanocytic tumors with diffuse choroidal thickening; 4) exudative retinal detachments; and 5) rapidly progressive

442

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cataract formation. Other clinical features noted less frequently include iris and ciliary body cysts and angle closure.161,201,227,239,280 Useful adjunct tests include B-scan ultrasonography to demonstrate choroidal thickening and OCT to confirm subretinal fluid. A unique “giraffe pattern” fundus secondary to nummular or polygonal patches of RPE atrophy circumscribed by adjacent orange zones of aggregated and hypertrophied RPE is considered typical for BDUMP.155,292,297 The fundus appearance in these cases is dominated by RPE atrophy, as evidenced by the abundance of round or polygonal window defects seen on FA. Encircling these islands are orange wreaths of intact, hypertrophied RPE, which in turn block background fluorescence on FA. Fundus autofluorescence imaging demonstrates complete loss of the expected RPE autofluorescence pattern within the nummular patches, while showing intensified levels of autofluorescence in the preserved intervening regions.256 OCT likewise reveals alternating zones of irregular RPE thickening and complete RPE loss.31

2.4.2.

Pathogenesis

Through unknown mechanisms, the primary tumor stimulates the proliferation of uveal tract melanocytes. A popular hypothesis centers around the production of melanocytic growth factors by tumor cells with subsequent release into the circulation.201 The observation of hyperpigmentation in extraocular tissue sites such as the skin or mucous membranes in a substantial number of BDUMP patients (26% in one review)201 adds credence to this theory, which is further supported by a case with simultaneous development of systemic hyperpigmentation and BDUMP.86 Circulating anti-retinal autoantibodies have been detected in BDUMP patients,111,177,246 but the significance of the various proteins they are directed against is not known, and may rather represent epiphenomena. Recent studies by Pulido et al,179,C however, show that the serum of some patients with BDUMP cause human melanocytes to proliferate and become disorganized. In addition, this effect was specific for melanocytes and not seen with other tested cell types. The isolated IgG antibody is termed cultured melanocyte elongation and proliferation factor (CMEP). More specific characterization of CMEP and the mechanism whereby which it stimulates rapid melanocytic proliferation is currently under further investigation. In addition to melanocytic proliferation, Gass et al85 hypothesized that toxic or immunologic factors must also participate in the pathogenesis of BDUMP, contributing to the degeneration of the RPE, retina, and lens. Chahud et al46 suggested that ocular hypoxia secondary to the increased metabolic demand from replicating melanocytes creates a toxic milieu conducive to RPE, retina, and lens dysfunction.

2.4.3.

underlying neoplasm.59 Despite occasional transient improvement, most patients are non-responders and continue to deteriorate. Two new reports advocating plasmapheresis appear promising. Based on the premise that a circulating growth factor is responsible for the findings in BDUMP, plasma exchange therapy was initiated by both groups in hopes of removing the inciting agent. Jaben et al111 first used plasma exchange in two women with BDUMP secondary to gynecologic malignancies. The first presented with 3 months of decreased vision after being diagnosed with metastatic papillary serous adenocarcinoma involving the endometrium, bilateral ovaries, and left fallopian tube. Visual acuity at baseline was 20/40 bilaterally (OU), and funduscopic findings were consistent with BDUMP. A course of plasmapheresis was initiated, which consisted of seven volume exchange sessions every other day. During her post-treatment surveillance period, the pigmented fundus lesions remained stable in size, and visual acuity improved. She eventually underwent bilateral cataract extraction, and at follow-up 13 months since completing plasma exchange, her visual acuity was 20/25 OU. The second woman had a 7-month history of painless bilateral vision loss and a known history of metastatic uterine cancer.111 Her visual acuities were 20/200 OD and 20/400 OS at presentation. After BDUMP was diagnosed, she began a course of seven sessions of plasma exchange. Unfortunately, following the fifth session, a line infection necessitated discontinuation of plasmapheresis, and she was lost to follow-up. Nine months later in a telephone conversation, the patient stated that her vision remained stable. Mets et al177 described a patient with metastatic bronchogenic carcinoma who presented with bilateral decreased vision for one month and visual acuities of 20/40 OD and 20/50 OS. A diagnosis of BDUMP was made, and plasmapheresis was initiated three times per week. After 17 treatment sessions, visual symptoms had entirely resolved, and acuity had improved to 20/20 OU. There was corresponding resolution of subretinal fluid and reversal of choroidal thickening. After 7 months, the patient had become too ill to continue plasma exchange. His vision was 20/20 bilaterally at that time. Shortly afterwards, fundus abnormalities reappeared with decline in vision to 20/200 OD and 20/30 OS. He expired one month later. Ultimately, patients with BDUMP often die within a year of their diagnosis secondary to the underlying systemic tumor burden. Despite this poor prognosis, plasmapheresis may be a viable treatment option to improve and maintain visual function while a patient undergoes systemic treatment for the underlying malignancy.

3.

Paraneoplastic optic neuropathies

3.1.

Paraneoplastic optic neuropathy

3.1.1.

