Cancer-Associated Retinopathy - StatPearls - NCBI Bookshelf

2/1/24, 16:26 Cancer-Associated Retinopathy - StatPearls - NCBI Bookshelf
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.
Cancer-Associated Retinopathy
Authors
Dheerendra Singh1; Koushik Tripathy2.
Affiliations
1 ASG Eye Hospital, Bhopal
2 ASG Eye Hospital, BT Road, Kolkata, India
Last Update: February 22, 2023.
Continuing Education Activity

Recognizing the remote effects of cancer is important as they may point towards an undiagnosed malignancy or even
recurrence of a previously treated neoplasm. Cancer-associated retinopathy (CAR) is a rare retinal paraneoplastic
disorder associated with cancer that can cause blindness. Investigations helpful in identifying this condition include
visual fields, fundus autofluorescence (FAF), fundus fluorescein angiography (FFA), spectral-domain optical
coherence tomography (SD-OCT), electrophysiological tests, and antibody testing. This activity will highlight the
etiology, pathophysiology, evaluation, and management of cancer-associated retinopathy and the role of the
interprofessional team in managing the condition.
Objectives:
Outline the etiology of cancer-associated retinopathy.
Describe the findings and investigations required for the evaluation of cancer-associated retinopathy.
Review the different options for the management of cancer-associated retinopathy.
Summarize the importance of patient education and interprofessional team strategies to improve the outcomes.
Access free multiple choice questions on this topic.
Introduction
Acute or subacute loss of visual acuity caused by circulating antibodies formed against the retinal proteins in the
presence of systemic cancer is called cancer-associated retinopathy or carcinoma-associated retinopathy (CAR).[1][2]
[3] It is described under the broad spectrum of autoimmune retinopathy (AIR) diseases.[4] Autoimmune retinopathy
can be paraneoplastic (pAIR) and non-paraneoplastic (npAIR).[5]
Sawyer and colleagues first described visual loss along with retinal degeneration in patients suffering from lung
carcinoma in 1976.[6] The term paraneoplastic retinopathy (PR) was coined by Klingele and colleagues to describe
autoimmune retinopathy associated with a distant neoplasm.[7] They described PR as 'a nonmetastatic remote effect
of carcinoma and is characterized by rapid visual deterioration accompanied by narrow arterioles seen on
ophthalmoscopic examination and an extinguished electroretinogram'. In autoimmune retinopathy, autoantibodies
against retinal proteins are found in the serum of patients without a known malignancy, whereas, in paraneoplastic
retinopathy, retinal antibodies are seen in the presence of an underlying malignancy.[8]
CAR is a rare type of retinal paraneoplastic retinopathy. Paraneoplastic syndrome is defined as 'rare clinical
syndromes due to the systemic effects of tumors; they are unrelated to tumor size, invasiveness or
metastases.'[9] CAR is characterized by sudden and progressive vision loss.[10] Other entities included in the
paraneoplastic visual syndromes are melanoma-associated retinopathy (MAR), paraneoplastic optic neuropathy
(PON), and bilateral diffuse uveal melanocytic proliferation (BDUMP). The loss of visual acuity from CAR can occur
even before diagnosing cancer on many occasions.[11]
https://www.ncbi.nlm.nih.gov/books/NBK578183/?report=printable 1/19
It has been reported that the diagnosis of CAR (confirmed by the presence of anti-retinal antibodies in the
sera) precedes the diagnosis of cancer in up to 50% of the patients.[12] Management options for cancer-associated
retinopathy include systemic steroids, intravenous immunoglobulin, and various monoclonal antibodies.
Etiology
Small-cell lung carcinoma (SCLC) is the most important condition associated with neurologic paraneoplastic
syndrome.[13] Associations of CAR include:
Non-small-cell lung carcinoma[1]
Breast cancer
Endometrial cancer[14]
Invasive thymoma[12]
Lymphoma[15]
Uterine cervical cancer[16]
Endometroid sarcoma[6]
Myeloma
Basal cell carcinoma[17]
Colon cancer
Kidney cancer[18]
Leukemia
Mixed Müllerian tumor
Prostate cancer
Melanoma
Squamous cell carcinoma
Pancreatic cancer
Epidemiology
Autoimmune retinopathy accounted for less than 1% of all the cases seen at a tertiary eye center.[19] Paraneoplastic
syndrome can be seen in 1 out of 10,000 cancer patients.[20] Braithwaite et al. showed that paraneoplastic syndrome
eventually develops in approximately 10 to 15% of all cancer patients.[21]
CAR is more common in females as compared to males. Misiuk-Hojlo et al. noted that sera of 6 patients of the 295
breast cancer patients had immunoreactivity to retinal antigens though only 2 cases showed ocular features of
CAR. The mean age of onset of CAR ranges from 55 to 65 years.[22][23]
In a case series of 209 patients, Adamus showed that the mean age of CAR was between 40- 85 years. Adamus also
reported that CAR was mainly associated with malignancy of the breast (31%), followed by lung (16%) and
hematological malignancies (15%). Small cell lung cancer (SCLC) accounts for approximately 29,000 diagnosed
cases in the United States annually.[24]
The time interval between the onset of retinopathy and the cancer diagnosis can vary from weeks to months
(lymphoma and lung cancer) to even years (breast and prostate cancer).
Pathophysiology
The autoimmune theory was given by Keltner et al. in 1983. Suggesting this theory, the antibodies against the retinal
photoreceptors were present in the serum of lymphoma patients who developed acute loss of vision and retinal
degeneration. The pathological changes seen in CAR result from an interaction between the retinal antigen expression
in the cancerous tissues and their systemic immune response. These antigens trigger an autoimmune response within
the host to form antibodies that cross-react with the retinal antigen, ultimately causing cell death/apoptosis with retinal
degeneration. Thirkill and colleagues, in 1987, first observed the appearance of autoantibodies against the 23 kDa
retinal protein in patients of small cell carcinoma of the lung with CAR. The 23 kDa protein implicated as the CAR-
antigen was noted to be a 'photoreceptor cell-specific protein' or 'recoverin-like protein.'[25]
Recoverin is regarded as the most commonly involved antigen seen in CAR patients.[26] It is a calcium-dependent
activator of guanylate cyclase[27] responsible for light and dark adaptation of the photoreceptors.[28] The
conformational changes induced by activation of the calcium-binding domains present on recoverin protein play a
crucial role in the binding of the anti-recoverin antibodies.[29][30][31]
In cancer, the level of vascular endothelial growth factor (VEGF) increases, which causes retinal pericyte loss.[32]
This leads to increased permeability and vascular attenuation with subsequent breakdown of the blood-retina barrier.
[33][34] Antibodies penetrate the membranes of the living photoreceptors by the process of endocytosis and react
with recoverin.[34] Injection of recoverin in Lewis rats resulted in high antibody titer and cell-mediated immunity
against recovering, ultimately leading to features of uveoretinitis including perivasculitis, vitreous cells, retinal
lesions, and loss of retinal photoreceptors.[35]
Ohguro and colleagues demonstrated that recoverin dysfunction leads to increased phosphorylation of rhodopsin and
opening of cGMP-gated channels, causing a rise in the intracellular calcium.[36] This further leads to activation of
Bcl-2 proteins and caspases 3 and 9, initiating the apoptosis cascade with the breakdown of DNA and cell
degeneration.
The gene for recoverin is present on chromosome 17p13.1.[37] In patients with lung cancer, increased recoverin
protein expression caused by hypomethylation of DNA within the promoter region is seen.[38] Recoverin protein
within the cancer tissues with anti-recoverin antibodies can be demonstrated in cancer patients with no evidence of
CAR.[39] Recoverin antibodies may have an anti-tumor effect and may denote a longer survival rate with lesser
recurrence in patients with small cell carcinoma of the lung.[40]
Recoverin may aid in cancer treatment by causing cancer cells to become more sensitive to the chemotherapy or by
itself becoming the target for cancer treatment. Bazhin AV et al. analyzed serial samples of tumor tissues and sera
from 143 patients with lung cancer and showed that on account of a high occurrence of aberrant expression of
recoverin in lung tumors, targeting recoverin as a paraneoplastic antigen may play a role in immunotherapy of lung
cancer.[41] The autoimmune reactions that occur against the cancerous cells expressing recoverin can also contribute
to the systemic control of malignancy.[42]
Adamus et al. showed that anti-recoverin antibodies can be detected in only 10% of patients with visual
symptoms and identified the presence of auto-antibodies against α-enolase (46 kDa) and transducin-α (40 kDa) in the
serum of patients with CAR and non-neoplastic retinopathy.[43][44] Enolase is a glycolytic enzyme found in rods,
cones, ganglion cells, and Müller cells. Three different isoforms of enolase have been described, but the anti-α-
enolase antibodies have mostly been reported in CAR.[45]
Vision loss in enolase-associated retinopathy is less severe as compared to recoverin-associated

retinopathy. Recoverin-associated retinopathy has an acute onset with faster progression. Anti-enolase antibodies have
been associated with breast, prostate, and hematologic cancers.[46] Antibodies against α-enolase can be found in
about 11% of healthy individuals as well.[47] Other conditions showing autoantibodies against α-enolase include
Behçet disease, mixed cryoglobulinemia, inflammatory bowel disease, primary sclerosing cholangitis, systemic lupus
erythematosus (SLE), multiple sclerosis, and systemic sclerosis.[48][49]
Ohguro and colleagues suggested that humoral autoimmunity against recoverin and heat shock cognate protein 70 (65
kDa) may play a role in the pathogenesis of CAR.[50] Other antigens reported in CAR include:
Anti-Carbonic anhydrase II (30 kDa)[51]
Anti-GAPDH (glyceraldehyde 3-phosphate dehydrogenase)
Interphotoreceptor retinoid-binding protein (145 kDa)[52]
Neurofilament proteins[34]
Tubby-like protein 1 [TULP1][53]
Arrestin
Heat shock cognate protein HSC 70
GCAP 1 and 2 (guanylyl cyclase-activating proteins)
PNR photoreceptor cell-specific nuclear receptor
Rab6A GTPase (Rab6A), and other unidentified antibodies formed against the retinal proteins
T cells are also involved in the pathogenesis of CAR. Enhancement of CAR occurs by blockade of the negative T-cell
signaling via the CTLA-4 (cytotoxic T-lymphocyte antigen 4).[54] CTLA-4 receptor is expressed by the regulatory T-
cells, which blocks the IL-2 (interleukin-2) expression and inhibits T-cell activation. This leads to a downregulation of
the immune response. T-cell activation caused by the antagonism of the CTLA-4 is instrumental in various
autoimmune diseases and for causing immune-related regression of cancer.[55][56] Therefore, for CAR to develop,
exposure to recoverin or other retinal antigens along with immune modulation in the form of blockade of CTLA-4
signaling is required.
Histopathology
Histopathological examination reveals patchy photoreceptor loss.[34] Immunohistochemical analysis showed that
serum from patients with CAR selectively stained the outer retina (inner and outer segment of most photoreceptors,
outer nuclear layer, and outer plexiform layer). Though both the inner and outer segments of rods appeared to stain,
many of the cone inner segments of cones did not stain in a study.[57] Occurrence of cross-reactivity with the optic
nerve tissue has also been noted.[58]
The retinal pigment epithelium and choroid are usually not involved in CAR, contrary to retinitis
pigmentosa. Immunohistochemical staining of the retina varies depending upon the specific type of antibody involved
in the pathogenesis. Recoverin-mediated CAR shows predominant photoreceptor staining. Sawyer et al. showed
photoreceptor degeneration of rods and cones and scattered melanophages in the outer retina and sparing of the
ganglion cells in the inner retinal layer.
History and Physical

