I n 1984, Jampol and associates first described a series of 11 patients with transient visual disturbances and unilateral ocular findings, which included multiple white dots located at the level of the retinal pigment epithelium (RPE) or deep retina. They termed this condition “multiple evanescent white dot syndrome” (MEWDS). In subsequent years, numerous other forms of non-infectious posterior uveitis (NIPU) entities characterized by multiple whitish, cream-colored to yellow-orange lesions affecting the posterior ocular structures were further characterized. Despite their different clinical appearances and more pronounced destructive effects on the retina, choroid, and RPE, these conditions were collectively categorized as white dot syndromes (WDS), alongside MEWDS. ^,

It should be noted that some authors prefer the term “white spots” rather than “white dots,” as many NIPUs are characterized by lesions that are larger than true dot-like alterations. Although this terminology may more accurately reflect the funduscopic appearance of these diseases, the term WDS will be used throughout this manuscript, as it represents the original designation derived from MEWDS and remains the most widely adopted term in the literature.

While several non-uveitic retinal and RPE disorders, including inherited retinal diseases and age-related macular degeneration, may present with multiple whitish or yellowish lesions scattered throughout the fundus (eg, flecks, drusen), these conditions were never considered part of the WDS, as they do not share the underlying inflammatory pathophysiology characteristic of WDS.

On the other hand, the WDS group was expanded progressively, including many more inflammatory entities, often with different authors assigning various names to the same disease. This confusion arose from the lack of specific diagnostic tests for these conditions, their diverse clinical manifestations, and the limited understanding of their pathophysiology. Today, the WDS group has been narrowed down to 6 inflammatory conditions for which classification criteria have been provided by the Standardization of Uveitis Nomenclature (SUN) working group and additional imaging criteria added by the Multimodal Imaging in Uveitis (MUV) Task Force. ^,,,, These diseases include MEWDS, multifocal choroiditis and panuveitis (MFCPU), punctate inner choroiditis (PIC), acute posterior multifocal placoid pigment epitheliopathy (APMPPE), serpiginous choroiditis (SC), and birdshot chorioretinitis (BSCR).

Although the prevailing theories of pathogenesis are that these conditions are likely caused by an autoinflammatory or autoimmune process with unidentified antigenic triggers, advances in retinal and choroidal imaging technologies, have allowed for imaging-based hypotheses of immunopathogenesis of these entities. ^,

Most experts agree that these diseases are distinct entities and should not be grouped together. An MUV Task Force survey revealed that nearly 90% of the uveitis experts regard the term “WDS” as outdated, yet it remains widely used due to the lack of a widely accepted alternative. The objective of this paper is to evaluate whether the term “WDS” is indeed inappropriate, as it groups together several distinct unrelated conditions, and whether these 6 NIPUs should be considered as separate entities, based on the most recent scientific evidence.

The clinical conditions historically grouped under the umbrella of WDS have been said to exhibit a broadly similar funduscopic appearance. While the size, shape, and sharpness of lesions characteristic of each disease may differ, the appearances of some of the diseases can resemble one another on funduscopic examination ( Figure 1 ). However, much like exanthematous diseases of childhood that all present with a skin rash but differ in etiology, target tissues, and—most importantly—the underlying pathophysiological mechanisms, these ocular entities also exhibit significant differences in their inferred pathophysiology and biological behavior.

Color funduscopic appearance of the 6 main entities grouped under the “white dots” umbrella. All these conditions are characterized by the presence of multiple whitish to cream-colored or yellowish orange lesions (dots, spots or plaques) affecting the posterior structures of the eye with a variable size, depth, shape and coalescence. (A) A case of multiple evanescent white dots syndrome (MEWDS). The spots are barely visible. (B) A case of acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Multiple white/yellowish lesions are visible at the posterior pole. (C) A case of multifocal choroiditis and panuveitis (MFCPU) with a widespread involvement of the entire fundus showing lesions of different size. (D) A case of punctate inner choroiditis (PIC) with a few lesions affecting the posterior pole. (E) A case of serpiginous choroiditis (SC) with multiple plaque-like whitish/yellowish lesions spreading from the peripapillary area. (F) A case of birdshot chorioretinitis (BSCR) with the characteristic dots deep in the choroid dispersed in the mid-periphery and in higher number nasal to the disc.