Clinical presentation

Management

Treatment for BDUMP has been largely futile, with eventual near complete blindness in most cases. Cataract surgery is frequently performed, but fails to improve visual function to the anticipated degree.201 Other interventions attempted include ocular radiation,25,36,61,65,161,244 drainage of subretinal fluid,237 corticosteroids,73,153,187,194,239,246 and treatment of the

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

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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 cerebellar ataxia who subsequently was found to have a small-cell lung carcinoma (SCLC). At least 56 cases of PON have been reported, the vast majority associated with an underlying SCLC.32,55,160,170,189,241,259,275,279 Other associations include Bcell lymphoma,54,197,234 pancreatic glucagonoma,154 neuroblastoma,133,254 uterine sarcoma,272 breast,18,228 prostate,44 nasopharyngeal,105 bronchial,220 papillary thyroid,55,151 nonsmall cell lung,21,192 and renal cell carcinomas.55,108,268 Patients classically present with subacute, bilateral, painless vision loss that progresses over days to weeks. The optic nerve head may appear normal, edematous, or atrophic at the time of initial examination. The lack of diagnostic criteria has led to an open and often variable interpretation of what may constitute PON; Cross et al,55 however, described a clinical triad of optic neuritis, retinal vascular leakage, and vitreous cells. FA often displays optic disk hyperfluorescence consistent with leakage (Fig. 4). Peripheral retinal vascular leakage may

443

also be seen. Visual fields show enlarged blind spots, arcuate and altitudinal defects, paracentral scotomas, peripheral constriction, or generalized depression.55 Bitemporal hemianopsia has also been described in a patient with PON primarily affecting the optic chiasm, which was confirmed by postmortem histopathological findings of chiasmal demyelination.211 ERG abnormalities are not consistently noted, but have been described, notably prolongation of the maximal rodecone, cone, and 30-Hz flicker responses.55 Neuroimaging may reveal patchy, hyperintense T2 signal changes in the brain parenchyma, enhancement of the optic nerves, spinal cord abnormalities, or may be unremarkable.55,259 Most of these patients test positive for a serum antibody to the 62-kDa neuronal antigen, collapsin response-mediating protein-5 (CRMP-5), which has also been called CV2.107 The CSF typically reveals a lymphocytic-predominant pleocytosis, elevated protein, oligoclonal bands, and CRMP-5-IgG titers that equal or may significantly exceed serum levels.55,300 Additionally, CSF cytology shows no neoplastic cells. PON almost always coexists in the setting of multifocal neurological dysfunction, explaining why some reports classify the optic neuropathy as a component of paraneoplastic brainstem or cerebellar degeneration.55,300 Several patients have even presented with optic neuropathy and myelopathy

Fig. 4 e PON in a 62-year-old man presenting with subacute progressive bilateral vision loss (20/150 right eye, 20/400 left eye) with associated photopsias. Examination was remarkable for minimal anterior chamber reaction and vitritis bilaterally. Color fundus photography (A, only right eye pictured) was unremarkable, but corresponding fluorescein angiography (B) revealed pronounced papillary and peri-papillary leakage bilaterally. Humphrey visual field (C, D) displayed severely enlarged blind spots bilaterally. MRI of the orbits and brain failed to demonstrate any mass or infiltrative lesions. Chest X-ray did show hilar and paratracheal adenopathy, however, which was subsequently found to be secondary to biopsy-proven small cell adenocarcinoma of the lung.

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strikingly similar to neuromyelitis optica.60,197 In the original publication detailing clinical findings in 116 patients with CRMP-5 seropositivity, Yu et al300 described a myriad of neurologic findings, including peripheral neuropathy (47%), autonomic neuropathy (31%), cerebellar ataxia (26%), subacute dementia (25%), cranial neuropathy (17%, subdivided into 10% loss of olfaction/taste and 7% optic neuropathy), neuromuscular junction disorders (12%), and chorea (11%). The largest cohort to date with PON is Cross et al’s55 16 cases out of 172 patients seropositive for CRMP-5-IgG. Symptomatic vision loss occurred in 15, with visual acuities ranging between 20/20 and 20/400 at presentation. Visual complaints included blurring, dimming, dazzling, or tunnel vision. Fifteeen individuals had disk edema, often with adjacent nerve fiber layer hemorrhages. Interestingly, nine patients had vitreous cells. The authors commented that the cells lacked the characteristic homogeneity, clumping, and larger size commonly seen with intraocular lymphoma. Subsequent vitreous biopsy in four of these patients revealed a pleomorphic reactive lymphocytic response without evidence of lymphoma.

3.1.2.