CAR leads to progressive and rapid visual loss caused by rod and cone dysfunction with retinal degeneration. It is
characterized by acquired, acute, or subacute sudden, bilateral, progressive, painless visual deterioration, which can
sometimes have a chronic presentation. Even though CAR is usually bilaterally symmetrical, it can be asymmetric
and sequential or rarely even have a unilateral presentation.[59]
Early cases of CAR may mimic various other conditions and may be difficult to diagnose. Nonspecific complaints are
not uncommon and include glare, photosensitivity, reduced vision, especially in scotopic conditions, floaters,
photopsia, apparent graying or darkening of the surrounding environment, transient visual obscurations, and 'bizarre
visual sensations.' Clinical features of cone dysfunction are decreased visual acuity, abnormal color
vision, metamorphopsia, central scotoma, and abnormal cone-mediated electroretinogram (ERG).[60][61]
Rod dysfunction leads to prolonged dark adaptation, nyctalopia, constricted visual fields, mid-peripheral or ring
scotomas, and abnormal rod-mediated ERG. Loss of vision in patients with CAR can occur over weeks to
months. Patients with recoverin antibodies in their serum have a diffuse involvement of both rods and cones and
suffer from profound visual impairment compared to patients with anti-α-enolase antibodies. Patients with anti-α-
enolase antibodies are also less likely to develop nyctalopia due to more limited central cone involvement.[62]
Visual symptoms in CAR may manifest even months or years before the diagnosis of the neoplasm and occur as a
result of the remote effect of the neoplasm. The interval may be as long as 11 years.[63] Jacobson and colleagues
suggested that pAIR should be suspected in patients with the triad of 'photosensitivity, ring scotomatous visual field
loss, and attenuated retinal arteriole caliber.'[64]
Recent onset acquired nyctalopia in an elderly patient with no family history of retinitis pigmentosa or no evidence of
vitamin A deficiency are other clinical clues for CAR diagnosis.
A slit-lamp examination may reveal the presence of low-grade inflammation in the anterior chamber or cellular debris
in the anterior vitreous. The fundus may appear normal, but some patients may have retinal pigment abnormalities in
the form of bony spicules or atrophy of the retinal pigment epithelium, vascular attenuation, and optic disc
pallor. Other fundus findings include vascular sheathing, macular edema, periphlebitis, chorioretinal atrophy, and
vitritis. Vitritis may be seen in up to 20% of patients. Cancer patients also develop cataracts at an early age.[65]
Malignancy is associated with the overproduction of reactive oxygen species (ROS).[66] This oxidative stress may
damage the lens proteins resulting in lens opacification and early-onset cataracts.[67]
Evaluation
Various modalities to confirm the diagnosis of CAR are as follows:
Visual Fields - Visual field testing usually shows constriction of fields. Other visual field defects include central,
cecocentral, or equatorial scotomas and enlargement of the blind spot.[21]
Fundus autofluorescence (FAF) - This is an important non-invasive tool used to analyze patients with CAR. It uses a
scanning laser ophthalmoscope and is based on the evaluation of lipofuscin.[68] Lipofuscin is a fluorophore derived
from photoreceptor outer segments.[69] Photoreceptor death and retinal pigment epithelium (RPE) atrophy cause
hypo autofluorescence (decreased autofluorescence), whereas increased RPE function cause hyper autofluorescence
(increased autofluorescence).[70][71]
CAR is characterized by the presence of a hyper-autofluorescent parafoveal ring with normal autofluorescence within
the ring and hypo autofluorescence outside the ring primarily centered in the macular and peripapillary region. Hyper-
autofluorescent rings can also be seen in multiple disorders, including retinitis pigmentosa, X-linked
retinoschisis, Leber congenital amaurosis, and cone dystrophy.[72][73][74] In Retinitis Pigmentosa, a parafoveal ring
of increased autofluorescence (Robson-Holder ring) can be seen in up to 59 % of patients.[75]
The Robson-Holder ring represents an area of lipofuscin accumulation around a preserved subfoveal RPE.[76] FAF
can detect even minute structural changes in patients with CAR, which are difficult to identify on ophthalmoscope.
Hence, it should be incorporated as a part of the standard imaging protocol for such patients.
Fundus Fluorescein Angiography (FFA) - It is usually normal. Infrequent findings include optic nerve head
staining, perivascular leakage in vasculitis, and petaloid leak at the macula in cystoid macular edema. Peripheral
subtle window defects corresponding to retinal degeneration may also be seen.[63]
Spectral-Domain Optical Coherence Tomography (SD-OCT) - This provides an objective measure of the amount
of retinal damage that has occurred and is also helpful in diagnosing CAR. It may detect the presence of CAR in the
early stages.[77][78]
SD-OCT shows loss of the outer retinal complex, including disruption of the ellipsoid zone (EZ) and thinning of the
photoreceptor layer. Abazari et al. showed the presence of outer retinal abnormalities and/or decreased central macular
thickness on SD-OCT in CAR patients. Similarly, Sepah et al. showed statistically significant loss of the
photoreceptor layer in CAR patients.[79]
OCT findings depend upon both the severity and the duration of the disease. Diagnostic delay accounts for
deterioration in the visual acuity and imminent reduction in the sub-foveal EZ. Cystic spaces or the presence of
cystoid macular edema (CME) is also a frequent finding. Larson et al., in a study among 17 patients with autoimmune
retinopathy, showed CME to be the most prevalent finding seen in 24% of the patients. Patients with CME at initial
presentation have a greater rate of EZ loss than those without CME.[80]
The condition is also more aggressive in patients with CME, which manifests in reduced a and b waves in the
electroretinogram.[81] Vitreomacular traction induced by an epiretinal membrane has also been reported in patients
with CAR.[82] Occasionally, mild schisis-like changes can also be seen. Intact EZ and external limiting membrane on
OCT in a patient before treatment may denote good visual recovery.[83]
Electrophysiological tests - These measure the electrical activity generated by the eye, the optic pathways, and the
visual cortex. The full-field electroretinogram (ffERG) provides information about activity in the rod and cone
systems and other neural elements.[84]
ERG may be a more sensitive tool than OCT, and ffERG is abnormal in the very early stage of the disease. However,
some cases may have involvement of the central cones, which is only evident on multifocal ERG (mfERG). The
mfERG indicates the topographical location of the response within the retina. Measurement of the integrity of the
retinal pigment epithelium is given by the electrooculogram (EOG). The a-wave of full-field ERG indicates the
response of the photoreceptors. The b wave can be photopic and scotopic. The photopic, cone-driven b wave reflects
the activity of the on and off bipolar cells whereas, the scotopic, rod-driven b wave reflects the activity of the on-type
bipolar cells. Photoreceptor damage affects both the a and b waves, while conditions affecting the bipolar cells result
in an absent b wave with a wave showing negative deflection. Oscillatory potentials (OPs) represent the activity of a
complex feedback circuit which includes the amacrine cells, bipolar cells, and interplexiform cells.[85] Responses
such as delayed b wave, the extinguishing of a and b waves involving the rods and cones, reduced b wave, and an
electronegative ERG may be seen in patients with CAR.[86][87]
Electronegative ERG is more typical of melanoma-associated retinopathy. Full-field ERG is almost always abnormal,
showing absent or attenuation flash responses in photopic and scotopic conditions. When cones are mainly affected,
full-field ERG might be normal, but the multifocal ERG is abnormal.[88]
In a case series of 10 patients by Thirkill et al., loss of rod and cone amplitudes with normal or prolonged implicit
times were seen in patients with anti-recoverin antibody-associated CAR. Weleber et al., in a case series of 12
patients, showed that anti-enolase-associated retinopathy is associated with more central or global cone dysfunction
than rod dysfunction. In a case series of 39 patients, Adamus et al. showed abnormal electroretinogram findings in
patients with anti-rod transducin-α associated with npAIR and CAR.
Antibody testing - The presence of antiretinal antibodies in cancer patients was first shown by Kornguth et al.
[89] This can be done using immunohistochemistry, western blotting, ELISA (enzyme-linked immunosorbent assay),
or multiplex assay systems. Adamus and colleagues first showed that clinical manifestations in CAR vary based on
the triggering antigens and the circulating antibodies. Diffuse rod and cone involvement is seen in CAR patients with
anti-recoverin antibodies.[62]
Patients with anti-α-enolase antibodies have limited involvement of the central cones. CAR associated with
transducin-α antibodies has more rod degeneration. Serum antibody levels may be found to be elevated even after
completion of treatment of the primary neoplasm, and it may also be associated with the progression of
CAR. However, fluctuating auto-antibody levels in the serum do not indicate cancer recurrence or progression.
The role of serial serum anti-retinal antibody levels for longitudinal monitoring requires further research and technical
difficulty, and cost limits its regular use. It is important to note that anti-retinal antibodies can be found even in the
normal population and patients with non-paraneoplastic autoimmune retinopathy. Ko et al. showed the presence of
anti-retinal antibodies in 42% of normal individuals. Hence, positive anti-retinal antibodies alone are not diagnostic of
CAR. Anti-retinal antibodies can also be found in the sera of patients with systemic autoimmune diseases like Behçet
disease, systemic lupus erythematosus (SLE), and age-related macular degeneration.[90] Khanna et al., in a review of
20 eyes of 15 patients with autoimmune retinopathy, showed a higher percentage of anti-enolase antibodies in the
serum and staining of the photoreceptor layer in patients that developed cystoid macular edema (CME).[80]
