Cancer-Associated Retinopathy

What is Cancer-Associated Retinopathy?

Cancer-associated retinopathy, or CAR, is a sudden or progressively worsening vision loss caused by the body creating antibodies that attack retinal proteins. This usually happens when there’s cancer somewhere else in the body. CAR falls under a larger group of conditions called autoimmune retinopathy diseases, which includes both conditions linked to cancer (paraneoplastic) and those that are not (nonparaneoplastic).

The first mention of vision loss accompanying retinal deterioration in patients with lung cancer happened in 1976. The term paraneoplastic retinopathy was later used to refer to autoimmune retinopathy that’s associated with cancer found elsewhere in the body. This type of retinopathy is generally identified by rapid vision loss, visibly narrowed blood vessels in the eye, and a non-functioning electroretinogram, a test that measures the electrical responses of light-sensitive cells in your eyes.

CAR is a rare form of retinal paraneoplastic retinopathy. In simple terms, paraneoplastic syndrome is when cancers cause unusual symptoms due to your body’s reaction to them, rather than their size, location, or spread. Other conditions related to paraneoplastic vision problems include melanoma-associated retinopathy, paraneoplastic optic neuropathy, and bilateral diffuse uveal melanocytic proliferation.

It’s important to note that vision loss from CAR can sometimes occur even before a person is diagnosed with cancer. In fact, it’s been reported that in up to half of patients, the diagnosis of CAR (confirmed by finding antibodies against the retina in their blood) comes before their cancer diagnosis. Treatment options for CAR may include systemic steroids, intravenous immunoglobulin (a substance made from human blood plasma that helps your immune system fight off diseases), and various other antibodies.

What Causes Cancer-Associated Retinopathy?

Small-cell lung carcinoma (SCLC), a type of lung cancer, is the condition most often linked with npAIR syndrome, a rare neurological disorder. But there are also other cancers that have been connected to this syndrome, which includes:

* Non-SCLC, another type of lung cancer
* Breast cancer
* Endometrial cancer, a type of cancer that begins in the lining of the uterus
* Invasive thymoma, a tumor in the thymus gland
* Lymphoma, a cancer of the lymphatic system
* Cervical cancer, a type of cancer that begins in the cervix
* Endometroid sarcoma, a rare uterine cancer
* Myeloma, a cancer of the plasma cells in the bone marrow
* Basal cell carcinoma, the most common type of skin cancer
* Colon cancer
* Kidney cancer
* Leukemia, a cancer of body’s blood-forming tissues

Other cancers linked with npAIR syndrome include mixed Müllerian tumor, prostate cancer, melanoma (a type of skin cancer), squamous cell carcinoma (a cancer that begins in the squamous cells), pancreatic cancer, laryngeal carcinoma (cancer of the voice box), and urinary bladder carcinoma (bladder cancer).

Risk Factors and Frequency for Cancer-Associated Retinopathy

AIR is a relatively rare condition representing less than 1% of cases at an eye center. The pAIR syndrome, a related condition, is observed in about 1 out of 10,000 cancer patients. Additionally, it’s estimated that around 10% to 15% of all cancer patients will eventually develop pAIR syndrome.

Now, let’s talk about CAR. This condition is more commonly found in females than males. Out of 295 breast cancer patients, only 6 showed signs of immune response to retinal antigens, a potential indicator of CAR. However, only 2 of these patients showed visible ocular signs of the condition. CAR typically starts to appear later in life, with the average age of onset ranging from 55 to 65.

In a study with 209 patients, it was found that the average age of CAR patients ranged from 40 to 85. Furthermore, the condition was mainly associated with specific types of cancer. A breakdown of the most common types of cancer associated with CAR is as follows:

• Breast cancer – 31%
• Lung cancer – 16%
• Hematological malignancies (cancers of the blood, bone marrow, and lymph nodes) – 15%

In the US, Small Cell Lung Carcinoma (SCLC), a type of lung cancer closely related to CAR, accounts for about 29,000 diagnosed cases each year. The time it takes for retinopathy (damage to the retina) to lead to a cancer diagnosis can differ greatly. It can range from weeks to months in cases of lymphoma and lung cancer, to even years for breast and prostate cancer.