Pathogenesis

Collapsin response-mediating proteins are believed to regulate growth guidance cues during neurogenesis.48 Specifically, the CRMP-5 subtype is found in normal adult retina, optic nerve, and central and peripheral neurons.55,300 Aberrant expression of this protein is also detected in the cytoplasm of SCLC tumor cells.55,300 The resultant host immune response initiated by neoplastic CRMP-5 is believed to cross-react with native tissue sites, leading to the intra- and extraocular clinical manifestations of PON. Given the widespread production of CRMP-5 throughout the central and peripheral nervous system, it comes as no surprise that these patients present with such extensive neurological dysfunction. Pathologic specimens of the optic nerve show perivascular lymphocytic infiltration in conjunction with axonal demyelination, consistent with chronic optic neuritis.55,108,211,259 Immunohistochemical studies of the infiltrate have revealed an excess of CD8þ T-cells invading the optic nerve.55 Meanwhile, histologic sections from brain and spinal cord displayed widespread microglial activation with rare microglial nodules and prominent perivascular cuffs, again composed mainly of CD8þ T-cells.55

3.1.3.

Management

The most important diagnosis to exclude in the patient with known malignancy whose clinical picture is consistent with PON is metastatic optic nerve infiltration or direct external compression of the nerve. Even more challenging is securing the diagnosis of PON in the absence of any history of cancer. Indeed, a patient presenting with subacute vision loss, accompanying disk edema, and vitreous cells poses a broad differential, including vasculitic, infectious, infiltrative, or demyelinating disease. A thorough history and review of systems, especially for unexplained neurological deterioration, while maintaining a high index of suspicion for potential neoplasia, may avoid a delay in diagnosis.

A CRMP-5 autoantibody assay should be obtained whenever the diagnosis is entertained, and is available through the Mayo Clinic Laboratories by submitting a standard serum specimen.D The presence of CRMP-5-IgG in the serum or cerebrospinal fluid obviates the need for vitreous biopsy and should expedite the search for lung cancer. In rare cases, one must entertain the possibility of an extrapulmonary primary small-cell carcinoma,134 or other malignancies associated with PON as listed previously. Treatment of the primary tumor may stabilize or even improve visual outcomes in some patients,48,241 whereas others progress to severe visual loss.259 Interestingly, the longest published survival duration for PON secondary to SCLC is over 14 years in a patient treated with surgery, chemotherapy, and radiation therapy.160,216 Best-corrected visual acuity was 20/30 OD and 20/40 OS without a relative afferent pupillary defect. Early detection of the systemic malignancy thanks to timely recognition of the paraneoplastic syndrome may have contributed to this favorable outcome. In addition to managing the underlying malignancy, adjunctive systemic immunosuppression is considered a treatment option for PON based on its presumed autoimmune mechanism. Results from individual cases treated with systemic steroids (oral or intravenous), usually given to supplement cancer therapy, have been variable.105,189,279 Intraocular therapy may also be a consideration depending on the severity of vitritis and retinal vascular leakage. Pulido et al228 presented the outcomes in four eyes of two patients with PON treated with intravitreal triamcinolone (IVTA). Both patients were CRMP5-IgG positive in serum and CSF samples and demonstrated vitritis and optic disk edema. Each received 4 mg IVTA with subsequent stabilization or improvement of visual acuity. The first stabilized at the 20/50 level for 3 months, and the second patient improved to 20/200 OD and 20/60 OS from counting fingers OU at baseline by 3 months post-IVTA injection. The optic disk swelling and vitritis resolved in each patient by the final follow-up.

3.2. Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome 3.2.1.

Clinical Presentation

POEMS syndrome is a rare paraneoplastic disorder secondary to an underlying plasma cell dyscrasia. In contrast to some of the previous entities, POEMS syndrome manifests with multisystem involvement, targeting numerous tissue sites in addition to the eyes.63,64 Affected individuals typically present in their 50s, with a slight male predominance.63 To date, several hundred cases have been reported; this is still considered to be an underdiagnosed condition, however. The acronym POEMS was initially coined in 1980 by Bardwick et al.23 Although capturing several dominant characteristics of the syndrome, this designation is limited by its exclusion of several others. Furthermore, not all of the components of the acronym are required to establish the diagnosis. The most recently proposed diagnostic classification requires the presence of three major criteria, two of which must include monoclonal plasma cell proliferative disorder and chronic progressive polyneuropathy, and at least one minor criterion (Table 2).64 The clinical picture is typically

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Table 2 e Criteria for the diagnosis of pOEMS syndrome Mandatory Major Criteria Other Major Criteria (1 required)

Minor Criteria (1 required)

Other Signs and Symptoms

1. Polyneuropathy (typically demyelinating) 2. Monoclonal plasma cell-proliferative disorder 1. VEGF elevation 2. Castleman disease 3. Sclerotic bone lesions 1. Organomegaly (splenomegaly, hepatomegaly, lymphadenopathy) 2. Extravascular volume overload (edema, pleural effusion, ascites) 3. Endocrinopathy (adrenal, pituitary, gonadal, parathyroid) 4. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora) 5. Papilledema 6. Thrombocytosis/polycythemia Clubbing, weight loss, hyperhidrosis, pulmonary hypertension/restrictive lung disease, thrombotic diatheses, diarrhea, low vitamin B12 values

The diagnosis of POEMS syndrome is confirmed when both of the mandatory major criteria, one of the three other major criteria, and one of the six minor criteria are present. Reproduced from Dispenzieri64 with permission from John Wiley and Sons.

