Noninfectious Posterior Uveitides — Atypicals, Variants, and Masquerades: The Jungle of Differential Diagnosis

Purpose

Consensus efforts by the Multimodal Imaging in Uveitis (MUV) Task Force have established standardized diagnostic criteria for the major non-infectious posterior and panuveitides (NIPUs), historically referred to as “white dot syndromes”. Nevertheless, a substantial proportion of cases deviate from classical presentations and fall into diagnostic “grey zones”, blurring boundaries between diseases entities and complicating both differential diagnosis and management. This paper aims to describe the broad spectrum of atypical, variant, and secondary forms of NIPUs as well as masquerade syndromes.

Methods

Perspective article with narrative review and illustrative cases.

Results

Atypical multiple evanescent white dot syndrome (MEWDS) includes bilateral presentations or complicated courses, while multifocal choroiditis and panuveitis/punctate inner choroiditis (MFCPU/PIC) with outer retinal atrophy emerges as a notable entity with unclear therapeutic implications. Inflammatory reactions resembling both MEWDS and MFCPU/PIC may also occur as secondary phenomena, triggered by other chorioretinal disorders, most notably inherited retinal diseases (IRDs). Placoid chorioretinopathies, including acute posterior multifocal placoid pigment epitheliopathy, persistent placoid maculopathy, serpiginous choroiditis, and relentless placoid chorioretinitis, are often distinguished only a posteriori based on disease course, but likely represent a continuum of disorders unified by choroidal ischemia. Atypical presentations of birdshot chorioretinopathy may feature extensive outer retinal damage, mimicking IRDs. Equally important is the consideration of masquerade syndromes in all suspected cases of NIPUs, as they can present with similar features yet require entirely different treatments. Infectious masquerades include tuberculosis-associated serpiginous-like choroiditis, acute syphilitic posterior placoid chorioretinopathy, and West Nile virus chorioretinitis, whereas vitreoretinal lymphoma is the most frequent neoplastic masquerade.

Conclusions

Integrating clinical context with high-quality multimodal imaging remains essential to navigate the jungle of differential diagnosis in NIPUs. Future studies should aim to integrate imaging phenotypes with immunologic and molecular biomarkers to refine disease classification and support more targeted therapeutic strategies.

INTRODUCTION

N oninfectious posterior and panuveitides (NIPUs) represent a heterogeneous group of ocular disorders characterized by chorioretinal inflammation of presumed autoimmune origin and unknown etiology, often leading to significant vision loss. Within this spectrum, a number of distinct clinical entities share the hallmark feature of multiple, discrete white lesions located at the level of the outer retina and choroid. These conditions have traditionally been grouped under the umbrella term “white dot syndromes” (WDS). ^, However, as recently emphasized by the Multimodal Imaging in Uveitis (MUV) Task Force, this terminology is a misnomer, and these entities are more appropriately referred to as NIPUs. In this manuscript, we will adopt the term NIPU throughout, while using WDS only when referring to the historical classification. Although these conditions share certain imaging and clinical features, they differ substantially in presentation, course, prognosis, and therapeutic approach. For most NIPUs, the absence of specific laboratory or radiologic tests, as well as the lack of consistent systemic associations, means that diagnosis rests heavily on multimodal retinal imaging (MMI). Advances in MMI over the past decade have substantially refined our understanding of NIPU, leading to the Standardization of Uveitis Nomenclature (SUN) criteria for most of these entities. ^,^,^,^,^,^, However, consensus is lacking regarding the minimal set of imaging modalities required for accurate diagnosis, as well as the specific findings that reliably indicate disease activity. To address this, the MUV initiative of the International Uveitis Study Group (IUSG) has developed evidence- and expert-based imaging guidelines for the five major NIPUs traditionally included under WDS: Multiple Evanescent White Dot Syndrome (MEWDS), Multifocal Choroiditis with Panuveitis (MFCPU)/ Punctate Inner Choroiditis (PIC), Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE), Serpiginous Choroiditis (SC), and Birdshot Chorioretinopathy (BSCR). ^,^,^,^,^,^, While these guidelines standardize core disease definitions and imaging features, they inevitably leave a wide “grey zone” in which atypical or variant presentations occur, blurring the boundaries of diagnostic categories, hinder accurate assessment of disease activity, and present significant therapeutic challenges. Furthermore, infectious and neoplastic conditions can masquerade as autoimmune NIPU, with overlapping imaging features that can result in misdiagnosis and inappropriate treatment.

