Comparing and analyzing the differences between SERMs retinochoroidopathy and Macular Telangiectasia Type 2: a new pathogenic hypothesis

Comparing and analyzing the differences between SERMs retinochoroidopathy and Macular Telangiectasia Type 2: a new pathogenic hypothesis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Comparing and analyzing the differences between SERMs retinochoroidopathy and Macular Telangiectasia Type 2: a new pathogenic hypothesis donghao yu, jianbin an This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3827512/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background：Because Tamoxifen Retinopathy and Macular Telangiectasia Type 2 (Mac Tel-2) have similar manifestations, many researchers are identifying and exploring the mechanisms of the two diseases. Here we report a patient with selective estrogen receptor modulators(SERMs)-induced retinochoroidopathy. And she has a history of tamoxifen and toremifene use , presenting the classic phenotype of TR. It is the first time, we use comprehensive examination to observe one patient. Case presentation: A 52-year-old woman presented gradual and progressive visual acuity decrease of both eyes about 1 year. She had received oral tamoxifen followed by toremifene for 57 months. Indocyanine green angiography(ICGA), optical coherence tomography angiography(OCTA), electrooculogram(EOG), revealed salient distinct from Mac Tel-2 phenotype in patient’s choroidal. The patient’s ocular vessels did not show any tendency to proliferate, so we serve the cessation of anti-estrogen drugs as her treatment. Conclusion: Combined with the positive results of increasing choroidal thickening, ICGA hypofluorescence, and decreased Arden ratio, SERMs-induced retinopathy is considered to be a type of retinochoroidopathy. Tamoxifen Toremifene selective estrogen receptor modulators(SERMs) choroidal thickness Pachychoroid spectrum disease Electrooculogram Optical coherence tomography angiography Subfoveal choroidal thickness Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Background Ocular toxicity of tamoxifen was first reported in the 1970s[1]. Tamoxifen retinopathy characterized by yellow crystals in funduscope, the intraretinal cavitations, pseudocystic foveal cavitations, disruptions of the ellipsoid zone in OCT and late paramacular leakage in FFA[2-4]. Most of these researches and reports were based on long history of tamoxifen use. According to the patient's endocrine condition, mammary surgeons often adjust tamoxifen to toremifen. And we found another case of same SEMRs used histories[5] with similar symptoms. Toremifene is a chlorinated analogue of tamoxifen. Tamoxifen and toremifen are first-generation selective estrogen receptor modulators（SERMs), which have similar efficacy and mechanism of actionactivity[6]. Also previous researches showed that there was no difference in ocular toxicity between the two drugs[7]. So we call this drug-induced retinochoroidopathy SERMs retinochoroidopathy(SR). Because the classical phenotype of SR is very similar to which of mac tel-2, many researchers have compared the two diseases together and tried to explore the mechanism behind this[5,8-11]. We report here a case of a patient with classic SR manifestations and provide additional findings that are very differentiating from MacTel-2. Case Presentation In 2023, a 52-year-old Chinese woman was referred to our outpatient clinic for evaluation and treatment of gradual and progressive visual acuity decrease of both eyes about 1 year. The patient received oral "Tamoxifen citrate tablet"10mg/ day for more than one year, and then replaced with "Toremifen citrate tablet" 60mg/ day for more than three years because of menopause, also, injecting "Leuprelin acetate microspheres for injection" 3.75mg/ month uninterrupted since she surgery for left breast cancer (T1N0M0) in January 2019. Those drugs had been used for 57 months until she went to our clinic. She had no significant personal or family medical history, except for breast cancer. Her best-corrected visual acuity (BCVA) was 20/70(0.3) OD and 20/50(0.4 )OS with light astigmatism. The cornea and lens were clear OU. Analysis of Multimodality Imaging Data: Color fundus photographs: The magnify fundus photographs showed bilateral classical diffuse tiny yellow crystals.(Figure 1) (Figure1) Blue-wavelength autofluorescence BFA show that the physiological hypofluorescence in the temporal macular area of both eyes is reduced.