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Enter the name of the assigned editor for this page. Enter the name of the reviewer for this page. "Parul.Ichhpujani"67.142.130.44A.Nicole.SomaniA.Paula.GrigorianALBERTO CALVO ÁLVAREZAMIR ABDULAMEER.MADHLOOMANAIS.CARNICIUANKITA AISHWARYAASHRAF.ELBATARNYAa hfzAakriti.GargAalsuhaibaniAaron.Lindeke-MyersAaron.M.Miller.EICAashish.PantAbanoob TadrosseAbdala.SirajeldinAbdulaziz.Anazi.AlshamraniAbdulla.EllaithyAbdullah. GalalAbdullah.GalalAbdulrahman.Faisal.AlBloushiAbhishek.PaulAbhishek.sheemarAbigail.GordonAbraham.SarabiaAbubakar.dogoAcef AssaudAcef.AssaudAcp1961Acs97388AdaAda.Carol.Apaza.AvilaAdam.AltmanAdam.C.WeberAdam.G.ChunAdam.HartAdam.SweeneyAdam.mclaughlinAdeela M. 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Walsman M.DScott.M.WalsmanScoville.NicholasSean.F.Pieramici.cmtSean.M.RodriguezSean.PaulSeanrodriguez0Sebastian.HeersinkSebastian.SiebelmannSeda.L.UzunSeema.afzalSejal.JhawerSenthil.RathinaveluSepide.JamaliSergio CanabravaSergio.fantaguzziSeshubabu.GosalaSeth.BricelSeth.FoxSevugapandian.SankaranarayananSevugapandiansankaranarayananSeyed-FarzadSeyyed.Hamed.Hosseinikhah-ManshadiSezen.KarakusShaan.SomaniShadi.A.HrafshehShadi.HrafshehShailesh.PokharelShaminah suffeeShaminah.SuffeeShane J Havens MDShane.Brent.GollerShane.GollerShane.HavensShane.MarsiliShannath.MerbsShannon.Ali.PhilanderShanti.BoesoirieSharah.RahmanSharmini.A.BalakrishnanSharon.F.FreedmanSharon.Fekrat.CMTShauna.BerryShaunak.PatelShawn.GulatiShawn.SellSheel.PatelShehzad.BatliwalaShelly.MishraShikha.SinghShikha211985Shipra.GuptaShira.L.Robbins.CMTShivam.AminShivani.SethiShraddha.SurekaShreya.PrabhuShruthi.harishShruti.AggarwalShruti.ChandraShu.FengShubham.UpadhyayShubhra.GoelShyam VyasShyam.PatelShyam.VyasSibel.AksoySibi.RajendranSiddhartha.RajanSilvestro.CaputoSilvia.MuñozSilviabrogelliSima.sheikhghomiSimanta.KhadkaSimone.V.SantosSina.RezaeiSina.VahediSkamjooSmiksha.fouzdarjainSmita.vittalSneha.KondaSneha.KumariSneha.jainSnehal.Rajendra.GanatraSoham.DaveSohani AmarasekeraSohani.AmarasekeraSomya.kumariSonal.YadavSonia.costaSonya.B.ShahSophie.LiaoSophie.LinSoumyadeep.majumdarSoungmin.choSpageSpencer.HarrisSpieramiciSreelakshmip.amarSrilathaa.GunasekaranSrivindhya.KolluruSrujana.nalaboluStacy.V.SmithStacy.l.pineles.cmtStanley.R.ShorbStephan.ChiuStephanie.CramerStephanie.SaadehJacksonStephanie.kimStephen.CohenStephen.G.WallerStephen.J.WinklerStephen.KaufmanStephen.W.ChiStephen.lauSteve.AdebusoyeSteven.G.StockslagerSteven.R.CohenSteven.ShieldsSteymoorStuart SeiffStuti.SharmaSubahari.RaviskanthanSubhan.tabbaSudarshan Mysore JaykumarSudha.NallasamySudhir.SinghSugi.panneerselvamSujata Prabhu MDSujata.S.ChahandeSukhanya.SubramaniamSultan AldreesSumalee.BoonyaleephanSumayya.ahmadSumet.SupalasetSun Young LeeSun.Y.LeeSunir.J.GargSunita.RadhakrishnanSunny.Bharat.PatelSurabhi.MadadiSurbhi.BansalSurya.Prakash.PandeySusan.K.Burden.CMTSusan.M.WakilSusan.sunSusanMacDonaldSusanMacDonald.CMTSusana.P.HenriquesSusanapintohenriquesSushant.adigaSushmita.KaushikSuzie.GasparianSvkmanSwathi.KalikiSwati. AgarwalSydney.WendtSyed.Amal.HussnainSyed.AzharuddinSyed.Gibran.KhurshidTaciana.GuerraTaehong81Tahira.MathenTahreem.A.MirTahsin.Z.KhundkarTal.RubinsteinTala.Al-KhaledTalau.AncaTalisa.deCarloTamara.LenisTamer.Fathi.SalemTanner.fergusonTanveer