Paraneoplastic retinopathies (PRs) represent visual dysfunctions and retinal degeneration associated with known or suspect malignancies, without direct involvement of the eye. PRs are believed to originate from an autoimmune process involving circulating autoantibodies elicited against cancer antigens that also recognize retinal antigens. PRs include cancer-associated retinopathy, melanoma-associated retinopathy, and bilateral diffuse uveal melanocytic proliferation syndrome ( Table 76.1 ).
|Symptoms and signs||Paraneoplastic||Nonparaneoplastic|
|CAR syndrome||MAR syndrome||Autoimmune retinopathy||Retinal dystrophy|
|Visual loss||Bilateral||Bilateral||Initially unilateral/asymmetric||Bilateral/symmetric|
|Age at onset (years)||60+||30+||∼40||Variable|
|Symptoms||Photopsia, progressive vision loss||Photopsia, night blindness||Photopsia, vision loss||Variable symptoms|
|Visual fields||Ring scotomas||Normal/central loss||Ring scotomas||Variable|
|Electroretinogram||Flat/severe loss||Loss of b-wave||Loss of b-wave/diffuse loss/flat||Variable|
|Systemic diseases||Carcinomas, lymphomas, thymoma||Cutaneous metastatic melanoma||Autoimmune disease with familiar history||None|
|Histopathology||Photoreceptor degeneration||Bipolar cells, unknown||Unknown||Unknown|
|Circulating antibodies||Recoverin, enolase, others||Bipolar cells, others||Enolase, CAII, p35, p40, others||Various|
Key symptoms and signs
Cancer-associated retinopathy (CAR) syndrome
CAR was first recognized as a paraneoplastic disorder, in association with small cell lung cancer (SCCL) and retinal dysfunction and degeneration. Besides SCCL, CAR occurs with other associated tumors, mostly carcinomas of the breast, endometrium, ovary, colon, bladder, and prostate, as well as lymphomas and thymoma.
In CAR, the progression of retinal degeneration is examined by electroretinogram (ERG), visual field, and fundus examination. Patients frequently describe the sudden onset of a sensation of flickering or shimmering lights and night blindness, with additional visual loss over weeks to several months. Rod dysfunction is characterized by night blindness and prolonged dark adaptation. Cone degeneration features include decreased visual acuity, sensitivity to light and glare, reduced color vision, and central and ring scotomas. The fundus can initially appear normal, but narrowed retinal arteries, retinal pigment epithelial mottling, and optic nerve pallor can be observed on ophthalmic examination. Vision loss is associated with decreased responses of cone and rod responses. Ocular symptoms may precede the diagnosis of cancer by months to years; thus, recognition of CAR facilitates early diagnosis of malignancy.
Antiretinal CAR autoantibodies are detected in blood by Western blotting ( Figure 76.1 ). The most recognized autoantibodies are against recoverin and α-enolase, but autoantibodies with other specificities can also be detected ( Table 76.2 ). Patients with different antiretinal autoantibodies may have different clinical manifestations ( Box 76.1 ). Antirecoverin CAR presents with symptoms of night blindness, photopsias, loss of peripheral or pericentral visual field, reduced central acuity, and widespread rod and cone dysfunction. Anti-α-enolase CAR presents with varying degrees of central or pericentral visual field loss, shimmering photopsias, loss of color vision, reduced vision in bright light, and night blindness. Thus, autoantibodies can serve as a biomarker for the prognosis and management of CAR.