Structural Optical coherence tomography (OCT) provides critical specific retinal and/or choroidal layer depth localization. In MEWDS, lesions are confined to the outer photoreceptor segments and RPE, with no apparent alterations extending beyond these structures. ^,, Conversely, lesions in MFCPU and PIC, while differing in size and distribution across the fundus, ^, show a similar appearance on OCT with disruption of Bruch’s membrane and hyper-reflectivity extending from the inner choroid into the outer retina. ^,, Acute APMPPE lesions present as hypo-reflective zones within a thickened choriocapillaris on enhanced depth imaging OCT (EDI-OCT), ^, sometimes accompanied by hyper-reflectivity in the overlying outer retina and Henle fiber layer (angular sign of Henle fiber layer hyper-reflectivity or ASHH), though Bruch’s membrane remains intact. ^,

SC shares some features with APMPPE, such as preserved Bruch’s membrane and outer retinal hyper-reflectivity, but shows more extensive choroidal involvement, affecting the middle vascular layer of the choroid (Sattler’s layer). These lesions eventually evolve into fibrotic scars within the inner and middle choroid during disease quiescence. In BSCR active choroidal infiltrates originate deep within the choroid and involve overlying retinal structures mostly in advanced disease stages. A concomitant inner retinal involvement is often detectable as perivasculitis. Clearly these so-called “dots” are in fact the visible consequences of profoundly different alterations involving diverse structures of the eye ( Figure 2 ).

Optical coherence tomography (OCT) appearance of the typical lesions (white dots) in each of the 6 entities discussed in the manuscript. In multiple evanescent white dots syndrome (MEWDS) (A), the scan demonstrates hyper-reflective changes at the level of the ellipsoid zone (white arrowheads) and a corresponding disruption of the external limiting membrane, the myoid zone, the outer segments, the ellipsoid zone, the interdigitation zone. The retinal pigment epithelium (RPE) seems also altered. By contrast, the Bruch’s membrane (BrM) and the choriocapillaris (CC) appear intact (black arrows). In acute posterior multifocal placoid pigment epitheliopathy (APMPPE) (B) the outer layers of the retina and the RPE are damaged (black arrowheads), the BrM is intact, while the underlying CC (white arrows) appears thickened and with loss of the typical dotted pattern. Serpiginous choroiditis (SC) (C) shows similar changes in the outer retina and the RPE (black arrow) with a still intact BrM. However, the changes in reflectivity, thickness and loss of pattern involve not just the CC, but also the Sattler’s layer of the choroid in this condition (white arrows). In multifocal choroiditis and panuveitis (D) mid/hyper-reflective material is visible breaking through the BrM (Black arrow) and the RPE and the outer retinal layers up to the outer nuclear layer (yellow arrow). The underlying CC appears thickened and hypo-reflective (pink arrow). These features are also seen in punctate inner choroiditis (PIC). Finally in birdshot chorioretinitis (BSCR) (E) the typical lesion corresponds to a round-shaped hypo-reflective area in the deep choroid (blue arrows) with and apparently spared overlying CC (black arrows). No alteration is visible in the retina, the RPE and the BrM over the lesion.

A detailed study of imaging, especially ICGA and OCT angiography (OCTA), reveals distinct perfusion differences between the entities included in the term WDS. These differences may contribute to morphological differences in lesion appearance and help distinguish the diseases from each other. As discussed in the previous section, there are several structural differences clearly delineated by OCT. However, entities other than MEWDS exhibit a certain degree of choroidal flow disturbance on OCTA. ^,,,, MFCPU, PIC, and APMPPE show perfusion alterations in the choriocapillaris, ^, SC shows alterations in both the choriocapillaris and Sattler’s layer, and BSCR shows alterations primarily in the deep choroidal circulation ( Figure 3 ).