This review builds on the core MUV studies of NIPUs ^,^,^,^,^,^, to examine the broader spectrum of conditions presenting with white spots, including atypical forms, variants, and masquerades. By integrating evidence from the literature with selected illustrative cases, we aim to underscore the main pitfalls in the differential diagnosis of NIPUs, with emphasis on the role of MMI in these challenging scenarios and its implications for clinical management and therapeutic decisions.

ATYPICAL AND VARIANTS OF NIPUs

MEWDS

MEWDS is an inflammatory outer retina disease first described by Jampol et al. , which typically occurs in mildly myopic young females with sudden-onset photopsias, blurred vision, or visual field defects. It is usually unilateral and characterized by multiple white spots at the level of the outer retina, foveal granularity, and a “wreath-like” pattern of leakage on fluorescein angiography (FA) with minimal or no vitritis. MMI has refined its characterization, as highlighted in the MUV consensus guidelines. Fundus spots are hyperautofluorescent on fundus autofluorescence (FAF) and correspond to areas of ellipsoid zone (EZ) disruption on optical coherence tomography (OCT); late-phase indocyanine green angiography (ICGA) reveals matching hypofluorescent dots without early-phase choroidal hypoperfusion, and OCT angiography (OCTA) typically shows no choroidal flow deficits. ^,^, These findings support the hypothesis of idiopathic outer retinal inflammation rather than ischemic choriocapillaritis, though the primary site of insult- photoreceptors vs RPE- remains debated. ^, Typical MEWDS resolves spontaneously within weeks to months without treatment, although incomplete visual recovery has been reported.

Atypical MEWDS

Atypical MEWDS encompasses presentations that deviate in disease onset, lesion pattern or characteristics, or clinical course. These include bilateral or recurrent involvement, absence of visible lesions on one or more imaging modalities, atypical lesion morphology or distribution, and prolonged recovery or persistent EZ disruption after clinical resolution. ^,^,^, Although atypical presentations may account for up to 20% of MEWDS cases reported in the literature, recurrent primary MEWDS remains exceptionally rare, occurring in approximately 5% of cases. Among the limited number of recurrent cases described, a temporal association with vaccination (most commonly COVID-19 vaccination) has been reported, although causality remains unproven and reporting bias cannot be excluded. Recognition of these atypical presentations is essential, as they may mimic or overlap with other NIPUs. Still, in all patients clinically diagnosed with MEWDS, given the overlap of MMI features, syphilitic posterior uveitis must be excluded, particularly in cases with bilateral involvement, whether asynchronous or asymmetric, or when spontaneous resolution is delayed or absent. ^,^,

