Ординатура / Офтальмология / Английские материалы / The Retina and its Disorders_Besharse, Bok_2011

Glossary

Allied disorders – Retinitis pigmentosa (RP) is often grouped with a class of more stable, inherited retinal disorders collectively referred to as RP and allied disorders. Some of these allied disorders cause similar clinic findings as RP, e.g., nyctalopia (night blindness), but usually do not show progression and deterioration with time. An example is congenital stationary night blindness (CSNB), which can present with nyctalopia and decreased rod and cone function on the electroretinogram (ERG). Unlike RP, most patients with CSNB have stable visual function. X-linked CSNB is caused by mutations in nyctalopin (NYX) and L-type voltage dependent calcium channel (CACNA1F). Although the majority of mutations of rhodopsin causes typical RP, rare mutations, such as G90D in rhodopsin, produce night blindness with such mild progression late in life that they have been called stationary night blindness. Another allied disorder is achromatopsia, which is caused by mutations in cyclic nucleotide-gated channel subunits (CNGA2, CNGB3) or guanine nucleotide alpha-binding protein 2 (GNAT2). Achromatopsia is associated with severely decreased central and color vision, photophobia, and nystagmus. These symptoms are similar to those that can be seen with some cone–rod dystrophies. Indeed, later in life some modest foveal atrophy can occur and cases of progressive cone–rod dystrophy have been associated with mutations of some of the achromatopsia genes. However, unlike cone–rod dystrophies, which invariably progress, achromatopsia is, in the vast majority of cases, stationary.

Cone dystrophy – Cone photoreceptors are affected and rod photoreceptors are minimally affected or spared in cone dystrophy. Many cases of early cone dystrophies with time will develop significant rod abnormalities.

Cone–rod dystrophy – Cone-rod dystrophy, as a group, involves both photoreceptors with cones affected more than rods. Certain forms of RP present with greater cone than rod involvement on ERG and these patients have been termed to have cone–rod RP. However, in cone–rod dystrophies as a group the primary defect lies in cones and secondaryrod loss

occurs with time. Most investigators consider primary cone–rod dystrophy separate from RP.

Extrinsic factor – An agent external to the organism that contributes to or is causative of a disease state. This can include drugs, foods, normal nutrients (excess or deficiency), toxins, inhaled chemicals, infectious agents, and exposures to radiation such as light, sound, and high-energy particles.

Intrinsic factor – An agent that is inherent to the organism that contributes to or is causative of a disease state.

Mixed intrinsic and extrinsic etiology for a secondary photoreceptor degeneration – This occurs when a person has a genetic variant that creates a toxic metabolite in the presence of an extrinsic molecule that would normally not be encountered.

Mixed model of primary and secondary photoreceptor degeneration – This is considered when a genetic alteration within the photoreceptors is insufficient to cause photoreceptor degeneration by itself, but predisposes to degeneration in the presence of an extrinsic or intrinsic agent. A second mode of combined primary and secondary photoreceptor degeneration is when one group of photoreceptors, such as the rod photoreceptors, undergoes a primary degenerative process that is due to a mutation in a gene that is expressed in those photoreceptors and precipitates apoptosis, which leads to a secondary degenerative process, in this example cones, due to alterations in the cellular environment induced by death of neighboring cells.

Primary retinal degeneration – This occurs when cells in the retina, usually photoreceptors, die secondary to a process that originates within the retina itself. An example of a primary retinal degeneration is RP, which is caused by mutations in genes that encode proteins important for retinal function. A disease can be classified as a primary retinal degeneration if the genetic defect is such that correction of expression of the normal gene product in the photoreceptors is required to correct the abnormality and arrest the degeneration.

Primary retinal degeneration with secondary photoreceptor degeneration – This occurs when photoreceptor degeneration is the result of mutation(s) of a gene that exists in other retinal cells, for example,

retinal pigment epithelial (RPE) cells. Correction of the genetic defect would require modification of the effects of those other retinal cells (e.g, RPE cells).

Retinal atrophy – A broad term encompassing not only processes that occur with retinal degenerations, but also abnormal retinal tissue or cellular loss due to developmental defects and malnutrition.

