Challenges in posterior uveitis—tips and tricks for the retina specialist

Purpose Posterior uveitis is a common chorioretinal pathology affecting all ages worldwide and is a frequent reason for referral to the retina clinic. The spectrum of etiologies for uveitis is very broad and includes infectious and auto-immune diseases. Inflammation can be confined to the eye or may be a part of systemic disease. A useful outline is therefore proposed to aid in the correct diagnosis of these challenging entities. The situation is further complicated by the fact that many neoplastic conditions resemble features of posterior uveitis; they are known as “masqueraders of uveitis”. Here, we summarize different posterior uveitides that present with rare findings, along with masqueraders that can be difficult to distinguish. These conditions pose a diagnostic dilemma resulting in delay in treatment because of diagnostic uncertainty. Methods An extensive literature search was performed on the MEDLINE/PUBMED, EBSCO and Cochrane CENTRAL databases from January 1985 to January 2022 for original studies and reviews of predetermined diagnoses that include posterior uveitic entities, panuveitis and masquerade syndromes. Results We described conditions that can present as mimickers of posterior uveitis (i.e., immune check-points inhibitors and Vogt-Koyanagi-Harada-like uveitis; leukemia and lymphoma associated posterior uveitis), inflammatory conditions that present as mimickers of retinal diseases (i.e., Purtscher-like retinopathy as a presentation of systemic lupus erythematosus; central serous chorioretinopathy masquerading inflammatory exudative retinal detachment), and uveitic conditions with rare and diagnostically challenging etiologies (i.e., paradoxical inflammatory effects of anti-TNF-α; post vaccination uveitis; ocular inflammation after intravitreal injection of antiangiogenic drugs). Conclusion This review of unique posterior uveitis cases highlights the overlapping features of posterior uveitis (paradoxical inflammatory effects of anti -TNF α and uveitis; Purtscher-like retinopathy as a presentation of systemic lupus erythematosus, …) and the nature of retinal conditions (ischemic ocular syndrome, or central retinal vein occlusion, amyloidosis, inherited conditions like retinitis pigmentosa, autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), etc.…) that may mimic them is represented. Careful review of past uveitis history, current medications and recent vaccinations, detailed examination of signs of past or present inflammation, eventually genetic testing and/ or multimodal retinal imaging (like fluorescein angiography, EDI-OCT, OCT-angiography for lupus Purtscher-like retinopathy evaluation, or ICG for central serous retinopathy, or retinal amyloid angiopathy) may aid in correct diagnosis. Supplementary Information The online version contains supplementary material available at 10.1186/s12348-023-00342-5.


Introduction
Ocular inflammatory disease is a leading cause of vision loss worldwide.In the United States, uveitis has a reported incidence of 52.4/100 000 person-years [1].Uveitis encompasses a wide spectrum of diseases that can affect virtually every part of the eye.Inflammation can be confined to the eye or may be part of systemic disease.Thus, ocular inflammation possesses a significant challenge as many diseases may present as posterior uveitis masqueraders, mimickers of retinal diseases or inflammatory diseases with obscure, rare etiologies.When using the term "Uveitis Masqueraders", most of these are simply different conditions with similar phenotypes or clinical appearance.
Uveitis masquerade syndromes represent as many as 5% of patients seen in uveitis clinics and the frequency of neoplastic masquerade syndrome is usually 2.5% of patients [2].
Oncologic conditions such as lymphoma, hematologic malignancy, and paraneoplastic syndrome can present with ophthalmic manifestations, mimicking uveitis [2][3][4][5][6][7].Infectious conditions, like Lyme disease, tuberculosis, syphilis, herpes and zoster virus have diverse ocular presentations, and treatment modalities.Patients who are immuno-compromised, either as a result of HIV infection, cancer, or the treatment thereof, are at increased risk of infectious uveitis with atypical presentations.Additionally, ocular syphilis and toxoplasmosis may be misdiagnosed for herpetic acute retinal necrosis.
The growing field of drug-related uveitis should also be considered.Vaccines, working primarily to stimulate an immune response against a target infection, can rarely and inadvertently cause uveitis, which may have implications for treatment and subsequent personal vaccine management [8][9][10][11][12][13][14][15].
Ischemic vascular conditions can often present with concomitant inflammation reminiscent of uveitis [16,17].It is also important to consider drug-related uveitis when discussing masquerading presentations [18,19].The correct diagnosis often requires a comprehensive rheumatologic and ophthalmological evaluation including: clinical history, multimodal imaging and systemic workup.
The purpose of this article is to review some of these conditions, including clinical features that aid in identification and distinct findings on multi-modal imaging.The present study attempts to concentrate knowledge of ocular conditions that might mimic intraocular inflammation diseases.
We reviewed the most common conditions that present as mimickers of posterior uveitis and conversely, inflammatory conditions that present as mimickers of retinal diseases, and uveitis conditions with rare and diagnostically challenging etiologies.
Their typical and atypical presentations are reviewed as outlined below.Diagnostic strategies among the entities described below are also presented and discussed.
1. Common drug related, retinal vascular, neoplastic and other conditions that may present as uveitis masqueraders a Drug related: a. 1