Signs and Symptoms of Cancer-Associated Retinopathy

Cancer-associated retinopathy (CAR) is a disease that can cause rapid and progressive vision loss. It results from the malfunction and degeneration of cells in the retina, which are crucial for vision. Major symptoms include sudden decline in your ability to see, without any accompanying pain. It tends to affect both eyes, although in some instances, it only affects one eye.

Early CAR can be hard to identify because it may resemble other conditions. People with CAR may experience a range of symptoms like:

• Glare or sensitivity to light
• Reduced vision, particularly in dim light
• Floaters or spots in your field of vision
• Flickering lights or flashes, also known as photopsia
• Change in how colors are perceived

The disease also causes problems with the functionality of rods and cones in the eye, vital structures for vision. Issues with cones might result in loss of sharpness, abnormal color vision, and an unusual pattern in eye tests. Problems with rods might cause difficulty adjusting to low light, night blindness, or narrowed visual fields.

Symptoms can worsen over weeks or months. In some cases, visual symptoms may appear a long time before the presence of an associated tumor. The time interval might be as long as 11 years.

In older people with newly developed night blindness, without a family history of inherited eye disease or signs of vitamin A deficiency, CAR might be a possible diagnosis. Clinical signs might show mild inflammation in the front part of the eye, or cellular debris. The retina might look normal, but some patients may see changes or irregularities.

Associated cancer might also cause early onset of cataracts. This is because cancer might lead to an overproduction of reactive oxygen species, which can damage lens proteins and cause early cataracts.

Testing for Cancer-Associated Retinopathy

To verify a diagnosis of Cancer-associated Retinopathy (CAR), several testing methods are used.

The first of these is Visual Field testing, which usually shows a decrease in your field of vision. It may also highlight specific vision defects like blind spots.

Another technique is Fundus Autofluorescence (FAF). This is an important, noninvasive tool where a scanning laser ophthalmoscope is used to evaluate an element in the eye called lipofuscin. Changes in lipofuscin levels can offer clues about the health of your eye. In CAR patients, the test often shows a brightly lit (hyperautofluorescent) ring in the back of the eye with lower brightness (hypoautofluorescent) outside the ring. Although this ring can also appear in other disorders, FAF is a useful tool as it can detect minute eye changes that are hard to identify otherwise.

Fundus Fluorescein Angiography (FFA) is another method used. While FFA results are normally standard in CAR patients, in infrequent instances, it may show interesting findings like optic nerve head staining or petaloid leak at the macula in cystoid macular edema.

Spectral-Domain Optical Coherence Tomography (SD-OCT) is a technique that offers a quantitative measure of retinal damage. It helps in diagnosing CAR and may even detect presence of CAR in the early stages. In CAR patients, SD-OCT shows loss of the outer retinal complex, and reduction in the thickness of the photoreceptor layer, among other details. Findings from this test can also hint at the severity and duration of the disease.

Another set of tests are Electrophysiological tests that measure the electrical activity generated by the eye and other neural pathways. Abnormal results on these tests, like delayed b-waves or reduced b-waves, may be seen in patients with CAR.

Lastly, Antibody Testing is conducted. This test seeks out antiretinal antibodies in patients with cancer. Different antibodies indicate different conditions – for example, in CAR patients with antirecoverin antibodies, there is usually diffuse rod and cone involvement. However, the presence of antiretinal antibodies alone is not enough to confirm a diagnosis of CAR – they can be found in healthy individuals as well as patients with nonparaneoplastic autoimmune retinopathy. 