Retinal degeneration – A process whereby cells in the retina undergo cell death by apoptosis. Most retinal degenerations affect both rod and cone photoreceptors, but some disorders reflect damage that occurs principally in other cell types, e.g., the RPE in Stargardt’s disease and other ABCA4-related retinopathies. Secondary degeneration of the RPE is also common. Transsynaptic degeneration of higher-order cells, bipolar and ganglion cells, can also occur. The general term retinal degeneration should be distinguished from the more specific term, photoreceptor degeneration.

Retinal dystrophy – A broad term that not only encompasses retinal degenerations, but also includes abnormal retinal function due to developmental defects and malnutrition.

Retinitis pigmentosa (RP) – A heterogeneous group of diseases that result in degeneration of the rod and cone photoreceptors and secondarily the RPE. This degeneration usually leads to a loss of night vision due to the early degeneration of rods, constricted visual fields, decreased responses on ERG, and ultimately a decrease in visual acuity once macular cones begin to degenerate. Typical fundus findings include midperipheral atrophy of the pigment epithelium, bone spicule pigments, retinal vessel attenuation, and waxy pallor of the optic nerve. The term RP usually refers to only rod-cone dystrophies; however, cone-rod dystrophies and cone dystrophies are sometimes grouped under this term. Rod–cone dystrophy – A retinal dystrophy in which the rod photoreceptors are affected more than the cones. Most forms of RP manifest as rod–cone dystrophies.

Secondary photoreceptor degeneration of the extrinsic type – A secondary photoreceptor degeneration of the extrinsic type exists if, despite the underlying molecular defect, one could avoid the photoreceptor degeneration by preventing an individual’s exposure to an extrinsic agent or condition (e.g., toxin, drug, infectious agent, light, and trauma).

Secondary photoreceptor degeneration of the intrinsic type – If one can prevent photoreceptor degeneration by correcting or reversing a systemic or

ocular metabolic or immune process, then it is a secondary photoreceptor degeneration of the intrinsic type.

Background

Retinitis pigmentosa (RP) is caused by a large number of genetic defects that result in a characteristic pattern of degeneration of the rod and cone photoreceptors and the retinal pigment epithelium (RPE). This degeneration usually leads to a loss of night vision due to the early degeneration of rods, constricted visual fields, decreased responses on electroretinogram (ERG), and ultimately a decrease in visual acuity once macular cones begin to degenerate. The typical fundus exam in RP reveals midperipheral atrophy of the pigment epithelium, bone spicule pigmentation, retinal vessel attenuation, and waxy pallor of the optic nerve (Figure 1).

RP was first named by the Dutch ophthalmologist, Frans Cornelius Donders, in the mid-nineteenth century, although earlier clinical descriptions of the disease exist. The term retinitis pigmentosa is somewhat of a misnomer because inflammation is not thought to be the primary pathological mechanism. Rather, mutations in over 100 genes have been shown to cause RP and its allied disorders, and there still remain a significant number of genes yet to be identified. To keep track of the ever-growing list of genes implicated in this disease, a comprehensive online database, Retnet, has been established by Dr. Stephen Daiger.

One of the most fascinating aspects of RP is that mutations in genes that encode functionally distinct

Figure 1 Classic fundus appearance in retinitis pigmentosa demonstrating bone spicule pigmentation, vascular atrophy, retinal pigment epithelium atrophy, and waxy pallor of the optic nerve. From Weleber, R. and Evan, K. G. (2006). Retinitis pigmentosa and allied disorders. In: Ryan, S. J. (ed.) The Retina, 4th edn., vol. 1, chap. 17, pp. 395–498. Philadelphia, PA: Elsevier.

proteins result in a common degenerative pathway. Some of the many examples include genes involved in the structural integrity of the photoreceptors and cilia, the retinoid cycle, the phototransduction cascade, the extracellular matrix, cellular metabolism, intracellular trafficking, and RNA processing.

Prevalence

The worldwide prevalence for all forms of RP has been reported to be approximately 1:4000. While most studies have focused on the prevalence in European/Caucasian populations, the occurrence of RP has been reported throughout the world.

Inheritance

All forms of Mendelian inheritance have been reported but autosomal dominant, recessive, and X-linked traits are most frequently seen. Rarely RP is inherited as a digenic disorder or through the maternal line as a mitochondrial disease.

