Ocular Paraneoplastic Syndromes

Ocular-involving paraneoplastic syndromes present a wide variety of clinical symptoms. Understanding the background pathophysiological and immunopathological factors can help make a more refined differential diagnosis consistent with the signs and symptoms presented by patients. There are two main pathophysiology arms: (1) autoimmune pathomechanism, which is presented with cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), cancer-associated cone dysfunction (CACD), paraneoplastic vitelliform maculopathy (PVM), and paraneoplastic optic neuritis (PON), and (2) ectopic peptides, which is often caused by tumor-expressed growth factors (T-exGF) and presented with bilateral diffuse uveal melanocytic proliferation (BDUMP). Meticulous systematic analysis of patient symptoms is a critical diagnostic step, complemented by multimodal imaging, which includes fundus photography, optical coherent tomography, fundus autofluorescence, fundus fluorescein angiography, electrophysiological examination, and sometimes fundus indocyjanin green angiography if prescribed by the clinician. Assessment of the presence of circulating antibodies is required for diagnosis. Antiretinal autoantibodies are highly associated with visual paraneoplastic syndromes and may guide diagnosis by classifying clinical manifestations in addition to monitoring treatment.


Introduction
Sawyer et al. reported the first report of systemic cancer causing visual deterioration and retinal changes in 1976. This opened a new era of research into ocular paraneoplastic syndromes (OPNS). Surprisingly, strict diagnostic criteria remain to be developed. The reason is perhaps the various presentations of OPNS, such as paraneoplastic retinopathy, paraneoplastic optic neuropathy, and paraneoplastic tonic pupils. However, the majority of Paraneoplastic Syndrome (PNS) occur when immune-mediated cross-reactivity involving tumor antigens causes collateral damage to normal host tissues. Alternatively, there are PNS that appear to be caused by the ectopic production of hormones or growth factors that act at a great distance from their production site ( Figure 1) [1]. Understanding this main division contributes to a better understanding of OPNS pathophysiology.

Introduction
Sawyer et al. reported the first report of systemic cancer causing visual deterioration and retinal changes in 1976. This opened a new era of research into ocular paraneoplastic syndromes (OPNS). Surprisingly, strict diagnostic criteria remain to be developed. The reason is perhaps the various presentations of OPNS, such as paraneoplastic retinopathy, paraneoplastic optic neuropathy, and paraneoplastic tonic pupils. However, the majority of Paraneoplastic Syndrome (PNS) occur when immune-mediated cross-reactivity involving tumor antigens causes collateral damage to normal host tissues. Alternatively, there are PNS that appear to be caused by the ectopic production of hormones or growth factors that act at a great distance from their production site ( Figure 1) [1]. Understanding this main division contributes to a better understanding of OPNS pathophysiology. Autoimmune pathomechanism is presented with cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), cancer-associated cone dysfunction (CACD), paraneoplastic vitelliform maculopathy PVM), and paraneoplastic optic neuritis (PON). Ectopic peptides, caused by tumor-expressed growth factors (T-exGF), are presented with bilateral diffuse uveal melanocytic proliferation (BDUMP) and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome (POEMS).
The overall incidence of PNS is estimated at about 10% of neoplastic patients. Darnell et al., similar to De Salvo et al., estimated the incidence of OPNS and neurologic paraneoplastic syndromes to be even lower at 0.01% of cancer patients [2,3].
The aim of this paper is to summarize the clinical symptoms and signs associated with different OPNS. Our database search strategy is discussed in the attached file (Supplementary Materials). After removing duplicated studies, we selected 312 published reports for our analysis. We narrowed our review to publications in the past six years that address clinical evaluation and diagnosis.