As CAR can sometimes precede the diagnosis of underlying cancer by several months, it is necessary to run a full systemic evaluation under the guidance of a primary care doctor. This would involve a comprehensive medical history, physical examination, complete blood investigations, MRI of the brain, CT scans of the chest, abdomen, and pelvis, whole-body PET, and other necessary tests depending upon your medical history. This extensive process is crucial in deciding the appropriate treatment plan and determining the prognosis of the patient.

Therefore, a diagnosis of CAR is usually confirmed by considering the patient’s clinical symptoms, examination findings, diagnosis of systematic cancer, and presence of antibodies against retinal proteins in a comprehensive manner. Diagnosing CAR can initially be difficult as a patient’s visual symptoms may precede the diagnosis of cancer.

Treatment Options for Cancer-Associated Retinopathy

Starting treatment quickly is essential for individuals with CAR (Cancer-Associated Retinopathy), a condition that affects vision due to cancer. Without treatment, CAR can lead to severe vision loss and even total blindness. We treat CAR by focusing on the eye condition itself because getting rid of the underlying cancer doesn’t impact CAR’s progression. However, shrinking the primary tumor can reduce the autoantibodies that trigger CAR. Treating CAR can be challenging, and unfortunately, sometimes vision loss can continue despite treatment.

One treatment option is steroids, but their effectiveness varies from person to person. Steroids can be particularly useful in short-term management, especially when CAR involves recoverin-mediated autoantibodies (proteins that react negatively with patients’ cells). Initial treatment can involve steroids taken by mouth, or they can be injected directly into the eye. But there can be side effects, including an increase in eye pressure, and this has to be carefully managed with other medications.

High-dose intravenous steroids can also show short-term improvement, particularly when combined with treatment to remove the primary tumor. There’s evidence to support the use of intravenous steroids over oral ones. In some cases, a treatment called plasmapheresis, which filters the blood, may be combined with steroids and prove beneficial to patients.

Different substances that change the immune system’s response (immunomodulatory agents) have been used to treat CAR, but none have shown consistent long-term effectiveness. Immunosuppressive agents (drugs that reduce the immune system’s response) have been used, and sometimes a combination is used to slow down the losing of vision. Some research has shown improvement in visual acuity (the sharpness of vision) and visual fields when this kind of treatment is combined with recoverin autoantibodies.

A treatment called IntraVenous ImmunoGlobulins (IVIG) has been found to stabilize and sometimes improve vision. However, CAR associated with certain kinds of antibodies is difficult to manage even with IVIG. Administering IVIG and plasmapheresis together is recommended if done before irreversible damage to nerve cells occurs.

Newer treatments use monoclonal antibodies (molecules created in a lab that can mimic the immune system’s attack on foreign substances), such as alemtuzumab and rituximab, particularly if other treatments haven’t worked. When combined with immunosuppressive agents, rituximab has been shown to give stable or improved visual outcomes in a significant percentage of patients.

Another approach that showed promise in experimental settings involves reducing the level of calcium inside cells. However, patients might still experience a progressive loss in their vision quality despite this treatment. Therefore, the effectiveness of such treatments in humans needs more investigation.

Antioxidants and vitamins (like lutein, vitamin C, vitamin E, and beta carotene) may help slow down the death of retinal cells and the progression of the disease. But more research is needed to understand their exact role. Other future treatments for CAR might involve inhibiting certain growth factors, manipulating calcium levels, or transferring certain genes. Safely treating CAR with monoclonal antibodies that inhibit B-cells (a type of white blood cell that makes antibodies) is another possibility.

What else can Cancer-Associated Retinopathy be?