Secondary MEWDS

While MEWDS, either typical or atypical, occurs in otherwise healthy eyes, it can also develop in association with other chorioretinal disorders. This form, referred to as secondary MEWDS (previously also “MEWDS-like reactions” or “epiphenomenon MEWDS”), ^, most often follows conditions involving substantial disruption of the RPE-Bruch’s membrane (BM) complex. Reported triggers include MFCPU/PIC, ^, Inherited Retinal Diseases (IRDs), such as Best Vitelliform Macular Dystrophy and North Carolina Macular Dystrophy, ^,^, Extensive Macular Atrophy with Pseudodrusen-like appearance (EMAP), as well as infectious chorioretinopathies, particularly ocular toxoplasmosis, ^, congenital anomalies such as optic disc pits and colobomas, ^, and vitreoretinal surgical procedures. Disruption of the RPE-BM complex may compromise the immune privilege of the outer retina, exposing sequestered antigens to the systemic immune system and allowing access to circulating lymphoid cells and cytokines, possibly triggering an inflammatory response in predisposed individuals. Clinically and on imaging, secondary MEWDS closely resembles the primary form but typically presents with fewer, smaller, and more asymmetrically distributed lesions on late-phase ICGA and FAF, often clustered around the inciting lesion and expanding centrifugally ( Figure 1 ). ^, Secondary MEWDS rarely arises concurrently with the triggering event and may instead occur years later, often coinciding with recurrent activity of the underlying disease, such as in MFCPU/PIC. Evidence regarding the natural history and optimal medical management of secondary MEWDS remains extremely limited. In our experience, secondary MEWDS episodes warrant a short course of oral glucocorticoids, which usually leads to resolution of the superimposed inflammatory findings. When the triggering condition is MFCPU/PIC, secondary MEWDS lesions may exhibit a delayed response to oral glucocorticoids compared with more typical focal chorioretinal inflammatory lesions ( see section 2.2 ). This delayed response may reflect distinct underlying immunologic mechanisms; however, it does not appear to influence the long-term course or sequelae of the underlying disease.

MFCPU/PIC

MFCPU, first described by Dreyer and Gass, is an idiopathic posterior uveitis characterized by a combination of active, ill-defined yellow-white chorioretinal lesions and inactive, punched-out atrophic scars with hyperpigmented borders, often accompanied by mild anterior chamber and vitreous inflammation. In the same year, Watzke et al. introduced PIC as a posterior pole-confined form of the disease with minimal or no intraocular inflammation but a high risk of choroidal neovascularization (CNV). Both conditions share overlapping imaging features and are now considered part of a disease spectrum, with PIC representing the more localized phenotype. ^,^,^, MFCPU/PIC predominantly affects young myopic females, but phenotypic variability exists. High myopia likely acts as a structural and immunologic modifier, predisposing to a more aggressive inflammatory course with recurrent activity, multifocal lesions, and increased treatment burden. ^, Hady et al. reported that 11% of eyes with patchy atrophy secondary to pathologic myopia exhibited active lesions consistent with PIC, with an increased risk of CNV and progression toward chorioretinal atrophy. Indeed, management often requires a combination of oral glucocorticoids, and long-term immunomodulatory theraphy (IMT) to prevent relapses and limit irreversible complications such as fibrosis and atrophy, and intravitreal anti-VEGF injections when CNV is present. ^, The MUV consensus guidelines for MFCPU/PIC highlighted how OCT is the preferred modality for detecting lesions with active chorioretinal inflammation. Typical OCT findings include subretinal hyperreflective material with EZ disruption extending beyond the lesion margins, often associated with pigment epithelium detachment (PED) and discontinuity of the RPE. Careful inspection of the choroid may also reveal focal thickening. Furthermore, OCTA is particularly valuable for the noninvasive detection of CNV. ^,^,^, However, its ability to assess lesion activity remains limited, and treatment decisions still rely on the evaluation of leakage on FA. However, atypical findings or variant phenotypes of MFCPU/PIC can be noted using the full of MMI.

Outer retinal atrophy (ORA) in MFCPU/PIC

Zonal, multizonal, or diffuse ORA is an increasingly recognized, vision-threatening complication of MFCPU/PIC. ^,^, On OCT, it typically manifests as diffuse EZ loss, while FAF demonstrates hyperautofluorescent areas attributable to a window effect, in the absence of associated RPE or choroidal abnormalities. However, late-phase ICGA usually show no hypofluorescent spots, unlike in secondary MEWDS. These changes may develop adjacent to clinically inactive lesions, or even at a distance ( Figure 2 ). Clinically, patients report acute-onset photopsias accompanied by persistent zonal visual field loss. ^,^, However, it remains unclear whether the resulting ORA reflects recurrent inflammatory episodes, persistent low-grade activity, or a single acute event that may have been amenable to early treatment. Outcomes of ORA complicating MFCPU/PIC are reported as variable. In most cases, it appears irreversible and may either progress or remain stable irrespective of ongoing IMT. However, partial or complete recovery of visual function and retinal structure has been reported following prompt administration of oral glucocorticoids or IMT, or even spontaneously. ^, Thus, to date, the role of local or systemic therapies in preventing or limiting the development of ORA in MFCPU/PIC remains uncertain because of the extremely limited available evidence, warranting further studies on its prevalence, risk factors, and medical management. Of note, it must be born in mind that also inactive PIC lesions may exhibit a narrow hyperautofluorescent cuff corresponding to a region of EZ loss, which may persist even in the absence of other signs of active inflammation. Such a finding does not warrant treatment or escalation of ongoing IMT, although it may be associated with an increased risk of recurrent chorioretinal inflammation.