Methods
The study was conducted according to the Preferred Reporting Items of Systematic Reviews (PRISMA) guidelines [20].
A literature search and subsequent screening of articles was conducted in December 2021 by three authors (MPE, SC and MHE).PubMed served as the primary database for the electronic literature search, although EBSCO and Cochrane were also surveyed.We systematically reviewed the available literature on neoplastic and nonneoplastic inflammatory masquerade syndromes.Literature searches were performed using electronic medical databases of the following keywords: masquerade syndromes, inflammatory ocular diseases and uveitis.The search timeframe was not limited by a specific date, but rather by the results of the articles retrieved.
The retrieved articles were initially screened by title and abstract, and articles with the relevant titles were then screened by full text using predefined inclusion and exclusion criteria.Inclusion criteria included 1) the paper must be written in or available in English and 2) the paper discussed the presentation and management of masquerade syndromes, inflammatory and infectious ocular diseases and uveitis.Exclusion criteria included 1) papers involving patients only with other inflammatory ocular diseases (episcleritis, scleritis) and anterior uveitis, intermediate uveitis.This article specifically excluded entities such as AZOOR, and autoimmune retinopathy for the reason that typically patients with this condition do not present with sign of overt intraocular inflammation; 2) the paper did not clearly diagnose the patient with a masquerade syndrome.
3) citations were from grey literature.The full article was screened in cases where the relevance was unclear from the abstract.Relevant articles were ultimately compiled into a database and removed of duplicates (Supplemental table ).
No research ethics approval was needed for this study, as there were no human or animal participants included.The study protocol complied with the tenets of the Declaration of Helsinki.

Results
A total of 535 studies were identified in the literature search.After screening study titles and abstracts and excluding duplicates, 148 articles were excluded and 387 articles remained eligible for full-text examination.Of these, 230 met all inclusion criteria (Supplemental figure).Specific diagnoses selected to be included in the study can be found in the Supplemental table.

Common drug related, retinal vascular, neoplastic
and other conditions that may present as uveitis masqueraders a Drug related a.1.Immune check-points inhibitors (ICI) and Vogt-Koyanagi-Harada (VKH)-like uveitis.
Herein, we highlight the VKH-like uveitis (Fig. 1) that has been frequently reported in association with checkpoint inhibitors . .To date, 126 cases of anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis have been reported in the literature [24].Patients have been reported to typically develop intraocular inflammation at a median of 9 weeks after initiation of ICI, while 83.6% of patients develop uveitis within 6 months [24].
Furthermore, in melanoma, the development of VKH-like uveitis and skin-related toxicities, such as rash and vitiligo, secondary to immune checkpoint inhibitors correlates with increased tumor response and prolonged survival.In those patients, malignant melanoma cells and normal choroidal melanocytes share a common target epitope for T-cell recognition.Therefore, the release and activation of Tcells from PD-1 inhibition and the CTLA-4 pathway would lead to T cells targeting of both malignant melanocytes and nonmalignant choroidal melanocytes [25].
Usually, cessation of ICI use is discussed with the oncologist taking into account the risk/benefit ratio.Treatment with topical or systemic corticosteroid therapy is often associated with improvement in symptoms and disease rarely recurs [26][27][28].