As CAR can precede the underlying cancer diagnosis by several months, running a systemic survey facilitated by the
primary care physician is essential. This includes a thorough medical history with physical examination, complete
blood investigations, magnetic resonance imaging (MRI) of the brain, computerized tomography (CT) of the chest,
abdomen, and pelvis, whole-body positron emission tomography (PET), and other appropriate tests such as
mammogram, colonoscopy, prostate and genitourinary system evaluation, and others. This extensive methodology is
pivotal in determining the treatment protocol and prognosis of the patient.[34]
There are no set diagnostic criteria for CAR. The diagnosis is made by combining the patient's clinical symptoms,
exam findings, diagnosis of systematic cancer, and positive antibodies against retinal proteins. A patient's visual
symptoms may precede cancer diagnosis, making the diagnosis of CAR difficult initially.
Treatment / Management
Primary treatment initiation is critical for the preservation of vision. CAR associated with untreated anti-recoverin
antibodies may lead to severe vision loss and even no perception of light.[62] The treatment must be targeted towards
the ocular condition because removal of underlying cancer does not affect the course of CAR. However, regression of
the primary neoplasm brings about a significant decline in the circulating autoantibodies.[91] No standardized
approach or protocol has been laid for the treatment of paraneoplastic retinopathy. The management is often difficult,
and the visual loss may progress despite therapy.
Systemic steroids can be used for treatment, but they have variable outcomes. The use of corticosteroids has been seen
to be more efficient in the short-term management of CAR associated with recoverin-mediated auto-
antibodies. Keltner and colleagues first used serum auto-antibody guided prednisone to control the intraocular disease
in a cancer patient. The dose of initial oral prednisone may be as high as 1 to 2 mg/kg/day. Intravitreal
triamcinolone and sub-tenon triamcinolone (40 to 60 mg) are other treatment options.[92][93] However, periocular or
intraocular steroids can cause a rise in intraocular pressure, which has to be controlled with topical medications.[94]
Intravenous methylprednisolone (500 mg/day for three days) when integrated with resection of the primary neoplasm
can lay down notable short-term improvement as reported by C Dot et al. The use of intravenous methylprednisolone
is associated with more favorable outcomes as compared to oral prednisone and hence can be used to initiate the
treatment.[95] Plasmapheresis coupled with prednisone may also show beneficial effects in patients with CAR.[91]
Multiple steroid-sparing immunomodulatory agents have been used in the treatment of CAR, but no single therapy
has shown consistency or long time efficacy. Systemic azathioprine (100 mg/day), cyclosporine (100 mg/day), and
mycophenolate mofetil (2 g/day) have been used in the management of CAR. Parallel and synchronous use of
multiple agents can be done to hold up the visual decline.
Ferreyra and colleagues showed that supplementation of immunosuppressive agents [azathioprine (100
mg/day), cyclosporine (100 mg/day)] causes improvement in visual acuity and visual fields with stabilization in ERG
(electroretinogram) in CAR patients associated with recoverin autoantibodies.[94]
Guy and colleagues showed stabilization in patients with CAR using intravenous immunoglobulins (IVIG). IVIG (400
mg/kg/per day for five days) can improve both visual acuity and visual field.[96] However, CAR associated with anti-
α-enolase antibodies is challenging to manage even with intravenous immunoglobulins.
The use of IVIG and plasmapheresis in the treatment of CAR is appropriate if given before the onset of irreversible
neuronal degeneration.
Newer treatment modalities include the use of newer monoclonal antibodies such as alemtuzumab (anti-CD52, pan-
lymphocyte) in the dose of 30 mg intravenously three times a week for four months) and rituximab (anti-CD20, B-
cell) in patients who have failed prednisone and intravenous immunoglobulins.[97][34]
Rituximab in the dose of 1000 mg twice a week of 2 doses or 375 once a week for four weeks, when combined with
immunosuppressive agents (such as prednisone, azathioprine, infliximab, cyclosporine, and mycophenolate), gave
beneficial effects in the form of stable or improved visual outcomes in 77% of eyes in a retrospective case series of 16
patients (30 eyes) with autoimmune retinopathy (including one melanoma-associated retinopathy, six CAR, and nine
npAIR patients).[98]
Ohguro and colleagues showed improvement in ERG and a delay in the progression of the disease
by pharmacological reduction of intracellular calcium (nilvadipine) in experimental animals. The anti-recoverin
antibodies get localized in the photoreceptor cells to block the recoverin function and regulate rhodopsin, resulting in
enhancement of phosphorylation of rhodopsin and induction of apoptotic cell death.[99]
By decreasing the phosphorylation of light-dependent rhodopsin or by antagonism of the intracellular calcium levels,
retinal dysfunction may be prevented. Adamus and associates demonstrated that nifedipine might protect from
apoptosis in an experimental CAR model.[100] However, there might be progressive loss in visual acuity despite the
use of calcium channel blocker monotherapy in humans. Hence, the effectiveness of using calcium channel blockers
or tinted glasses to reduce the ambient light in curbing the pathogenesis of CAR in human beings is still undiscovered.
Antioxidants and vitamins like lutein, vitamin C, vitamin E, and beta carotene (in non-smokers) may help stabilize the
retinal degeneration and the disease course, though their exact role may need further evaluation. Future treatment for
CAR is directed towards the inhibition of VEGF receptor 1 to prevent the penetration of antibodies. Calcium
modulation and ciliary neurotrophic factor (CNTF) gene transfer may cause a delay in apoptosis.[101] Monoclonal
antibodies targeted towards B-cell inhibition can also be used as a safer mode of treatment for patients with CAR.
Differential Diagnosis
It is important to differentiate CAR from the following:
Retinitis Pigmentosa - This entity is associated with family history and is inherited by various modes (autosomal
dominant, X-linked, autosomal recessive, or sporadic).[102][103] Anti-retinal antibodies can be found circulating in
around 10 to 37% of patients with retinitis pigmentosa.[104] Features like retinal degeneration may also be seen
secondary to retinitis pigmentosa; however, in CAR, minimal inflammation occurs, and usually, there is sparing of the
retinal pigment epithelium and choroid. The reason for eliciting similarity is sharing a common target in the form
of S-antigen and interphotoreceptor retinoid-binding protein.[105]
In retinitis pigmentosa, there is a predominant rod photoreceptor dysfunction with a later cone photoreceptor and
retinal pigment epithelium dysfunction. The disease manifests during adolescence with the chief complaint of night
blindness and mid-peripheral visual loss (due to rod cell damage) and development of tunnel vision at later stages.
[106] Typical features of retinitis pigmentosa include arteriolar attenuation, changes in the retinal pigment epithelium
(RPE), and a waxy disc pallor. Other features such as RPE depigmentation and atrophy, cystic macular lesions,
posterior subcapsular cataracts, vitreous cells, and refractive errors (myopia and astigmatism) may also be seen.
[107] CAR is differentiated by acquired nyctalopia, which usually starts at or after the 6th decade, and usually, there is
no family history.
Non-paraneoplastic autoimmune retinopathy (npAIR) - Description of npAIR was first done in 1997. The
phenotype and electrophysiological tests seen in npAIR are similar to those in CAR. It is usually associated with an
autoimmune family history, and hence, it needs a more intense immunosuppressive therapy. Non-paraneoplastic
autoimmune retinopathy has a slower progression rate than CAR, the visual changes are more subtle, and the age of
presentation is usually younger. npAIR can be associated with photopsia, dyschromatopsia, and nyctalopia. The
presence of macular edema and chorioretinal atrophy also points towards non-paraneoplastic autoimmune retinopathy.
[108]
The anti-recoverin antibodies are usually found in the sera of patients with suspected npAIR. Other antiretinal
antibodies associated with npAIR include anti-carbonic anhydrase II, anti-α-enolase, anti-recoverin, and anti-rod
transducin-α antibodies. Adamus and colleagues, after analyzing 193 patients with retinopathy with or without
neoplasia, reported that antibodies against recoverin are found in the serum of patients with cancer, whereas α-enolase
antibodies were found in all the other patients. Systemic conditions associated with npAIR include hypothyroidism,
rheumatoid arthritis, multiple sclerosis, autoimmune hepatitis, Hashimoto thyroiditis, Myasthenia gravis, Graves
disease, bullous pemphigoid.
Melanoma-associated retinopathy (MAR) - CAR is most commonly associated with small cell carcinoma of the
lung, whereas MAR is commonly associated with cutaneous melanoma. CAR usually precedes the diagnosis of
neoplasm, whereas MAR usually presents after the diagnosis of melanoma. MAR typically has a normal fundus, but it
can also present with vitelliform material and multiple serous retinal detachments.[109]
Electroretinogram in MAR reveals reduced B-wave and preserved dark-adapted A wave (electronegative ERG)
showing bipolar cell dysfunction. Circulating autoantibodies against TRPM1 (transient receptor potential cation
channel, subfamily M, member 1) and bestrophin-1 can be found in patients with MAR. Other antibodies associated
with MAR include anti-aldolase A and C, anti-α-enolase, anti-interphotoreceptor retinoid-binding protein, anti-
recoverin, anti-rhodopsin, and anti-transducin antibodies.
Acute Zonal Outer Occult Retinopathy (AZOOR) and other White Dot Syndromes - Although AZOOR can
present with symptoms, electroretinogram findings, and visual fields showing an enlarged blind spot similar to CAR,
AZOOR is typically a bilateral but asymmetric entity. Hypo-autofluorescence is observed in the majority of eyes with
AZOOR. Patients with AZOOR show partial recovery or stabilization even without treatment. Multiple evanescent
white dot syndrome (MEWDS) shows unilateral retinopathy associated with optic nerve edema, afferent pupillary