PIC within the pachychoroid diesease spectrum

The pachychoroid disease spectrum (PDS) encompasses a group of disorders- including central serous chorioretinopathy, pachychoroid pigment epitheliopathy, pachychoroid neovasculopathy, and focal choroidal excavation- characterized by increased subfoveal choroidal thickness, dilated outer choroidal (Haller’s layer) vessels, attenuation of the choriocapillaris, and choroidal vascular hyperpermeability. Recent studies have shown that a subset of patients who meet clinical and imaging criteria for PIC may instead exhibit features of PDS rather than the more typical findings of high myopia and choroidal thinning. In such cases, focal choroidal excavation is more common, and late-phase ICGA often demonstrates choroidal hyperpermeability, findings that are atypical for PIC, which is classically associated with myopia. Ramtohul et al. proposed the term “punctate inner pachychoroidopathy” (PIP) to describe emmetropic or minimally myopic patients with PIC-like lesions in the setting of a pachychoroid. The pathophysiology remains incompletely understood, but the coexistence of PDS features suggests a role for choroidal venous congestion in initiating or sustaining the chorioretinal inflammatory process.

Chrysanthemum phenotype of MFCPU

The chrysanthemum phenotype is a recently described variant of MFCPU characterized by a distinctive lesion morphology and clinical course. Lesions consist of a central gray-yellow core surrounded by multiple radially arranged satellite dots, resembling layered chrysanthemum petals. They are best visualized on en face OCT and infrared reflectance imaging and may coexist with more typical MFCPU/PIC lesions. Also this phenotype occurs predominantly in emmetropic or mildly myopic eyes. Clinically, it is associated with a high risk of recurrence, subretinal fibrosis, and CNV, as well as secondary MEWDS, which has been reported in approximately 60% of eyes.

Secondary MFCPU/PIC

MFCPU/PIC-like lesions can also arise secondarily in eyes with other chorioretinal disorders, including IRDs such as pseudoxanthoma elasticum (PXE), marked by extensive disruption of the RPE-BM complex, and retinitis pigmentosa (RP) or rod-cone dystrophy (RCD), characterized by primary photoreceptor degeneration. In 2019, Gliem et al. described an acute inflammatory retinopathy in PXE, likely triggered by exposure of outer retinal antigens through RPE-BM breaks, known as angioid streaks, and leading to significant visual impairment in affected patients. This autoimmune reaction usually presents with features of MFCPU/PIC, including hyperreflective subretinal material protruding into the outer retina through a discontinuity of the RPE-BM accompanied by choroidal thickening. These lesions regress with permanent outer retinal damage and may relapse multiple times, ultimately culminating in widespread alterations with subretinal fibrosis at the posterior pole and mid-peripheral punched-out atrophic scars ( Figure 3 ). ^,^,^, Alternatively, acute retinopathy in PXE may also manifest with MEWDS-like features, such as those mentioned in the previous section, most notably focal or diffuse EZ disruption. ^, Although the relationship between these inflammatory manifestations remains poorly understood and warrants further investigation, Ramtohul et al. proposed that secondary MFCPU/PIC represents the predominant phenotype of acute retinopathy in PXE, with MEWDS features occasionally superimposed. Differently, in IRDs with primary photoreceptor degeneration such as RP or RCD, secondary MFCPU/PIC may be explained by the frequent association of these conditions with high myopia, itself a recognized risk factor for MFCPU/PIC, rather than by substantial disruption of the RPE-BM complex. ^, Clinically, secondary MFCPU/PIC complicating RP/RCD often presents with acute or subacute visual decline. On fundus examination and MMI, chorioretinal inflammatory lesions resemble those observed in the primary form of MFCPU/PIC ( Figure 4 ). ^, Acute episodes can be effectively managed with short courses of oral glucocorticoids, although frequent relapses may necessitate long-term IMT. As with primary MFCPU/PIC, secondary forms can lead to vision-threatening complications, including macular atrophy, subretinal fibrosis, and CNV, the latter requiring adjunctive intravitreal anti-VEGF therapy. ^, In some cases, the coexistence of MFCPU/PIC lesions with features typical of RP/RCD, such as diffuse EZ loss or bone-spicule pigmentation, makes it difficult to determine whether the presentation represents an IRD complicated by secondary MFCPU/PIC, or primary MFCPU/PIC complicated by extensive ORA, particularly when findings are unilateral or markedly asymmetric ( Figure 5 ). In such cases, evaluation by an IRD specialist is essential and should include careful assessment of family history, symptom chronology and clinical presentation, particularly distinguishing impaired dark adaptation or night blindness from acute onset photopsias and visual field loss, electrophysiological testing, and ultimately molecular genetic analysis using up to date large gene panels or genome sequencing. ^,