Clinical Evaluation
Tables 1 and 2 provide a summary of clinical presentations that cover the main types of paraneoplastic retinopathies and neuropathies.
The overall incidence of PNS is estimated at about 10% of neoplastic patients. Darnell et al., similar to De Salvo et al., estimated the incidence of OPNS and neurologic paraneoplastic syndromes to be even lower at 0.01% of cancer patients [2,3].
The aim of this paper is to summarize the clinical symptoms and signs associated with different OPNS. Our database search strategy is discussed in the attached file (Supplementary Materials). After removing duplicated studies, we selected 312 published reports for our analysis. We narrowed our review to publications in the past six years that address clinical evaluation and diagnosis.

Clinical Evaluation
Tables 1 and 2 provide a summary of clinical presentations that cover the main types of paraneoplastic retinopathies and neuropathies.
Clinicians must take into account the fact that misdiagnosis potential is increased with other ophthalmological changes, such as age-related macular degeneration, pigment epithelium detachment, vitelliform maculopathy, retinitis pigmentosa, stationary night blindness, intraocular inflammation, glaucomatous optic nerve atrophy, or typical optic neuritis. Table 3 summarizes underlying neoplasm, circulating antibodies or growth factors, and target cells within the visual system.
Other clinical symptoms include fundus changes. Initially normal fundus can be registered with time periphlebitis and with mild vitritis. Later stages may reveal arteriolar narrowing, retinal pigment epithelial thinning or molting ("salt-and-pepper" appearance), cells in anterior chamber, sheathing of retinal arterioles, and pallor of the optic disc. In optical coherence tomography, loss of outer retinal structures, including ellipsoid and interdigitation zone, can be registered. Fundus autofluorescence (FAF) reveals hyperautofluorescence macular ring area with hypoautofluorescence of the zone outside the macular ring. Fundus fluorescein angiography (FFA) can be normal or may reveal periphlebitis. Central or ring scotomas should be detected in visual field examination. In electroretinography (ERG), rod-and cone-mediated responses are not recordable or significantly decreased, firstly affecting the a-wave and subsequently lining rapidly to a "flat ERG" [8,[11][12][13][14][15][16][17][18][19][20]. Figure 2 illustrates mechanisms that enable autoantibodies to access retinal targets.
Other clinical symptoms include fundus changes. Initially normal fundus can be registered with time periphlebitis and with mild vitritis. Later stages may reveal arteriolar narrowing, retinal pigment epithelial thinning or molting ("salt-and-pepper" appearance), cells in anterior chamber, sheathing of retinal arterioles, and pallor of the optic disc. In optical coherence tomography, loss of outer retinal structures, including ellipsoid and interdigitation zone, can be registered. Fundus autofluorescence (FAF) reveals hyperautofluorescence macular ring area with hypoautofluorescence of the zone outside the macular ring. Fundus fluorescein angiography (FFA) can be normal or may reveal periphlebitis. Central or ring scotomas should be detected in visual field examination. In electroretinography (ERG), rod-and cone-mediated responses are not recordable or significantly decreased, firstly affecting the a-wave and subsequently lining rapidly to a "flat ERG" [8,[11][12][13][14][15][16][17][18][19][20]. Figure 2 illustrates mechanisms that enable autoantibodies to access retinal targets. The recoverin regulates rhodopsin phosphorylation in a calcium-dependent manner. Mechanisms shown in Figure 2 inhibit normal recoverin function, activate calcium-sensitive endonucleases, degrade caspase substrate Procaspase-3 and Poly (ADP) ribose polymerase (PARP), and fragment DNA. These, in turn, induce apoptosis via the mitochondrial pathway involving the caspase enzymes [4,7,11,[21][22][23]. Research on classical complement pathway to evaluate the presence of factors C3 and C9 on photoreceptors and retinal pigment epithelium (RPE) surfaces has found that in normal and affected retinas, the C3 and C9 factors can be seen only in the endothelium of the choroidal blood vessels. Possibly, survival of RPE cells during classical complement pathway activation is due to expression of inhibitory proteins on their surface. Clearly, further research is needed [10].