Mitogen-activated protein kinase inhibitors
MEKi are now largely used for treatment of advanced melanoma in combination with B-rab enzyme inhibitors (BRAFi) such as vemurafenib and dabrafenib.MEKi have been associated with a wide phenotype of retinal damage with an incidence that ranges from 5 to 75% [29][30][31].The incidence of retinopathy has been reported at its highest in the first two cycles [32].The incidence of retinopathy is also drug-specific, with higher incidence (57%) reported in patients who receive vemurafenib combined with cobimetinib.[32,33].Patients often present with symptoms of photosensitivity, blurred vision and reduced vision [32].Clinical presentation ranges from mild, with small multifocal and bilateral subretinal detachments [34], to severe, with intraretinal fluid or cysts, and a disarrangement of the outer retinal layers (see Fig. 2) [35][36][37].The mechanism behind BRAF/MEK inhibitor induced panuveitis, which clinically closely resembles the VKH disease, might be related to its interference with the MAPK pathway, which is involved in the T-cell receptor signaling pathway.In the VKH disease pathogenesis, CD4 + and CD8 + cells (T cells) target melanocytic antigens in the choroid and RPE, which impair the outer blood retinal barrier [38].
Ocular adverse effects impact dosing of MEKi.The United States Prescribing Information for trametinib and cobimetinib recommends: "an ophthalmological examination at regular intervals during therapy and at any time a new or worsening visual disturbance is reported.In the case of a grade 2-3 retinal pigment epithelial (RPE) detachment, trametinib should be withheld without change of the dose of dabrafenib and restarted at a lower dose if resolution or improvement is documented within three weeks.If no improvement after three weeks, recurrence, or retinal vein occlusion (RVO), the drug should be Fig. 2 OCT showing a cystoid macular edema and a serous neuroretinal detachment of the fovea in a 39-year-old male with widespread metastatic melanoma, stage IV disease, treated by BRAF/MEK inhibitor therapy (ecorafenib/binimetinib) since the last 3 months discontinued" [39].For cobimetinib, therapy should be withheld for serous retinopathy until visual symptoms improve with resumption at a lower dose only if symptoms improve over four weeks.For recurrent symptoms or any RVO, the drug should be discontinued permanently [39].MAPK pathway inhibition can rarely lead to severe panuveitis, which tends to resolve within months with treatment discontinuation and/or treatment with corticosteroids either systemic or local [35].
The possible causal mechanisms for the development of these post-vaccination uveitis are delayed-type hypersensitivity reaction and immune complex deposition following vaccination with the role of adjuvants in the immunologic process.Type III hypersensitivity reaction involving antigenantibody complexes present in the aqueous humor may apply to the mechanism of COVID-vaccine-related uveitis [68].There is also an implication of a vaccine-induced type I interferon secretion.The authors proposed that the vaccine mRNA activates RNA-sensing molecules including TLR3, TLR7, MDA5, and RIG-I which drive autoimmune processes in these patients.
The possible cause of varicella zoster virus (VZV) reactivation following COVID-19 vaccination is induction of a strong T-cell response with increased CD8 + T cell and T helper type 1 CD4 + T cells.The VZV-specific CD8 + cells are temporally incapable of controlling VZV after the massive shift of naïve CD8 + cells.The other hypothesis of VZV reactivation is that aberrations in tolllike receptors (TLR) expression after vaccination induce of type I interferon (IFN-I) and potentiation of pro-inflammatory cytokines, which, may negatively modulate antigen expression [42,69].
Brolucizumab (Beovu) is a novel singlechain antibody fragment that inhibits all isoforms of VEGF-A.It is the smallest of the anti-VEGF antibodies, with a molecular weight of 26 kDa, compared with 115 kDa for aflibercept and 48 kDa for ranibizumab, which have proven useful in the management of diabetic macular edema (DME).
Oral diethylcarbamazine (DEC) is a powerful microfilaricide used to treat onchocerciasis and it thought to be a possible cause of anterior uveitis, transient retinal pigment epithelial lesions, chorioretinitis, and optic nerve inflammation, which have been described previously in the literature [75][76][77].
b Neoplastic conditions: leukemia and lymphoma associated posterior uveitis The prevalence of neoplastic inflammatory masquerade syndromes among the total population presenting with inflammatory intraocular disease was 1.8% in Rothova's epidemiology study in the Netherlands and increased to 4.5% in patients older than 60 years [78].
In cases of leukemia and lymphoma, ocular symptoms can be the presenting symptoms of systemic disease or its relapse after remission [7].Some studies cite a prevalence of roughly 32 to 35% with the most common presentation being leukemic retinopathy [79][80][81].It is important to note that leukemia and lymphoma-associated uveitis are part of the Uveitis Masquerade Syndromes (UMS) whereby the pathological process arises as a consequence of intraocular infiltration with malignant cells and is not secondary to an immune-mediated or infectious process.Among studies examining the prevalence of ocular manifestations of leukemia and lymphoma, an incidence of 20% has been reported [80].Leukemias (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML)) are more commonly associated with anterior uveitis presenting with hypopyon [5,6].When the posterior segment is involved, it can be the result of direct invasion or secondary indirect effects of systemic disease.Malignant cells have been documented to infiltrate the uvea, optic nerve, cranial nerves, and peri-orbital tissues.Retinal hemorrhage, vitreous hemorrhage, vascular occlusion, and secondary infections all represent indirect sequelae of systemic malignant disease [7,[79][80][81][82].
The designation of intraocular lymphoma includes primary intraocular lymphoma, mainly arising from the central nervous system (CNS) and secondary IOL, arising from outside the CNS as metastasis from a non-ocular neoplasm.Roughly 60-85% of primary IOLs will progress to involve the CNS [83][84][85][86][87][88].Most lymphomas are low-grade B-cell lymphomas, with extranodal marginal zone B-cell lymphoma of MALT type (mucosa-associated lymphoid tissue) being the most common type.Follicular lymphoma also encompasses a high percentage of intraocular lymphoma [89].Cases of marginal zone lymphoma and follicular lymphoma primarily involve the ocular adnexa [89,90].The other types of lymphomas include lymphoblastic lymphomas (of T-lineage and of precursor B-cell type), B-cell lymphoma, peripheral T-cell lymphoma, NK/Tcell lymphoma, classic Hodgkin lymphoma, Burkitt lymphoma, T-cell lymphoma, and NK-cell lymphoma, and these usually present with ocular adnexal involvement as well [90].Systemic Hodgkin lymphomas have been reported to be associated with secondary ophthalmic involvement in the form of bilateral panuveitis, anterior uveitis, vitritis, white chorioretinal lesions, papillitis and vasculitis [3].Mucosa associated lymphoid tissue (MALT) lymphomas have been associated with retinochoroidal infiltration or panuveitis and secondary extramedullary location of acute myeloid leukemia can present as an anterior uveitis with anterior segment cell, dust-like pigmented keratic precipitate, iris bombe, ischemic bilateral retinal vasculitis and goniosynechiae, with associated retinal detachment and a sub-retinal space occupying lesion [2].The issue with lymphomas is that usually a masquerade syndrome is suspected when intraocular inflammation is not responsive to steroids, although vitreoretinal lymphoma might initially be responsive to steroids [91].
For instance, isolated case reports have described peripheral uveal melanoma with clinical signs consistent with an anterior uveitis or panuveitis [93,94].Importantly, retinoblastomas can be misdiagnosed as pars planitis [95,96] and Shields and al. reported that 3.9% of retinoblastomas were referred to their clinics as uveitis [97]. ) with a non-neoplastic inflammatory masquerade syndrome.Only two (0.1%) had a paraneoplastic syndrome (one patient had cancer-associated retinopathy and the second patient had bilateral diffuse uveal melanocytic proliferation) [78].Paraneoplastic vitelliform retinopathy can also mimic white dot syndromes [103].c Retinal vascular diseases: giant cell arteritis (GCA), ischemic ocular syndrome (IOS), and central retinal vein occlusion (CRVO) Giant cell arteritis (GCA) is a systemic granulomatous inflammatory vasculitis of medium and large vessels that leads to vision loss most commonly from arteritic anterior ischemic optic neuropathy (AAION) secondary to involvement of the short posterior ciliary arteries [17,104].This vascular occlusion results in ischemia to laminar and prelaminar segments of the optic nerve.Delayed choroidal perfusion on fluorescein angiography (FA) has been reported as a highly suggestive indicator of active GCA [105].
Case reports have demonstrated the presence of cotton wool spots (CWS) as an early manifestation of GCA (Fig. 3) [17], corresponding to localized accumulations of axoplasmic debris due to focal inner retinal ischemia [16,106].They have been reported as present in GCA even without other classic ocular findings, such as optic disc edema [107].A recent study using Optical Coherence Tomography-angiography (OCTA) has shown focal areas of superficial and deep retinal capillary non-perfusion in eyes with AAION in the context of GCA, confirming delayed retinal perfusion, particularly in the peripapillary region [105].A positive temporal artery biopsy (TAB) is the gold standard test for a histological diagnosis of GCA (Fig. 3a-d).Rai et al., have explained the etiology of CWS in CGA as likely being multifactorial: microembolization of platelets and/or hypoperfusion of terminal portions of retinal vasculature involved by giant cell arteritis [17].
The differential for CWS often includes ischemia (diabetes, hypertension, and retinal vein occlusion), neoplasia (leukemia and lymphoma), infections (human immunodeficiency virus), medications (interferon), and radiation retinopathy.However, the presence of CWS should prompt the clinician to include GCA in the differential diagnosis, especially when associated with the characteristic systemic symptoms of GCA, since this should  Typically, an exudative retinal detachment (RD) is associated with various forms of ocular inflammatory diagnoses: VKH syndrome, posterior scleritis, sympathetic ophthalmia, panuveitis, multifocal choroiditis (MFC) with panuveitis, posterior uveitis and necrotizing scleritis [116].However, rhegmatogenous RDs can rarely present with features of inflammation such as Schwartz-Matsuo syndrome.Canonically, Schwartz-Matsuo is associated with increased intraocular pressure along with anterior chamber inflammation, often believed to be due to liberated photoreceptors from retinal breaks migrating to the anterior chamber, mimicking anterior chamber cells and occluding the trabecular meshwork [117,118].Apart from the Schwartz-Matsuo syndrome, rhegmatogenous RDs can also present with anterior chamber inflammation and exhibit features usually seen in uveitic serous RDs, specifically diffuse choroidal thickening, choroidal detachment, and/or white blood cells as well as fibrin in anterior chamber [119].
There are a couple of reports of chronic rhegmatogenous RD presenting as a panuveitis with anterior uveitis and hypotony [119,120].The visualization of retinal breaks is sometimes difficult.For instance, preoperative undetected retinal tears are not rare findings in routine rhegmatogenous RD management when the retinal breaks are positioned anteriorly.Despite clear visualization of the fundus, it has been reported that retinal breaks are not found in 2.2% to 4% of phakic rhegmatogenous RDs [121].Identifying underlying breaks in the setting of severe inflammation can be even more challenging due to posterior synechiae and hazy media [119].The lack of visualization of a retinal break should not preclude its possible existence when examining the undifferentiated patient with purported intraocular inflammation.