Optical coherence tomography angiography (OCTA) appearance of the typical lesions (white dots) in each of the 6 entities discussed in the manuscript. The OCTA scans of the exact same lesions described in Figure 2 are reported with the aim to analyze the blood flow signal in the affected areas. In multiple evanescent white dots syndrome(MEWDS) (A), there is no flow disturbance (black arrows) neither in the choriocapillaris (CC) nor in the deeper choroid. In acute posterior multifocal placoid pigment epitheliopathy (APMPPE) (B) by contrast the CC appears clearly hypo-perfused in the affected areas (white arrows). In serpiginous choroiditis (SC) (C) the flow deficit (white arrows) involves not just the CC but also the deeper layers of the choroid. In multifocal choroiditis and panuveitis (D) the choriocapillaris flow appears focally impaired (white arrows) at the lesion area. Similar findings characterize punctate inner choroiditis (PIC) lesions. Finally in birdshot chorioretinitis (BSCR) (E) the flow in the choroidal lesion appears less intense then in the surrounding choroid, although not completely blocked (blue arrows). The overlaying CC appears normally perfused (black arrows).

These findings could suggest that WDS, excluding MEWDS, might possibly be considered as primarily vascular inflammatory diseases. However, OCTA alone cannot discern whether such flow alterations are the representation of a primary vascular occlusion or the consequence of other pathophysiological events secondarily impairing the blood circulation in an otherwise normally functioning vascular network. ICG angiography analysis is necessary to overcome these OCTA limitations.

In MEWDS, lesions are not clearly visible in the early phases of ICG angiography and appear hypo-fluorescent during the mid-phase of the angiogram and become increasingly hypo-fluorescent in the late phases. Interpreted by Herbort and associates as a sign of choriocapillaris hypo-perfusion, ^, this finding is now believed by most experts to reflect impaired dye uptake by a dysfunctional RPE, ^,, as no structural or functional abnormalities of the choriocapillaris are detected on OCT or OCTA. The debate, however, remains open as others argue that OCTA may not allow visualization of the end-choriocapillaris circulation possibly affected in MEWDS, and choriocapillaris perfusion delay may be seen on very early ICGA frames of some MEWDS cases. ^,,

In contrast, APMPPE lesions exhibit findings consistent with genuine choriocapillaris hypo-perfusion as suggested with ICG angiography and then corroborated with OCTA. These lesions appear hypo-fluorescent in the early ICG angiography phases and darken over time, likely due to severe vascular lumen occlusion. ^, Following resolution of the acute phase, lesions may show either complete angiographic normalization or residual thinning and tissue loss in the choriocapillaris, visible as a partial window defect with early/mid-phase visibility of large choroidal vessels and iso-fluorescence in the late phases. ^,,

On ICG angiography, SC lesions during active phases are angiographically indistinguishable from APMPPE, ^, reinforcing the impression of a similar ischemic pathophysiology. However, their inactive phase features are different. While early/mid-phase ICGA shows a window defect similar to APMPPE, late-phase images reveal persistent hypo-fluorescence. This suggests the complete absence of dye diffusion and accumulation, indicative of irreversible choriocapillaris loss ^, ( Figure 4 ).