Some studies have shown that tumor-secreted vascular endothelial growth factor (VEGF) as well as placental growth factor (PlGF) act by the retinal VEGF receptor 1 and induce loss of pericytes The recoverin regulates rhodopsin phosphorylation in a calcium-dependent manner. Mechanisms shown in Figure 2 inhibit normal recoverin function, activate calcium-sensitive endonucleases, degrade caspase substrate Procaspase-3 and Poly (ADP) ribose polymerase (PARP), and fragment DNA. These, in turn, induce apoptosis via the mitochondrial pathway involving the caspase enzymes [4,7,11,[21][22][23]. Research on classical complement pathway to evaluate the presence of factors C3 and C9 on photoreceptors and retinal pigment epithelium (RPE) surfaces has found that in normal and affected retinas, the C3 and C9 factors can be seen only in the endothelium of the choroidal blood vessels. Possibly, survival of RPE cells during classical complement pathway activation is due to expression of inhibitory proteins on their surface. Clearly, further research is needed [10].
Some studies have shown that tumor-secreted vascular endothelial growth factor (VEGF) as well as placental growth factor (PlGF) act by the retinal VEGF receptor 1 and induce loss of pericytes within the retinal vasculature (breaking the blood-retinal barrier) (shown in Figure 2). CAR-affected retinas show perivascular lymphocytic invasion, normally without or with minimal inflammation [24]. It can be hypothesized that exosome-associated form of CD95L (Fas ligand/FasL), released probably from the two components of the inner blood-retinal barrier (endothelium and retinal pigmented epithelium), may play a crucial role in regulating immune privilege in the eye [25,26]. After initial access due to the vasculitis process, retinal cell damage exacerbates as the RPE damage process spreads via choroidal vasculature (see also Figure 2) [11,27]. Moreover, several works have reported immunomodulatory action by RPE cells. An intriguing study indicated that small RPE-derived exosomes promoted an immunoregulatory phenotype in monocytes [25,28]. Additionally, human RPE cells are known to release from their apical side αB-crystallin in association with exosomes, which is a negative regulator of both innate and cellular immunity [29][30][31]. All of the functions of RPE described above are restricted during CAR, and this in turn may be key to the exacerbation of photoreceptor damage.
Taking into account the role of RPE in maintaining the eye as an immune-privileged site, the destruction of retinal pigment epithelium can be crucial for exacerbation of antigen-dependent cytotoxic tissue damage during CAR. Additionally, exosomes are responsible for cell surface removal of complementary immune regulators, including CD46, CD55, and CD59 from RPE. The trigger condition is oxidative stress, making RPE cells more vulnerable to complement attack [32]. Cells are able to protect themselves from excessive complement activation by, but not restricted to, cell membrane molecules, such as CD46, CD55, and CD59. CD46 and CD55 regulate the C3 and C5 convertases, and CD59 prevents the formation of C5b-9 complexes [25,32].
Another main autoantigen is alpha-enolase, which is involved in cellular energy production like many other glycolytic enzymes (such as aldolase, glyceraldehyde-3-phosphate dehydrogenase, and pyruvate kinase M2). In this process, the glucose is metabolized to pyruvate in a chain of enzymatic reactions, resulting in production of cellular adenosine triphosphate (ATP). Retina is a very energy-demanding tissue, and in this respect, blocking of the cellular ability to produce ATP by the autoantibodies could be a signal to cell death. The functioning intracellular ATP production pathway is crucial for cell survival [33]. Apart from the function in the glycolytic process, it has been suggested enolase has a role in initiation of a pathological process by modulating the pericellular and intravascular fibrinolytic system. During this process, the enolase is being transferred from the cytoplasm to the cell surface and here serves as a plasminogen receptor that enhances pericellular plasmin production for cell invasion and destruction. Interestingly, the epitopes responsible for plasminogen binding differs significantly from typical pathogenic epitope found in patients with CAR. This suggest that the last mechanism is of low significance in the pathogenesis of CAR [33].