d.3. Coats disease
Coats disease is a rare idiopathic telangiectatic neovascular disease of the retina.The definite diagnosis of Coats disease can be challenging especially in its advanced stage, as it could mimic other ophthalmic conditions, such as retinoblastoma but also posterior uveitis.Coats disease is among the differential diagnoses for leukocoria, intermediate and posterior uveitis, and multifocal non-infectious exudative RDs, especially in young patients [122].When diagnosed in the adult population, its manifestations are often smoldering presenting as persistent floaters and visual distortion.[126,127].Furthermore, familial exudative vitreoretinopathy (FEVR) of childhood is sometimes misdiagnosed as uveitis (Fig. 4).FEVR is an inherited disorder characterized by retinal traction, peripheral vitreous opacities, and subretinal and intraretinal exudates [128].
Conversely, retinitis pigmentosa-like retinal pigmentary changes are attributed to chronic uveitis [129].Uveitis is a rare feature of VCAN-related vitreoretinopathy which includes Wagner syndrome and erosive vitreoretinopathy (ERVR), and which is characterized by "optically empty vitreous", myopia, cataract, night blindness associated with progressive chorioretinal atrophy, retinal traction and retinal detachment in the advanced stages of disease [130].The posterior segment presents with changes of the retinal pigment epithelium and overlying retina (pigment condensation, vascular sheathing, pigmented lattice degeneration, and later chorioretinal atrophy in the retinal periphery).VCAN-related vitreoretinopathy is autosomal dominant [131].
Moreover, subretinal scarring in autosomal recessive bestrophinopathy (ARB) can mimic chorioretinitis.ARB is a specific and recognizable phenotype that can be differentiated clinically from other overlapping clinical syndromes or retinal dystrophies, without prior knowledge of the inheritance pattern, or genotype [132].