AhmedTanveer.AhmedTanya.TrinhTao.Ming.Thomas.ChiaTara.M.GoecksTara.McCannelTaravelmTarek.ShoalaTarib.ImaneTariq.Abdulaziz.Ibrahim.Al-ZahemTariq.AnsariTariq.BhattiTatsuhiko SatoTatyana.BeketovaTavish.NandaTavish.nandaTaylor.DrakeTayyaba.MalikTching.QA.AAOTebogo.B.MalekaTedi.BegajTejasviTeresa.MartzTerry BiaggiTerry.BiaggiTest AccountTgonderThad.KlimpelThakker1Thandra.S.ShreyaThao.Phuong.LeThellea.levequeTheodor.C.SauerTheodorapetratosTheodore.LengTheodore.PasqualiThiago.barrosThomas A. Ciulla MDThomas Ciulla MDThomas.CiullaThomas.H.MatskoThomas.HwangThomas.KidwellThomas.MooreThomas.SmithThomas.meirickTiago.L.FerreiraTiago.MoraisSarmentoTianyu.LiuTiffany.YuenTigran.KostanyanTim.I.KimTimConradTimothy.BoyceTimothy.D.McGarityTjebo.HeerenTjeboheerenTmharveyTobin.ThumaTodd.A.GoodglickTodd.MondzelewskiTom.EkeTomas.LoureiroTony.Ching.AAOTony.t.chenTova.GoldsteinTova.MannisTracy.C.CrnicTracy.LaiTravis.MitchellTravis.PeckTrevor.Alan.SmithTrinh LongTrinh.LongTrizoltriTszlunernest.wongTthumaTtytaiTu.tranTuan.TranTuan.tranTuantranmdTudymol.DevasiaTulika.ChauhanTurki.Bin.DakhilTurkiBinDakhilTuvanluatTyler.HudishTyler.OlsonTyler.ScullenTyler.ZeoliTânia.P.Almeida.RochaUbaid.YasinUma.VaidyanathanUmar.AkbarUmmer.FarooqUnnati shuklaUserBotUsha.R.KumarUtkarsh.mishraUyanga.BayarsaikhanVaibhav.sharmaValerie.AbiolaValliVamsi.KolluruVan.NguyenVance.ThompsonVandana.ReddyVannessa.LeungVashali.JainVasudeva.PalimaruVasueyeVatinee.BunyaVbioussVchen1Vedant.SathyeVeena.MedikondaVeena.T.MathewVeeral.shahVenita.Juliet.NoronhaVenkata.S.AvadhanamVenkatkrish.KasettyVerlyn.YangVeronica RodriguezVerónica.OsunaVictor.A.ChenVictor.D.LiouVictor.M.GomezVictor.NeamtuVictoria.ChangVidhi.solankiVijaya.PaiVikas Singh MDVikash.BadaseeVikram.D.Durairaj.CMTViktor WildnerVinay.A.Shah.SECVinay.a.shah.secVinciguerra.riccardoVinita. 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{{Infobox disease | Name = {{PAGENAME}} | DiseasesDB = 2064 | ICD9 = | ICD10 = | OMIM = | MeshID = D010257 | MedlinePlus = }} = Disease Entity = Paraneoplastic syndrome (PNS) is defined as signs and symptoms observed from cancer but not directly as a cause of the cancer tissue or its associated sites of metastasis.<ref name="rahimy1">Rahimy E, Sarraf D. Paraneoplastic and non-paraneoplastic retinopathy and optic neuropathy: Evaluation and management. Survey of Ophthalmology 2013;58:430-458.</ref> Thus, the manifestations of PNS are a result of sites distant from the cancer origin. == Etiology == PNS result from immune mechanisms of the body directed against tumor related antigens but presumably cross react with normal antigens in other parts of the body. The host produces antibodies against the cancer antigen, resulting in an autoimmunization and then autoantibodies against normal host tissue.<ref name="adamus2">Adamus G. Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy. Autoimmunity Reviews 2009;8(5):410-414.</ref><ref name="albert3">Albert ML, Darnell RB. Paraneoplastic neurological degenerations: Keys to tumor immunity. Nature 2004;4(1)36-44.</ref> The exact response varies on the malignancy and carries some autoantibody specificity. For example, in cancer-associated retinopathy (CAR), it has been reported that antibodies against recoverin, a retinal protein that binds calcium, may lead to vision deterioration observed in CAR.<ref name="alabduljalil4">Alabduljalil T, Behbehani, R. Paraneoplastic syndromes in neuro-ophthalmology. Current Opinions in Ophthalmology 2007;18:463-469.