Cancer-Associated Cone Dysfunction (CACD)
Cancer-associated cone dysfunction, a standalone cone dysfunction, is rarely reported. Clinical symptoms originate only from cone dysfunction without any symptoms or electrophysiological signs of rod system failure. Clinical presentation includes mild to moderate BCVA loss, sudden photosensitivity, and total or subtotal loss of color perception. Patients often report improved visual acuity while wearing sunglasses. The ERG shows only cone response suppression [16,34]. According to some researchers, this type of paraneoplastic retinopathy is a subtype of CAR that is caused mainly by antienolase antibodies. Therefore, CACD is presented with overlapping clinical symptoms with CAR as well as other paraneoplastic retinopathies where antienolase antibodies cause retinal tissue damage with or without optic nerve atrophy [1,35,36].
The fundus examination usually reveals yellow-orange vitelliform lesions that may be accompanied by serous retinal detachment ("pseudo-hypopion" appearance). In optical coherent tomography (OCT) scans, the vitelliform submacular deposits on the pigment epithelium elevate the neurosensory retina. In the fundus, fluorescein angiography lesion is presented with a blocking effect on the choroid. In the late phase, the contrast uptake by lesion is recorded [37,39]. The ERG is usually within normal limits, but some reports indicate aberrant nonspecific findings. On the other hand, the electrooculography (EOG) can indicate a pathological Arden ratio of 1.1, similar to what is elicited in Best disease [1,42].
The pathogenesis is not fully understood. Scarce reports discuss the presence of certain antiretinal and anti-RPE antibodies in peripheral blood samples. It is hypothesized that autoimmune-mediated retinal pigment epitheliopathy occurs, which is based on the presence of antiperoxiredoxin 3 (anti-PRDX3) antibodies. The PRDX3 protein is a mitochondrial peroxidase that is crucial in protection against cellular oxidative damage. Lack of this protection leads to the accumulation of unprocessed cellular debris and (probably) lipofuscin that macroscopically reveals itself as yellowish subretinal deposits [1].
Taking into account the clinical presentation and morphological characteristics, PVM and CACD may be categorized as a group of paraneoplastic retinopathies that affects central vision.

Melanoma-Associated Retinopathy
Melanoma-associated retinopathy (MAR) is a rare condition. In contrast to CAR, with MAR, the neoplasm is already known. MAR is characterized by bilateral presentation with the time-shift between the eyes ranging from weeks to months. Clinical presentations include sudden shimmering, flickering, difficulty with the night vision (nyctalopia), photopsia (pulsating, continuous, or intermittent, often with visual hallucinations), decrease of BCVA (less pronounced than in CAR), sensation of color desaturation or conversely increased contrast (hyperphotosensitivity), and bilateral peripheral vision loss [41,[43][44][45]. Progression occurs usually over a few weeks to months but, in rare cases, may be sudden. Usually, eye fundus examination is normal in the majority of cases. In the most advanced cases, signs similar to CAR may be observed, namely, disc pallor, attenuated vascular reflexes, zones of retinal pigment epithelial atrophy ("salt-and-paper"), and vitritis accompanied by vasculitis. OCT scans often present macular atrophy with thinning of the inner retina. Fundus fluorescence angiography is usually normal or, in cases of vasculitis, show vascular diffusion. Typical ERG readings are observed, such as disappearance or microvoltage of b-waves while a-waves remain normal in scotopic conditions. In addition, there may be significant dysfunction of bipolar cells with preservation of photoreceptor function. In some studies, a mild reduction of both a-wave and b-wave amplitudes for both scotopic and photopic waveform dependent systems dysfunction. In EOG, the retinal pigment epithelium dysfunction can be evaluated by a reduced Arden ratio [41,[43][44][45][46][47].
MAR is defined by three classical characteristics: (1) symptoms of night blindness (nyctalopia) with positive visual phenomena or visual field defects; (2) reduction in b-wave amplitude in ERG; and (3) presence of serum autoantibodies that are reactive with retinal bipolar cells [43].

Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP)
Bilateral diffuse uveal melanocytic proliferation is a very rare paraneoplastic syndrome characterized by benign proliferation of uveal tract melanocytes. The bilateral visual loss can be profound and rapidly progressive. Patients with BDUMP experience slow, painless, bilateral (in most cases asymmetric), progressive loss of vision over several months. BCVA can also deteriorate due to secondary causes, such as cataract, glaucoma, or iridocyclitis [48][49][50][51][52][53][54][55][56][57][58][59][60]. The proliferation of melanocytes results in subretinal infiltration and an exudative retinal detachment (an outer retinal damage). Fundus examination presents with multiple, bilateral round or oval red (dark) spots or patches at the level of pigment epithelium that can be usually found in the posterior pole. The examiner should perform detailed examination of the peripheral fundus and the peripheral arterial nonperfusion area. Nummular or dermal loss of retinal pigment epithelium in FFA and funduscopy can be found.
In the slit-lamp examination, the iris nodules, pigmented keratic precipitates, anterior chamber, and vitreous cells can be observed. In some cases, conjunctival melanocytic proliferation occurs. Hypo-or hyperautofluorescence characteristic "giraffe-like" pattern lesions can be seen during FAF examination. Similar multifocal hyperfluorescence may be revealed during fluorescein angiography in corresponding lesions. Additionally, exudative retinal detachment occurs in the later phases of FFA. Moreover, in OCT, a diffuse thickening of the uveal tract with multiple elevated pigment and nonpigment uveal melanocytic tumors can be recorded. Deep scans in OCT reveal possible atrophy of the choroidal vasculature, which has to be differentiated from age-related macular dystrophy. There are no specific ERG symptoms. The reduction of scotopic and photopic a-and b-wave amplitude can be observed [48][49][50][51][52][53][54][55][56][57][58]61,62].
Pathophysiologically, there are two main causes of this type of paraneoplastic changes: (1) production of melanocytic growth factors by tumor cells with subsequent release into the circulation and (2) antiretinal autoantibodies (suggested anti-α-hepatocyte growth factor (HGF)) in circulation. The impact of the antiretinal autoantibodies appears to be rare compared to that of growth factors. The known and previously isolated IgG antibody is named cultured melanocyte elongation and proliferation factor (CMEP). In addition, the HGF has been suggested [1,57,61,62]. The damage in the RPE layer results in outer blood-retina dysfunction due to RPE malfunctions, and antiretinal autoantigens can subsequently invade the subretinal space [48,57,61].

Ancillary Tests
The following antibodies should be included in the evaluation of OPNS: antirecoverin, antienolase, anti-GAPDH, and antitransducin. There are several well-known mechanisms of action of these autoantibodies.
Antienolase antibodies appear to act via similar mechanism as antirecoverin, but this conjecture needs further investigation [22,36]. The alpha-enolase is engaged in the process of glycolysis in retinal photoreceptors and some other cells within retinal tissue (e.g., Muller cells). The enolase is one of the most common autoantigens. Additionally, it has been reported in several systemic autoimmune, connective tissue and inflammatory disorders, such as Behcet disease, Hashimoto's encephalopathy, associated antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, primary sclerosing cholangitis, and inflammatory bowel disease [33]. Antienolase antibody appears to target the ganglion cells and inner retinal layers [1].
The tubby-like protein 1 (TULIP1) is characteristic of the rods and cones, participating in normal transport during phototransduction proteins. Anti-TULIP1 antibodies interrupt the phototransduction process, and this leads to accumulation of metabolic products [22].
GAPDH is involved in energy metabolism, cell signaling, and synaptic neurotransmission. Anti-GAPDH antibodies appear to contribute to cell damage due to inhibition of membrane fusion, vesicle transportation, or activation of transcription. The GAPDH also plays a role in the processes of apoptosis and oxidative stress, which are other possible mechanisms by which aberrant functions can lead to cell destruction [22,23]. Antitransducin antibody is focused on the outer and inner segments of photoreceptors as well as the cytoplasm of ganglion cells [1,77,78].
Multimodal imaging is critical to diagnosis [79] along with antiretinal antibody testing for diagnosis and treatment. However, the Ocular Immunology Laboratory in USA offers standard procedures for antibody testing and serves clinicians around a world to help them with diagnosis and to monitor treatment (https://www.ohsu.edu/casey-eye-institute/ocular-immunology-lab). The clinician should include fundus photography, OCT with choroid visualization, FFA, FAF, ERG, and multifocal ERG (mf ERG). However, there is no reliable research available on large scale studies for multimodal imaging. There is a great need to conduct a multicenter large data analysis that will include all additional modalities in clinical presentation, such as OCT, FFA, FAF, indocyanine green angiography, and others.
During the past few decades, a wide range of autoantibodies and molecular markers of OPNS have been proposed and evaluated (Table 3 presents a comprehensive list). Unfortunately, many of them have overlapping characteristic as described above, and the visual system appears to be normal in some cases [80]. The evaluation of molecular markers may aid in the diagnosis of an OPNS. However, this is not an absolute requirement since, certain autoantibodies, growth factors, and other molecules are produced in the absence of PNS.