dominated by peripheral neuropathy, which is initially sensory, but progresses to include the motor system.127 Involvement is bilateral, symmetric, and spreads proximally, resulting in profound muscle atrophy and weakness.63 Intraocular manifestations of POEMS syndrome, limited to single case reports and small case series, are nevertheless well documented, as evidence by the inclusion of “papilledema” among the minor diagnostic criteria (Table 2).64 The most common ocular finding in POEMS syndrome is bilateral optic disk edema (ODE), occurring in 29e73% of patients.34,38,45,52 Kaushik et al,125 in the largest study to date, found ODE in 17 of 33 patients (52%). Of note, five (29%) of the patients had asymptomatic ODE at the time of initial examination, leading the authors to advocate screening ophthalmologic examinations for all patients diagnosed with POEMS.125 When presenting with symptomatic ODE, patients often complained of blurry vision, ocular pain, or diplopia. In addition to ODE, there are at least five cases with associated CME52,94,110,290 and one of bilateral serous macular detachment.209 Adjunctive testing can aid in the evaluation of these patients and augment physical examination findings. Visual field testing usually demonstrates enlargement of the blind spot,125,291 although arcuate defects are also described.24,52,94 FA typically shows late optic disk leakage and may also demonstrate petaloid leakage consistent with CME. OCT may also confirm the presence of CME or macular detachment. Additionally, serological testing reveals significantly elevated VEGF levels, sometimes to over 2,000 pg/ml (normal range, 62e707 pg/ml).110,266,286 Watanabe et al287 found a mean serum VEGF level of 1,673.2 pg/ml in 10 patients with POEMS syndrome, as compared with <131 pg/ml in control subjects. Increased production of the associated cytokines interleukin6 (IL-6), IL-1 beta (IL-1b), and tumor necrosis factor-alpha (TNF-a) may also be detected.87,88,240

3.2.2.

Pathogenesis

Although significant progress has been made in our understanding of POEMS syndrome, its pathogenesis remains complex. Elevated production of proangiogenic and proinflammatory cytokines are believed to be the hallmark of this disorder. Specifically, excess VEGF produced by the abnormal

plasma cells is thought to be the major contributor to its development and correlates best with disease activity.64,180,252 VEGF is known to target endothelial cells, where it induces a rapid increase in vascular permeability while also being an important promoter of angiogenesis. As previously stated, patients with POEMS syndrome have also demonstrated higher circulating levels of IL-6, IL-1 b, and TNF-a, and both IL6 and IL-1b are known to stimulate VEGF production.88,266 The etiologies of ODE, CME, and macular detachments associated with POEMS syndrome are controversial. Current hypotheses include elevated intracranial pressure,56 vasculitis,181 infiltration of the optic nerve,37 increased VEGF levels,52 or any combination thereof. Increased vascular permeability of the optic nerve and macula secondary to raised serum VEGF levels is an appealing theory and is supported by the presence of extravascular volume overload elsewhere in POEMS syndrome (e.g., peripheral extremity edema, pleural effusion, pericardial effusion, ascites).52 Alternatively, the development of CME and macular detachment may be caused by an osmotic gradient created by deposition of high molecular weight immunoglobulins within and beneath the neurosensory retina. This pathologic mechanism has been similarly offered to explain the macular detachments observed in some patients with multiple myeloma and Waldenstro¨m macroglobulinemia.30,39,79,104,221

3.2.3.

Management

There are no randomized controlled trials evaluating the treatment of POEMS. Although directing therapy against the increased VEGF load seems logical, use of intravenous bevacizumab has yielded mixed results.123,249,269 Rather, the majority of successful outcomes are the result of targeting the underlying plasma cell dyscrasia itself. Treatment of the systemic disease process is beyond the scope of this discussion, but may include radiation therapy for localized bone lesions, high-dose chemotherapy with autologous stem cell transplantation, and systemic steroids.63,64 Overall, ODE and associated ocular symptoms respond variably to systemic treatment. Wiaux et al290 observed resolution of macular edema in two patients upon institution of systemic steroids in combination with oral acetazolamide, but

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disk edema persisted in both patients. Okada et al209 reported a patient with bilateral macular detachment who was treated with autologous peripheral blood stem cell transplantation. Serum VEGF levels subsequently declined from >2,000 pg/ml to 221 pg/ml with resolution of the subretinal fluid and improvement of visual acuity. Imai et al110 injected sub-Tenon triamcinolone acetonide twice to treat CME in the more affected eye of their patient. Because of persistent CME, the eye underwent pars plana vitrectomy and additional intravitreal triamcinolone injection with a resulting decrease in macular thickness, but visual acuity remained poor. Of note, vitreous levels of VEGF obtained at the time of vitrectomy were <31 pg/ml, in stark contrast to serum levels, which consistently exceeded 2,000 pg/ml. The fellow eye was observed throughout the follow-up period, and macular thickness paralleled changes with serum VEGF levels. They concluded that the CME was a response to elevated VEGF in the circulation and not that locally produced by the retina. That being said, there are no reports to date evaluating the response to intravitreal anti-VEGF agents. Such a treatment strategy is appealing and could warrant consideration in the appropriate clinical scenario to augment systemic therapy.