(Figure2) (Figure2) Fundus fluorescein angiography Both eyes show vascular leakage just within the macular region which temporal leakages were more serious than nasal. (Figure3) (Figure3) Indocyanine green angiography (ICGA)： The leaking area in FFA are matched with the parts in ICGA figure keeping hyporfluorescence in both eyes.(Figure 4) (Figure 4) optical coherence tomography angiography: In SS-Scan mode show Crystalline deposits, , the intraretinal cavitations, pseudocystic foveal cavitations(doshi) and disruptions of the ellipsoid zone. (Figure 5) (Figure 5) False color image of retinal thickness analysis: SVision's Van Gogh software automatically measures the thickness from the internal limiting membrane to the Bruch membrane and note abnormal areas with red and yellow. (Figure 6) Red and yellow areas means thinning retinal thickness (Figure 6) subfoveal choroidal thickness(SFCT) and The choroidal vascular index (CVI) Choroidal thickness were 482μm in right eye and 483μm in left eye ，both of which were significantly higher than the normal level. Submacular choroid thickness (SFCT) increased, and the central choroid was thickest in ETDRS mode. The choroidal vascular index (CVI) was increased in the ETDRS model in both eyes. CVI is the ratio of choroidal vessel volume to choroidal volume. This phenomenon is also consistent with other reports and studies.[13-16] Two of these cases were diagnose as Pachychoroid pigment epitheliopathy (PPE)[13,14] OCT Angiography: Using three-layer method to observe the retinal capillary plexus, we found a ball of bulging vessels at temporal parafoveal in right eye. Then we use a FFA figure align with the abnormal ICP by the superficial vessel and found that the abnormal area in ICP figure located in the obvious leaking in FFA figure. OCT at the corresponding location of the lesion showed thickening of the outer nuclear layer and thinning of the outer plexiform layer with hyperreflective. (Figure 7) (Figure 7) From left to right are the superficial capillary plexus (SCP) and the intermediate capillary plexus (ICP) and the deep capillary plexus (DCP) in right eye (Figure 8) The Red circle marking ICP figure was covered by a transparency FFA figure with the salient leakage(circled by orange line) and OCT image of a thickened outer nuclear layer corresponding to angiocele. The image of the left eye did not observe such a significant anomaly. But when we look at the retinal blood vessels in the same way through the abnormal areas on the FA, we can see that the blood vessel density in the lesion area was reduced.(Figure 9) (Figure 9) Electrophysiological examination: (full-field electroretinogra,ffERG): No obvious abnormalities were found, which indicated that the retinal function is basically normal. This also prove the result in other imaging examination that no peripheral retinal abnormalities were found. Electrooculogram, EOG :The Arden Ratio in both eyes was reduced heavily(Figure 10). We also found another case report examined patient by EOG have similar consequence[17]. Abnormal EOG usually indicates abnormal function of the choroid or RPE . (Figure 10) Microperimetry： The center of fixation deviated from the fovea, and visual sensitivity decreased in the macular region. The birth of paracentral fixation need a long period of time, which means this patient impaired central vision for a long time.(Figure 11) Discussion And Conclusion We discuss the positive test results in this case and propose hypotheses. ICGA imaging shows that the macular area is always hyporfluorescence, which may be due to the presence of fluid in the choroidal mesenchyme with fluorescence shielding effect(hemorrhagic effusion) in the hyporfluorescence zone , or the fluid flow rate in the hyporfluorescence zone is faster the surrounding zone so that the oozing ICG cannot accumulate. Also, choriocapillaris flling patterns were determined by the network of perfusion pressure gradient[12], If there are pressure gradient changing in the lesion area, it can also cause the choroidal venous in the lesion area drain faster or fill slower. When the RPE is damaged, the subretinal fluid drain more quickly, probably because the choroidal vessels have hyperosmotic pressure[18-22], which spaide[23] believes is a more efficient and rational way to the metabolism. This may be the reason why remarkable retinal vascular exudation is observed but the retina is atrophied without edema. Combined with the fact that the retina is thinning, these microsacs maybe cavitation, a form of atrophy, as Doshi considered[24]. In our case,FFA showed capillary leaking, but OCTA showed retinal thinning. This