Comparison between indocyanine green angiography (ICGA) in serpiginous choroiditis (SC) and acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Late ICGA of the acute stage of SC (top) and APMPPE (Bottom) is reported in the lefthand column (encircled in red). Early, mid and late-phase of an ICGA exam in the inactive stage of the same SC (top) and APMPPE (bottom) cases are reported in the rest of the image (encircled in blue). During the acute phase of the disease, when there is active hypo-perfusion of the choriocapillaris both conditions show hypo-fluorescent areas masking the underlying choroidal vessels in the late phases of the angiogram (A and E). The diseases are indistinguishable on ICG at this stage except for the pattern of lesion distribution. However, in healed stage, SC inactive lesions (top row) show a window defect unveiling the large choroidal vessels of the Haller’s layer, still perfused under the atrophic area (B and C). The atrophy remains dark even in late ICGA (D), demonstrating a complete absence of the choriocapillaris, likely wiped out by the profound ischemic insult involving it and the Sattler’s layer during the acute phase. By contrast, APMPPE inactive lesions (bottom row), change from iso- (F and G) to slightly hypo-fluorescent (H), over the course of the exam, indicating the choriocapillaris is still partially present and functioning even though vessels density may be reduced compared to spared areas.

MFCPU and PIC lesions are hypo-fluorescent on ICG angiography. ^, However, they gradually become less hypo-fluorescent over time ( Figure 5 ). This dynamic pattern does not align with true non-perfusion, which would maintain persistent hypo-fluorescence throughout the exam. Instead, early hypo-fluorescence may be due to inflammatory infiltrates that obscure dye diffusion and exert a mechanical effect displacing normally perfused choriocapillaris lobules. This mechanism is similar to the so-called “mass effect” described by Herbort and associates for choroidal granulomas. The partial late-phase decrease in hypo-fluorescence, likely reflects slow dye diffusion into the inflammatory infiltrate from the adjacent normally perfused choriocapillaris ( Figure 5 ).

Comparison between indocyanine green angiography (ICG) in acute posterior multifocal placoid pigment epitheliopathy (APMPPE) and multifocal choroiditis and panuveitis (MFCPU). A typical case of APMPPE with active lesions is presented in the top row. The affected areas are seen in the wide field image (A), while their behavior in the different phases of the exam is better appreciated in the close-ups (B, C, and D).The active lesions (white arrows) appear hypo-fluorescent in the early phases of the exam (B) suggesting flow impairment in the choriocapillaris. Then they turn even more hypo-fluorescent in mid (C) and late (D) phase ICG confirming complete hypo-perfusion of the choriocapillaris. In the bottom row a case of MFCPU with active lesions is reported. The affected areas are seen in the wide field image (E), while their behavior in the different phases of the exam is better appreciated in the close-ups (F, G, and H). In early ICG (F) the active inflammatory lesions appear hypo-fluorescent, suggesting hypo-perfusion of the choriocapillaris similar to what observed in APMPPE (B). However, the lesions become less hypo-fluorescent in mid-phase (G) and finally iso-fluorescent in late-phase ICG (H) suggesting a progressive pooling of the dye within the lesions. This behavior, which is quite the opposite to what is encountered in APMPPE lesions, but similar to that of choroidal granulomas (Figure 6 bottom row), suggests that the flow impairment in the choriocapillaris of MFCPU lesions is more likely secondary to a mass “effect” exerted by inflammatory cells infiltration shifting the choriocapillaris aside rather than a true vascular occlusion.

Finally, in BSCR, ICG angiography reveals lesions that are hypo-fluorescent in the mid-phases and persist into the late phases, but with less intensity than the deep hypo-fluorescence typical of ischemic conditions such as APMPPE or SC. This milder signal is likely due to the deep choroidal location of the lesions, allowing some dye diffusion from the intact overlying vasculature.

BSCR has been historically considered a primary stromal choroiditis alongside other conditions characterized by choroidal granulomatous inflammation, like Vogt-Koyanagi-Harada disease. Some patients with sarcoidosis, a multisystem granulomatous disease, may also present with a multifocal choroiditis clinically similar to BSCR. However, BSCR lesions differ in their angiographic pattern from true granulomas, which usually appear hypo-fluorescent early and fade later depending on their depth. This difference may reflect underlying histopathology. Granulomas are highly structured, displacing choroidal vessels and blocking dye via a pronounced mass effect. In contrast, pathology evidences demonstrate that BSCR lesions have no granulomatous structure and consist of disorganized lymphocytic infiltrates lacking this dense morphology and thus exert a weaker mass effect. As a result, choroidal blood flow is only partially impeded, and dye diffusion is merely limited—not entirely obstructed—leading to the persistent yet moderate hypo-fluorescence observed in BSCR during ICG angiography ( Figure 6 ).