4. 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 chest X-ray and CT scan of the chest as starting points. Some experts recommend CT and PET scanning of the whole body (usually orbits to thighs).58,176 In selected patients known to be seropositive for a paraneoplastic antibody, PET may be more sensitive than CT158,285,298; by doing both PET and CT, however, sensitivity is higher than with either alone.158 McKeon et al,176 in 56 consecutive patients with clinical suspicion for paraneoplastic retinopathy, but negative CT evaluation, found that 22 patients (39%) demonstrated abnormalities suggestive of cancer by PET, and 10 patients (18%) later had this confirmed histologically. In many centers, a CT scan is performed along with the PET scan (PET-CT)58 to enhance accuracy and localization so that metabolic PET abnormalities are correlated with anatomic CT abnormalities.176 However, because the CT portion of the PET-CT generally uses a lower dose of radiation, thicker sections, and no contrast, it is less sensitive than a dedicated CT. Therefore, a negative PET would still require a dedicated body CT, and conversely, a negative body CT would require a PET scan.58 Important sources of false-positive PET uptake include inflammatory lesions, trauma, benign tumors, and stray tracer that has infiltrated outside of the injection site and is picked up by an axillary lymph node.58 Sources of a false-

negative PET scan may include a tumor with low metabolic activity, as well as tumors smaller than 1 cm.50 In patients with autoantibodies predictive for SCLC, such as CRMP-5 in cases of suspected PON, more detailed thoracic imaging may be warranted when initial CT findings have been negative. This tumor is typically limited in its spread and thus more difficult to detect. Cases of PON with negative CT survey have subsequently demonstrated a tumor focus utilizing chest magnetic resonance imaging (MRI)141; MRI is generally not used as a primary oncologic screening tool, however.176 If no cancer is found, imaging may be repeated at future intervals.260 A report issued by the European Federation of Neurologic Societies task force on management of paraneoplastic neurologic syndromes recommends, in general, repeat surveillance every 6 months for 4 years.284 Darnell and Posner58 recommend closer follow-up examinations and studies at least initially (every 3 months, and then progress to every 6 months).

5.

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.

5.1.

Acute zonal occult outer retinopathy

Originally described by Gass82 in 1992, AZOOR is an idiopathic retinal disease characterized by the acute onset of sectoral outer retinal dysfunction at the level of the photoreceptors.116,267 Like the paraneoplastic retinopathies, AZOOR is rare but increasingly recognized, with over 150 cases reported to date.186 Overlapping features among these entities can be cause for confusion. AZOOR typically affects young (average age, 36.7 years) white (89% of patients) females (3.2:1 ratio over males).186 In contrast, paraneoplastic retinopathies most commonly present during the sixth to seventh decades of life, show no racial preference, and, with the exception of MAR, which affects males more than females, have no sex predilection. Additionally, patients with AZOOR are more likely to have a history of antecedent viral-like illness (11e20%), and may have an associated systemic autoimmune disease (18e28%).84,186 Gass observed that AZOOR presents acutely as a scotoma accompanied by photopsias.82 In fact, visual acuity is minimally affected in AZOOR (20/40 or better in 74% of eyes),186 similar to MAR, and in stark contrast to CAR. Furthermore, whereas paraneoplastic retinopathies are classically bilateral at onset, AZOOR more commonly presents unilaterally (62% of patients).186 Fundus examination on presentation is usually unremarkable in AZOOR, MAR, and CAR. Over time in AZOOR, RPE mottling analogous to retinitis pigmentosa may develop in the zones of visual field loss. Retinal vascular abnormalities, however, are rare in AZOOR,186 unlike the vascular