PLACOID CHORIORETINOPATHIES

Formal diagnostic criteria for APMPPE have been established in a MUV consensus guidelines, defining the disease as an acute, bilateral, multifocal disease characterized by inner choroidal hypoperfusion and outer retinal disruption on MMI. However, APMPPE represents only one part of a broader group of idiopathic placoid chorioretinopathies that share inner choroidal and outer retinal ischemia as pathophysiologic mechanisms but differ in clinical course, prognosis, and therapeutic needs. These include persistent placoid maculopathy (PPM), serpiginous choroiditis (SC), and relentless placoid chorioretinitis (RPC). All present with creamy yellowish-white placoid lesions, acute-phase angular sign of Henle’s fiber layer hyperreflectivity (ASHH) on OCT, early-phase ICGA hypofluorescence, and confluent choriocapillaris flow deficits on OCTA, but their patterns of lesion distribution, duration of activity, recurrence risk, and long-term outcomes vary substantially. ^,

APMPPE typically affects young adults of both sexes and presents bilaterally. Although the disease is usually self-limiting with spontaneous resolution in most cases, incomplete functional and structural recovery may occur, and treatment with oral glucocorticoids may therefore be considered despite limited evidence. Importantly, APMPPE has been associated with cerebral vasculitis and an increased risk of stroke, warranting neuroimaging even in patients without overt neurological symptoms. ^, PPM generally affects middle-aged adults and and presents bilaterally, often with asymmetrically distributed ill-defined placoid lesions primarily involving the macula. The disease course is chronic and frequently complicated by macular atrophy, subretinal fibrosis, and CNV, which occurs in up to half of cases. Similarly, SC typically affects affects middle-aged adults, manifesting as bilateral yet asymmetric peripapillary amoeboid or serpentine lesions, and carries a high risk of CNV when the macula becomes involved, as highlighted in the MUV consensus guidelines. RPC (sometimes referred to as “ampiginous choroiditis”) shares MMI features with APMPPE but involves the mid- and far peripheral retina, where lesions tend to coalesce and extend toward the macula, ultimately resulting in widespread retinal atrophy. ^,^, Early initiation of IMT can be indicated for SC and RPC because of their progressive nature and high risk of irreversible visual loss, whereas APMPPE and PPM often resolve spontaneously and usually do not require long-term therapy. However, clinical overlap is common, and atypical presentations increasingly blur these distinctions. APMPPE may rarely present with hyperacute manifestations, such as bacillary layer detachment or papillitis, mimicking Vogt-Koyanagi-Harada (VKH) disease ( Figure 6 ). ^,^, Ultra-widefield imaging has revealed peripheral involvement in some APMPPE cases, challenging its distinction from RPC at presentation. Also, although APMPPE typically follows a monophasic, self-resolving course, relapses have occasionally been reported. Conversely, RPC may occasionally stabilize spontaneously, leaving stationary chorioretinal atrophy, that does not always require prolonged IMT ( Figure 7 ). Likewise, PPM can follow a “relentless” course with recurrent lesions or neovascular complications, necessitating extended corticosteroid or IMT use ( Figure 8 ). SC may also present with isolated macular lesions, mimicking PPM; in such cases, tubercular serpiginous-like choroiditis should be ruled out, as discussed later in this manuscript. Taken together, these observations suggest that APMPPE, PPM, SC, and RPC might represent a disease continuum driven by choroidal hypoperfusion and ischemia, and consequent clinical outcomes ranging from spontaneous resolution to chronic but stationary disease or even relentless progression. Notably, also the MUV expert committee acknowledged that MMI alone is insufficient to reliably differentiate among the various placoid chorioretinopathies, particularly at early stages or at presentation. Given that current classification largely relies on clinical course, which is assessed retrospectively and is possibly influenced by treatment, future imaging research is needed to identify early biomarkers with prognostic value that could guide evidence-based therapeutic strategies. In this context, widefield swept-source OCTA may allow improved localization and quantification of choroidal flow deficits.