may be caused by the leakage from retinal capillary is drained into the choroid, which also explain the reason that the fluid flow rate in the hyporfluorescence zone in choroid is faster. The capillary density around the Foveal Avascular Zone is reduced, occluded, so paramacular capillaris near the impaired vessels are enlarged due to blood flow resistance. This may be leading the the damage and leaking of the vascular endothelium in the “ball” of vessels located in the temporal of the macular of the right eye in ICP figure in OCTA . Special differential diagnosis with Mac Tel-2: Hess[10] has identified the slight differences in the similar manifestations of the two diseases, so here we will mainly identify the obvious differences between the two diseases. SERMs retinochoroidopathy. Mac Tel-2 SFCT thickening - [25] ICGA Hyporfluorescence in the abnormal zone - [26] EOG the Arden Ratio reduced[27] - [28] SFCT: subfoveal choroidal thickness; ICGA: Indocyanine green Angiography; EOG: electrooculogram; (-): compare with the health group, this exam has no statistically significant in Mac Tel-2 group in the randomized controlled trial. No salient choroidal abnormality was found in the study of Mac Tel-2. Considering that the retinal manifestations of the two diseases are similar, but the choroidal conditions are different, we tried to analyze the choroidal abnormalities as the cause of retinal abnormalities. Mantel[29] reported three cases of choroidal hemorrhagic thickening due to vortex-venous obstruction. In animal experiments of vortexeal suture, Choroidal thickening were observed in both mouse[30] and cynomolgus monkeys[31]. In Chen's experiments with cynomolgus monkeys after the two vortexes were sutured, choroidal thickness and CVI increased at first and then decreased. Choroid showing a self-regulation ability in this experiment. The FFA images in the acute phase showed panretinal leaking, while the retina in the 12-week recovery phase showed paramacular capillary leaking heavier in temporal which is similar to that in the present case. The damage of RPE was also observed under electron microscope [31]. FFA has similar manifestations in patients with pachychoroid neovasculopathy(PNV)，those patients also show choroidal thickening and vorticular venous dilation. FFA images provided by Matsumoto [32] showed that the patient also had heavier capillary oozing in the temporal macular area and window defects representing the RPE damage. In other words, choroidal thickening caused by abnormal hemodynamics can induce SR-like phenotypes, and similar retinal phenotypes can also occur in PNV patients with abnormal hemodynamics. SERMs can affect the levels of sex hormones and range the tissue-specific effect from estrogenic in mammary tissue to antiestrogens in other tissue[6]. Sex hormones also affect eye blood flow. The cornea, lens, iris, ciliary body, retina, lacrimal gland, meibomian gland, and conjunctiva of the eye all have estrogen receptors [33-35]. Sex hormones can affect blood flow in the eyes. Estrogen therapy can improve retinal vascular velocity, resistance, and blood flow [36,37]. Progesterone and testosterone have antagonistic effects with estrogens, which can increase the resistance of ocular artery and retinal blood vessels and antagonize the vasodilator effect of estrogen [38-40]. The patient also had a history of leprerelin use, so we could not completely ignore its effects. But compared to the other patients who had the same symptoms as her and had a history of taking SERMs, leprerelin was not common. Also we do not found any report demonstrated leprerelin have similar ocular toxicity. Therefore,We believe that the influence of SERM on eye blood flow leads to abnormal choroidal blood flow, which leads to macular disease and affects visual function. Exploring the regulatory role and mechanism of SERM in the eye is of great significance for understanding SR and even pachychoroid spectrum disease. Abbreviations SERMs: Selective estrogen receptor modulators; TR: Tamoxifen retinopathy; Mac Tel-2: Macular telangiectasia Type 2; ICGA: Indocyanine green angiography; OCTA: Optical coherence tomography angiography; EOG: Electrooculogram; SR: Selective estrogen receptor modulators retinochoroidopathy; RPE: Retinal pigment epithelium; FFA: Fundus fluorescein angiography; SR: SERMs retinochoroidopathy; BFA: Blue-wavelength autofluorescence; SFCT: Subfoveal choroidal thickness; CVI: Choroidal vascular index; SCP: The superficial capillary plexus; ICP: The intermediate capillary plexus; DCP: The deep capillary plexus; PPE: Pachychoroid pigment epitheliopathy Declarations Acknowledgements None. Author’s contributions DY drafted the manuscript, interpreted the data, and critically reviewed the manuscript, JA interpreted the data, and critically reviewed the manuscript. Both authors read and approved the final manuscript. Funding None. Availability of data and materials All data generated or analyzed during this study are included in this published article. Ethics approval and consent to participate Informed consent was obtained after an explanation of the nature and possible consequences of the study, which followed the tenets outlined in the Declaration of Helsinki. Consent for publication Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Competing interests The authors declare that they have no competing interests. References Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer Treat Rep 1978; 62:315–320. Kim H, Lee S, Eah KS, Yoon YH. Prevalence and risk factors of tamoxifen retinopathy. Ophthalmology. 2020;127(4):555–7. https://doi.org/10.1016/j.ophtha.2019.10.038. Lee S, Kim HA, Yoon YH. OCT Angiography Findings of Tamoxifen Retinopathy: Similarity with Macular Telangiectasia Type 2. 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version.\u003c/p\u003e","description":"","filename":"floatimage10.png","url":"https://assets-eu.researchsquare.com/files/rs-3827512/v1/8048f0927ed81efbb35f8a29.png"},{"id":49236585,"identity":"0960e1d0-9226-477d-9a0c-75acce63b406","added_by":"auto","created_at":"2024-01-05 17:57:12","extension":"png","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":398087,"visible":true,"origin":"","legend":"\u003cp\u003eFigure legend not available with this version.\u003c/p\u003e","description":"","filename":"floatimage11.png","url":"https://assets-eu.researchsquare.com/files/rs-3827512/v1/e7362a4afff910815b7e7787.png"},{"id":57917106,"identity":"ac10e7bd-617f-4da0-a319-f18d4cd5ca10","added_by":"auto","created_at":"2024-06-07 12:22:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3275679,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3827512/v1/df924e3a-1162-4a59-a642-3b95cd15c944.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparing and analyzing the differences between SERMs retinochoroidopathy and Macular Telangiectasia Type 2: a new pathogenic hypothesis","fulltext":[{"header":"Background","content":"\u003cp\u003eOcular toxicity of tamoxifen was first reported in the 1970s[1]. \u0026nbsp;Tamoxifen retinopathy characterized by yellow crystals in funduscope, the intraretinal cavitations, pseudocystic foveal cavitations, disruptions of the ellipsoid zone in OCT and late paramacular leakage in FFA[2-4]. Most of these researches and reports were based on long history of tamoxifen use. According to the patient\u0026apos;s endocrine condition, mammary surgeons often adjust tamoxifen to toremifen. And we found another case of same SEMRs used histories[5] with similar symptoms. Toremifene is a chlorinated analogue of tamoxifen. Tamoxifen and toremifen are first-generation selective estrogen receptor modulators（SERMs), \u0026nbsp;which have similar efficacy and mechanism of actionactivity[6]. Also previous researches showed that there was no difference in ocular toxicity between the two drugs[7]. So we call this drug-induced retinochoroidopathy SERMs retinochoroidopathy(SR). Because the classical phenotype of SR is very similar to which of mac tel-2, many researchers have compared the two diseases together and tried to explore the mechanism behind this[5,8-11]. We report here a case of a patient with classic SR manifestations and provide additional findings that are very differentiating from MacTel-2.\u0026nbsp;\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eIn 2023, a 52-year-old Chinese woman was referred to our outpatient clinic for evaluation and treatment of gradual and progressive visual acuity decrease of both eyes about 1 year.\u003c/p\u003e\n\u003cp\u003eThe patient received oral \"Tamoxifen citrate tablet\"10mg/ day for more than one year, and then replaced with \"Toremifen citrate tablet\" 60mg/ day for more than three years because of menopause, also, injecting \"Leuprelin acetate microspheres for injection\" 3.75mg/ month uninterrupted since she surgery for left breast cancer (T1N0M0) in January 2019. Those drugs had been used for 57 months until she went to our clinic. She had no significant personal or family medical history, except for breast cancer. Her best-corrected visual acuity (BCVA) was 20/70(0.3) OD and 20/50(0.4 )OS with light astigmatism. The cornea and lens were clear OU.