defect, and spontaneous recovery.[110][111]
Cone Dystrophy - Here, the rods usually remain normal or are at least partly spared even during the late stages.
[112] Features include dyschromatopsia, photophobia, loss of visual acuity, and exclusive cone involvement in the
electroretinogram (ERG) characterized by diminished or nonrecordable photopic ERGs and normal or reduced
amplitudes in the scotopic ERGs.[113]
Toxic Retinopathy or Toxic Optic Neuropathy - Visual impairment occurs due to optic nerve damage caused by a
toxin.[114] This entity can occur at any age, with both the genders and all the races being affected equally. It mainly
affects the ganglion cell axons and particularly the papillomacular nerve fiber bundle. It clinically presents as
bilaterally symmetrical and progressive loss of vision with dyschromatopsia and presence of central or cecocentral
scotoma on visual fields. Toxins causing retinopathy can be found in the blood, urine, and even hair. The most
common causes of toxic optic neuropathy include ethambutol, isoniazid, methanol, amiodarone, tobacco, and alcohol.
[115]
Leber Hereditary Optic Neuropathy (LHON) - It is a rare mitochondrial disorder affecting young males between
15 to 35 years of age. There occurs a sequential vision loss caused by optic neuropathy.[116][117] It has a
predominant maternal inheritance pattern.[118] Degeneration of the retinal ganglionic cells and their axons results in
acute or subacute central vision loss. Presymptomatic features include telangiectatic vessels around the optic discs and
variable degrees of retinal nerve fiber layer edema.[119][120]
Red-green color vision abnormalities suggesting optic nerve dysfunction, reduced contrast sensitivity, and subnormal
visual electrophysiological parameters can also be seen.[121] Central retinal vessel tortuosity, retinal nerve fiber layer
edema, and circumpapillary telangiectatic microangiopathy are seen in acute phases.[122] The optic disc can appear
normal in the acute phase in ∼20% of cases. The chronic phase is characterized by retinal nerve fiber layer
degeneration and optic atrophy seen after six months of the onset of the condition.[123]
Nutritional Optic Neuropathy - There is a visual impairment resulting from the optic nerve damage occurring
secondary to nutritional deficiency. It mainly occurs due to vitamin deficiency. Deficiency of vitamin B1 (thiamine),
vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin), and/or folic
acid is associated with nutritional optic neuropathy. The clinical features and pathophysiology involved are similar to
toxic retinopathy. Nutritional Optic Neuropathy can present as a non-specific retrobulbar optic neuropathy.[114]
Bilateral diffuse uveal melanocytic proliferation (BDUMP) - It is a rare paraneoplastic disorder first described
by Machemer R et al. in 1966.[124] The term BDUMP was coined by Barr et al. in 1982.[125] The usual age of
presentation ranges between 34 to 89 years, with the median age being 64 years.[126] It presents with acute onset,
rapid, bilateral (rarely unilateral), and painless loss of visual acuity with a female predilection. The primary
malignancy usually associated with BDUMP in females is urogenital cancer (most commonly ovarian cancer), and in
males is lung cancer.[127]
The cardinal signs of BDUMP as described by Gass et al. include multiple, subtle, round, or oval, orange-red patches
at the level of retinal pigment epithelium (RPE); multifocal early hyper fluorescence; multiple, focally elevated,
pigmented, and non-pigmented uveal melanocytic tumors with diffuse uveal tract thickening; the presence of an
exudative type of retinal detachment; and rapid cataract progression.[128] Fundus autofluorescence usually shows
nummular changes giving a giraffe pattern with inverse changes in fluorescein angiogram.[129]
Treatment options available for BDUMP include radiation therapy, use of local and systemic
corticosteroids, plasmapheresis, drainage of the subretinal fluid, and vitrectomy. However, it has a very poor visual
prognosis and survival rate. Most of the patients become legally blind within one year or succumb to death within
three years of initial presentation secondary to the systemic malignancy.[130]
Chronic Central Serous Chorioretinopathy (CSCR) - Central Serous Chorioretinopathy is a retinal disorder seen in
young males between the ages of 20 and 45 years.[131] It is usually unilateral; however, a bilateral presentation has
been noted in 40% of cases.[132] Chronic CSCR (or diffuse retinal epitheliopathy) is characterized by the persistence
of a well-defined, circular or oval area of localized serous retinal detachment over the posterior pole beyond 3 to 6
months of initial presentation. It can be seen in older patients or those on long-term steroid therapy.[133]
Presenting complaints in acute CSCR include the presence of micropsia, blurring of vision, metamorphopsia,
disturbances in color vision, relative scotoma, and temporary hyperopia. whereas chronic form is associated with a
more severe or even permanent loss in visual acuity. The extent of visual damage depends on the damage to the
photoreceptor outer segments and the external limiting membrane.[134] Fundus autofluorescence (FAF) in chronic
CSCR shows vertical tracks in the inferior retina.[135]
Patchy areas of hyper-fluorescence (areas of RPE atrophy) can be seen on Fundus fluorescein angiography
(FFA). OCT (optical coherence tomography) findings in chronic CSCR comprise elongation of photoreceptor outer
segments, the presence of intraretinal cysts, and hyperreflective dots.[135] Chronic CSCR with retinal pigment
epithelial detachments can develop an RPE rip with secondary exudative retinal detachment.[135]
Paraneoplastic Optic Neuropathy (PON) - PON is a rare paraneoplastic entity affecting middle-aged patients with
malignancy. It is characterized by bilateral, subacute, progressive, painless, and profound loss of visual acuity.[136] It
is caused by the cross-reactivity of antibodies generated by the tumor-associated antigens with the neuronal and glial
proteins.[137] The fundus examination reveals optic disc edema.[136]
Other findings include an abnormal ERG, visual field defects (tubular vision, enlargement of blind spot, and an
inferior scotoma), and visual evoked potential (VEP) changes (decreased amplitude and a delayed implicit period).
[138] Important serological tests include anti-Hu or AANA-1(antineuronal nuclear antibody type-1), anti-Tr (anti-
Purkinje cell antibody), anti-Yo (anti-Purkinje cell cytoplasmic antibody type 1), anti-CV2/CRMP5 (anti-collapsin
response mediator protein-5), anti-Ri (antineuronal nuclear antibody type-2), anti-Ma2/TA (anti-PNMA2 or anti-
paraneoplastic antigen Ma2), and anti-amphiphysin antibody testing. Out of these, anti-Hu and anti-CV2/CRMP5
antibodies are more consistently associated with paraneoplastic neuropathy.[139][140]
PON leads to irreversible optic nerve changes and, hence, the visual prognosis of PON remains poor as even
immunosuppressive therapy and steroids have not been very effective in management. Prompt treatment of the
underlying malignancy is the only way to halt the progression of the disease.[141]
Vitamin A Deficiency - Vitamin A is a fat-soluble vitamin required for vision, overall cellular development,
immunity, metabolism, and reproductive functions.[142][143] The recommended dietary allowance (RDA) of vitamin
A for an adult male is 900 micrograms/day and for an adult female is 700 micrograms/day.[144] The RDA of vitamin
A for children is 300 to 900 micrograms/day, and for pregnant and lactating women, it is 770 micrograms/day and
1300 micrograms/day, respectively.[145]
Serum retinol concentrations of fewer than 20 micrograms/dL are regarded as vitamin A deficiency. Ocular symptoms
of vitamin A deficiency develop when the serum retinol concentration drops below 10 micrograms/dL.[146] It usually
occurs following malabsorption, infections, or poor nutrition. Night blindness or nyctalopia is the first presenting
feature of vitamin A deficiency caused by profound rod dysfunction. Fundus examination may reveal multiple white
or grey-white spots or dots in the peripheral retina.[147]
ERG shows undetectable or reduced rod response with reduced amplitudes and increased latency of cone
response. Optical coherence tomography (OCT) may show hyperreflective elevated lesions just below the ellipsoid
zone corresponding to the white dots.[148] Other early external ocular findings include Bitot spots (oval or triangular,
foamy lesions of the conjunctiva) and conjunctival xerosis (wrinkling of the conjunctiva). Late signs of vitamin A
deficiency such as corneal xerosis, corneal ulceration, and eventually keratomalacia may lead to permanent visual
damage. Prompt management of vitamin A deficiency at a subclinical stage has a very good prognosis.
[145] Permanent vision loss or blindness may be seen in case of severe vitamin A deficiency.[149]
Hence, to diagnose CAR, it is important to correlate the findings of the sera with the electroretinogram and clinical
features with due help from other investigative modalities.
Prognosis
Visual decline and even loss of visual acuity due to CAR may occur even before the diagnosis of cancer. When CAR
is associated with recoverin antibodies, the condition can progress to profound vision loss to even no perception of
light.[62]
Early diagnosis and initiation of treatment is a prerequisite for the preservation of vision. However, a targeted
decimation of the photoreceptors and the support cells occurs; thus, despite even immunomodulatory therapy, the
visual prognosis remains poor. Hence, in any patient, if there is an acute or subacute loss of visual acuity, visual field
alterations, and vascular attenuation in the fundus without any other etiology, a suspicion for CAR should be
made. Visual prognosis is not affected by treatment of underlying cancer. Overall survival of the patient depends upon
the underlying tumor and stage at which it was diagnosed and the available treatment options.[150]
Adamus et al., after examination of 209 cancer patients, concluded that patients who are at risk for developing CAR
could be identified early using the anti-retinal autoantibodies. This may prevent vision loss in such vulnerable
patients.
Complications
Choroidal neovascularization can occur secondary to CAR.[52] Other causes of vision loss in patients with CAR
include macular edema, foveal thinning, and secondary optic atrophy.[64]
Deterrence and Patient Education