d.4. Other: Myopic degenerations, drusen
A large cohort study of 111 patients previously diagnosed with MEWDS were reviewed and showed that 26% of patients were subsequently given an alternative diagnosis, including other posterior uveitis, primary vitreoretinal lymphoma, myopic degeneration, and central serous chorioretinopathy [133].
In punctate inner choroidopathy (PIC), stage II lesions appear as a focal elevation of the RPE with corresponding disruption of the inner and outer segments of the photoreceptor interface using spectral-domain (SD)-OCT.Therefore, PIC lesion can mimic drusen that are found in Bruch' s membrane and may represent precursors for the development of agerelated macular degeneration [134].
e Systemic disorders e.1.Purtscher-like retinopathy as a presentation of Systemic lupus erythematosus (SLE) Purtscher retinopathy is characterized by patches of retinal whitening and hemorrhage around the optic nerve and in the posterior pole which are classically identified in patients who have suffered from severe trauma, including long-bone fracture, cephalic or thoracic compression, and crush injury (Fig. 5).Purtscher-like retinopathy may occur due to acute pancreatitis, renal failure, collagen vascular diseases, hemolysis, elevated liver enzymes, low platelets (HELLP syndrome), and multiple myeloma [135].Purtscher-like retinopathy is also a rare and severe complication of systemic lupus erythematosus (SLE) or as a distinct category of severe retinal vasocclusive disease in SLE [136].The pathogenesis of Purtscher-like retinopathy associated with SLE is not fully understood.It is likely due to the formation of microemboli that results in retinal vascular occlusion and microvascular infarcts of the retinal nerve fiber layer [135].Some authors have suggested that precapillary arteriole occlusion is followed by altered retinal microvascular permeability [137].SLE-related eye involvement can be diagnosed in approximately one-third of the patients and is usually indicative of disease activity [138,139].SLE retinopathy, either unilateral or more often bilateral, is responsible for visual loss secondary to vasculitis of the retinal capillaries and arterioles (Fig. 4).Interestingly, a reduction in retinal vessel density measured by Optical Coherence Tomography (OCTA) but also seen on FA may be a good marker of SLE activity.

e.2. Amyloidosis
Familial transthyretin amyloidosis (FTA) is a rare and severe autosomal dominant disease that is caused by a mutation in the transthyretin (TTR) gene.
Ocular manifestations of amyloidosis are found in 10% of patients, presenting as deposition of amyloid in the lacrimal glands, conjunctiva (abnormal conjunctival vessels), lens capsule, iris epithelium, ciliary pigment epithelium, cornea (loss of corneal sensitivity and neurotrophic corneal ulcers; keratoconjunctivitis sicca), chronic open-angle glaucoma, optic neuropathy and vitreous (vitreous deposits adhering to the posterior lens capsule, as pseudopodia lentis) [140,141].The appearance of amyloid in the vitreous has Fig. 5 Fundus color picture of a 52-year-old female with systemic lupus erythematosus and lupus nephrosis.She was diagnosed as a case of lupus retinopathy owing (A) to patches of polygonal retinal whitening nasal to the nerve and on the fovea and (B) occlusion vasculitis of the retinal capillaries and arterioles on fluorescein angiography been described as sheet-like, film-like, band-like, cobweb-like, glass wool-like, cotton-like and stringy fibril-like [142].
Retinal amyloid angiopathy presents with microaneurysms, retinal hemorrhages, pinpoint white deposits, needle-shaped deposits, retinal cotton-wool spots and retinal ischemia of variable extent with amyloid deposition in the vitreous fluid (Fig. 6) [143][144][145].Retinal changes occur in about 20% of patients and is more prevalent in patients with Y114C mutation [146].Choroidal amyloid angiopathy has also been described in the form of late hyperfluorescence on ICG along the choroidal vessels (Fig. 6E) [147,148].
Transthyretin amyloidosis may be misdiagnosed as any posterior uveitis with vitreous opacities resulting in a significant diagnostic delay [149,150].[151].