\u003c/p\u003e\n\u003cp\u003eAnalysis of Multimodality Imaging Data:\u003c/p\u003e\n\u003cp\u003eColor fundus photographs:\u003c/p\u003e\n\u003cp\u003eThe magnify fundus photographs showed bilateral classical diffuse tiny yellow crystals.(Figure 1)\u003c/p\u003e\n\u003cp\u003e(Figure1)\u003c/p\u003e\n\u003cp\u003eBlue-wavelength autofluorescence\u003c/p\u003e\n\u003cp\u003eBFA show that the physiological hypofluorescence in the temporal macular area of both eyes is reduced.(Figure2)\u003c/p\u003e\n\u003cp\u003e(Figure2)\u003c/p\u003e\n\u003cp\u003eFundus fluorescein angiography\u003c/p\u003e\n\u003cp\u003eBoth eyes show vascular leakage just within the macular region which temporal leakages were more serious than nasal. (Figure3)\u003c/p\u003e\n\u003cp\u003e(Figure3)\u003c/p\u003e\n\u003cp\u003eIndocyanine green angiography (ICGA)：\u003c/p\u003e\n\u003cp\u003eThe leaking area in FFA are matched with the parts in ICGA figure keeping hyporfluorescence in both eyes.(Figure 4)\u003c/p\u003e\n\u003cp\u003e(Figure 4)\u003c/p\u003e\n\u003cp\u003eoptical coherence tomography angiography:\u003c/p\u003e\n\u003cp\u003eIn SS-Scan mode show Crystalline deposits, , the intraretinal cavitations, pseudocystic foveal cavitations(doshi) and disruptions of the ellipsoid zone. (Figure 5)\u003c/p\u003e\n\u003cp\u003e(Figure 5)\u003c/p\u003e\n\u003cp\u003eFalse color image of retinal thickness analysis:\u003c/p\u003e\n\u003cp\u003eSVision's Van Gogh software automatically measures the thickness from the internal limiting membrane to the Bruch membrane and note abnormal areas with red and yellow. (Figure 6)\u003c/p\u003e\n\u003cp\u003eRed and yellow areas means thinning retinal thickness\u003c/p\u003e\n\u003cp\u003e(Figure 6)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;subfoveal choroidal thickness(SFCT) and The choroidal vascular index (CVI)\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Choroidal thickness were 482\u0026mu;m in right eye and 483\u0026mu;m in left eye ，both of which were significantly higher than the normal level. Submacular choroid thickness (SFCT) increased, and the central choroid was thickest in ETDRS mode. The choroidal vascular index (CVI) was increased in the ETDRS model in both eyes. CVI is the ratio of choroidal vessel volume to choroidal volume.\u003c/p\u003e\n\u003cp\u003eThis phenomenon is also consistent with other reports and studies.[13-16] Two of these cases were diagnose as Pachychoroid pigment epitheliopathy (PPE)[13,14]\u003c/p\u003e\n\u003cp\u003eOCT Angiography:\u003c/p\u003e\n\u003cp\u003eUsing three-layer method to observe the retinal capillary plexus, we found a ball of bulging vessels at temporal parafoveal in right eye. Then we use a FFA figure align with the abnormal ICP by the superficial vessel and found that the abnormal area in ICP figure located in the obvious leaking in FFA figure. OCT at the corresponding location of the lesion showed thickening of the outer nuclear layer and thinning of the outer plexiform layer with hyperreflective. (Figure 7)\u003c/p\u003e\n\u003cp\u003e(Figure 7)\u003c/p\u003e\n\u003cp\u003eFrom left to right are the superficial capillary plexus (SCP) and the intermediate capillary plexus\u003c/p\u003e\n\u003cp\u003e(ICP) and the deep capillary plexus (DCP) in right eye\u003c/p\u003e\n\u003cp\u003e(Figure 8)\u003c/p\u003e\n\u003cp\u003eThe Red circle marking ICP figure was covered by a transparency FFA figure with the salient leakage(circled by orange line) and OCT image of a thickened outer nuclear layer corresponding to angiocele.\u003c/p\u003e\n\u003cp\u003eThe image of the left eye did not observe such a significant anomaly. But when we look at the retinal blood vessels in the same way through the abnormal areas on the FA, we can see that the blood vessel density in the lesion area was reduced.(Figure 9)\u003c/p\u003e\n\u003cp\u003e(Figure 9)\u003c/p\u003e\n\u003cp\u003eElectrophysiological examination:\u003c/p\u003e\n\u003cp\u003e(full-field electroretinogra,ffERG): No obvious abnormalities were found, which indicated that the retinal function is basically normal. This also prove the result in other imaging examination that no peripheral retinal abnormalities were found.\u003c/p\u003e\n\u003cp\u003eElectrooculogram, EOG :The Arden Ratio in both eyes was reduced heavily(Figure 10). We also found another case report examined patient by EOG have similar consequence[17]. Abnormal EOG usually indicates abnormal function of the choroid or RPE .