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attenuation in both RP and paraneoplastic retinopathy. In contrast to RP, intra-retinal bone spicule migration is rare with either AZOOR or paraneoplastic retinopathy; meanwhile, the presence of CME is more typical of RP and paraneoplastic retinopathy than AZOOR. Ancillary testing with ERG can be invaluable in differentiating among AZOOR and paraneoplastic degenerations. In AZOOR, the ERG is abnormal in the vast majority of cases. Despite the focal nature of AZOOR clinically, the ERG changes depict a more global retinal dysfunction.186 In a long-term follow-up study in 90 eyes of 51 patients with AZOOR, Gass et al84 detected abnormal scotopic and photopic ERGs in 55 eyes, photopic only in 16 eyes, and scotopic only in 8 eyes. The most consistent abnormality noted by Francis et al78 in a series of 28 patients is a markedly delayed implicit time of the 30-Hz cone flicker response. Moderate reductions in a- and b-wave amplitudes are also common, but not to the extent of the severely depressed to extinguished waveforms described in CAR. Furthermore, the electronegative ERG pattern of MAR is not usually observed with AZOOR, although Piao et al219 described one such case. Anti-retinal antibody testing may not be as valuable a distinguishing factor between AZOOR and paraneoplastic retinopathy as previously thought. Adamus3 reported that, of the 53 patients suspected of having AZOOR that underwent serological testing, more than half (53%) had circulating autoantibodies to various retinal proteins. Autoantibodies to a-enolase and CAII, which are often associated with paraneoplastic retinopathies, were detected in 14 (27%) and 9 (17%) of AZOOR patients. In 25 patients with AZOOR, Heckenlively and Wang99 likewise detected strong immunoreactivity to anti-retinal antibody bands by Western blot. Other reported retinal antigens include cellular retinaldehyde binding protein (CRALBP) and retinal soluble antigen (S-Ag) in one case by Neutzner et al199 and an unnamed 45-kDa antigen in one of four patients presented by Mkrtchyan et al.184 The term AZOOR complex has been used to describe a group of diseases including punctate inner choroidopathy, multifocal choroiditis and panuveitis, multiple evanescent white dot syndrome, acute idiopathic blind spot enlargement, and acute macular neuroretinopathy that share overlapping demographic and clinical features with AZOOR and may all have a common autoimmune mechanism.83,92,118,121 Fine et al74 described three cases of multiple evanescent white dot syndrome that atypically developed progressive multifocal zonal degeneration of the outer retina and RPE characteristic of AZOOR. Similarly, Holz et al106 identified seven patients with punctate inner choroidopathy who demonstrated widespread retinal dysfunction in excess of what would be expected from the visible fundus findings that they attributed to AZOOR. Some experts feel that AZOOR is a unique entity that may be more precisely defined by multimodal imaging: 1) autofluorescence, demonstrating characteristic zonal degeneration of the outer retina and RPE, typically beginning around the nerve and progressing to the periphery, and 2) high-definition spectral domain OCT, showing zonal or annular loss of the photoreceptor layer and IS/OS complex.81,143,184,199,263,267

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5.2. Autoimmune-related retinopathy and optic neuropathy A patient’s clinical, electrophysiological, and immunological profile may be suggestive of paraneoplastic retinopathy, although the systemic work-up is unremarkable for malignancy (Fig. 5). The appropriate classification for this situation has been the subject of much confusion and discord, with different designations being adopted by different groups. Terms such as non-paraneoplastic autoimmune retinopathy, recoverin-associated retinopathy, and autoimmune-related retinopathy and optic neuropathy (ARRON) are variably used to describe this subgroup. Historically, the earliest reports of this condition described patients with a steroid-responsive optic neuropathy.66,80,112,150,235,243,E Although laboratory techniques at the time did not allow detection of autoantibodies, these cases were felt to represent a localized autoimmune-mediated optic neuropathy. It has since become apparent, however, that many patients with steroidresponsive optic neuropathy additionally manifested a retinal immune component. KeltnerE offered a rationale for the use of ARRON: 1) “autoimmune-related,” rather than “autoimmune” reflects the uncertainty whether the antibodies generated from the retina and optic nerve are directly responsible for the vision loss or just epiphenomena; and 2) the addition of “optic neuropathy” encompasses the full disease spectrum, ranging from cases of isolated retinal involvement, to isolated optic nerve involvement, to simultaneous retinal and optic nerve involvement. In Keltner et al’s130 initial report detailing ARRON in 12 patients, the average age of symptom onset was 50 years (range, 37e75 years), and women were preferentially affected (2:1 over men). Vision loss was painless, asymmetric at onset, and varied from 20/20 to no light perception. Only 3 of 12 patients experienced photopsias. Nonspecific retinal changes were present in 8 of 12 patients, optic disk pallor was noted in 11 of 12, and ERG abnormalities were present in 10 of 11. The presence of CME may be a distinctive feature of this retinopathy.72,103 Reported antigenic targets in presumed cases of have included a 22-kDa neuronal antigen found in retina and optic nerve,129 a 35-kDa component of Mu¨ller cells,76,217 and even recoverin in a single case.289 Adamus et al12 observed antiretinal antibodies in 41% of patients (58 of 141) with a clinical presentation resembling ARRON, most commonly directed against a-enolase and a 35-kDa protein unidentified at the time. In the same report, they were able to identify antirecoverin antibodies only in patients with paraneoplastic retinopathy. Patients with ARRON may have been previously diagnosed with simplex RP; in the absence of any family history, however, investigators alternatively proposed an autoimmune etiology for the retinal degeneration. Attempting to show causality, Heckenlively et al102 detected anti-retinal antibodies by Western blot in 90% of patients with RP and CME (27 of 30), compared with only 13% of patients with RP and no CME (3 of 30) and 6% of controls (3 of 50). Complicating matters further, a follow-up study by Heckenlively et al100 analyzing sera from 521 patients diagnosed with RP found