Comparison of indocyanine green (ICG) angiography features in birdshot chorioretinitis (BSCR) versus choroidal granulomas in sarcoidosis. Active lesions in BSCR (Top row) are hypo-fluorescent compared to the surrounding areas throughout the entire ICG angiography examination. They can be detected in the early phases of the angiogram (A) but become more evident in the mid (B) and late (C) phases. By contrast, choroidal nodules in a case of sarcoidosis (bottom row) are markedly hypo-fluorescent in early (D) and mid (E) phases of the ICG angiography but become less evident or iso-fluorescent in the late frames (F). This different angiographical behavior could depend on the different histological organization between granulomatous formations in sarcoid and non-granulomatous infiltrates in BSCR.

Understanding the aggregate of the information provided in this analysis, the various NIPU disorders differ across many levels, including the anatomical layer of structural damage incurred in addition to the underlying pathophysiological mechanisms leading to disease. An understanding of these concepts provides greater appreciation of the clinical variability across this group of disorders and a greater insight into the extremely variable prognosis of the different entities, ranging from full recovery of structure and function to more profound loss of tissue and sight.

Thus far, we have focused on structural alterations identified by OCT and on choroidal perfusion assessed by OCTA and ICG. Two additional imaging modalities, fundus autofluorescence (FAF) and fundus fluorescein angiography (FFA), also play a major role in the diagnosis and management of the NIPU entities historically grouped within the WDS spectrum.

Fundus autofluorescence arises from the emission of light by endogenous fluorophores located primarily within the outer segments of photoreceptors and the RPE when excited by light in the blue–green spectrum. Increased FAF signal generally reflects either enhanced visibility of a structurally intact RPE (eg, due to thinning of the overlying retina) or accumulation of fluorophores within the tissue. Conversely, reduced FAF may result from a masking effect (eg, blood or pigment) or, more commonly, from loss or dysfunction of fluorophore-containing cells, particularly the RPE.

In MEWDS, FAF is particularly useful diagnostically, as lesions that are often subtle or inapparent on funduscopic examination appear distinctly hyper-autofluorescent. Notably, this increased FAF signal does not conform to the typical mechanisms described above. Following photobleaching, the hyper-autofluorescence disappears, indicating that the signal is related to transient photopigment dysfunction. Light exposure reduces photopigment availability, allowing increased transmission of excitation light to the RPE and resulting in diffuse hyper-fluorescence. This finding suggests that MEWDS lesions appear hyper-fluorescent because photopigment within the affected photoreceptors does not properly absorb incident light. However, this observation does not clarify whether photoreceptors represent the primary target of inflammation or whether their dysfunction is secondary to RPE or choriocapillaris involvement. Importantly, the reversibility of FAF abnormalities supports a transient dysfunction rather than permanent structural damage.

In contrast, active lesions in APMPPE and SC also show increased FAF, but this signal does not diminish with photobleaching. In these conditions, RPE cells are significantly affected by underlying choriocapillaris hypo-perfusion and exhibit increased metabolic activity prior to cell death, resulting in increased autofluorescence. As the disease evolves, loss of RPE cells leads to a progressive transition from hyper- to hypo-autofluorescence, consistent with irreversible tissue damage secondary to sustained ischemia.

The FAF pattern observed in MFCPU and PIC differs from both MEWDS and ischemic choriocapillaropathies. In the active stage, lesions typically demonstrate a central area of hypo-fluorescence surrounded by a halo of increased FAF. This pattern likely reflects focal RPE disruption at the lesion center, combined with displacement and apparent thickening of RPE cells at the lesion margins. In inactive stages, lesions become uniformly hypo-fluorescent due to RPE loss.