|Autoantigen||Molecular weight||Binding in the retina||Molecular function||Presence in cancer||First described|
|Recoverin||23 kDa||Photoreceptor cells, ONL, BCL||Calcium-binding protein, phototransduction||SCCL, endometrial, others||Thirkill et al 1987 |
Polans et al 1991
|Neurofilament proteins||70, 145 200 kDa||Ganglion cells||Structural proteins||SCCL||Kornguth et al 1986|
|α-enolase||46 kDa||GCL and diffuse staining of all layers||Glycolysis||Endocrine cancers||Adamus et al 1993|
|Photoreceptor cell nuclear receptor (PNR)||46.5 kDa||ONL, INL, and photoreceptor cells||Photoreceptor cell development or maintenance||Lung, poorly differentiated carcinoma||Eichen et al 2001|
|Bipolar cell antigen||?||Bipolar cells||?||Cutaneous melanoma, colon||Milam et al 1993 ; Jacobson and Adamus 2001|
|P60||60 kDa||?||?||SCCL||Murphy et al 1997|
|P35||35 kDa||Miller cells||?||None||Peek et al 1998|
|P22||22 kDa||Retina; optic nerve||?||Melanoma||Keltner and Thirkill 1999|
|Hsc 70||70 kDa||?||Heat shock protein chaperone cytosolic peptides||SCCL||Ohguro et al 1999|
|P45||45 kDa||?||?||Ovarian||Yoon et al 1999|
|Tubby-like protein 1 (TULP1)||78 kDa||OPL, INL, ONL at the myoid to the synaptic terminal of rods and cones||Transcription factor or rhodopsin transport||Endometrial||Kikuchi et al 2000|
|PTB-like protein (PTBLP)||58 kDa||Nuclei of GCL||RNA-binding protein||Endometrial||Kikuchi et al 2000|
|P65||65 kDa||ONL||?||Lymphoma||To et al 2002|
|P75/LEDGF||75 kDa||?||A survival factor||None||Chin et al 2006|
|P40||40 kDa||Outer segments||Cone-specific||Laryngeal carcinoma||Parc et al 2006|
|Arrestin||48 kDa||Photoreceptor cells||Phototransduction||Breast||Jacobson 1996 ; Misiuk-Hojlo et al 2007|
|Carbonic anhydrase II||30 kDa||GCL and photoreceptor cells||pH control||Colon, rectal||Adamus 2009|
|120 kDa||120 kDa||Photoreceptor cells||Phototransduction||Melanoma||Sotodeh et al 2005|
|Transducin-β||35 kDa||Photoreceptor cells||Phototransduction||Melanoma||Potter et al 2002|
|Transducin-α||40 kDa||Photoreceptor cells||Phototransduction||Breast, lung, prostate, uterine||Adamus et al 2008|
Different autoantibodies, such as antirecoverin and anti-α-enolase, can be associated with different clinical presentations, phenotypic findings, and electroretinogram patterns
Melanoma-associated retinopathy (MAR) syndrome
MAR is associated with visual loss, antiretinal autoantibodies, and diagnosed cutaneous malignant melanoma, often at the end-stage of metastasis. MAR was first described in 1988 by Berson and Lessell. Patients with MAR have nearly normal vision but develop night blindness, shimmering light, photopsia, and loss of peripheral vision that appear months to years after diagnosis of a tumor. The average time from the diagnosis of cancer to diagnosis of MAR averages 3.6 years. The typical ERG pattern in MAR shows a slight reduction in scotopic a-wave, and a marked reduction or absence of dark-adapted b-wave ( Box 76.2 ). Autoantibodies against bipolar cells were first reported in patients with MAR, and recently, autoantibodies against other retinal proteins have also been found in these patients ( Table 76.2 ).
Electroretinograms, visual field analysis, and autoantibody detection, in combination with an evaluation for a systemic malignancy, are essential for diagnosing cancer- and melanoma-associated retinopathy
Autoimmune retinopathy (AR)
Patients can have symptoms resembling CAR or MAR, and antiretinal autoantibodies, but have no tumor at the time of initial evaluation. AR is the preferred term for this acquired autoimmune-mediated condition ( Table 76.1 ). The presence of autoantibodies without known malignancy leads to several speculations on the origin of autoimmune responses. Most likely, they originate from a very small tumor, too small to be detected by conventional methods, but the immune system detects it. The tumor might be detected clinically in the subsequent years. The length of the diagnostic follow-up period necessary to detect the tumor in clinical PR is under investigation. Thus far, it ranges from months up to 5 years, but it can be longer. Antirecoverin antibodies are typically associated with CAR and have rarely been reported in AR patients. In such cases, antiretinal autoanti bodies may be involved in tumor regression. This “new class” of retinopathies with autoantibodies cannot be ignored and needs to be followed up in ophthalmic examination. The condition can be classified as CAR or AR (= probable PR), based on clinical symptoms, the presence or absence of autoantibodies, and the presence or absence of cancer ( Box 76.3 ).