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Fig. 5 e ARRON in a 53-year-old woman referred for rapidly declining vision in both eyes. Color fundus photography (A, only left eye pictured) revealed marked attenuation of the arterioles, and diffuse RPE changes bilaterally. Autofluorescence imaging (B) showed patchy areas of absent autofluorescence suggestive of RPE atrophy, which was supported by the hyperfluorescent window defects seen on fluorescein angiography (C ). Spectral domain OCT imaging (D) displayed CME bilaterally, which did not leak on fluorescein angiogram. Visual fields were severely constricted, and ERG was extinguished. Anti-retinal antibody testing was positive for antibodies to alpha-enolase; a comprehensive systemic workup for malignancy was negative, however. Oral acetazolamide therapy resulted in limited improvement of the CME.

anti-retinal antibodies in 51 and specifically, anti-recoverin antibodies in 10 patients in the absence of underlying malignancy. In an editorial response, Adamus1 highlighted that the patients in the study often demonstrated nonspecific antiretinal antibodies recognizing multiple retinal proteins, often up to 10, on the Western blots. Thus, in the absence of measuring titers to demonstrate higher intensity or quantity of one antibody over others, it would be impractical to assign such a high importance to the presence of any one particular antibody, let alone anti-recoverin antibodies.

Although not a suggested diagnostic criteria for ARRON (Table 3), 8 of 12 patients in Keltner et al’s130 cohort had concurrent systemic autoimmune diseases, a finding corroborated by other reports.101,183,296 Ferreyra et al72 were also able to elicit a strong family history of autoimmune disease, affecting the patient and at least one first-degree relative in 67% of cases (16 of 24). This may explain these patients’ susceptibility to developing retinal disease, and theoretically, justify treatment with steroids or other immunomodulatory therapy. Results of such interventions have been mixed and

Table 3 e Suggested criteria for the diagnosis of ARRON All four of the following

One of the following Modifiers

1. Visual loss as demonstrated either by visual acuity or visual field examination 2. No malignancy found after extensive evaluationa 3. Evidence of optic nerve or retinal abnormalities 4. No identifiable cause for optic neuropathy and/or retinopathy 1. Serum autoantibodies against retina and/or optic nerve not usually found in normal healthy individualsb 2. Response to immunomodulation demonstrated either by stabilization, slowing, or reversal of visual field deficit Type A: Associated with other autoimmune disease Type B: Not associated with other autoimmune disease

a Includes a history of remote malignancy that may better explain visual loss as being associated with CAR, PON, or MAR. b The presence of autoantibodies to retina and/or optic nerve antigens does not prove causality. Reproduced from Oyama et al213 with permission from Wolters Kluwer Health Publishing Group Ltd.

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have generated more controversy than definitive answers.72,119 Generally speaking, if a coexisting autoimmune disease is present, it should be treated first. In the absence of systemic disease, corticosteroids are initially attempted, and depending on the response, additional aggressive immunotherapies may be used singly or in combination. Oyama et al213 more recently reported a case of ARRON in a patient resistant to conventional therapies who underwent successful autologous hematopoietic stem cell transplantation with improvement in symptoms, visual acuity, and visual fields. Whether these results can be duplicated remains to be seen. Equally important as choice of therapy is counseling to help the patient understand the goals of therapy. Recovery of visual function already lost may not occur. Rather, stabilization of vision and prevention of further deterioration may be the best that can be hoped for.E Ultimately, ARRON is a diagnosis of exclusion that is made following an extensive systemic evaluationdand often reevaluation at future intervalsdthat rules out an underlying malignancy (see section IV). Unexplained vision loss should always lead to consideration of an underlying paraneoplastic syndrome. The longest known latency period between onset of retinopathy and discovery of systemic malignancy is 11 years, in a patient with bronchioloalveolar carcinoma and associated circulating anti-recoverin antibodies.245 That case highlights the importance of diligent regular screenings in patients with presumed ARRON, as at the time of tumor diagnosis, no metastases had occurred, and the patient did well after lobectomy. Conversely, a patient with ARRON has gone 32 years without detectable malignancy (personal communication with John Keltner). Whether ARRON stands as an independent entity or is a prelude to a malignancy raises an intriguing issue concerning the practicality of serological tests and their overall contribution to the physician’s acumen.

6.

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 antiretinal 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 protein/tissue varies in different laboratories. Fresh human tissue obtained within 6 hours after death is optimal, because the ensuing degradation of protein and tissue may contribute to erroneous results. Whereas some investigators have not had difficulty obtaining fresh human tissue, others have, and instead utilized porcine,E rodent,51,169 monkey,289 primate,157 and bovine6,102 tissues with success. Recent progress towards streamlining serological testing for paraneoplastic and non-paraneoplastic retinopathies include the introduction of a commercially available anti-recoverin assay through Athena DiagnosticsF as well as more extensive autoantibody testing offered at several academic institutions (University of California at Davis Ophthalmology Research