Misdiagnoses among
Acute syphilitic posterior placoid chorioretinitis (ASPPC) that presents as a large, yellowish, circular or oval, placoid lesion at the level of the RPE in or near the macula [152].But one must keep in mind that syphilis has variable manifestations and can mimic many other inflammatory dis- eases, both infectious and autoimmune.Its nickname as 'the great impostor" is wellearned [153].A retrospective observational case series of patients who had intraocular inflammation due to syphilis over a 15-year period showed that presentations included: isolated anterior non-granulomatous uveitis, intermediate uveitis, panuveitis, papillitis, placoid chorioretinitis and frank retinitis.Among those with a late diagnosis, spreading retinitis was observed.Syphilitic retinitis can mimic a viral ARN.Although it is easy to identify syphilis-related placoid lesions as syphilis-related, retinitis lesions can be difficult to relate to syphilis as the differential for retinitis is broad, including large retinochoroiditis secondary to toxoplasmosis, viral ARN, and fungus endophthalmitis among others.Specific features of syphilitic retinitis have been described to narrow the differential of retinitis.These include superficial retinal precipitates, inner retinitis, and outer retinitis [154,155].Patients may also display yellowwhite patches of diffuse retinitis and coalescent posterior pole retinal whitening representing necrosis [156].Retinal vascular sheathing may also be noted, representative of occlusive pathology with retinal ischemia due to endarteritic changes in the setting of syphilis [157].Another pattern of disease occasionally reported is a punctate retinitis limited to more peripheral retina that is otherwise interpreted as miliary lesions.They are small round to oval, yellow retinal lesions, measuring less than one-fourth of a disc diameter size, with distinct margins, involving complete thickness of retina on OCT, in a pillar like manner, associated with ground glass retinitis, and an outer retinal placoid lesion or with retinal vasculitis [158,159].These lesions are of particular interest because they may be characteristic of ocular syphilis but misdiagnosed as another uveitis entity [158].
a.1.2.Retinochoroiditis secondary to Toxoplasma gondii Toxoplasmosis is the most common cause of posterior uveitis in many countries and presents commonly as a typical retinochoroiditis with unilateral focal retinitis at the border of a preexisting pigmented retinochoroidal lesion and overlying vitritis [160].In immunocompetent patients older than fifty and in immunocompromised patients, the toxoplasmic infection remains an important cause of posterior/ panuveitis and its presentation in those populations are notably atypical.These atypical lesions consist of large areas of retinal necrosis or retinochoroiditis without adjacent preexisting pigmented retinal scar or retinochoroiditis in both eyes [160][161][162][163][164].
The value of performing an anterior chamber paracentesis for laboratory evidence of ocular toxoplasmosis in the aqueous humor is paramount in differentiating Patients with Tb-SLC come from highly endemic regions, and some clinical features in favor of presumed Tb-SLC rather than SC, include significant vitritis, multifocal lesions, and serpiginous lesions in the posterior pole and periphery [165].Cases of SC, in contrast, reveal minimal or no vitritis and frequently show bilateral involvement with larger solitary lesions extending primarily from the juxtapapillary area and sparing the periphery [166].Bansal et al., reported that in eyes with Tb-SLC, vitreous inflammation was present in 81% of eyes, multifocal lesions in 94%, and noncontiguous to optic disc in about 87% of eyes [165].
Interestingly, it has been shown that OCT may help differentiate between Tb-SLC and SC since vitreous hyper-reflective spots, intraretinal fluid, sub-RPE drusenoid deposits, and choroidal granulomas on OCT images may indicate Tb-SLC [167].
There are specific diagnoses thought to be related to MEWDS: acute idiopathic blind spot enlargement syndrome (AIBSE), acute zonal occult outer retinopathy (AZOOR) which can affect the retina around and away from the disc; acute macular neuroretinopathy with unilateral para-central scotoma; and also cancer and melanoma-associated retinopathies (CAR).Below we will focus on various entities that can mimic the white dots syndromes: b.1.1.Acute Posterior Multifocal Pigment (APMPPE) misdiagnosed for Vogt-Koyanagi-Harada (VKH) disease.
APMPPE is an immune-driven, rare inflammatory eye disease.Choriocapillaris hypoperfusion has been recently described as the primary event in the pathogenesis of APMPPE with the hypothesis being that, in APMPPE, an isolated disruption to the choriocapillaris leaves the choroid in a sufficiently functional state to largely maintain the RPE/photoreceptor integrity [185][186][187].
Some APMPPE cases may have overlapping findings with VKH.In such atypical APMPPE cases, inflammation may manifest as a retinal detachment at the level of photoreceptor inner segment myoids that is named as a bacillary layer detachment [188].This phenomenon has also been previously documented in VKH [189] and in macular toxoplasmosis chorioretinitis with the hypothesis that degenerating cone photoreceptors are capable of shedding their inner segments and that patients with preexisting pachychoroid spectrum disease may manifest a more significant retinal fluid accumulation in the setting of superimposed chorioretinal inflammation.In sum these phenomena result in a bacillary layer detachment.Li et al. and Ketamura et al. have described case reports with unilateral fundus placoid and typical FA findings for APMPPE [190,191].On OCT however, patients had cystic retinal detachments and outer retinal disruption that was more suggestive of VKH than APMPPE.However, the absence of the 'starry sky' appearance that is typically seen in VKH sug-gested instead an atypical presentation of APMPPE.In our experience we have also encountered similar atypical APMPPE findings with a detachment that apparently separated the photoreceptor inner segment myoids from inner segment ellipsoids.
b However, it is usually unilateral and not associated with neurologic signs or cutaneous findings.B-Scan ultrasonography remains an important modality which may show the classic but non-pathognomonic T-sign, which represents fluid collection in the sub-Tenon space and the optic nerve sheath, with variable degree of thickening of choroid and sclera [109].
VKH itself is one of the most common causes of misdiagnosis of CSCR.The similarities between the two conditions are subretinal detachment, leakage from RPE in FA as well as bullous retinal detachment in certain atypical CSCR [109].FA shows multifocal pinpoint leaks in both, but less numerous in CSCR and with the addition of late prominent pooling in the area of subretinal fluid and late optic disc staining in VKH [109].ICG demonstrated multiple areas of choroidal hyperpermeability in CSCR, in contrast to VKH, where it demonstrates diffuse choroidal hyperpermeability and hypofluorescent dark dots [192,193].FAF shows diffusely speckled hyperautofluorescence related to longer duration of CSCR, a feature not seen in VKH [194].
b.1.3.Choroidal granulomas (CGs) in sarcoidosis masquerading like birdshot chorioretinopathy lesions (BC) lesions on Indocyanine Green Angiography (ICG) Choroidal granulomas (CG) in the absence of anterior uveitis are rare but well-recognized manifestation of sarcoidosis, occurring in approximately 5% of patients with ocular sarcoidosis [195].CGs manifesting as the sole lesion in ocular sarcoidosis has been previously described [195][196][197][198].All CGs showed increased transmission of the OCT signal as compared with the surrounding choroid [203].EDI-OCT may also be more sensitive than ICG in detecting early variations in the size of choroidal granulomas in response to treatment [204].Furthermore, the location of CG (optic disc nodules and/or solitary choroidal nodules) can be suggestive of a sarcoidosis rather than other hypofluorescent lesions on ICG like BC (≥ 3 peripapillary birdshot lesions are required for diagnosis) [205,206] Sarcoidosis typically affects the eyes in the form of both anterior, posterior and panuveitis.Peripheral sarcoid lesions can be mistaken for pavingstone degenerative lesions that are commonly seen on dilated fundus exam, though upon closer examination there are clear clinical differences.Multiple chorioretinal peripheral lesions or small clustered yellowish lesions located in the peripheral infero-temporal retina are suggestive of sarcoidosis.The consensus workshop of an international committee for diagnostic criteria for ocular sarcoidosis have shown that multiple chorioretinal peripheral lesions (active and/or atrophic) are suggestive of ocular sarcoidosis [222].These white lesions can be the earliest manifestation of sarcoidosis, even when systemic work-up is negative for the disease, and they differ from late pavingstone lesions in that they are fine looking, smaller, and lack atrophic changes [223].Etanercept is the most commonly implicated drug and patients with spondylarthropathies are more commonly affected by this adverse reaction.However, there have been documented cases in patients with rheumatoid arthritis, psoriatic arthritis and juvenile idiopathic arthritis.There are also select cases published implicating adalimumab, and infliximab [36,39,[224][225][226][227][228].With etanercept, uveitis, scleritis and a sarcoidosis-like syndrome with ocular granulomas have been reported [225,229].
Infliximab has been linked to uveitis, and sterile endophthalmitis.
Adalimumab has been found to paradoxically cause retinal toxicity [225].
Etanercept is significantly more likely to be associated with uveitis than either infliximab (odds ratio 5.375) or adalimumab (odds ratio 8.6).Etanercept is known for worsening the uveitis course or even for inducing inflammation, as a paradoxical effect [230].
Etanercept is a dimeric protein that is part-TNF-a receptor and part-Fc molecule of IgG.It prevents TNF from binding to cell-surface receptors.Etanercept is unique in the anti-TNF α medication category in that it preferentially inhibits the TNFα receptor, acting as a decoy.Unlike infliximab and adalimumab, which preferentially inhibit the free-floating soluble TNF α molecule.Several theories exist as to why etanercept causes intraocular inflammation, contrary to its TNF α counterparts, it does not inhibit interferon gamma (IFN-γ) which has been shown to cause intraocular inflammation, scleritis, and a sarcoidosis-like syndrome.
Moreover, the relationship between anti-TNF α and induction of optic neuritis associated with demyelinating diseases remains unclear, but in several cases the etiology suggests both golimumab and certolizumab.