Patients with cancer-associated retinopathy need proper guidance and in-depth evaluation. They need to be
enlightened about this condition and the various available treatment options. The patients need to understand that
CAR is a potentially blinding and devastating condition, and the features of the same may develop even before the
neoplasm is clinically evident. The patient must understand that although there is no standard treatment protocol for
this entity, proper compliance to the treatment is needed to stall or rarely reverse this condition.[34]
Enhancing Healthcare Team Outcomes

A comprehensive approach is crucial for managing patients with cancer-associated retinopathy. An appropriately high
index of suspicion and early diagnosis and treatment plays an imperative role in curtailing the risk of irreversible
immunological damage to the retinal cells in these patients. Hence, a multi-disciplinary approach for complete
evaluation and treatment is vital for properly managing this condition, even though there is no consensus on the
standard treatment protocol.
For instance, when a patient is suspected of having cancer-associated retinopathy, a prompt referral by the treating
physician or oncologist to the ophthalmologist is recommended. This is to be followed by collaborative planning
between the oncologist, ophthalmologist, rheumatologist, dermatologist, radiologist, or even a uveitis specialist
accustomed to administering the immunomodulatory agents.
Therefore, this condition requires interprofessional teamwork. This includes evaluation by the physician/clinician or
oncologist, the ophthalmologist, dispensing of medicines by the pharmacist, aiding in patient education for treatment
compliance as well as monitoring the vitals by the nurses, and thorough evaluation of the visual acuity by the
optometrist. This united interprofessional approach is decisive in managing the patients and acquiring favorable
outcomes. [Level 5]
Review Questions
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Comment on this article.
References
1. Thirkill CE, Roth AM, Keltner JL. Cancer-associated retinopathy. Arch Ophthalmol. 1987 Mar;105(3):372-5.
[PubMed: 2950846]
2. Keltner JL, Thirkill CE, Tyler NK, Roth AM. Management and monitoring of cancer-associated retinopathy. Arch
Ophthalmol. 1992 Jan;110(1):48-53. [PubMed: 1310001]
3. Thirkill CE, FitzGerald P, Sergott RC, Roth AM, Tyler NK, Keltner JL. Cancer-associated retinopathy (CAR
syndrome) with antibodies reacting with retinal, optic-nerve, and cancer cells. N Engl J Med. 1989 Dec
07;321(23):1589-94. [PubMed: 2555714]
4. Heckenlively JR, Ferreyra HA. Autoimmune retinopathy: a review and summary. Semin Immunopathol. 2008
Apr;30(2):127-34. [PubMed: 18408929]
5. Dutta Majumder P, Marchese A, Pichi F, Garg I, Agarwal A. An update on autoimmune retinopathy. Indian J
Ophthalmol. 2020 Sep;68(9):1829-1837. [PMC free article: PMC7690499] [PubMed: 32823399]
6. Sawyer RA, Selhorst JB, Zimmerman LE, Hoyt WF. Blindness caused by photoreceptor degeneration as a remote
effect of cancer. Am J Ophthalmol. 1976 May;81(5):606-13. [PubMed: 179323]
7. Klingele TG, Burde RM, Rappazzo JA, Isserman MJ, Burgess D, Kantor O. Paraneoplastic retinopathy. J Clin
Neuroophthalmol. 1984 Dec;4(4):239-45. [PubMed: 6240497]
8. Mizener JB, Kimura AE, Adamus G, Thirkill CE, Goeken JA, Kardon RH. Autoimmune retinopathy in the
absence of cancer. Am J Ophthalmol. 1997 May;123(5):607-18. [PubMed: 9152066]
9. Henry K. Paraneoplastic syndromes: Definitions, classification, pathophysiology and principles of treatment.
Semin Diagn Pathol. 2019 Jul;36(4):204-210. [PubMed: 30876820]
10. Naramala S, Ahmad J, Adapa S, Gavini F, Konala VM. Case Series of Cancer-associated Retinopathy (CAR).
Cureus. 2019 Jun 10;11(6):e4872. [PMC free article: PMC6687430] [PubMed: 31417817]
11. Keltner JL, Roth AM, Chang RS. Photoreceptor degeneration. Possible autoimmune disorder. Arch Ophthalmol.
1983 Apr;101(4):564-9. [PubMed: 6838414]
12. Katsuta H, Okada M, Nakauchi T, Takahashi Y, Yamao S, Uchida S. Cancer-associated retinopathy associated
with invasive thymoma. Am J Ophthalmol. 2002 Sep;134(3):383-9. [PubMed: 12208250]
13. Chan JW. Paraneoplastic retinopathies and optic neuropathies. Surv Ophthalmol. 2003 Jan-Feb;48(1):12-38.
[PubMed: 12559325]
14. Dot C, Guigay J, Adamus G. Anti-alpha-enolase antibodies in cancer-associated retinopathy with small cell
carcinoma of the lung. Am J Ophthalmol. 2005 Apr;139(4):746-7. [PubMed: 15808190]
15. Adamus G. Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy.
Autoimmun Rev. 2009 Mar;8(5):410-4. [PMC free article: PMC2680817] [PubMed: 19168157]
16. Misiuk-Hojło M, Ejma M, Gorczyca WA, Szymaniec S, Witkowska D, Fortuna W, Miedzybrodzki R,
Rogozińska-Szczepka J, Bartnik W. Cancer-associated retinopathy in patients with breast carcinoma. Arch
Immunol Ther Exp (Warsz). 2007 Jul-Aug;55(4):261-5. [PMC free article: PMC2766466] [PubMed: 17659379]
17. Raghunath A, Adamus G, Bodurka DC, Liu J, Schiffman JS. Cancer-associated retinopathy in neuroendocrine
carcinoma of the fallopian tube. J Neuroophthalmol. 2010 Sep;30(3):252-4. [PMC free article: PMC3491900]
[PubMed: 20724944]
18. Wagley S, Tran TM, Mallory PW, Lee MS, Armbrust KR, Trautman B, Montezuma SR. Cancer-Associated
Retinopathy due to Clear Cell Renal Carcinoma. Ocul Oncol Pathol. 2021 Mar;7(1):31-35. [PMC free article:
PMC7989776] [PubMed: 33796514]
19. Grange L, Dalal M, Nussenblatt RB, Sen HN. Autoimmune retinopathy. Am J Ophthalmol. 2014
Feb;157(2):266-272.e1. [PMC free article: PMC3946999] [PubMed: 24315290]
20. Honnorat J, Antoine JC. Paraneoplastic neurological syndromes. Orphanet J Rare Dis. 2007 May 04;2:22. [PMC
free article: PMC1868710] [PubMed: 17480225]
21. Braithwaite T, Vugler A, Tufail A. Autoimmune retinopathy. Ophthalmologica. 2012;228(3):131-42. [PubMed:
22846442]
22. Adamus G, Ren G, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and autoimmune
retinopathy. BMC Ophthalmol. 2004 Jun 04;4:5. [PMC free article: PMC446200] [PubMed: 15180904]
23. Keltner JL, Thirkill CE, Yip PT. Clinical and immunologic characteristics of melanoma-associated retinopathy
syndrome: eleven new cases and a review of 51 previously published cases. J Neuroophthalmol. 2001
Sep;21(3):173-87. [PubMed: 11725182]
24. Carrera W, Tsamis KA, Shah R. A case of cancer-associated retinopathy with chorioretinitis and optic neuritis
associated with occult small cell lung cancer. BMC Ophthalmol. 2019 May 02;19(1):101. [PMC free article:
PMC6498699] [PubMed: 31046716]
25.
Thirkill CE, Tait RC, Tyler NK, Roth AM, Keltner JL. The cancer-associated retinopathy antigen is a recoverin-like
protein. Invest Ophthalmol Vis Sci. 1992 Sep;33(10):2768-72. [PubMed: 1388144]
26. Ohguro H, Yokoi Y, Ohguro I, Mamiya K, Ishikawa F, Yamazaki H, Metoki T, Takano Y, Ito T, Nakazawa M.
Clinical and immunologic aspects of cancer-associated retinopathy. Am J Ophthalmol. 2004 Jun;137(6):1117-9.
[PubMed: 15183799]
27. McGinnis JF, Stepanik PL, Baehr W, Subbaraya I, Lerious V. Cloning and sequencing of the 23 kDa mouse
photoreceptor cell-specific protein. FEBS Lett. 1992 May 11;302(2):172-6. [PubMed: 1386025]
28. Polans AS, Witkowska D, Haley TL, Amundson D, Baizer L, Adamus G. Recoverin, a photoreceptor-specific
calcium-binding protein, is expressed by the tumor of a patient with cancer-associated retinopathy. Proc Natl
Acad Sci U S A. 1995 Sep 26;92(20):9176-80. [PMC free article: PMC40947] [PubMed: 7568096]
29. Adamus G, Amundson D. Epitope recognition of recoverin in cancer associated retinopathy: evidence for
calcium-dependent conformational epitopes. J Neurosci Res. 1996 Sep 15;45(6):863-72. [PubMed: 8892098]
30. Adamus G, Machnicki M, Seigel GM. Apoptotic retinal cell death induced by antirecoverin autoantibodies of
cancer-associated retinopathy. Invest Ophthalmol Vis Sci. 1997 Feb;38(2):283-91. [PubMed: 9040460]
31. Maeda T, Maeda A, Maruyama I, Ogawa KI, Kuroki Y, Sahara H, Sato N, Ohguro H. Mechanisms of
photoreceptor cell death in cancer-associated retinopathy. Invest Ophthalmol Vis Sci. 2001 Mar;42(3):705-12.
[PubMed: 11222531]
32. Cao R, Xue Y, Hedlund EM, Zhong Z, Tritsaris K, Tondelli B, Lucchini F, Zhu Z, Dissing S, Cao Y. VEGFR1-
mediated pericyte ablation links VEGF and PlGF to cancer-associated retinopathy. Proc Natl Acad Sci U S A.
2010 Jan 12;107(2):856-61. [PMC free article: PMC2818941] [PubMed: 20080765]
33. Suzuki T, Obara Y, Sato Y, Saito G, Ichiwata T, Uchiyama T. Cancer-associated retinopathy with presumed
vasculitis. Am J Ophthalmol. 1996 Jul;122(1):125-7. [PubMed: 8659589]
34. Shildkrot Y, Sobrin L, Gragoudas ES. Cancer-associated retinopathy: update on pathogenesis and therapy. Semin