\u003c/p\u003e\n\u003cp\u003e(Figure 10)\u003c/p\u003e\n\u003cp\u003eMicroperimetry：\u003c/p\u003e\n\u003cp\u003eThe center of fixation deviated from the fovea, and visual sensitivity decreased in the macular region. The birth of paracentral fixation need a long period of time, which means this patient impaired central vision for a long time.(Figure 11)\u003c/p\u003e"},{"header":"Discussion And Conclusion","content":"\u003cp\u003eWe discuss the positive test results in this case and propose hypotheses.\u003c/p\u003e\n\u003cp\u003eICGA imaging shows that the macular area is always hyporfluorescence, which may be due to the presence of fluid in the choroidal mesenchyme with fluorescence shielding effect(hemorrhagic effusion) in the hyporfluorescence zone , or the fluid flow rate in the hyporfluorescence zone is faster the surrounding zone so that the oozing ICG cannot accumulate. Also, choriocapillaris flling patterns were determined by the network of perfusion pressure gradient[12], If there are pressure gradient changing in the lesion area, it can also cause the choroidal venous in the lesion area\u0026nbsp;drain faster or fill slower.\u003c/p\u003e\n\u003cp\u003eWhen the RPE is damaged, the subretinal fluid drain more quickly, probably because the choroidal vessels have\u0026nbsp;hyperosmotic\u0026nbsp;pressure[18-22], which spaide[23] believes is a more efficient and rational way to the metabolism. This may be the reason why remarkable retinal vascular exudation is observed but the retina is atrophied without edema. Combined with the fact that the retina is thinning, these microsacs maybe cavitation, a form of atrophy, as Doshi considered[24].\u003c/p\u003e\n\u003cp\u003eIn our case,FFA showed capillary leaking, but OCTA showed retinal thinning. This may be caused by the leakage from retinal capillary is drained into the choroid, which also explain the reason that the fluid flow rate in the hyporfluorescence zone in choroid is faster.\u003c/p\u003e\n\u003cp\u003eThe capillary density around the Foveal Avascular Zone is reduced, occluded, so paramacular capillaris near the impaired vessels are enlarged due to blood flow resistance. This may be leading the the damage and leaking of the vascular endothelium in the \u0026ldquo;ball\u0026rdquo; of vessels located in the temporal of the macular of the right eye in ICP figure in OCTA .\u003c/p\u003e\n\u003cp\u003eSpecial differential diagnosis with Mac Tel-2:\u003c/p\u003e\n\u003cp\u003eHess[10] has identified the slight differences in the similar manifestations of the two diseases, so here we will mainly identify the obvious differences between the two diseases.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eSERMs\u0026nbsp;retinochoroidopathy.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eMac Tel-2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eSFCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003ethickening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e- \u0026nbsp; [25]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eICGA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eHyporfluorescence in the abnormal zone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e- \u0026nbsp; [26]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003eEOG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003ethe Arden Ratio reduced[27]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e- \u0026nbsp; [28]\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eSFCT: subfoveal choroidal thickness; ICGA: Indocyanine green Angiography; EOG:\u0026nbsp;electrooculogram;\u0026nbsp;(-): \u0026nbsp;compare with the health group, this exam has no statistically significant in Mac Tel-2 group in the randomized controlled trial.\u003c/p\u003e\n\u003cp\u003eNo salient choroidal abnormality was found in the study of Mac Tel-2. Considering that the retinal manifestations of the two diseases are similar, but the choroidal conditions are different, we tried to analyze the choroidal abnormalities as the cause of retinal abnormalities.\u003c/p\u003e\n\u003cp\u003eMantel[29] reported three cases of choroidal hemorrhagic thickening due to vortex-venous obstruction. In animal experiments of vortexeal suture, \u0026nbsp;Choroidal thickening were observed in both mouse[30] and cynomolgus monkeys[31].\u003c/p\u003e\n\u003cp\u003eIn Chen\u0026apos;s experiments with cynomolgus monkeys after the two vortexes were sutured, choroidal thickness and CVI increased at first and then decreased. Choroid showing a self-regulation ability in this experiment. The FFA images in the acute phase showed panretinal leaking, while the retina in the 12-week recovery phase showed paramacular capillary leaking heavier in temporal which is similar to that in the present case. The damage of RPE was also observed under electron microscope [31].