It’s essential to distinguish CAR (Cancer-Associated Retinopathy) from a number of other conditions, including:

• Retinitis pigmentosa, which is usually inherited and can display similar features, such as retinal degeneration, but has less inflammation.
• npAIR, identified in 1997, displays symptoms and test results similar to CAR but typically progresses more slowly and is associated with a family history of autoimmune disorders.
• Melanoma-associated retinopathy, typically occurring after a melanoma diagnosis, can display signs similar to CAR.
• Acute Zonal Outer Occult Retinopathy and other white dot syndromes present symptoms and visual field changes similar to CAR but usually stabilizes or partially recovers without treatment.
• Cone dystrophy, where the rod cells are often spared, resulting in color recognition issues, light sensitivity and loss of visual acuity.
• Toxic retinopathy or toxic optic neuropathy, where a toxin leads to damage and vision impairment. Its symptoms can look like CAR.
• Leber hereditary optic neuropathy, a rare mitochondrial disorder affecting young males, which causes sequential vision loss in both eyes due to optic neuropathy.
• Nutritional optic neuropathy, linked to vitamin deficiency, that results in visual impairment due to optic nerve damage and has similar to toxic retinopathy features.
• BDUMP, a rare paraneoplastic disorder that primarily presents as acute onset, a rapid loss of visual acuity.
• Chronic Central Serous Chorioretinopathy, an eye disorder seen in young men which can be unilateral or bilateral.
• PON, a rare paraneoplastic condition affecting middle-aged patients with various forms of cancer. This condition is characterised by bilateral, subacute, progressive loss of visual acuity.
• Vitamin A Deficiency, which affects overall cellular development, immunity, metabolism and reproductive functions. When the serum retinol concentration drops, ocular symptoms like night blindness or nyctalopia can occur.

To diagnose CAR accurately, examination results from serum, along with electroretinogram and clinical features, should be evaluated in conjunction with other investigative methods.

What to expect with Cancer-Associated Retinopathy

Visual problems or even loss of vision can occur from a condition called CAR (Cancer Associated Retinopathy), sometimes even before cancer is diagnosed. If CAR is linked with a type of protein called recoverin antibodies, the condition can lead to severe vision loss, even to the point where a person cannot perceive light.

Quick diagnosis and starting treatment early are crucial to preserving vision. However, CAR can damage the photoreceptors – the cells in your eye that allow you to see light – and the cells that support them. Because of this, chances for visual recovery remain low, even with treatment that modulates the immune system.

Therefore, if a patient experiences sudden or gradual visual issues, changes in visual field (the entire area that can usually be seen), and vascular attenuation (narrowing of the blood vessels) in the ‘fundus’ (the back of the eye), and no other cause is found, CAR should be suspected.

The patient’s chances for recovering vision is not influenced by treating the underlying cancer. The patient’s overall survival hinges on the type and stage of the cancer when it was found, and the treatment options that were available.

Adamus et al, in a study of 209 cancer patients, suggested that patients who are at risk for developing CAR could be identified early using antiretinal autoantibodies (substances that the body produces against its own eye cells). This early detection could prevent vision loss in patients who are especially at risk.

Possible Complications When Diagnosed with Cancer-Associated Retinopathy

Choroidal neovascularization, a condition where new blood vessels grow beneath the retina, can happen due to CAR, a rare eye disorder. Other reasons that can lead to vision loss in those with CAR include cataract, fluid build-up in the macula (macular edema), thinning in the central part of the retina (foveal thinning), and optic atrophy that occurs secondary to another condition. The survival rate depends on the cause of CAR, and managing the main cancer condition properly is crucial.

Common Reasons for Vision Loss:

• Choroidal neovascularization due to CAR
• Cataracts
• Macular edema, a build-up of fluid in the macula
• Foveal thinning, thinning in the central part of the retina
• Secondary optic atrophy, optic nerve damage happening due to another condition

Preventing Cancer-Associated Retinopathy

People with CAR, a type of condition that could lead to severe vision loss or even blindness, need thorough guidance, detailed assessments, and clear information about their condition and the various treatment methods that could help them. It’s important for these patients to realize that symptoms of CAR might show up even before there are visible signs of the related tumor. It’s also crucial to understand that no set treatment plan exists for this condition, but following any prescribed treatments faithfully is necessary to hold off or, in rare cases, reverse the progression of this disease.