Conclusions
In this review, we described both ophthalmic pathology that can falsely mimic posterior uveitis as well as often under-considered etiologies of posterior uveitis.We highlighted posterior uveitis mimickers that are not included in the group of immune-mediated uveitis entities, classically identified as "Uveitis Masquerade Syndromes".
Our review yields several important takeaways.In cases of recurrent or persistent ocular inflammation, or in cases with an unclear history, it is important to rule out underlying neoplastic disease, as these entities often require different treatment, and may carry systemic implications along with implications on patient survival.
Additionally, it is always important to consider nonmalignant, mimickers of posterior uveitis.Inherited retinal conditions, such as retinitis pigmentosa and the vitreoretinopathy, FEVR, can mimic chronic posterior and intermediate uveitis.Conversely, a rare, heterogeneous, group of inherited vitreoretinopathies (ADNIV, VCNA-related vitreoretinopathy) and inherited retinal diseases can present with uveitis and vitreoretinal degeneration.This highlights the overlapping features of these conditions with more common etiologies of posterior uveitis and the importance of genetic testing.The ability to make a correct diagnosis is crucial for patient treatment as well as genetic counseling.
Having a high suspicion for infectious uveitis is also crucial, since the correct diagnosis and treatment can potentially prevent rapid vision loss, such as in ARN, serpiginous-like tuberculosis, T. gondii, and syphilis.Misdiagnosing one of these infectious conditions and starting an immunosuppressive treatment may lead to exacerbation of tuberculous infection and even death.The lack of accurate diagnosis in some uveitis entities like serpiginous-like tuberculosis makes it difficult to differentiate with idiopathic SC, especially in non-endemic areas for tuberculosis.The distinct location of the fundus lesions is the only clear way to decipher between the two entities.This is particularly confusing since the angiographic pattern is similar in both classic SC and presumed Tuberculosis-SLC and the labs/imaging are often negative except for positive interferon-gamma (IFNγ) release assay or tuberculin skin test results in the latter entity.
In a systemic disease like in SLE, the clinical inflammatory features can be difficult to detect.A noninflammatory, Purtcher retinopathy can be wrongly suspected.Moreover, the ocular involvement with multiple CWS, and retinal whitening may also lead to a misdiagnosis of viral retinitis and not to a Purtscherlike retinopathy especially when presenting as an initial manifestation of SLE.This is a sight threatening condition if not immediately appropriately treated.Similarly, missing a diagnosis of GCA with presence of isolated CWS can lead to devastating visual outcomes.We provided insights into distinct clinical features and specific findings on multimodal imaging in the outline above.OCTA may be useful by demonstrating a decrease in retinal vessel density as a marker of SLE retinopathy.Moreover, the delayed choroidal perfusion on FA can be a marker of GCA.
The relative rarity of some diseases, like ocular amyloidosis that can present as a choroidal amyloid angiopathy mimicking an intermediate/ posterior uveitis makes the diagnosis even more challenging.
Drug and vaccine related etiologies of uveitis have been increasingly important to consider.Indeed, growing data has implicated targeted cancer therapies (i.e., ICIs or MEKi), intravitreal injections and vaccines with intraocular inflammation.Macular edema or a serous retinal detachment can be a VKH-like disease secondary to ICIs or a MEK inhibitors retinopathy.The recent reports of posterior uveitis cases (including MEWDS, APMPEE, ampiginous choroiditis, VKH, herpetic disease and associated uveitis) after COVID-19 vaccines are particularly worrisome, especially when considering future COVID-19 vaccinations.
A high index of suspicion must be maintained for masqueraders of posterior uveitis, which can include serious inflammatory, infectious, and neoplastic disorders.This study highlights the overlapping features of posterior uveitis and retinal conditions and mimickers of posterior uveitis.Careful review of past uveitis history, current medications and recent vaccinations, along with detailed examination looking for signs of past or present inflammation and distinct findings on multimodal imaging may all be required to make the correct diagnosis.
Making the correct diagnosis for posterior uveitis and its masqueraders can be challenging even for the experienced uveitis or retina specialist, and one must maintain a broad differential initially to identify rare entities.This review provides insights into distinct clinical features and specific findings on multimodal imaging.We hope it will aid the general ophthalmologist or retina specialist to narrow the diagnosis to the correct one, perhaps preventing unnecessary vision loss in a patient who presents with an atypical clinical picture.