\u003c/p\u003e\n\u003cp\u003eFFA has similar manifestations in patients with pachychoroid neovasculopathy(PNV)，those patients also show choroidal thickening and vorticular venous dilation. FFA images provided by Matsumoto [32] showed that the patient also had heavier capillary oozing in the temporal macular area and window defects representing the RPE damage.\u003c/p\u003e\n\u003cp\u003eIn other words, choroidal thickening caused by abnormal hemodynamics can induce SR-like phenotypes, and similar retinal phenotypes can also occur in PNV patients with abnormal hemodynamics.\u003c/p\u003e\n\u003cp\u003eSERMs can affect the levels of sex hormones and range the tissue-specific effect from estrogenic in mammary tissue to antiestrogens in other tissue[6]. Sex hormones also affect eye blood flow.\u003c/p\u003e\n\u003cp\u003eThe cornea, lens, iris, ciliary body, retina, lacrimal gland, meibomian gland, and conjunctiva of the eye all have estrogen receptors [33-35]. Sex hormones can affect blood flow in the eyes. Estrogen therapy can improve retinal vascular velocity, resistance, and blood flow [36,37]. Progesterone and testosterone have antagonistic effects with estrogens, which can increase the resistance of ocular artery and retinal blood vessels and antagonize the vasodilator effect of estrogen [38-40].\u003c/p\u003e\n\u003cp\u003eThe patient also had a history of leprerelin use, so we could not completely ignore its effects. But compared to the other patients who had the same symptoms as her and had a history of taking SERMs, leprerelin was not common. Also we do not found any report demonstrated leprerelin have similar ocular toxicity.\u003c/p\u003e\n\u003cp\u003eTherefore,We believe that the influence of SERM on eye blood flow leads to abnormal choroidal blood flow, which leads to macular disease and affects visual function. Exploring the regulatory role and mechanism of SERM in the eye is of great significance for understanding SR and even pachychoroid spectrum disease.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eSERMs: Selective estrogen receptor modulators; TR: Tamoxifen retinopathy; Mac Tel-2: Macular telangiectasia Type 2; ICGA: Indocyanine green angiography; OCTA: Optical coherence tomography angiography; EOG: Electrooculogram; SR: Selective estrogen receptor modulators retinochoroidopathy; RPE: Retinal pigment epithelium; FFA: Fundus fluorescein angiography; SR: SERMs retinochoroidopathy; BFA: Blue-wavelength autofluorescence; SFCT: Subfoveal choroidal thickness; CVI: Choroidal vascular index; SCP: The superficial capillary plexus; ICP: The intermediate capillary plexus; DCP: The deep capillary plexus; PPE: Pachychoroid pigment epitheliopathy\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthor\u0026rsquo;s contributions\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDY drafted the manuscript, interpreted the data, and critically reviewed the manuscript, JA \u0026nbsp;interpreted the data, and critically reviewed the manuscript. Both authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFunding\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNone.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this\u0026nbsp;\u003c/p\u003e\n\u003cp\u003epublished article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained after an explanation of the nature and possible consequences of the study, which followed the tenets outlined in the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting interests\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer Treat Rep 1978; 62:315\u0026ndash;320.\u003c/li\u003e\n\u003cli\u003eKim H, Lee S, Eah KS, Yoon YH. Prevalence and risk factors of tamoxifen retinopathy. Ophthalmology. 2020;127(4):555\u0026ndash;7. https://doi.org/10.1016/j.ophtha.2019.10.038.\u003c/li\u003e\n\u003cli\u003eLee S, Kim HA, Yoon YH. OCT Angiography Findings of Tamoxifen Retinopathy: Similarity with Macular Telangiectasia Type 2. Ophthalmol Retina. 2019 Aug;3(8):681\u0026ndash;689. doi: 10.1016/j.oret.2019.03.014. Epub 2019 Apr 4.\u003c/li\u003e\n\u003cli\u003eDoshi RR, Fortun JA, Kim BT, Dubovy SR, Rosenfeld PJ. Pseudocystic foveal cavitation in tamoxifen retinopathy. Am J Ophthalmol. 2014 Jun;157(6):1291\u0026ndash;1298.e3. doi: 10.1016/j.ajo.2014.02.046. Epub 2014 Feb 26.