Cancer Associated Retinopathy
Cancer associated retinopathy
Cancer associated retinopathy (CAR) is a member of a spectrum of disease called autoimmune retinopathy. It was first described by Sawyer et al. in 1976 with three cancer patients with blindness caused by diffuse retinal degeneration . In CAR, retinal degeneration occurs in the presence of auto-antibodies that cross react with tumor-tissue and retinal-tissue antigens which are recognized as foreign. In many instances, visual loss from CAR precedes the diagnosis of cancer.
There has been different antibodies isolated against many specific retinal proteins:
- Carbonic anhydrase II
- Transducin B
- TULP1 [Tubby-like Protein 1]
- PNR photoreceptor cell-specific nuclear receptor
- Heat shock cognate protein HSC 70
- Glyceraldehyde 3-phosphate dehydrogenase
- GCAP 1 and 2 (guanylyl cyclaseactivating proteins)
- Rab6A GTPase (Rab6A)
There are many more antibodies against different retinal proteins that have not yet been identified.
Many different cancers have been associated with CAR. Small cell lung carcinoma, breast cancer, and gynecologic cancer are the most common cancers associated with CAR. However CAR has been found in other types of lung cancer, colon cancer, mixed Müllerian tumor, skin squamous cancer, kidney cancer, pancreatic, lymphoma, basal cell tumor, and prostate cancer.
Keltner et al developed an autoimmune theory in 1983 when he found antibodies against retinal photoreceptors in patient with lymphoma who developed acute vision loss and retinal degeneration. Autoimmunity occurs when tumor antigens trigger an immune response from the host which creates antibodies that cross react with a retinal protein. This leads to cell apoptosis/death and retinal degeneration.
Patients usually present with acute/subacute painless vision loss over few weeks to months with associated positive visual phenomena (such as flashes/photopsia or flickering of lights) and photosensitivity. They are usually bilateral but may by asymmetric and sequential. Patient symptoms depend on which retinal tissue is affected as CAR can cause damage to the rods (causing nyctalopia, constricted visual fields, prolonged dark adaptation, and midperipheral (ring) scotomas) and/or cones (causing photosensitivity, reduced visual acuity, central scotomas, and decreased color perception). Anti-recoverin antibody, which is the most common antibody associated with CAR, usually presents with acute severe vision loss and paracentral or equatorial scotoma. CAR with anti-enolase antibodies causes cone dysfunction typically leading to asymmetric central vision loss with slower progression.
- Decreased central visual acuity
- Visual field defects (central, paracentral, or equatorial scotomas)
- Prolonged glare after light exposure
- Prolonged dark adaptation
- Afferent pupillary defect if asymmetric involvement
- Decreased color vision
- Fundus can appear normal initally. With progression there develops evidence of retinal degenerations (RPE thinning and mottling, attenuation of the arterioles, optic nerve pallor). Other fundus findings such as macular edema, vitreous cells, vascular sheathing, and periphlebitis have been documented.
There is no set diagnostic criteria for CAR. The diagnosis is made by a combination of patient's clinical symptoms, exam findings, diagnosis of systematic cancer, and positive antibodies against retinal proteins. Patient's visual symptoms may precede the diagnosis of systematic cancer, making the diagnosis of CAR difficult initially. Other causes of retinal degeneration must be ruled out such as any hereditary or toxic retinal degeneration. In the absence of retinal changes, optic nerve diseases like retrobulbar optic neuropathy, optic neuropathy related to smoking/nutritional deficiency and hereditary optic neuropathy may need to be ruled out. Drug related damage to the optic nerve (carmustine/vincristine and others) or retina (chloroquine/thioridazine and others) also needs to be excluded.
Positive anti-retinal antibodies alone does not give the diagnosis of CAR since anti-retinal antibodies can be found in the normal population and in patient with non-paraneoplastic autoimmune retinopathy.
- Visual fields: central, cecocentral, or equatorial scotomas
- Fundus Angiography - is usually normal. Rarely, it could show areas of leakage if vasculitis or macular edema is present
- Optical Coherence Tomography (OCT) - may show retinal thinning on OCT
- Electroretinogram (ERG): Full field ERG are almost always abnormal (attenuated or absent photopic and scotopic response). In CAR where mainly the cones are affected, full field ERG could be normal but multifocal ERG will be abnormal.
- Fundus autofluorescence (FAF): Parafoveal ring of enhanced autofluorescence with normal autofluorescence within the ring and hypoautofluorescence outside the ring.
Below demonstrates a bilateral paracentral visual field defect in a CAR patient
The right fundus of the same CAR patient as above appears normal.
Anti-retinal antibody testing is now commercially available. (http://www.mayomedicallaboratories.com/test-catalog/Overview/57647, http://www.athenadiagnostics.com/view-full-catalog/r/recombx-trade;-car-(anti-recoverin)-autoantibody-t, http://www.ohsu.edu/xd/health/services/casey-eye/diagnostic-services/ocular-immunology-lab/, and others)
- Retinitis Pigmentosa
- Cone Dystrophy
- Toxic Retinopathy
- Acute Zonal Outer Occult Retinopathy
- Toxic-Nutritional Optic Neuropathy
- Hereditary Optic Neuropathy
Long term immunosuppression is the main therapy for CAR. Many different systematic immunosuppressive medications (high-dose steroid with methylprednisolone and prednisone, cyclosporin, azathioprine, alemtuzumab), intravenous immunoglobulin, plasmapheresis, and combination of these treatments have been tried with variable results. These treatments may provide mild to moderate transient visual acuity and field improvement, but overall there is no significant long lasting improvement and the visual prognosis remains poor. The treatment of the systematic cancer usually do not lead to improvement of the vision.
If patient with suspected CAR and without any history of malignancy, work up for occult malignancy should be performed including a thorough medical history and physical exam, chest x-ray/contrast enhanced computed tomogram (CECT) of chest, and basic blood work (such as liver enzymes). Additional testing including CECT abdomen, whole body PET scan may be necessary depending on the findings of the initial work up. In females, clinical and imaging evaluation of breast and genitourinary system is critical.
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