Ophthalmol. 2011 Jul-Sep;26(4-5):321-8. [PubMed: 21958182]
35. Adamus G, Ortega H, Witkowska D, Polans A. Recoverin: a potent uveitogen for the induction of photoreceptor
degeneration in Lewis rats. Exp Eye Res. 1994 Oct;59(4):447-55. [PubMed: 7859820]
36. Ohguro H, Ogawa K, Maeda T, Maruyama I, Maeda A, Takano Y, Nakazawa M. Retinal dysfunction in cancer-
associated retinopathy is improved by Ca(2+) antagonist administration and dark adaptation. Invest Ophthalmol
Vis Sci. 2001 Oct;42(11):2589-95. [PubMed: 11581204]
37. McGinnis JF, Austin B, Klisak I, Heinzmann C, Kojis T, Sparkes RS, Bateman JB, Lerious V. Chromosomal
assignment of the human gene for the cancer-associated retinopathy protein (recoverin) to chromosome 17p13.1.
J Neurosci Res. 1995 Feb 01;40(2):165-8. [PubMed: 7745609]
38. Bazhin AV, De Smet C, Golovastova MO, Schmidt J, Philippov PP. Aberrant demethylation of the recoverin gene
is involved in the aberrant expression of recoverin in cancer cells. Exp Dermatol. 2010 Nov;19(11):1023-5.
[PubMed: 20812967]
39. Bazhin AV, Shifrina ON, Savchenko MS, Tikhomirova NK, Goncharskaia MA, Gorbunova VA, Senin II,
Chuchalin AG, Philippov PP. Low titre autoantibodies against recoverin in sera of patients with small cell lung
cancer but without a loss of vision. Lung Cancer. 2001 Oct;34(1):99-104. [PubMed: 11557119]
40. Kobayashi M, Ikezoe T, Uemura Y, Ueno H, Taguchi H. Long-term survival of a patient with small cell lung
cancer associated with cancer-associated retinopathy. Lung Cancer. 2007 Sep;57(3):399-403. [PubMed:
17397962]
41. Bazhin AV, Savchenko MS, Shifrina ON, Demoura SA, Chikina SY, Jaques G, Kogan EA, Chuchalin AG,
Philippov PP. Recoverin as a paraneoplastic antigen in lung cancer: the occurrence of anti-recoverin
autoantibodies in sera and recoverin in tumors. Lung Cancer. 2004 May;44(2):193-8. [PubMed: 15084384]
42. Maeda A, Maeda T, Ohguro H, Palczewski K, Sato N. Vaccination with recoverin, a cancer-associated
retinopathy antigen, induces autoimmune retinal dysfunction and tumor cell regression in mice. Eur J Immunol.
2002 Aug;32(8):2300-7. [PubMed: 12209643]
43. Adamus G, Brown L, Weleber RG. Molecular biomarkers for autoimmune retinopathies: significance of anti-
transducin-alpha autoantibodies. Exp Mol Pathol. 2009 Dec;87(3):195-203. [PMC free article: PMC2783245]
[PubMed: 19744478]
44. Adamus G, Aptsiauri N, Guy J, Heckenlively J, Flannery J, Hargrave PA. The occurrence of serum
autoantibodies against enolase in cancer-associated retinopathy. Clin Immunol Immunopathol. 1996
Feb;78(2):120-9. [PubMed: 8625554]
45. Magrys A, Anekonda T, Ren G, Adamus G. The role of anti-alpha-enolase autoantibodies in pathogenicity of
autoimmune-mediated retinopathy. J Clin Immunol. 2007 Mar;27(2):181-92. [PubMed: 17235687]
46. Grewal DS, Fishman GA, Jampol LM. Autoimmune retinopathy and antiretinal antibodies: a review. Retina.
2014 May;34(5):827-45. [PubMed: 24646664]
47. Forooghian F, Adamus G, Sproule M, Westall C, O'Connor P. Enolase autoantibodies and retinal function in
multiple sclerosis patients. Graefes Arch Clin Exp Ophthalmol. 2007 Aug;245(8):1077-84. [PubMed: 17219105]
48. Terrier B, Degand N, Guilpain P, Servettaz A, Guillevin L, Mouthon L. Alpha-enolase: a target of antibodies in
infectious and autoimmune diseases. Autoimmun Rev. 2007 Jan;6(3):176-82. [PubMed: 17289554]
49. Pratesi F, Moscato S, Sabbatini A, Chimenti D, Bombardieri S, Migliorini P. Autoantibodies specific for alpha-
enolase in systemic autoimmune disorders. J Rheumatol. 2000 Jan;27(1):109-15. [PubMed: 10648026]
50. Ohguro H, Ogawa K, Nakagawa T. Recoverin and Hsc 70 are found as autoantigens in patients with cancer-
associated retinopathy. Invest Ophthalmol Vis Sci. 1999 Jan;40(1):82-9. [PubMed: 9888430]
51. Adamus G, Karren L. Autoimmunity against carbonic anhydrase II affects retinal cell functions in autoimmune
retinopathy. J Autoimmun. 2009 Mar;32(2):133-9. [PMC free article: PMC2692195] [PubMed: 19269136]
52. Querques G, Thirkill CE, Hagege H, Soubrane G, Souied EH. Choroidal neovascularization associated with
cancer-associated retinopathy. Acta Ophthalmol. 2010 Aug;88(5):571-5. [PubMed: 19141145]
53. Kikuchi T, Arai J, Shibuki H, Kawashima H, Yoshimura N. Tubby-like protein 1 as an autoantigen in cancer-
associated retinopathy. J Neuroimmunol. 2000 Feb 01;103(1):26-33. [PubMed: 10674986]
54. Maeda A, Maeda T, Liang Y, Yenerel M, Saperstein DA. Effects of cytotoxic T lymphocyte antigen 4 (CTLA4)
signaling and locally applied steroid on retinal dysfunction by recoverin, cancer-associated retinopathy antigen.
Mol Vis. 2006 Aug 10;12:885-91. [PubMed: 16917481]
55. Gough SC, Walker LS, Sansom DM. CTLA4 gene polymorphism and autoimmunity. Immunol Rev. 2005
Apr;204:102-15. [PubMed: 15790353]
56. Serrano NC, Millan P, Páez MC. Non-HLA associations with autoimmune diseases. Autoimmun Rev. 2006
Mar;5(3):209-14. [PubMed: 16483921]
57. Rizzo JF, Gittinger JW. Selective immunohistochemical staining in the paraneoplastic retinopathy syndrome.
Ophthalmology. 1992 Aug;99(8):1286-95. [PubMed: 1325045]
58. Adamus G, Guy J, Schmied JL, Arendt A, Hargrave PA. Role of anti-recoverin autoantibodies in cancer-
associated retinopathy. Invest Ophthalmol Vis Sci. 1993 Aug;34(9):2626-33. [PubMed: 7688357]
59. Almeida DR, Chin EK, Niles P, Kardon R, Sohn EH. Unilateral manifestation of autoimmune retinopathy. Can J
Ophthalmol. 2014 Aug;49(4):e85-7. [PubMed: 25103665]
60. Ohguro H, Maruyama I, Nakazawa M, Oohira A. Antirecoverin antibody in the aqueous humor of a patient with
cancer-associated retinopathy. Am J Ophthalmol. 2002 Oct;134(4):605-7. [PubMed: 12383822]
61. Whitcup SM, Vistica BP, Milam AH, Nussenblatt RB, Gery I. Recoverin-associated retinopathy: a clinically and
immunologically distinctive disease. Am J Ophthalmol. 1998 Aug;126(2):230-7. [PubMed: 9727517]
62. Weleber RG, Watzke RC, Shults WT, Trzupek KM, Heckenlively JR, Egan RA, Adamus G. Clinical and
electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with antienolase
antibodies. Am J Ophthalmol. 2005 May;139(5):780-94. [PubMed: 15860281]
63. Saito W, Kase S, Ohguro H, Furudate N, Ohno S. Slowly progressive cancer-associated retinopathy. Arch
Ophthalmol. 2007 Oct;125(10):1431-3. [PubMed: 17923561]
64. Jacobson DM, Thirkill CE, Tipping SJ. A clinical triad to diagnose paraneoplastic retinopathy. Ann Neurol. 1990
Aug;28(2):162-7. [PubMed: 2171418]
65. Chiang CC, Lin CL, Peng CL, Sung FC, Tsai YY. Increased risk of cancer in patients with early-onset cataracts:
a nationwide population-based study. Cancer Sci. 2014 Apr;105(4):431-6. [PMC free article: PMC4317801]
[PubMed: 24450445]
66. Klaunig JE, Kamendulis LM, Hocevar BA. Oxidative stress and oxidative damage in carcinogenesis. Toxicol
Pathol. 2010 Jan;38(1):96-109. [PubMed: 20019356]
67. Michael R, Bron AJ. The ageing lens and cataract: a model of normal and pathological ageing. Philos Trans R
Soc Lond B Biol Sci. 2011 Apr 27;366(1568):1278-92. [PMC free article: PMC3061107] [PubMed: 21402586]
68. Lima LH, Greenberg JP, Greenstein VC, Smith RT, Sallum JM, Thirkill C, Yannuzzi LA, Tsang SH.
Hyperautofluorescent ring in autoimmune retinopathy. Retina. 2012 Jul;32(7):1385-94. [PMC free article:
PMC4377132] [PubMed: 22218149]
69.
Eldred GE, Katz ML. Fluorophores of the human retinal pigment epithelium: separation and spectral characterization.
Exp Eye Res. 1988 Jul;47(1):71-86. [PubMed: 3409988]
70. von Rückmann A, Fitzke FW, Bird AC. Distribution of fundus autofluorescence with a scanning laser
ophthalmoscope. Br J Ophthalmol. 1995 May;79(5):407-12. [PMC free article: PMC505125] [PubMed:
7612549]
71. Kennedy CJ, Rakoczy PE, Constable IJ. Lipofuscin of the retinal pigment epithelium: a review. Eye (Lond).
1995;9 ( Pt 6):763-71. [PubMed: 8849547]
72. Aguirre-Lamban J, Riveiro-Alvarez R, Maia-Lopes S, Cantalapiedra D, Vallespin E, Avila-Fernandez A,
Villaverde-Montero C, Trujillo-Tiebas MJ, Ramos C, Ayuso C. Molecular analysis of the ABCA4 gene for
reliable detection of allelic variations in Spanish patients: identification of 21 novel variants. Br J Ophthalmol.
2009 May;93(5):614-21. [PMC free article: PMC2668911] [PubMed: 19028736]
73. Tsang SH, Vaclavik V, Bird AC, Robson AG, Holder GE. Novel phenotypic and genotypic findings in X-linked
retinoschisis. Arch Ophthalmol. 2007 Feb;125(2):259-67. [PMC free article: PMC2757628] [PubMed:
17296904]
74. Scholl HP, Chong NH, Robson AG, Holder GE, Moore AT, Bird AC. Fundus autofluorescence in patients with
leber congenital amaurosis. Invest Ophthalmol Vis Sci. 2004 Aug;45(8):2747-52. [PubMed: 15277500]
75. Pichi F, Abboud EB, Ghazi NG, Khan AO. Fundus autofluorescence imaging in hereditary retinal diseases. Acta