Autosomal Recessive

RP patients with a family history of similarly affected relatives are called multiplex, whereas those with no family history are classified as simplex. Simplex individuals are usually assumed to represent autosomal recessive inheritance, although some of these cases may be de novo dominant mutations or unrecognized X-linked inheritance. When simplex cases are included, autosomal recessive cases of RP have been reported to account for approximately 50–60% of all cases, with the exact percentage varying from country to country. Some of the most commonly affected genes are usherin (USH2A), a gene that is involved in both Usher syndrome and autosomal recessive RP, and the phosphodiesterase beta subunit (PDE6B), a gene involved in phototransduction.

X-Linked RP

X-linked RP results from mutations of genes on the X chromosome and represents approximately 5–15% of patients with RP. To date, six genes that cause retinal degeneration have been linked to the X chromosome. Two genes, retinitis pigmentosa GTPase regulator (RPGR) and retinitis pigmentosa 2 (RP2), are known, and several genes remain to be identified.

Males with X-linked RP typically have more severe retinal degeneration compared to autosomal recessive and dominant forms of the disease. The actual rate of degeneration is likely similar to the other forms, but the age of onset appears to be earlier.

Female carriers are thought to have a mosaic retina in which some of the cells express the normal allele, while others express the mutant allele. The fundus findings in female carriers of X-linked RP can vary from very subtle changes, such as mottling of the RPE, to more severe disease with some patients showing the classic bone spicule pigmentation. Even in the cases of female carriers with a normal appearing fundus, changes are usually apparent on the ERG.

Autosomal Dominant

Patients with autosomal dominant RP often have a family history of the disease, although there are cases of incomplete penetrance and de novo mutations. Autosomal dominant mutations account for approximately 30–40% of patients with RP. In general, patients with autosomal dominant RP tend to be less affected than patients with X-linked or autosomal recessive RP. Some of the most commonly mutated genes include rhodopsin (RHO) and retinitis pigmentosa 1 (RP1).

Nonsyndromic versus Syndromic Retinal Degeneration

Most cases of RP are nonsyndromic and the pathology is limited to the eye. However, RP can also be associated with dysfunctions in other organ systems, with many of these cases comprising defined syndromes.

The most common syndromic association with RP is Usher syndrome, which is an autosomal recessive disorder and is divided into three subtypes based on clinical findings. Patients with type I Usher syndrome present with severe, but nonprogressive congenital hearing loss, balance problems, and RP. In type II Usher syndrome, patients have less severe hearing loss, RP, and normal balance. Patients with type III Usher syndrome, start with symptoms similar to type II but later progress to type I. The retinal findings in Usher syndrome are indistinguishable from those characteristic of nonsyndromic autosomal recessive RP. Eleven genes have been found to cause Usher syndrome. Considering the presumed shared evolutionary ancestry of photoreceptors and cochlear hair cells, it is likely that some of these genes share similar functions.

Bardet–Biedl syndrome (BBS) is an autosomal recessive disorder in which RP is a universal finding. Other commonly associated features include postaxial polydactyly, truncal obesity, abnormalities of cognition, and renal disease. Mutations in 12 genes have been implicated in BBS. Many of these genes encode proteins that are important for the formation or function of the cilia (Figure 2).

Some other syndromes that can present with RP include: abetalipoproteinemia (Bassen–ornzweig disease), Alstro¨m

syndrome, chronic progressive external ophthalmoplegia (CPEO), Friedreich’s ataxia, incontinentia pigmenti (Bloch–Schulzberg syndrome), Joubert syndrome, Kearns– Sayre syndrome, mucopolysaccharide disorders, neuronal ceroid lipofuscinoisis (Batten disease), Refsum disease (infantile and adult), Senior–Loken syndrome, and spinocerebellar ataxia type 7.

Classification of RP

One often confounding feature of RP is the many different ways in which the disease can be classified. RP can be classified by its mode of inheritance, age of onset, fundus appearance, pattern of functional vision loss, or by genetic mutation.

As mentioned previously, RP is often characterized by its pattern of inheritance. With the advent of genetic testing, patients are increasingly being tested and classified according to which genes are mutated (see Table 1 for the most common mutations and Table 2 for description of genes). The phenotype and course of the disease can show significant variation with different mutations in the same gene. Likewise, there can also exist significant phenotypic variations between two people who harbor the same mutation. Ultimately, classification by genetic

Table 1 Most common genes causing retinitis pigmentosa by inheritance

defects will likely prove to be the most useful way to segregate and treat patients with RP. However, many genes remain to be discovered and genetic testing is not yet universally available to test for all mutations in known genes. For these reasons, it is useful to examine the ways in which RP has been categorized in the past.