BSCR

BSCR is a bilateral posterior uveitis that almost exclusively affects middle-aged Caucasian individuals and is strongly associated with the HLA-A29 major tissue histocompatibility antigen (hence sometimes referred to as “HLA-A29 uveitis”). Classically, BSCR presents with multiple cream-colored choroidal lesions radiating from the optic disc, although early stages may be ophthalmoscopically subtle and detected only on ICGA as hypofluorescent dots. FA typically shows typically shows optic disc and perineural leakage along large venous vessels. ^, Inflammation is typically mild, yet chronic vasculopathy and macular edema can cause progressive retinal dysfunction. ^, An atypical presentation of BSCR with outer retinal disruption (ORD) has recently been described, particularly in early-onset disease. This variant is characterized by EZ attenuation, external limiting membrane interruption, and focal hyperreflective mounds protruding into the outer nuclear layer on OCT. FAF typically shows irregular hyperautofluorescence with either a zonal distribution (peripapillary or along arcades) or diffuse macular pattern; the latter is associated with worse visual acuity at onset. Notably, these changes are invisible on color fundus photographs and may spare the foveal region, possibly explaining the frequent preservation of central vision. ^, ORD in BSCR appears largely reversible, with EZ restoration following prompt initiation of IMT. Thus, early recognition is critical to prevent permanent photoreceptor degeneration and irreversible vision loss. However, if left untreated, BSCR may progress to a burned-out stage characterized by extensive ORD and EZ loss, possibly leading to a diagnostic confusion with an IRD ( Figure 9 ). ^,

MASQUERADE SYNDROMES

Masquerade syndromes are a critical subset of conditions that may present with chorioretinal lesion patterns that closely mimic NIPUs on MMI but have an underlying infectious or neoplastic etiology. Although uncommon, they carry major diagnostic and therapeutic implications. In large uveitis cohorts, approximately 6% of patients ultimately prove to have a masquerade syndrome; of these, nearly one-third are due to neoplasms, most frequently primary vitreoretinal lymphoma (VRL), while the remainder reflect non-neoplastic causes, particularly infections in endemic regions or immunocompromised individuals. ^, These statistics underscore that a small yet clinically important proportion of cases initially labeled as idiopathic autoimmune uveities may in fact represent masquerades requiring entirely different treatment. In such cases, a definitive diagnosis often requires targeted laboratory, molecular, or histopathologic investigations, including infectious serologies or PCR assays on intraocular fluids for pathogens, as well as diagnostic vitrectomy. These ancillary investigations should be considered in any case of insidious-onset uveitis with atypical features, prolonged course, or poor therapeutic response, and should be tailored to the most likely diagnostic hypothesis, guided by MMI, in order to to establish the underlying etiology and guide appropriate management.