Patients can have symptoms resembling cancer- or melanoma-associated retinopathy and antiretinal autoantibodies, but without diagnosed tumor
Bilateral diffuse uveal melanocytic proliferation (BDUMP)
BDUMP is a rare syndrome that involves painless, bilateral vision loss, serous retinal detachment, and a systemic malignant neoplasm. Visual loss is due to the proliferation of uveal melanocytes occurring throughout the uvea without metastasis outside the eye. The most common tumors are ovary and uterus in women and the lung in men. Most patients die from metastasis of their primary tumor within a year of BDUMP diagnosis. Autoantibodies against retinal or uveal antigens are not usually tested.
In 1976, Sawyer et al first described PR as the progressive loss of vision with ring scotomas and nearly absent ERG in 3 women with SCCL. Interestingly, visual symptoms preceded the cancer diagnosis, leading them to postulate that photoreceptor degeneration was caused by remote effects from the cancer. In later years, circulating antibodies against retinal proteins were reported in sera from cancer patients with visual problems, suggesting that antiretinal autoantibodies may play a role in PR pathogenicity. Immunostaining of the outer retina with CAR antibodies further supported the autoimmune nature of the syndrome, as did beneficial effects of steroids on vision. The hypothesis was that vision loss was due to serum autoantibodies, originating from the immune response against tumor antigens and cross-reacting with retinal proteins, which led to rod and cone dysfunction. The syndrome was named “cancer-associated retinopathy,” and the associated 23-kDa reactive protein was called “the CAR antigen.” The CAR antigen has since been sequenced and identified as “recoverin.” However, 50% of symptomatic patients have high titers of autoantibodies against proteins other than recoverin ( Table 76.2 ). Therefore, the absence of antibodies to recoverin does not exclude a diagnosis of PR ( Box 76.4 ).
Various antiretinal autoantibodies can be found in sera from patients with paraneoplastic retinopathies; thus, the absence of autoantibodies against recoverin (23 kDa) does not exclude a paraneoplastic retinopathy diagnosis
PRs are rare. It is estimated that paraneoplastic diseases occur in fewer than 1% of cancer patients. Although more PR cases have been reported in recent years and the number is growing, the incidence of CAR and MAR remains unknown. Moreover, most patients with cancers, including melanoma, may not consider their vision symptoms due to their malignancy, and consequently, they do not report vision problems. The average age of a CAR patient is 63 years, with women affected more than men at a ratio of 2 : 1. At an average age of 57.5 years, males with melanoma appear to have a higher risk of developing MAR than women, even though cutaneous malignant melanoma affects men and women equally. AR affects twice as many women as men, at an average age of 55. BDUMP is very rare and also affects more women than men, at a ratio of 2 at an average of 63 years. Thus far, there is no known genetic involvement in CAR and MAR development.
Diagnosis of PRs is difficult ( Table 76.3 ), and patients are frequently misdiagnosed. Ocular symptoms may develop before diagnosis of cancer, and CAR and MAR can occur in patients without tumors ( Table 76.1 ). About 50% of patients have retinopathy symptoms as the first manifestation. Nearly 50% of symptomatic patients initially have negative antibody tests, and few of the seropositive patients have antirecoverin antibodies. Importantly, the presence of antirecoverin autoantibodies indicates a high likelihood of associated neoplasm, particularly SCCL and gynecological cancers in women ( Box 76.5 ). Anti-α-enolase CAR occurs predominantly with cancers with endocrine features, and visual symptoms typically develop months to years after discovery of the malignancy. Antienolase autoantibodies have also been reported in a diverse range of inflammatory, degenerative, and psychiatric disorders ( Table 76.4 ), and in ~10% of normal subjects (0–11%). The production of MAR autoantibodies has rarely been linked to the remission or stabilization of melanoma, indicating that an antibody response is usually insufficient to protect against spreading. If ophthalmologic findings, including ERG and antibodies, are indicative of CAR and MAR, a cancer workup is recommended. A worsening of symptoms may precede a recurrence or metastasis.