Ophthalmol. 2018 Aug;96(5):e549-e561. [PubMed: 29098804]
76. Murakami T, Akimoto M, Ooto S, Suzuki T, Ikeda H, Kawagoe N, Takahashi M, Yoshimura N. Association
between abnormal autofluorescence and photoreceptor disorganization in retinitis pigmentosa. Am J Ophthalmol.
2008 Apr;145(4):687-94. [PubMed: 18242574]
77. Pepple KL, Cusick M, Jaffe GJ, Mruthyunjaya P. SD-OCT and autofluorescence characteristics of autoimmune
retinopathy. Br J Ophthalmol. 2013 Feb;97(2):139-44. [PubMed: 23221966]
78. Abazari A, Allam SS, Adamus G, Ghazi NG. Optical coherence tomography findings in autoimmune retinopathy.
Am J Ophthalmol. 2012 Apr;153(4):750-6, 756.e1. [PMC free article: PMC3495560] [PubMed: 22245461]
79. Sepah YJ, Sadiq MA, Hassan M, Hanout M, Soliman M, Agarwal A, Afridi R, Coupland SG, Nguyen QD.
Assessment of Retinal Structural and Functional Characteristics in Eyes with Autoimmune Retinopathy. Curr
Mol Med. 2015;15(6):578-86. [PubMed: 26238366]
80. Khanna S, Martins A, Oakey Z, Mititelu M. Non-paraneoplastic autoimmune retinopathy: multimodal testing
characteristics of 13 cases. J Ophthalmic Inflamm Infect. 2019 Feb 26;9(1):6. [PMC free article: PMC6391508]
[PubMed: 30806850]
81. Finn AP, Thomas AS, Stinnett SS, Keenan RT, Grewal DS, Jaffe GJ. The role of cystoid macular edema as a
marker in the progression of non-paraneoplastic autoimmune retinopathy. Graefes Arch Clin Exp Ophthalmol.
2018 Oct;256(10):1867-1873. [PubMed: 30128606]
82. Igarashi N, Sawamura H, Kaburaki T, Aihara M. Cancer-associated Retinopathy Developing After 10 Years of
Complete Breast Cancer Remission. Neuroophthalmology. 2019 Feb;43(1):36-42. [PMC free article:
PMC6351012] [PubMed: 30723523]
83. Neena R, Jain A, Anantharaman G, Antony MA. Carcinoma -associated Retinopathy(CAR): Role of
Electroretinography(ERG) and Optical coherence Tomography(OCT) in diagnosis and predicting treatment
outcome. Am J Ophthalmol Case Rep. 2021 Mar;21:101008. [PMC free article: PMC7816002] [PubMed:
33511304]
84. Holopigian K, Hood DC. Electrophysiology. Ophthalmol Clin North Am. 2003 Jun;16(2):237-51. [PubMed:
12809161]
85. Wachtmeister L. Oscillatory potentials in the retina: what do they reveal. Prog Retin Eye Res. 1998
Oct;17(4):485-521. [PubMed: 9777648]
86. Link B, Schlötzer-Schrehardt U, Jünemann A. Carcinoma-associated retinopathy-an electrophysiological and
immunohistochemical correlation. Retina. 2009 Jan;29(1):69-72. [PubMed: 18728619]
87. Goetgebuer G, Kestelyn-Stevens AM, De Laey JJ, Kestelyn P, Leroy BP. Cancer-associated retinopathy (CAR)
with electronegative ERG: a case report. Doc Ophthalmol. 2008 Jan;116(1):49-55. [PubMed: 17721792]
88. Mohamed Q, Harper CA. Acute optical coherence tomographic findings in cancer-associated retinopathy. Arch
Ophthalmol. 2007 Aug;125(8):1132-3. [PubMed: 17698766]
89. Kornguth SE, Klein R, Appen R, Choate J. Occurrence of anti-retinal ganglion cell antibodies in patients with
small cell carcinoma of the lung. Cancer. 1982 Oct 01;50(7):1289-93. [PubMed: 6286090]
90. Forooghian F, Cao S, Cui J, Matsubara JA. The enigma of autoimmune retinopathy. Int Ophthalmol Clin. 2015
Spring;55(2):81-91. [PMC free article: PMC4942272] [PubMed: 25730621]
91. Murphy MA, Thirkill CE, Hart WM. Paraneoplastic retinopathy: a novel autoantibody reaction associated with
small-cell lung carcinoma. J Neuroophthalmol. 1997 Jun;17(2):77-83. [PubMed: 9176775]
92. Huynh N, Shildkrot Y, Lobo AM, Sobrin L. Intravitreal triamcinolone for cancer-associated retinopathy
refractory to systemic therapy. J Ophthalmic Inflamm Infect. 2012 Sep;2(3):169-71. [PMC free article:
PMC3438305] [PubMed: 22415770]
93. Javaid Z, Rehan SM, Al-Bermani A, Payne G. Unilateral cancer-associated retinopathy: a case report. Scott Med
J. 2016 Aug;61(3):155-159. [PubMed: 26246524]
94. Ferreyra HA, Jayasundera T, Khan NW, He S, Lu Y, Heckenlively JR. Management of autoimmune retinopathies
with immunosuppression. Arch Ophthalmol. 2009 Apr;127(4):390-7. [PubMed: 19365013]
95. Jacobzone C, Cochard-Marianowski C, Kupfer I, Bettembourg S, Dordain Y, Misery L, Cochener B, Sassolas B.
Corticosteroid treatment for melanoma-associated retinopathy: effect on visual acuity and electrophysiologic
findings. Arch Dermatol. 2004 Oct;140(10):1258-61. [PubMed: 15492190]
96. Guy J, Aptsiauri N. Treatment of paraneoplastic visual loss with intravenous immunoglobulin: report of 3 cases.
Arch Ophthalmol. 1999 Apr;117(4):471-7. [PubMed: 10206574]
97. Mahdi N, Faia LJ, Goodwin J, Nussenblatt RB, Sen HN. A case of autoimmune retinopathy associated with
thyroid carcinoma. Ocul Immunol Inflamm. 2010 Aug;18(4):322-3. [PubMed: 20662664]
98. Davoudi S, Ebrahimiadib N, Yasa C, Sevgi DD, Roohipoor R, Papavasilieou E, Comander J, Sobrin L.
Outcomes in Autoimmune Retinopathy Patients Treated With Rituximab. Am J Ophthalmol. 2017 Aug;180:124-
132. [PubMed: 28483493]
99. Adamus G, Machnicki M, Elerding H, Sugden B, Blocker YS, Fox DA. Antibodies to recoverin induce apoptosis
of photoreceptor and bipolar cells in vivo. J Autoimmun. 1998 Oct;11(5):523-33. [PubMed: 9802939]
100. Adamus G, Webb S, Shiraga S, Duvoisin RM. Anti-recoverin antibodies induce an increase in intracellular
calcium, leading to apoptosis in retinal cells. J Autoimmun. 2006 Mar;26(2):146-53. [PubMed: 16426815]
101. Adamus G, Sugden B, Shiraga S, Timmers AM, Hauswirth WW. Anti-apoptotic effects of CNTF gene transfer
on photoreceptor degeneration in experimental antibody-induced retinopathy. J Autoimmun. 2003
Sep;21(2):121-9. [PubMed: 12935781]
102. Fishman GA. Retinitis pigmentosa. Visual loss. Arch Ophthalmol. 1978 Jul;96(7):1185-8. [PubMed: 307377]
103. Fishman GA, Farber MD, Derlacki DJ. X-linked retinitis pigmentosa. Profile of clinical findings. Arch
Ophthalmol. 1988 Mar;106(3):369-75. [PubMed: 3257866]
104. Heckenlively JR, Aptsiauri N, Nusinowitz S, Peng C, Hargrave PA. Investigations of antiretinal antibodies in
pigmentary retinopathy and other retinal degenerations. Trans Am Ophthalmol Soc. 1996;94:179-200;
discussion 200-6. [PMC free article: PMC1312095] [PubMed: 8981696]
105. Takeuchi M, Usui Y, Okunuki Y, Zhang L, Ma J, Yamakawa N, Hattori T, Kezuka T, Sakai J, Goto H. Immune
responses to interphotoreceptor retinoid-binding protein and S-antigen in Behcet's patients with uveitis. Invest
Ophthalmol Vis Sci. 2010 Jun;51(6):3067-75. [PubMed: 20089879]
106. Naik A, Ratra D, Banerjee A, Dalan D, Jandyal S, Rao G, Sen P, Bhende M, Jayaprakash V, Susvar P, Walinjkar
J, Rao C. Enhanced S-cone syndrome: Clinical spectrum in Indian population. Indian J Ophthalmol. 2019
Apr;67(4):523-529. [PMC free article: PMC6446635] [PubMed: 30900587]
107. Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006 Nov 18;368(9549):1795-809. [PubMed:
17113430]
108. Heckenlively JR, Fawzi AA, Oversier J, Jordan BL, Aptsiauri N. Autoimmune retinopathy: patients with
antirecoverin immunoreactivity and panretinal degeneration. Arch Ophthalmol. 2000 Nov;118(11):1525-33.
[PubMed: 11074809]
109. Nieuwendijk TJ, Hooymans JM. Paraneoplastic vitelliform retinopathy associated with metastatic choroidal
melanoma. Eye (Lond). 2007 Nov;21(11):1436-7. [PubMed: 17693995]
110. Fujiwara T, Imamura Y, Giovinazzo VJ, Spaide RF. Fundus autofluorescence and optical coherence
tomographic findings in acute zonal occult outer retinopathy. Retina. 2010 Sep;30(8):1206-16. [PubMed:
20661173]
111. Yeh S, Forooghian F, Wong WT, Faia LJ, Cukras C, Lew JC, Wroblewski K, Weichel ED, Meyerle CB, Sen
HN, Chew EY, Nussenblatt RB. Fundus autofluorescence imaging of the white dot syndromes. Arch
Ophthalmol. 2010 Jan;128(1):46-56. [PMC free article: PMC3025103] [PubMed: 20065216]
112. Hamel CP. Cone rod dystrophies. Orphanet J Rare Dis. 2007 Feb 01;2:7. [PMC free article: PMC1808442]
[PubMed: 17270046]
113. Iijima H, Yamaguchi S, Kogure S, Hosaka O, Shibutani T. Electroretinogram in cone dystrophy. Jpn J
Ophthalmol. 1991;35(4):453-66. [PubMed: 1821435]
114. Sharma P, Sharma R. Toxic optic neuropathy. Indian J Ophthalmol. 2011 Mar-Apr;59(2):137-41. [PMC free
article: PMC3116542] [PubMed: 21350283]
115. Margolin E, Blair K, Shemesh A. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): May 16,
2023. Toxic and Nutritional Optic Neuropathy. [PubMed: 29763154]
116. Sajjadi H, Poorsalman H. Previously Diagnosed Leber's Hereditary Optic Neuropathy with Clinical Signs of
Idiopathic Intracranial Hypertension Responsive to Acetazolamide Therapy. J Ophthalmic Vis Res. 2019 Jan-
Mar;14(1):109-113. [PMC free article: PMC6388523] [PubMed: 30820297]
117. Mauri E, Dilena R, Boccazzi A, Ronchi D, Piga D, Triulzi F, Gagliardi D, Brusa R, Faravelli I, Bresolin N,