</ref><ref name="adamus5">Adamus, G Ren, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy. BMC Ophthalmology 2004;4:5.</ref> There are many different types of conditions that can lead to PNS with ophthalmic symptoms including, but not limited to, CAR, optic neuropathy (ON), bilateral diffuse uveal melanocytic proliferation (BDUMP), Lambert-Eaton myasthenic syndrome (LEMS) and melanoma-associated retinopathy (MAR).<ref name="alabduljalil4"/> == Risk Factors == The risk factors for developing PNS are related to the underlying malignancy from which the syndrome originates. The most common cancers associated with PNS are small cell lung cancer, (SCLC) non-small cell lung cancer, melanoma, and cancers of the breast, uterine, and thyroid.<ref name="alabduljalil4"/> == Pathophysiology == In CAR patients, antibodies produced against recoverin and other retinal antigens may lead to degradation of retinal photoreceptor cells.<ref name="adamus2"/> Autoantibodies against alpha-enolase, a protein implicated in skin, cervical, ovarian, and breast cancers, can result in death of retinal ganglion and bipolar cells, mediated by apoptosis.<ref name="adamus2"/> Another PNS is paraneoplastic optic neuropathy (PON), in which patients have autoantibodies against collapsin-responsive mediator protein-5 (CRMP-5) or other optic nerve antigens. CRMP-5 realted PON typically produces optic disc edema and optic atrophy. <ref name="rahimy1"/><ref name="ko6">Ko MW, Dalmau J, Galetta SL. Neuro-ophthalmic manifestations of paraneoplastic syndromes. J Neuro-Ophthal 2008;28:58-68.</ref> Other important PNS antibodies include anti-Hu, anti-Yo, anti-Ma2, anti-NMDA, anti-Ri, anti-GAD, and voltage-gated calcium channel antibody (VGCCA). Anti-Hu PNS involves the brainstem, cerebellum, and temporal lobes and are typically found in patients with SCLC, although a small percentage of people show no evidence of cancer anywhere in the body. <ref name="graus7">Graus F, Keime-Guibert F, René R et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001;124:1138-1148.</ref> Reported ophthalmic manifestations of anti-Hu PNS include tonicpupils, and ophthalmoplegia. <ref name="bruno8">Bruno MK, Winterkorn JMS, Edgar MA et al. Unilateral Adie pupil as sole ophthalmic sign of anti-Hu paraneoplastic syndrome. J Neuro-Ophthal 2000;20(4):248-249.</ref><ref name="gordon9">Gordon WC, Leach MTJ. Lung carcinoma with anti-Hu paraneoplastic syndrome. N Engl J Med 2006; 355(4).</ref><ref name="chan10">Chan JW. Subacute complete ophthalmoplegia: an anti-Hu paraneoplastic manifestation of myxoid liposarcoma. Clinical and Experimental Ophthalmology 2007;35:491-498.</ref> Anti-Yo mainly affects the cerebellum and has been involved with opsoclonus-myoclonus syndrome (OMS).<ref name="rojas11">Rojas I, Graus F, Keime-Guibert F, Reñé et al. Long-term clinical outcome of paraneoplastic cerebellar degeneration and anti-Yo antibodies. Neurology 2000;15(5):713-715.</ref><ref name="fanous12">Fanous I, Dillon P. Paraneoplastic neurological complications of breast cancer. Experimental Hematology & Oncology 2016;5(29).</ref> Additionally, thymoma-related PNS can present as myasthenia gravis-like illness.<ref name="suh13">Suh JW, Haam SJ, Song SW et al. Paraneoplastic encephalitis associated with thymoma: a case report. Korean J Thorac Cardiovasc Surg. 2013;46(3):234-236. </ref> Acetylcholine receptor (AChR) and striational antibodies are associated with thymomas and myasthenia gravis (MG).