Classification by Age of Onset

Severe forms of RP that manifest before the first year of life are referred to as Leber congenital amaurosis (LCA). The forms of RP occurring between 1 and 5 years have been termed juvenile RP or severe early childhood-onset retinal dystrophy (SECORD). LCA is characterized by

severe vision loss, nystagmus, unrecordable ERGs, and poorly responsive pupils (amaurosis). Mutations in at least 16 genes have been found to cause LCA and most of these are inherited in an autosomal recessive fashion. Juvenile RP/SECORD is thought to be caused by less severe mutations in the same set of genes as LCA, and more mild mutations in some of these genes have been implicated in recessive RP (Figure 3).

Classification by Fundus Appearance

The classic fundus appearance in RP is described below (see the subsection titled ‘Fundus findings’). Deviations from this classic fundus appearance have given rise to

several alternative terms for pigmentary retinopathies including: inverse RP, concentric RP, sector RP, retinitis punctata albescens, fundus albipunctatus, RP with preserved peri-arteriolar RPE, pigmented perivenous retinochoroidal atrophy, and retinitis sine pigmento. Some of these terms are falling out of usage as genetic characterization of the disease is becoming more common.

There have been many cases of unilateral RP described and it has been proposed that this could be caused by a somatic mutation. However, there is yet to be a histologically confirmed case of RP caused by a somatic mutation. Most of these cases likely represent other diseases that can mimic RP and cause a pigmentary retinopathy.

Classification by Functional Loss

Historically, adult RP was categorized as either type I (rod dysfunction) or type II (rod and cone dysfunction) based on psychophysical testing. These classifications were further refined on the basis of electrophysiological findings to include the categories: rod–cone dystrophy, cone–rod dystrophy, or cone dystrophy. Most forms of RP are rod–cone dystrophies in which rod photoreceptor death occurs first and is later followed by subsequent cone photoreceptor death. This article will use the term RP to describe the most common form, namely rod–cone dystrophy. The forms of RP that cause cone and cone–rod dystrophy will be denoted accordingly.

Mechanism of Disease

RP and its allied disorders are caused by mutations in over 100 genes and likely the same number remains to be elucidated. Ultimately, these mutations lead to photoreceptor death by apoptosis. It is still not fully understood how mutations in genes, which code for an array of functionally different proteins, result in a common pathway to photoreceptor death.

Mutations can result in decreased expression of a given protein, cause loss of function of that protein, or imbue a gain of function. In autosomal recessive forms of RP, there is a loss of expression or function when both copies of a given gene are mutated. In contrast, autosomal dominant forms of RP are thought to be caused by gain-of-function mutations, where the mutated protein becomes toxic or interferes with the function of the remaining normal forms of that protein (dominant negative effect). In autosomal dominant RP, the most common mutations are found in RHO. These dominant mutations can lead to forms of RHO that do not inactivate properly or are not transported to the outer segment.

An example of one well-studied mutation that causes autosomal dominant RP is the P23H mutation in the RHO gene. This mutation results in misfolding of the protein such that it is sequestered in the endoplasmic reticulum and is never transported to the outer segment. The misfolded proteins accumulate creating aggregations that activate an unfolded protein response. Dysregulation of these responses may lead to photoreceptor death although the exact mechanism has yet to be determined.

Clinical Presentation

Symptoms

Most frequently, the earliest symptom of RP is night blindness that precedes visual-field change and, in some, retinal pathology. In children, parents may comment that

their child is afraid or becomes distressed in the dark. Older children often comment on poor vision compared with their fully sighted peers. In adults, difficulties with night driving are frequent. The second cardinal symptom of RP is progressive peripheral visual-field loss. Since central vision is spared early in the course of the disease, some patients do not notice this loss of visual field until the degeneration has become quite advanced.

Another common symptom of RP is problems with dark adaptation, such as difficulties adjusting to dim illumination when entering a movie theater. Additionally, as the disease progresses, patients can develop photophobia. Color vision is typically normal early in the disease but with progression, blue–yellow defects become apparent. Flashes of light, or photopsias, are experienced by most patients.

Patients with cone and cone–rod dystrophies can present with early photophobia, decreased central vision, and impaired color vision. These patients will typically have worse visual acuity than patients with rod–cone dystrophies due to earlier involvement of macular cones.