Antiretinal Antibodies
There are auto-anti-retinal proteins associated with visual symptoms and structural disturbances of retina in paraneoplastic and nonparaneoplastic autoimmune retinopathies [20]. Interestingly, there are some similarities in the clinical presentation of retinopathy associated with specific autoantibodies.
In 2018, Adamus [20] indicated that there was a clinical phenotype for antirecoverin-associated retinopathy that is different from antienolase-associated changes. Differences include onset, ocular symmetry, and clinical presentation, as well as prognosis of the best corrected visual acuity and electrophysiological changes. In some cases, the autoantibodies are strongly associated with specific cancer and precedes its diagnosis. The clinical presentations also vary with respect to the number of cells affected. There is probably a critical number of cells that have to be destroyed before the symptoms are revealed; if the number of cells is below the threshold count, clinical evidence is obscured by the plasticity of retinal neuronal network or by the "filling-in" phenomenon of the whole visual system. Moreover, there are some similarities between hereditary retinitis and autoimmunological background, such as retinitis pigmentosa [22,24,35,77,81,82].
Retinal phenotypes based on the seropositivity comprise the following: Average age of onset is over 60 years, and patients are predominately female (female/male ratio = 2:1). This entry is highly symmetric, with acute (sudden) unexplained onset. Patient complaints are usually focused on photopsia, nyctalopia, and photophobia. Main presentation is severe central and peripheral vision loss, sometimes described as "ring scotoma". During the course of the disease, rapid rod and cone loss is seen, often with vision acuity reduced to light perception or to no light perception in some cases. The ffERG is useful since there is a severe decrease in response of rods and cones, in addition to abnormal multifocal ERG [7,20,22,83].
Antienolase antibodies are associated with a subacute or even chronic presentation that is often symmetric. There is a variable central and global visual field loss with gradual and variable rate of visual acuity loss. Usually, the best corrected visual acuity is no better than 20/300 after several years of onset. There is characteristic nonequal dysfunction in cone and rod responses in ERG. The cones are more damaged than the rods with mild to severe abnormal mfERG [22,36,63].
(C) Antitransducin This is characterized as sudden but slowly progressive, symmetric, mild, patchy to global visual field loss with visual acuity loss secondary to the visual field symptoms. In electroretinography, primary scotopic defect (rod function) is found, and in mfERG, both decreased amplitudes and delayed timing is seen [22,77,84].
(D) Anti-CAII This is usually a subacute, chronic, often symmetric presentation of paraneoplastic retinopathy with mild vitritis and mild to severe concentric constriction of visual field that occurs with color and visual acuity loss. In ERG, slight subnormal rod response can be found, but mfERG is of little use as it varies significantly from case to case [5,22,85].
(E) Anti-Rab6 The average age of onset is around 60 years, and patients are predominately female (female/male ratio = 2:1). Onset is sudden and often symmetric. Main patient complaints are photopsia and nyctalopia. Central and peripheral visual field loss can be found. In full-field ERG, the response of rods and cones are decreased, and severely abnormal mfERG can be found (which can progress over weeks to months) [7].
This is a type of paraneoplastic retinopathy that occurs in patients around 60 years of age with strong predominance of females over males (females/males = 3:1). Its characteristic can be described as subacute, slowly progressive, and mostly symmetric. Patient complaints are mostly focused on photopsia and nyctalopia with constriction of visual field, occurrence of central scotoma, or enlargement of blind spot. In ERG, generalized loss of response of rods and cones can be recorded [7].
The anti-GCAP1 retinopathy occurs equally in males and females. Its onset can be characterized as subacute, chronic, and symmetric. The main patient complaint is photophobia. In additional tests, maculopathy can be seen with loss of color vision and visual acuity. Progressive cone loss with gradual cone dysfunction is characteristic in ERG [7].
There are three possible causes of autoretinal antibody formation: (a) immunological response to the tumor; (b) immunological response to the microbiome of infection, including an asymptomatic infection that can trigger antibody formation in susceptible subjects due to conformational mimicry of antigens; and (c) autoimmunological response to the self-antigens that are first sequestrated and separated from the immune system and later released by the damaged retina [24,35,81].
The concept of the eye as an immune-privileged site is widely accepted, although its exact mechanisms is not completely understood. It is also known that the phenomenon is not absolute. Retina-specific T cells that are primed for effector function strongly resist conversion to suppressive T regulatory cells (before site-specific local antigen recognition). It is possible that T-effective cells can overcome the immunosuppressive ocular microenvironment to cause primary retinal tissue damage. Considering this scenario, antiretinal antibodies could be secondary causes of retinopathy. More research is needed to distinguish if cellular-rather than humoral-response is responsible for primary retinal tissue damage in paraneoplastic retinopathies [21,24,[86][87][88].