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Laboratories and Casey Eye Institute’s Ocular Immunology Lab). The presence of autoantibodies directed at recoverin should be considered highly indicative of a concurrent malignancy. Of the nearly 3,000 serum samples of patients with retinopathy analyzed at the University of California at Davis, only cancer-related cases had anti-recoverin antibodies.1 Likewise, Adamus et al1,2,12 have found anti-recoverin autoantibodies associated with cancer in almost all of their cases. Conversely, numerous authorities have advised against implying causation with any antigen other than recoverin, bringing a-enolase to the forefront of this discussion. Studies by Adamus et al2,12 have found anti-enolase antibodies to be far less predictive of an associated neoplasm. In fact, in approximately 60% of cases, no neoplasm can be found on extensive evaluation.2,12,288 The clinical utility of this antigen is further complicated by reports associating serum antienolase with numerous autoimmune diseases: autoimmune polyglandular syndrome type 1 (80%, 35 of 44 patients), primary (69%, 60 of 87) and secondary (58%, 14 of 24) membranous nephropathy, autoimmune hepatitis type 1 (60%, 12 of 20), mixed cryoglobulinemia with renal involvement (67%, 7 of 11), and endometriosis (50%, 21 of 41).89 Autoantibodies to enolase have also been noted in up to 12% of otherwise healthy individuals,89 although these antibodies in normal individuals may target a different epitope compared with diseased patients.5,288 Beyond their diagnostic value, the measurement of antiretinal antibodies has been proposed as a useful marker in monitoring the therapeutic response of a patient with these syndromes. Although careful monitoring of clinical parameters (including visual acuity, visual fields, color vision, ERG, OCT, and sometimes visual evoked potentials) remains key to assessing treatment response, anti-retinal antibody titers may be a clinically relevant surrogate marker of disease activity. Numerous investigators have documented a decline in anti-retinal antibody titers in response to their therapeutic intervention.131,195,276 With this increased accessibility to autoantibody testing, clinicians are strongly encouraged to interpret such test results with caution. Integration of these serological findings with the clinical presentation, rather than a reliance upon them, is paramount in order to make the appropriate diagnosis. Demonstration of anti-retinal antibodies, while necessary, is not sufficient alone for diagnosing paraneoplastic retinopathies, since such antibodies have been previously described in normal human sera as detailed by Shimazaki et al.261 In their study, 62% (57 of 92) of normal serum samples had detectable anti-retinal antibody activity by Western blot.261 In a separate study, Bazhin et al28 observed anti-recoverin seropositivity in 15% (15 of 99) and 20% (9 of 44) of patients with small cell and non-small cell lung cancers, respectively. None of the cumulative 143 patients developed visual compromise concerning for CAR, however. In a follow-up study by the same group,250 five patients with non-lung cancers (breast, ovary, stomach, and bladder) and anti-recoverin antibodies present in their sera were subject to ophthalmologic examination. Only one individual had narrowing of the visual field and corresponding

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retinal degeneration consistent with a diagnosis of CAR. Similarly, Ladewig et al152 found that out of 77 serum samples from 51 patients with melanoma but no signs or symptoms of MAR, 69% (53 of 77) were found to contain antibodies reactive with different components of the retina by indirect immunohistochemical assay. Of the 49 patients followed over 4 years since the initial report, only one individual developed MAR.E Despite numerous advancements and ongoing research efforts in the field, our overall understanding of these syndromes on an immunologic and likely genetic basis remains in its infancy, as suggested by Foorooghian.77 What determines why some cancer-bearing patients mount an immune response to tumor-derived antigens and others don’t? Of the subset of patients that do express anti-retinal antibodies, why do some never manifest any signs or symptoms of visual compromise? Is there a predetermined genetic susceptibility that is acted upon by an environmental “trigger,” as has been hypothesized for the development of other types of autoimmune disease? These, and many more questions remain to be answered. Moving forward, newer technologies such as the Luminex analyzer (Luminex Corp., Austin, TX) may enable screening for antibodies against up to 30 antigens in over 800 human serum samples, ideal for large, screening seroepidemiologic studies.26 However, given the increasing number of retinal antigens being reported and their seemingly ubiquitous nature, Jampol119 correctly questions just how many of these anti-retinal antibodies are merely epiphenomena, coincidentally present yet not causally related to the disease pathogenesis. Our challenge moving forward will be to differentiate the pathogenic and disease causing antibodies from the benign “innocent bystanders” if we hope to improve our diagnostic yield and add clarity to an elusive group of diseases that are challenging to both diagnose and treat.

7.

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 refer to, recognition of one of these syndromes instead requires an integration of clinical intuition, examination findings when present, and results from ancillary testing. Securing the diagnosis in a timely fashion can facilitate systemic treatment of the primary malignancy at an earlier stage, often months before it would have otherwise presented, and gives the patient an increased chance at survival. As we continue to gain insight into pathogenic mechanisms, we will likely find these disorders to be more similar than different. Along with this knowledge will hopefully come improved diagnostic measures as well as more effective, targeted ocular therapies to help preserve, or even restore vision.

8.

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, paraneoplastic optic neuropathy, PON, polyneuropathy organomegaly endocrinopathy M protein and skin changes, POEMS. Citations within material obtained from the Medline and PubMed searches were also used.

9.

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.

references

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