\u003c/li\u003e\n\u003cli\u003eShinkai A, Saito W, Hashimoto Y, Ishida S. Improvements in visual acuity and macular morphology following cessation of anti-estrogen drugs in a patient with anti-estrogen maculopathy resembling macular telangiectasia type 2: a pathogenic hypothesis. BMC Ophthalmol. 2019 Dec 30;19(1):267. doi: 10.1186/s12886-019-1280-1.\u003c/li\u003e\n\u003cli\u003eCurtis MG. Comparative tolerability of first-generation selective estrogen receptor modulators in breast cancer treatment and prevention. Drug Saf. 2001;24(14):1039-53. doi: 10.2165/00002018-200124140-00003.\u003c/li\u003e\n\u003cli\u003eGianni L, Panzini I, Li S, Gelber RD, Collins J, Holmberg SB, Crivellari D, Castiglione-Gertsch M, Goldhirsch A, Coates AS, Ravaioli A; International Breast Cancer Study Group (IBCSG). Ocular toxicity during adjuvant chemoendocrine therapy for early breast cancer: results from International Breast Cancer Study Group trials. 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Graefes Arch Clin Exp Ophthalmol. 2014 May;252(5):753-9. doi: 10.1007/s00417-013-2543-9. Epub 2013 Dec 21.\u003c/li\u003e\n\u003cli\u003eMatsumoto H, Mukai R, Hoshino J, Oda M, Matsuzaki T, Ishizaki Y, Shibasaki K, Akiyama H. Choroidal congestion mouse model: Could it serve as a pachychoroid model? PLoS One. 2021 Jan 28;16(1):e0246115. doi: 10.1371/journal.pone.0246115.\u003c/li\u003e\n\u003cli\u003eChen LL, Wang Q, Yu WH, Chen YX. Choroid changes in vortex vein-occluded monkeys. Int J Ophthalmol. 2018 Oct 18;11(10):1588\u0026ndash;1593. doi: 10.18240/ijo.2018.10.03.\u003c/li\u003e\n\u003cli\u003eMatsumoto H, Kishi S, Mukai R, Akiyama H. Remodeling of macular vortex veins in pachychoroid neovasculopathy. Sci Rep. 2019 Oct 11;9(1):14689. doi: 10.1038/s41598-019-51268-9.\u003c/li\u003e\n\u003cli\u003eWickham LA, Gao J, Toda I, Rocha EM, Ono M, Sullivan DA. 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Menstrual phase related differences in the pulsatility index on the central retinal artery suggest an oestrogen vasodilatation effect that antagonizes with progesterone. \u003cem\u003eArch Gynecol Obstet\u003c/em\u003e (2011) 283(3):569\u0026ndash;73. doi:10.1007/s00404-010-1403-7\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Tamoxifen, Toremifene, selective estrogen receptor modulators(SERMs), choroidal thickness, Pachychoroid spectrum disease, Electrooculogram, Optical coherence tomography angiography, Subfoveal choroidal thickness","lastPublishedDoi":"10.21203/rs.3.rs-3827512/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3827512/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground：Because Tamoxifen Retinopathy and Macular Telangiectasia Type 2 (Mac Tel-2) have similar manifestations, many researchers are identifying and exploring the mechanisms of the two diseases. Here we report a patient with selective estrogen receptor modulators(SERMs)-induced retinochoroidopathy. And she has a history of tamoxifen and toremifene use , presenting the classic phenotype of TR. It is the first time, we use comprehensive examination to observe one patient.\u003c/p\u003e\n\u003cp\u003eCase presentation: A 52-year-old woman presented gradual and progressive visual acuity decrease of both eyes about 1 year. She had received oral tamoxifen followed by toremifene for 57 months. Indocyanine green angiography(ICGA), optical coherence tomography angiography(OCTA), electrooculogram(EOG), revealed salient distinct from Mac Tel-2 phenotype in patient’s choroidal. The patient’s ocular vessels did not show any tendency to proliferate, so we serve the cessation of anti-estrogen drugs as her treatment.\u003c/p\u003e\n\u003cp\u003eConclusion: Combined with the positive results of increasing choroidal thickening, ICGA hypofluorescence, and decreased Arden ratio, SERMs-induced retinopathy is considered to be a type of retinochoroidopathy.\u003c/p\u003e","manuscriptTitle":"Comparing and analyzing the differences between SERMs retinochoroidopathy and Macular Telangiectasia Type 2: a new pathogenic hypothesis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-05 17:49:07","doi":"10.21203/rs.3.rs-3827512/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"084bfb71-64ae-4431-b8f3-d38945198762","owner":[],"postedDate":"January 5th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-07T12:14:50+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-05 17:49:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3827512","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3827512","identity":"rs-3827512","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}