Method of literature search
Databases and registries that were searched included Pubmed/Medline, EBSCO, and Cochrane Library to keywords and subject headings defined in Supplementary Table 1.Briefly, the search terms used were: Posterior uveitis OR Panuveitis OR inflammatory Uveitis OR Infectious Uveitis OR Neoplastic Uveitis OR Masquerader syndrome OR Uveitis mimickers OR medication induced uveitis OR White-Dot-Syndromes OR Post-Vaccination Uveitis).The search timeframe was not limited by a specific date, but rather by the results of the articles retrieved.
The retrieved articles were initially screened by title and abstract, and articles with the relevant titles were then screened by full text using predefined inclusion and exclusion criteria.Inclusion criteria.The full article was screened in cases where the relevance was unclear from the abstract.Relevant articles were ultimately compiled into a database and removed of duplicates.
Inclusion criteria for articles were: 1) the paper must be written in or available in English and 2) the paper discussed the presentation and management of masquerade syndromes, inflammatory and infectious ocular diseases and uveitis.Exclusion criteria included 1) the paper concerned patients only with other inflammatory ocular diseases and uveitis 2) the paper did not clearly diagnose the patient with masquerade syndromes 3) citations were from grey literature.

Fig. 1
Fig. 1 Multimodal imaging in a 51-year-old female with acute pseudo-Vogt-Koyanagi-Harada (VKH) following one month treatment with a combination of ipilimumab/nivolumab (CTLA-4 and PD-1 checkpoint blockade inhibitors) for a malignant melanoma of the skin.A The fundus photograph of the left eyes reveals multiple deep yellow choroidal lesions with areas of the subretinal detachments in the peripapillary region.B Note multiple hyperfluorescent retinal pigment epithelium leaks on fluorescein angiography with hyperfluorescent dye pooling beneath subretinal fluid.C Optical coherence tomography (OCT) in pseudo-VKH showed a multilobular serous macular detachments, with subretinal hyper-reflective material within the subretinal fluid that likely represents fibrin and a part of the outer segment layer

Fig. 3
Fig. 3 Fundus color pictures of a 75-year-old female with Giant cell arteritis (GCA) proven by a bilateral temporal artery biopsy.Note bilateral cotton-wool spots without optic disc edema seen in the right (A) and left (B) eyes

Fig. 4
Fig. 4 Multimodal image of a patient with familial exudative vitreoretinopathy.Wide field Optos fundus photos of the right (A) and left (B) eye show perivascular sheathing, worse on the right eye.Fluorescein angiogram shows focal venous leakage with staining of lesions temporal to the macula (C).Both the right and the left eye show diffuse peripheral leakage with capillary dropout in the periphery (D)

Fig. 6
Fig. 6 Fundus color picture of a 46-year-old female with transthyretin amyloidosis.She initially was referred for blurry vision as a case of intermediate uveitis (vitritis) and retinal vasculitis in the right eye and a pars plana vitrectomy was performed in the right eye.She later presented with a left eye involvement.The pictures demonstrate retinal vascular sheathing as shown in arrows in the right eye (A) and intermediate uveitis with vitritis in the left eye (B).The genetic diagnosis of transthyretin amyloidosis was made.Fluorescein angiography showed focal vascular staining in intermediate phase (arrow) (C).The Spectral Domain OCT (SD-OCT) showed a deposit perpendicular to the retinal surface towards the vitreous from the retinal vessel (arrow) (D), and hyperfluorescent foci and staining along choroidal and retinal vessels in the supero-, infero-and temporal periphery on ICG in late phase (E)

c. 3 .
Drug related.Paradoxical inflammatory effects of anti-Tumor necrosis factor α (TNFα) and uveitis Paradoxical inflammatory effects of anti-Tumor necrosis Factor-α (anti-TNFα) have been noted most probably because of a disequilibrium in cytokine balance and include exacerbation or initiation of druginduced autoimmune diseases, and uveitis.