Refraction

Refractive errors in patients with RP have been studied and, on average, these patients are more myopic and have a greater degree of astigmatism than those in the general population. By contrast, patients with early-onset forms of RP, such as LCA or SECORD, tend to have hyperopic refractions.

Anterior Segment and Cataract

The external ocular exam and anterior segment are typically unremarkable in nonsyndromic forms of RP. However, there does appear to be a higher rate of keratoconus and glaucoma in patients with RP. Posterior subcapsular cataracts are common and often can become visually significant. Cataract extraction is beneficial in patients with RP if the cataract is thought to be the vision-limiting factor.

Fundus Findings

The characteristic signs on fundus examination include midperipheral atrophy of the pigment epithelium, intraretinal pigment accumulation (bone spicules; Figure 1), retinal vessel attenuation, and waxy pallor of the optic nerve. A yellowish ring of peripapillary atrophy is sometimes seen in patients with RP as well as with optic nerve head drusen. A minor number of vitreous cells are commonly observed in patients with RP. Cystoid macular edema is common in patients with RP and can often result in significantly decreased vision. Rarely, patients can develop a Coats-like retinopathy.

Diagnostic Tests for RP

Dark Adaptation

Dark adaptation can be a useful test in patients with RP. Patients who manifest with a rod–cone dystrophy will usually have a detectable increase in final dark-adapted thresholds and show delayed dark-adaptation curves. Prolonged dark adaptation is especially common among patients with RHO mutations. Elevations of the early cone segment of the dark-adaptation curve may be particularly noticed by patients, more so than elevations of the rod segment (Figure 4).

Visual Fields

Visual fields are not only useful for making the diagnosis of RP, but are also one of the most useful objective

Minutes

Figure 4 Example of dark-adaptation curves in a normal subject (dashed lines represent the mean normal response, dotted lines represent the upper limit of normal) and patients with retinitis pigmentosa (solid lines). From Weleber, R. and Evan, K. G. (2006). Retinitis pigmentosa and allied disorders. In: Ryan, S. J. (ed.) The Retina, 4th edn., vol. 1, chap. 17, pp. 395–498. Philadelphia, PA: Elsevier.

methods for monitoring progression of the disease. Decreased visual-field sensitivity results from photoreceptor loss (Figure 5).

The earliest change seen as measured by kinetic perimetry is concentric constriction or decreased sensitivity with static perimetry in diffuse disease and relative midperipheral scotomas seen in the in regional disease. As these midperipheral scotomas or regions of decreased sensitivity enlarge and deepen, severe tunnel vision results. Eventually, macular function fails and visual field becomes difficult or impossible to measure by conventional perimetry. Although visual function may be reduced to light perception only, it is rare for patients to become completely blind. With the exception of female carriers in X-linked RP, visual-field loss is usually symmetrical. Marked asymmetry should raise concern for diseases that mimic RP (Figure 6).

The rate of visual-field loss has been shown to be exponential. This rate is thought to be similar for the different forms of inheritance once correction has been made for the critical age of onset. Massof and Finkelstein found that patients lost about 50% of their visual field every 4.5 years. The superior visual field, which corresponds to the inferior retina, is often more affected than inferior visual fields. Based on this finding, it has been suggested that increased levels of light may play a role in accelerating retinal degeneration and this in turn may play a role in the forms of RP with greater damage in the inferior retina.

Electroretinograms

ERGs play a crucial role in the diagnosis of RP because these electrophysiological recordings are sensitive enough to detect decreased photoreceptor function early in the disease when fundus findings and visual fields may be minimally altered. In addition, ERGs are particularly

useful to assess visual function in preverbal infants and children. Almost all patients with symptomatic RP will have detectable changes on the ERG at the time of diagnosis. While the ERG is useful for the diagnosis of RP, visual fields are better for monitoring of the course of the disease. In severe cases of RP, such as LCA, the ERG may be not recordable.

Patients with RP can show decreased amplitude and timing of the major components of the ERG. Caution must be taken when interpreting decreases in the amplitude of an ERG because poor contact of the electrodes, deviations of the eye, and high myopia can affect the amplitude of the signal. When present, delayed timing tends to be a more robust indicator of dysfunction.