In BSCR, FAF does not show a characteristic pattern. As this condition does not primarily involve the outer retina or the RPE until later stages, FAF provides limited information regarding its pathophysiology and has a relatively minor role in its characterization.

In addition to FAF, FFA plays a key role in the evaluation of NIPU, particularly by enabling assessment of the integrity of the inner and outer blood–retinal barriers. By detecting vascular leakage, FFA allows clinicians to evaluate the presence and degree of intraocular inflammation. The SUN Working Group recognizes its utility in the differential diagnosis between SC, APMPPE, and related mimickers. Furthermore, FFA is particularly valuable in identifying retinal vascular involvement in BSCR, which may accompany or even precede choroidal lesions.

In clinical practice, FAF and FFA are therefore essential tools for the diagnosis and monitoring of NIPU. However, due to their inherent limitations in visualizing the choroid, their contribution to understanding the underlying pathophysiological mechanisms of these entities remains more limited compared with ICGA and OCTA.

The etiology and pathogenesis of the NIPU grouped in the WDS family are still not well understood. Certainly, inflammation is the key underlying process characterizing all these entities with the most widely accepted model speculating an autoimmune and/or autoinflammatory response, against antigens presumably hidden from the immune system or under active suppression. Increased prevalence of autoimmunity has been demonstrated in patients affected by NIPU and in their first- and second-degree relatives. This suggests that NIPU may be occurring in subjects with an inherited predisposition to immune dysregulation that may confer susceptibility to autoimmunity. This process may be triggered by an external stimulus (eg, a systemic infection) in a subject with a specific immune diathesis (eg, a predisposing Human Leukocyte Antigen [HLA] variant). ^,, Case reports of the onset of different NIPU following vaccinations for diverse diseases ^,, have been used to further support this idea, but the absence of a control group or demonstration of an increased disease frequency in these reports renders this association speculative.

Despite the presumed similarities, the NIPUs grouped in the WDS family have unique imaging features and target different structures of the eye as highlighted by multimodal imaging analysis, thus suggesting a more complex and likely different pathophysiologic mechanisms, and allowing us to distinguish each of them from the others also under this point of view.

MEWDS was originally described as a disease affecting the outer retina and/or the RPE. Later, Herbort and associates proposed that it might primarily involve choriocapillaris based on the hypo-fluorescence of its lesions on ICGA. More recently, many authors consider it to predominantly involve the photoreceptors and/or the RPE. ^, Regardless, what remains of interest from a pathophysiological standpoint is the frequent, though variably reported history of a preceding flu-like illness. This temporal correlation suggests that MEWDS could be a manifestation of an autoimmune/autoinflammatory cross-reaction against outer retinal or RPE antigens triggered by a molecular mimicry between the ocular structures and an external, likely viral, pathogen. Although often suggested as a pathogenesis, this mechanism remains speculative.

Recent reports of secondary MEWDS (also known as MEWDS-like or epi-MEWDS) further supports an autoimmune/autoinflammatory mechanism. ^, This entity is a condition mimicking MEWDS in all its aspects except for the fact that it occurs alongside other ocular conditions affecting the outer retina and the RPE, including pseudoxanthoma elasticum, MFCPU, and PIC, infectious chorioretinopathies and retinal dystrophies among others. These conditions, apparently very different from one another, share a common feature, the breakdown of the outer retinal barrier often accompanied by a certain degree of inflammation. The speculation is that this could create the perfect environment to expose RPE and outer retinal antigens to an already triggered immune system leading to a MEWDS-like reaction. ^, Once again, despite the absence of definitive proof, this evidence strengthens the idea of an autoimmune/autoinflammatory reaction against these structures.