Magri F, Corti S, Comi GP. Subclinical Leber's hereditary optic neuropathy with pediatric acute spinal cord
onset: more than meets the eye. BMC Neurol. 2018 Dec 27;18(1):220. [PMC free article: PMC6307307]
[PubMed: 30591017]
118. Glover JM, Casmaer ML, April MD. An uncommon cause of vision loss: Leber hereditary optic neuropathy.
JAAPA. 2018 Nov;31(11):32-34. [PubMed: 30358677]
119. Savini G, Barboni P, Valentino ML, Montagna P, Cortelli P, De Negri AM, Sadun F, Bianchi S, Longanesi L,
Zanini M, Carelli V. Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers
with Leber's hereditary optic neuropathy mutations. Ophthalmology. 2005 Jan;112(1):127-31. [PubMed:
15629832]
120. Quiros PA, Torres RJ, Salomao S, Berezovsky A, Carelli V, Sherman J, Sadun F, De Negri A, Belfort R, Sadun
AA. Colour vision defects in asymptomatic carriers of the Leber's hereditary optic neuropathy (LHON) mtDNA
11778 mutation from a large Brazilian LHON pedigree: a case-control study. Br J Ophthalmol. 2006
Feb;90(2):150-3. [PMC free article: PMC1860163] [PubMed: 16424523]
121. Sadun AA, Salomao SR, Berezovsky A, Sadun F, Denegri AM, Quiros PA, Chicani F, Ventura D, Barboni P,
Sherman J, Sutter E, Belfort R, Carelli V. Subclinical carriers and conversions in Leber hereditary optic
neuropathy: a prospective psychophysical study. Trans Am Ophthalmol Soc. 2006;104:51-61. [PMC free
article: PMC1809912] [PubMed: 17471325]
122. Yu-Wai-Man P, Griffiths PG, Hudson G, Chinnery PF. Inherited mitochondrial optic neuropathies. J Med
Genet. 2009 Mar;46(3):145-58. [PMC free article: PMC2643051] [PubMed: 19001017]
123. Riordan-Eva P, Harding AE. Leber's hereditary optic neuropathy: the clinical relevance of different
mitochondrial DNA mutations. J Med Genet. 1995 Feb;32(2):81-7. [PMC free article: PMC1050224] [PubMed:
7760326]
124. Machemer R. [On the pathogenesis of the flat malignant melanoma]. Klin Monbl Augenheilkd.
1966;148(5):641-52. [PubMed: 5996537]
125. Barr CC, Zimmerman LE, Curtin VT, Font RL. Bilateral diffuse melanocytic uveal tumors associated with
systemic malignant neoplasms. A recently recognized syndrome. Arch Ophthalmol. 1982 Feb;100(2):249-55.
[PubMed: 7065942]
126. van Noort BC, Keunen JEE, Schlingemann RO, Marinkovic M. Long Survival and Preservation of Good Visual
Acuity in a Patient with Bilateral Diffuse Uveal Melanocytic Proliferation. Ocul Oncol Pathol. 2019
Jan;5(1):75-78. [PMC free article: PMC6341327] [PubMed: 30675481]
127. Klemp K, Kiilgaard JF, Heegaard S, Nørgaard T, Andersen MK, Prause JU. Bilateral diffuse uveal melanocytic
proliferation: Case report and literature review. Acta Ophthalmol. 2017 Aug;95(5):439-445. [PubMed:
28636126]
128. Gass JD, Gieser RG, Wilkinson CP, Beahm DE, Pautler SE. Bilateral diffuse uveal melanocytic proliferation in
patients with occult carcinoma. Arch Ophthalmol. 1990 Apr;108(4):527-33. [PubMed: 2322154]
129. Rahimy E, Soheilian M. Giraffe Pattern of Bilateral Diffuse Uveal Melanocytic Proliferation. Ophthalmology.
2016 Mar;123(3):483. [PubMed: 26902560]
130. Chahud F, Young RH, Remulla JF, Khadem JJ, Dryja TP. Bilateral diffuse uveal melanocytic proliferation
associated with extraocular cancers: review of a process particularly associated with gynecologic cancers. Am J
Surg Pathol. 2001 Feb;25(2):212-8. [PubMed: 11176070]
131.
Liu B, Deng T, Zhang J. RISK FACTORS FOR CENTRAL SEROUS CHORIORETINOPATHY: A Systematic
Review and Meta-Analysis. Retina. 2016 Jan;36(1):9-19. [PubMed: 26710181]
132. Gäckle HC, Lang GE, Freissler KA, Lang GK. [Central serous chorioretinopathy. Clinical, fluorescein
angiography and demographic aspects]. Ophthalmologe. 1998 Aug;95(8):529-33. [PubMed: 9782727]
133. Tittl MK, Spaide RF, Wong D, Pilotto E, Yannuzzi LA, Fisher YL, Freund B, Guyer DR, Slakter JS, Sorenson
JA. Systemic findings associated with central serous chorioretinopathy. Am J Ophthalmol. 1999 Jul;128(1):63-
8. [PubMed: 10482095]
134. Yalcinbayir O, Gelisken O, Akova-Budak B, Ozkaya G, Gorkem Cevik S, Yucel AA. Correlation of spectral
domain optical coherence tomography findings and visual acuity in central serous chorioretinopathy. Retina.
2014 Apr;34(4):705-12. [PubMed: 24100708]
135. Gupta A, Tripathy K. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Aug 25, 2023. Central
Serous Chorioretinopathy. [PubMed: 32644399]
136. Xu Q, Du W, Zhou H, Zhang X, Liu H, Song H, Wang X, Wei S. Distinct clinical characteristics of
paraneoplastic optic neuropathy. Br J Ophthalmol. 2019 Jun;103(6):797-801. [PubMed: 30021813]
137. Malik S, Furlan AJ, Sweeney PJ, Kosmorsky GS, Wong M. Optic neuropathy: a rare paraneoplastic syndrome.
J Clin Neuroophthalmol. 1992 Sep;12(3):137-41. [PubMed: 1328306]
138. Paul R, Ghosh AK, Sinha A, Bhattacharya R. Paraneoplastic optic neuritis as the first manifestation of
periampullary carcinoma. Int J Appl Basic Med Res. 2015 Jan-Apr;5(1):73-5. [PMC free article: PMC4318110]
[PubMed: 25664276]
139. Rosencher L, Maisonobe T, Lavole A, Milleron B, Ferroir JP. [Neurologic paraneoplastic syndrome with anti-
CV2/CRMP5 antibodies revealing a small cell lung cancer. Effectiveness of the lung cancer treatment]. Rev
Neurol (Paris). 2012 Apr;168(4):371-4. [PubMed: 22387203]
140. Langer JE, Lopes MB, Fountain NB, Pranzatelli MR, Thiele EA, Rust RS, Goodkin HP. An unusual
presentation of anti-Hu-associated paraneoplastic limbic encephalitis. Dev Med Child Neurol. 2012
Sep;54(9):863-6. [PubMed: 22320677]
141. Damek DM. Paraneoplastic Retinopathy/Optic Neuropathy. Curr Treat Options Neurol. 2005 Jan;7(1):57-67.
[PubMed: 15610708]
142. Wiseman EM, Bar-El Dadon S, Reifen R. The vicious cycle of vitamin a deficiency: A review. Crit Rev Food
Sci Nutr. 2017 Nov 22;57(17):3703-3714. [PubMed: 27128154]
143. D'Ambrosio DN, Clugston RD, Blaner WS. Vitamin A metabolism: an update. Nutrients. 2011 Jan;3(1):63-103.
[PMC free article: PMC3042718] [PubMed: 21350678]
144. Pfeiffer CM, Sternberg MR, Schleicher RL, Haynes BM, Rybak ME, Pirkle JL. The CDC's Second National
Report on Biochemical Indicators of Diet and Nutrition in the U.S. Population is a valuable tool for researchers
and policy makers. J Nutr. 2013 Jun;143(6):938S-47S. [PMC free article: PMC4822995] [PubMed: 23596164]
145. Hodge C, Taylor C. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jan 2, 2023. Vitamin A
Deficiency. [PubMed: 33620821]
146. Miller M, Humphrey J, Johnson E, Marinda E, Brookmeyer R, Katz J. Why do children become vitamin A
deficient? J Nutr. 2002 Sep;132(9 Suppl):2867S-2880S. [PubMed: 12221263]
147. McBain VA, Egan CA, Pieris SJ, Supramaniam G, Webster AR, Bird AC, Holder GE. Functional observations
in vitamin A deficiency: diagnosis and time course of recovery. Eye (Lond). 2007 Mar;21(3):367-76. [PubMed:
16341129]
148. Aleman TS, Garrity ST, Brucker AJ. Retinal structure in vitamin A deficiency as explored with multimodal
imaging. Doc Ophthalmol. 2013 Dec;127(3):239-43. [PubMed: 23900584]
149. Gilbert C. The eye signs of vitamin A deficiency. Community Eye Health. 2013;26(84):66-7. [PMC free article:
PMC3936686] [PubMed: 24782581]
150. Goldstein SM, Syed NA, Milam AH, Maguire AM, Lawton TJ, Nichols CW. Cancer-associated retinopathy.
Arch Ophthalmol. 1999 Dec;117(12):1641-5. [PubMed: 10604671]
Disclosure: Dheerendra Singh declares no relevant financial relationships with ineligible companies.
Disclosure: Koushik Tripathy declares no relevant financial relationships with ineligible companies.
Figures
Multicolor fundus images of the right and the left eye shows retinal pigmentary changes seen during early phase
of Cancer-Associated Retinopathy. Optical Coherence Tomography (OCT) of the both the eyes shows absence of
the ellipsoid zone (EZ) outside the fovea with thinning of the photoreceptor layer.
Contributed by Koushik Tripathy, MD
Copyright © 2023, StatPearls Publishing LLC.

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

Dheerendra Singh1; Koushik Tripathy2.

Last Update: February 22, 2023.

Continuing Education Activity

Outline the etiology of cancer-associated retinopathy.

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Non-small-cell lung carcinoma[1]

Uterine cervical cancer[16]

Basal cell carcinoma[17]

Mixed Müllerian tumor

Squamous cell carcinoma

Vision loss in enolase-associated retinopathy is less severe as compared to recoverin-associated

Anti-Carbonic anhydrase II (30 kDa)[51]

Anti-GAPDH (glyceraldehyde 3-phosphate dehydrogenase)

Interphotoreceptor retinoid-binding protein (145 kDa)[52]

Tubby-like protein 1 [TULP1][53]

Heat shock cognate protein HSC 70

GCAP 1 and 2 (guanylyl cyclase-activating proteins)

PNR photoreceptor cell-specific nuclear receptor

History and Physical

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