<ref name="hammoud14">Hammoud K, Kandimala G, Warnack W, Vernino S. Multifocal paraneoplastic cortical encephalitis associated with myasthenia gravis and thymoma. Arch Neurol. 2009;66(11):1407-9.</ref> {| class="wikitable" !colspan="4"|Table 1: Paraneoplastic syndrome antibodies, ophthalmic findings, and associated cancers. (PCD = paraneoplastic cerebellar degeneration, CRMP = collapsin-response mediator protein, GAD = glutamic acid decarboxylase, SPS = stiff person syndrome, ARRON = autoimmune-related retinopathy and optic neuropathy, NMDA = N-methyl D-aspartate, HSVE = herpes simplex viral encephalitis, VGCCA = voltage-gated calcium channel antibody, PCA = Purkinje-cell antibody) |- | <nowiki> </nowiki>'''Antibody''' | <nowiki> </nowiki>'''Ophthalmic Findings''' | <nowiki> </nowiki>'''Associated cancers''' | <nowiki> </nowiki>'''Associated disorders''' |- | <nowiki> </nowiki>Alpha-enolase | <nowiki> </nowiki>Decreased acuity <nowiki> </nowiki>Central cone dysfunction <nowiki> </nowiki>Optic nerve pallor | <nowiki> </nowiki>Skin <nowiki> </nowiki>Cervical <nowiki> </nowiki>Ovarian <nowiki> </nowiki>Breast | <nowiki> </nowiki>CAR |- | <nowiki> </nowiki>Anti-AChR/striational | <nowiki> </nowiki>Diplopia <nowiki> </nowiki>Ptosis | <nowiki> </nowiki>Thymoma | <nowiki> </nowiki>MG |- | <nowiki> </nowiki>Anti-CRMP5 | <nowiki> </nowiki>Optic disc edema <nowiki> </nowiki>Optic atrophy | <nowiki> </nowiki>SCLC <nowiki> </nowiki>Thymoma | <nowiki> </nowiki>PON |- | <nowiki> </nowiki>Anti-GAD | <nowiki> </nowiki>Ptosis <nowiki> </nowiki>Ophthalmoplegia | <nowiki> </nowiki>Breast <nowiki> </nowiki>SCLC | <nowiki> </nowiki>SPS <nowiki> </nowiki>Cerebellar ataxia <nowiki> </nowiki>ARRON |- | <nowiki> </nowiki>Anti-Hu | <nowiki> </nowiki>Tonic pupil <nowiki> </nowiki>Ophthalmoplegia | <nowiki> </nowiki>SCLC | <nowiki> </nowiki>Encephalomyelitis <nowiki> </nowiki>LEMS |- | <nowiki> </nowiki>Anti-Ma2 | <nowiki> </nowiki>Vertical gaze paresis <nowiki> </nowiki>Ophthalmoplegia | <nowiki> </nowiki>Testicular | <nowiki> </nowiki>Encephalitis |- | <nowiki> </nowiki>Anti-NMDA | <nowiki> </nowiki>Mild visual dysfunction <nowiki> </nowiki>Decreased acuity | <nowiki> </nowiki>Ovarian teratoma <nowiki> </nowiki>SCLC <nowiki> </nowiki>Testicular | <nowiki> </nowiki>HSVE <nowiki> </nowiki>ON |- | <nowiki> </nowiki>Anti-PCA-2 | <nowiki> </nowiki>Optic disc edema <nowiki> </nowiki>Large vitreous cells | <nowiki> </nowiki>SCLC | <nowiki> </nowiki>ON |- | <nowiki> </nowiki>Anti-recoverin | <nowiki> </nowiki>Progressive vision loss OU | <nowiki> </nowiki>SCLC | <nowiki> </nowiki>CAR |- | <nowiki> </nowiki>Anti-Ri | <nowiki> </nowiki>Eye movement disorders <nowiki> </nowiki>Ptosis | <nowiki> </nowiki>Breast <nowiki> </nowiki>SCLC | <nowiki> </nowiki>OMS <nowiki> </nowiki>Ataxia |- | <nowiki> </nowiki>Anti-Yo | <nowiki> </nowiki>Nystagmus <nowiki> </nowiki>Ptosis <nowiki> </nowiki>Oscillopsia | <nowiki> </nowiki>Ovarian <nowiki> </nowiki>Breast | <nowiki> </nowiki>OMS <nowiki> </nowiki>PCD |- | <nowiki> </nowiki>VGCCA | <nowiki> </nowiki>Mild dry eye <nowiki> </nowiki>Ocular motor abnormalities | <nowiki> </nowiki>SCLC <nowiki> </nowiki>Non-SCLC | <nowiki> </nowiki>LEMS <nowiki> </nowiki>Cerebellar degeneration |} {| class="wikitable" !colspan="3"|Table 2. Paraneoplastic visual syndromes and their associated antibodies and ophthalmic manifestations. |- | <nowiki> </nowiki>'''Condition''' | <nowiki> </nowiki>'''Associated Antibody''' | <nowiki> </nowiki>'''Ophthalmic Findings''' |- | <nowiki> </nowiki>ARRON | <nowiki> </nowiki>Anti-GAD <nowiki> </nowiki>Anti-CRMP5 | <nowiki> </nowiki>Asymmetric vision loss <nowiki> </nowiki>Optic disc pallor |- | <nowiki> </nowiki>BDUMP | <nowiki> </nowiki>Unknown | <nowiki> </nowiki>Rapid vision loss <nowiki> </nowiki>Patchy red fundus <nowiki> </nowiki>Retinal detachment |- | <nowiki> </nowiki>CAR | <nowiki> </nowiki>Anti-recoverin <nowiki> </nowiki>Anti-alpha enolase <nowiki> </nowiki>Anti-transducin <nowiki> </nowiki>Anti-carbonic anhydrase | <nowiki> </nowiki>Severe loss of vision <nowiki> </nowiki>Photosensitivity <nowiki> </nowiki>Ring scotoma <nowiki> </nowiki>Visual field defects |- | <nowiki> </nowiki>MAR | <nowiki> </nowiki>Anti-transducin b <nowiki> </nowiki>Anti-rhodopsin <nowiki> </nowiki>Anti-arrestin | <nowiki> </nowiki>Night blindness <nowiki> </nowiki>Photopsia <nowiki> </nowiki>Loss of peripheral vision |} = Diagnosis = Ophthalmic manifestations of PNS may present before or after the systemic cancer is detected. <ref name="pelosof15">Pelosof LC, Gerber DE. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2011;86(4):364.</ref> Prompt recognition of the PNS can lead to earlier diagnosis and treatment of the underlying cancer. The diagnosis of the specific syndrome depends on the clinical presentation, the ophthalmologic findings and finally the identification of the offending antibodies. In CAR, the ocular symptoms are observed before a diagnosis of cancer about 50% of the time. <ref name="rahimy1"/> Although there is a strong correlation between certain cancers and specific autoantibodies, the presence of a certain antibody in patient serum does not guarantee a specific underlying malignancy. <ref name="adamus5"/> == Physical examination == The results of a fundoscopic, again, depend on the type of malignancy that is causing the paraneoplastic syndrome<ref name="ko6"/>. Patients may have: * Visual field defects * Optic disc pallor * Retinal arterial attenuations * Vision loss * Decreased visual acuity * Photopsia * Retinal detachment, retinal pigmentation and cataracts (BDUMP) == Signs and Symptoms== Painless progressive vision loss and positive visual phenomena are frequent complaints among patients with CAR, MAR, or PON. <ref name="adamus5"/> <ref name="alabduljalil4"/><ref name="rahimy1"/> The vision loss is typically bilateral but may be asymmetric. Specifically, patients note decreased nighttime vision and worsened color detection.<ref name="pelosof15"/> Photopsias may also be observed along with photosensitivity.<ref name="alabduljalil4"/><ref name="pelosof15"/> Scotomas and peripheral vision loss are less frequent symptoms. == Clinical diagnosis == The clinical exam suggestive of CAR, MAR, or PON should prompt further evaluation for retinal and optic nerve autoantibodies (e.g., immunohistochemical assays and/or Western blot) and electroretinography (ERG). Once the antibodies are confirmed, referral to an oncologist is recommended to search for the underlying malignancy. <ref name="adamus5"/> == Possible diagnostic procedures == * ERG * Immunohistochemical