Similarly to that seen in MEWDS, MFCPU, and PIC-like reactions have been described secondary to other degenerative or inflammatory conditions affecting the outer retina and the RPE. PIC lesions are also substantially more common in myopic patients who are likely affected by micro-cracks in Bruch’s membrane and RPE atrophic changes. These could once again expose hidden antigens leading to an autoimmune/autoinflammatory reaction against the outer retina and the RPE. ^,, In contrast to MEWDS however, the stimulus is not transient but rather permanent (anatomical), thus explaining the more aggressive relapsing and remitting nature of these conditions. Of note, the onset of MEWDS has been described in patients with MFCPU, and the development of new-onset MFCPU lesions has been reported in patients previously diagnosed with MEWDS. This observation further supports the hypothesis that these two entities may share a common host susceptibility.

APMPPE ‘s features are most consistent with an occlusive disease of the choriocapillaris. ^,,, It has been proposed that this flow impairment can be secondary to an inflammatory process triggered by an external agent, such as a systemic flu-like illness that is reported to precede the development of the ocular disease in 1/3 of the cases. However, the likelihood of recall and confirmation biases in these data and the lack of control groups make this proposed pathogenesis speculative. On the other hand, in a minority of patients, APMPPE co-exist with an occlusive vasculitis affecting the central nervous system, whose vessels share some antigens with those of the choriocapillaris. ^, These findings together with the occurrence of lesions with a similar appearance with other vasculitidies, suggests that APMPPE could be an inflammatory process occurring at the level of the choriocapillaris, likely targeting elements of the vessels and eventually leading to occlusion of some of its lobules rather than an inflammatory reaction against ocular antigens like the outer retina or the RPE.

SC, like APMPPE is characterized by ischemic changes involving the choroid; however, in this case it is not just at the level of the choriocapillaris but also involves the deeper layers of the choroid. Another difference is the absence of a known correlation with inflammatory vascular diseases occurring outside the eye, suggesting that an immune response to ocular antigens may play a role in SC unlike in APMPPE.

Interestingly, classical SC is bilateral and in most cases it starts in the peripapillary area, a region of the eye with unique features. Around the optic nerve head, the outer retinal layers and the RPE become thinner and contain the boundaries of Bruch’s membrane. ^, This unique anatomical setting could indeed favor the exposure of some normally hidden ocular antigens to the immune system. Cases of SC affecting the macular region with sparing of the peripapillary region have been described. However, the authors who reported this series did not focus their attention on the presence of specific anatomical features that could facilitate the exposure of retinal antigens to the immune system in these eyes, neither excluded infectious diseases like tuberculosis which could explain the clinical picture.

In fact, SC has also been associated with infectious diseases and conditions mimicking SC, such as tubercular serpiginous-like choroiditis (TB-SLC), which can occur distinct from the peripapillary area in these eyes. The pathogenesis of TB-SLC is unknown with proposed mechanisms being an autoimmune reaction to mycobacterial cross-reactive antigens and a direct paucibacillary infection. The response of TB-SLC to antimicrobial therapy is consistent with the latter hypothesis. ^,, The authors also have a large series of cases showing the characteristic SC pattern in QuantiFERON positive patients (unpublished data). This allows to speculate that SC could be a purely ocular disease featuring an inflammatory reaction triggered by an external stimulus, possibly infectious conditions, leading to occlusive choroidal disease and ultimately an autoimmune/autoinflammatory self-sustaining ocular disorder.

While the cause of BSCR still remains unknown, the strong correlation with the HLA–A29 suggests an autoimmune/autoinflammatory nature; however, the presence of the same HLA haplotype in up to 7% of the unaffected population suggests the genetic predisposition alone is not sufficient to develop the disease (ie, HLA–A29 is a risk factor). Differently from what is seen in other NIPUs aging may play a role in BSCR with most affected patients being in their forties or older. That said, BSCR differs from all the other NIPUs since it exhibits a parallel and not necessarily synchronous inflammatory process both in the inner retina ^, and the choroid. Of note, the outer retina, is not the primary target of inflammation in BSCR, but rather a bystander that can be involved only later on in the course of the disease as the inflammatory process gets chronic and destroys the surrounding tissues.