INFECTIOUS

Tubercular serpiginous-like choroiditis

The cornerstone of infectious masquerade syndromes mimicking NIPUs is serpiginous-like choroiditis associated with ocular tuberculosis (TB). Patients with systemic tuberculosis may develop a form of choroiditis that initially presents with unilateral, multifocal lesions with irregular borders, which progressively coalesce into serpentine or geographic patterns involving the posterior pole, while typically sparing the peripapillary region. ^,^,^,^, This presentation contrasts with idiopathic autoimmune SC, which usually begins in the peripapillary area and is often bilateral and monofocal, and should prompt evaluation for prior TB exposure, even in nonendemic regions. Supportive evidence includes a positive tuberculin skin test or interferon-gamma release assay, radiographic signs of pulmonary TB on chest imaging, or detection of Mycobacterium tuberculosis DNA in ocular fluid. Because this condition represents an infectious process with a strong immune-mediated component, management requires a two-pronged approach: systemic anti-TB therapy with multidrug regimens for infection control, combined with systemic glucocorticoids (or even conventional IMT in refractory cases) to limit inflammatory tissue damage. ^, When promptly recognized and treated, lesions typically heal with residual atrophic scars, although paradoxical worsening can occur in the first weeks after treatment initiation.

Acute syphilitic posterior placoid chorioretinopathy (ASPPC)

Syphilis is known as the “great masquerader” in medicine, and ocular syphilis is no exception. Treponema pallidum infection can cause posterior uveitis that closely mimics NIPUs. The most characteristic manifestation is ASPPC, presenting as a large, placoid, posterior creamy yellow-white lesion with indistinct margin. ^,^,^,^, This lesion typically appear hypofluorescent on late-phase ICGA with marked leakage on FA. ^, Although this clinical and imaging presentation may resemble that of other placoid chorioretinopathies, particularly APMPPE and PPM, ASPPC is distinguished by the absence of early-phase hypofluorescence on both FA and ICGA, which are hallmark features of inner choroidal ischemia. In ASPPC, the late-phase ICGA hypofluorescence likely reflects primary involvement of the RPE, possibly due to direct bacterial invasion. This angiographic pattern is highly characteristic of ocular syphilis. Recent studies have also demonstrated that syphilitic posterior uveitis may present with atypical phenotypes deviating from the classic placoid appearance, including masquerades of MEWDS characterized by multifocal hyperautofluorescent spots on FAF that appear hypofluorescent on late-phase ICGA ( Figure 10 ) . ^,^, For this reason, all patients with a presumed diagnosis of MEWDS should undergo prompt serologic testing using both treponemal and nontreponemal assays, as early recognition is critical to ensure timely initiation of appropriate systemic antibiotic therapy. ^,^,

West Nile virus (WNV) chorioretinitis

WNV infection can rarely spread to the retina and choroid, producing multiple bilateral chorioretinal lesions that may appear linear, clustered, or target-like, possibly resembling some clinical presentations of NIPUs, including MFCPU/PIC or APMPPE ( Figure 11 ). ^,^, A characteristic feature is lesion alignment along retinal nerve fiber bundles. Systemic manifestations such as fever, headache, or neuroinvasive disease usually accompany ocular findings. The ocular disease course is generally benign: lesions typically resolve with observation, and most patients recover vision with minimal sequelae. ^, Sometimes it can lead to retinal or optic nerve ischemia, especially in patients with pre-existent diabetic retinopathy. Diagnosis relies on serological or PCR confirmation of WNV infection. Management is primarily supportive, as no specific antiviral therapy is available. Recognizing the characteristic radial streak-like lesion pattern, in the appropriate epidemiologic context, aids timely and accurate diagnosis. ^,^,^,