assays for retinal autoantibodies * Western blot * CT/MRI/PET (tumor detection) * Visual fields * Fundus fluorescein angiogram and fundus photography * Cerebrospinal fluid (CSF) analysis == Differential diagnosis == If paraneoplastic syndromes develop prior to diagnosis of cancer, there is a possibility that the ophthalmic symptoms are not the result of any underlying malignancy. The specificity of antibodies for certain neoplasms is not necessarily high. In fact, some studies have shown that people with antibodies for a certain antigen may have a non-cancer-related explanation for their visual symptoms. <ref name="whitcup17">Whitcup SM, Vistica BP, Milam AH, Nussenblatt RB, Gery I. Recoverin-associated retinopathy: a clinically and immunologically distinctive disease. Am J Ophthalmol. 1998;126(2):230-237.</ref><ref name="heckenlively18">Heckenlively JR, Fawzi AA, Oversier J, Jordan BL, Aptsiauri N. Autoimmune retinopathy patients with antirecoverin immunoreactivity and panretinal degeneration. Arch Ophthalmol. 2000;118(11):1525–1533.</ref> == Management and General treatment == Clinicians generally focus on treating the underlying malignancy, the tumor, in order to treat the PNS. <ref name="darnell19">Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med 2003;349:1543-54.</ref> Immunosuppression is often employed using corticosteroids in attempts to attenuate the immune response in PNS. <ref name="damek20">Damek DM. Paraneoplastic retinopathy/optic neuropathy. Curr Treat Options Neurol. 2005;7(1):57-67.</ref> Intravenous immunoglobulin (IVIG) has shown mixed effects in improving visual symptoms in CAR, MAR, ON, and OMS. <ref name="adamus2"/><ref name="chan16">Chan JW. Paraneoplastic retinopathies and optic neuropathies. Survey of Ophthalmology 2003;48(1):12-38.</ref> <ref name="subhadra21">Subhadra C, Dudek AZ, Rath PP, Lee MS. Improvement in visual fields in a patient with melanoma-associated retinopathy treated with intravenous immunoglobulin. J Neuroophthalmol. 2008;28(1):23-26.</ref> Successful treatments resulting in improvement of symptoms are either anecdotal or found in mice; no controlled human studies have shown improvement of visual symptoms by any means of treatment. <ref name="pelosof15"/><ref name="subhadra21"/> == Surgery == Ocular surgery is not indicated for PNS. Surgeries may be conducted for tumor excision, which may treat the underlying malignancy. Recently, there has been evidence that in thymoma-associated paraneoplastic syndrome, thymectomy actually improves patients’ symptoms. <ref name="suh13"/> == Prognosis == There is evidence suggesting that having a tumor with accompanying PNS may lead to a better prognosis than having a tumor and no accompanying PNS perhaps related to earlier detection of tumor. <ref name="darnell19"/> Overall, visual prognosis remains poor and unpredictable even through a wide variety of treatments. = References = <references /> Please note that all contributions to EyeWiki may be edited, altered, or removed by other contributors. If you do not want your writing to be edited mercilessly, then do not submit it. You are also promising us that you wrote this yourself, or copied it from a public domain or similar free resource (see EyeWiki:Copyrights for details). Do not submit copyrighted work without permission!
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