By analyzing the different components of the ERG, different forms of RP can be classified. Degeneration of the rod and cone photoreceptors leads to a decrease in the amplitude of different waveforms of the ERG and can also increase the timing or latency of the peaks of these waveforms. The most common forms of RP manifest as a rod–cone dystrophy and the first detectable changes will be apparent on the scotopic ERG. Decreases in the b-wave amplitude and timing of the peak of the b-wave are indicative of early rod photoreceptor death. Further loss of rod cells leads to further decreases in the b-wave amplitude and decreased amplitude of the a-wave responses at higher intensities. Patients with a cone–rod dystrophy have normal, or lesser defect of b-wave responses to dim scotopic stimuli, but typically have more markedly abnormal ERGs to 30-Hz flicker or single-flash stimuli measured under photopic conditions (Figures 7–9).

Fundus Photography/Fluorescein Angiography

Documentation by fundus photography can assist in monitoring changes in patients with RP. Fluorescein angiography in patients with RP will demonstrate hyperfluorescence in areas of RPE atrophy and can highlight areas of cystoid macular edema. However, fluorescein angiography has largely been supplanted by optical coherence tomography (OCT) for detecting cystoid maculopathy. In addition, concerns about light exposure accelerating certain forms of RP in animal models have prompted many ophthalmologists to exercise caution in obtaining excessive photographs.

Optical Coherence Tomography

OCT provides a noninvasive cross-sectional image of the retina. It is very useful in patients with RP when there is a question of cystoid macular edema. The ability to detect cystoid macular edema by OCT often obviates the need to get a fluorescein angiogram.

Differential Diagnosis

It is important to realize that RP is not the only cause of a pigmentary retinopathy but many other diseases can mimic RP. Significant asymmetry or the onset of symptoms in an elderly patient should raise suspicion for one of the diseases that mimics RP.

Trauma to the eye can disrupt the retina and result in pigment migration of the RPE into the retina with the formation of bone spicules. By a similar mechanism,

Blue (rod response)

200 μV

40 ms

ophthalmic artery occlusions and old retinal detachments can present with a pigmentary retinopathy.

Additionally, infections caused by syphilis, toxoplasmosis, and herpes viruses can lead to a pigmentary retinopathy. Congenital rubella infection can often be misdiagnosed as RP or Usher syndrome because these patients present with deafness and a fine, speckled pigmentary retinopathy. The key to differentiating patients with rubella from those with RP is that patients with rubella retinopathy will have normal or near normal responses by ERG (Figure 10).

Diffuse unilateral neuroretinitis (DUSN) is caused by a chronic infection with a nematode. In the early stages, this disease can be distinguished due to the appearance of crops of yellowish, deep choroidal infiltrates, neuroretinitis, and sometimes, visualization of the worm itself. However, late in the disease, with the exception of being unilateral, the fundus appearance is identical to RP with the fundus showing bone spicules, vascular attenuation, and optic atrophy (Figure 11).

Inflammatory diseases that cause a posterior uveitis can cause chronic changes that mimic the pigmentary changes of RP. Some examples include sarcoidosis, birdshot choroidoretinopathy, serpiginous retinopathy, Behcet disease, and acute zonal occult outer retinopathy (AZOOR).

Certain drugs can cause pigmentary retinopathies and their usage must be excluded prior to making a diagnosis of RP. One example is thioridazine (Mellaril), an antipsychotic drug, which mimics RP by causing decreased night vision, RPE atrophy, and a pigmentary retinopathy. Hydroxychloroquine (Plaquenil) is used to treat systemic lupus erythematous and rheumatoid arthritis and when taken for extended period of time or at higher doses can lead to central vision loss. Other drugs that have been found to cause pigmentary retinopathies include chlorpromazine, chloroquine, and quinine.

Autoimmune retinopathy is an incompletely understood disease resulting from antibodies to retinal antigens and can present with many of the same features of RP, such as decreased vision, visual-field loss, and decreased ERGs. Unlike the other diseases that mimic RP, autoimmune retinopathy does not present with a pigmentary retinopathy and, in many cases, the fundus appearance can be normal or only show vascular attenuation. A subset of cases of autoimmune retinopathy is associated with carcinomas in other parts of the body. Two examples of this entity are cancer-associated retinopathy (CAR), which often arises from small cell carcinoma of the lung and melanoma-associated retinopathy (MAR). CAR patients may test positive for antibodies directed against retinal