Others

Beyond WNV, several arthropod-borne viruses (including Dengue, Zika, and Yellow Fever) have occasionally been reported to cause posterior uveitis with fundus white dots mimicking NIPUs. ^,^, These occurrences are less common, but clinicians should remain alert to these emerging infectious “mimickers” in endemic regions or during outbreaks. Finally, non-necrotizing retinitis caused by herpes simplex virus or varicella-zoster virus may present with fundus findings that resemble NIPUs ( Figure 12 ). ^,^,

NEOPLASTIC

VRL

Among all masquerade syndromes imitating NIPUs, VRL is the most frequent and clinically relevant. ^, Primary VRL is classified as an aggressive primary large B-cell lymphoma of immune-privileged sites, a group that also includes primary central nervous system (CNS) lymphoma, with which it is intimately related. Indeed, as part of its natural history, most cases of primary VRL develop CNS involvement, either concurrently or subsequently. Similarly, secondary vitreoretinal involvement can be observed in large B-cell lymphomas originating at other anatomical sites. ^,^,^, VRL may involve the vitreous, subretinal, and/or sub-RPE spaces. ^,^,^, VRL can closely resemble NIPUs because it usually present with vitreous cells and multifocal dull yellow-white outer retinal lesions, possibly leading to misdiagnosis and inappropriate IMT. However, there are important clinical clues that help distinguish VRL from autoimmune NIPUs:

•
Age at onset: VRL typically presents in older individuals, around the sixth decade of life, whereas most NIPUs occur in younger adults;
•
Laterality: VRL often presents unilaterally or with marked asymmetry, unlike NIPUs, which are usually bilateral;
•
Response to treatment: VRL lesions may progress despite adequate glucocorticoid therapy or exhibit only transient improvement followed by relapse, whereas NIPUs generally respond favorably within weeks or a few months.

Accordingly, persistent NIPU-like presentations in older adults, particularly those with unilateral onset, disproportionate vitreous involvement, poor or transient response to glucocorticoid, should prompt suspicion for a neoplastic masquerade. Clinical examination may reveal characteristic patterns of vitreous haze (termed “aurora borealis” and “string of pearls”), while several MMI features are highly typical of VRL and exceedingly uncommon in NIPUs, including a macular leopard-spot or giraffe-skin appearance on FAF, arising from alternating hypo- and hyperautofluorescent lesions related to RPE involvement, ^,^, and vitelliform macular deposits, indicating subretinal infiltration. ^,^, In such instances, corresponding OCT features include RPE nodularities, small sub-RPE deposits or larger PEDs, dome-shaped subretinal hyperreflective lesions or subretinal vitelliform deposits. ^, More rarely, VRL can present with subtler signs, characterized by multiple faint white dots with mild hyperautofluorescence on FAF, mimicking MEWDS. The presence of a diffuse, fuzzy appearance of the EZ, which is an extremely atypical feature for MEWDS and other NIPUs, may facilitate earlier recognition of VRL ( Figure 13 ) . Vertical hyperreflective columns extending from the RPE toward the inner retina, sometimes reaching the ganglion cell layer or retinal nerve fiber layer, represent another characteristic OCT finding of VRL and may also be observed in the absence of conspicuous FAF abnormalities. ^, Spontaneous modification or regression of fundus lesions with subsequent relapse is a recognized feature of VRL that can be readily observed on MMI and may contribute to diagnostic uncertainty and treatment delay. ^,^,^, Indeed, a definitive diagnosis of VRL requires confirmation via cytology or histopathology of large atypical lymphoid cells with B-cell markers. Tissue samples can be obtained through invasive procedures such as vitrectomy or chorioretinal biopsy. ^, However, molecular testing for recurring somatic MYD88 and CD79 variants, which can now be routinely performed also on aqueous humor samples, shows high sensitivity in most cases of VRL and provides valuable, rapid diagnostic support when more invasive procedures cannot be readily performed or are contraindicated. ^,^,^, In addition, a cytokine profile in intraocular fluids characterized by an interleukin-10 to interleukin-6 ratio greater than 1 is highly suggestive of VRL. ^,

Tags: American Journal of Ophthalmology Volume 287

Sep 20, 2026 | Posted by drzezo in OPHTHALMOLOGY | Comments Off