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.

Autoantibody testing by Western blotting and immunocytochemistry. (A) Western blotting showing immunostaining of human retinal proteins by patient’s serum: 1, molecular standards; 2, retinal proteins; 3, human serum recognizing α-enolase; 4, human serum recognizing recoverin on the blot. (B) Immunohistochemistry: antirecoverin serum antibodies bind to photoreceptor cell layer (outer retina), and anti-α-enolase serum binds to the inner and ganglion cell layers, and also stains neuronal fibers. OS, outer segments; ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer.

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 ).

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 ).

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.