Tumor-Expressed Growth Factors
There are known mechanisms of action of different growth factors in paraneoplastic ocular syndrome development. The CMEP factor promotes RPE growth and melanocytic proliferation in the subretinal space. This, in turn, causes disruption of the outer blood-retinal barrier by RPE malfunction [1,48,61]. HGF, probably by prolonged high-level stimulation of this growth factor, combined with retinal autoantibodies may drive choroidal nevis growth and RPE damage [57]. VEGF and PlGF play roles in the reduction of endothelial cells in the retinal macrophages and lymphocytes to invade the retina. The described mechanism depends on damage to or destruction of tight junctions between endothelial cells that cause dysfunction of the inner blood-retina barrier [24].

Possible Role of Extracellular Vesicles (EVs) in the Development of Paraneoplastic Syndromes
Recently, the concept of the association between paraneoplastic syndromes and extracellular vesicles has emerged. The term EV encompasses exosomes, microvesicles, and apoptotic bodies [89]. EVs enable communication between cancer cells and other organs in the body [90]. For at least the past decade, exosomes have been considered as a factor that plays a potential role in the development of paraneoplastic syndromes [91], mostly in cancers other than those developing in the eye [91][92][93]. Usually, PNS occur when immune-mediated cross-reactivity activates tumor antigens, resulting in damage to normal host tissues. There are PNS that seem to be caused by the ectopic production of a hormone or a growth factor that acts at a great distance from the production site. The exact pathophysiologic mechanisms that contribute to breaking the eye immune privilege, enabling the occurrence of OPNS, have not been precisely described. Although not conclusive, it can be hypothesized that EVs participate in the onset and progression of OPNS. Funding: This research was funded by Russian Academic Excellence project "5-100" for Sechenov University, Moscow, Russia; GALLY International Research Institute, San Antonio, Texas, USA; and Human Photosynthesis Study Center, Aguascalientes, México.

Conflicts of Interest:
The authors declare no conflict of interest.