Punctate inner choroiditis (PIC) is a group of white dot syndromes that occurs predominately in young, myopic, female patients. This review provides an update on diagnostic criteria by the Standard Uveitis Nomenclature classification and discusses multimodal imaging characteristics for diagnosis and disease monitoring. The treatment of PIC is variable and must be tailored for each patient. Increasing evidence supports the use of systemic and local corticosteroids, immunomodulatory drugs, or biologics for the treatment of PIC in patients who suffer from disease recurrence, visually significant lesions, or the presence of secondary choroidal neovascularization.
Key points
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Punctate inner choroiditis (PIC) is a rare disease that typically is associated with young myopic female patients. The most common clinical presenting symptoms are blurred vision and scotoma.
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Combining multimodal imaging is crucial in the diagnosis and monitoring progression of the disease.
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No consensus exists on the standard treatment of PIC; corticosteroids and immunosuppressive drugs play an important role in controlling inflammation and preventing subsequent complications.
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The most common vision-threatening complication is secondary choroidal neovascularization, which can be treated with anti-vascular endothelial growth factor medications and control of active inflammation with corticosteroids and/or immunosuppressive therapy.
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The visual prognosis in PIC generally is favorable. Most patients with this condition maintain good visual outcomes.
Introduction
Punctate inner choroiditis (PIC) is an uncommon inflammatory disorder in the group of white dot syndromes, originally reported by Watzke and colleagues. It is more commonly seen in young women with relatively high myopia. The characteristics of PIC are the presence of small, circular, well-defined, yellow–white lesions in the posterior pole in the absence of other signs of intraocular inflammation [ ]. It is difficult to accurately estimate the incidence and prevalence of the condition because a wide variety of presentations occurs, which may lead to missed or incorrect diagnoses. Furthermore, an ongoing discussion exists as to whether PIC is a distinct entity from other white dot syndromes, such as multifocal choroiditis (MFC), or within a spectrum of similar conditions.
Epidemiology
Based on a retrospective study at a tertiary care referral ophthalmology center at the University of Iowa, 16 cases of PIC occurred over 15 years. In this population, the incidence of PIC is estimated to be 0.4 cases per 1,000,000 per year [ , ]. PIC prevalence in pathologic myopia eyes with patchy atrophy recently has been observed. Of the 500 eyes that were identified with patchy atrophy between 2014 and 2020, 55 (11%) had optical coherence tomography (OCT) features indicative of active MFC/PIC lesions [ ]. In a survey study of 77 patients through the PIC society, a group of individuals with PIC diagnoses from all over the world to raise awareness of the condition founded in 2003: 90% of reported cases were in women, 97% of patients were Caucasian, and the median age was 30 years [ ]. In another retrospective case study of patients at Moorfields Eye Hospital, 136 patients were followed over a period of 12 months. The average age was 32 years (range from 16 to 64 years), and 93% of patients were female [ ].
Bilateral PIC lesions have been reported in 49% to 57% of patients [ ]. A strong association exists between PIC and high myopia, with 80% to 90% of patients with PIC with associated myopia [ , , ]. In previous studies, the mean refractive error has ranged between −4.6 and −7.00 diopters in each eye [ , , ]. In contrast, emmetropia and hyperopia can be found in 16% of cases [ ]. A separate study characterizing patients with chorioretinal inflammatory disorders, including MFC and panuveitis, PIC, multiple evanescent white dot syndrome, and diffuse subretinal fibrosis syndrome, found that out of all inflammatory chorioretinopathies, PIC had the highest amounts (in diopters) of myopia [ ].
Pathophysiology
The pathophysiology of PIC remains unclear. However, several hypotheses have been proposed to explain the underlying mechanisms involved in the development of PIC. Similar to other white dot syndromes, it is thought that PIC is an autoimmune process. Given its predilection for female patients and pathology findings of immune system involvement from choroidal neovascularization (CNV) in PIC patients, substantial evidence occurs to suggest an autoimmune component in the pathogenesis of PIC.
Some cases exhibit familial patterns, suggesting a potential genetic susceptibility. However, specific genetic markers or mutations associated with these conditions have not been conclusively identified. For instance, in one case report of a mother and daughter who both presented with PIC, other genetic or environmental causes may have contributed to their concurrent development of PIC, such as high myopia [ ]. A positive family history of autoimmune disease in first- or second-degree relatives was seen in 26% of PIC cases. However, personal history of autoimmune disease has been found to vary from 3% to 23% [ , , ]. In a study of genetic markers in patients with MFC with panuveitis and PIC, both groups demonstrated connections to particular regions associated with tumor necrosis factor loci and interleukin-10 haplotypes, compared to a control group of healthy individuals [ ]. These genetic markers have been previously known to be linked to noninfectious uveitis [ , ]. The HLA-DRB1∗15 (HLA-DR2) allele was shown to be more common in the PIC group than in the control group, at 26% versus 16% [ ]. Complement factor H polymorphisms and PIC/MFC exhibited a high correlation, indicating abnormal regulation of the alternative complement pathway [ , ]. The findings imply that coagulation and complement cascades are important components of the underlying pathophysiology of PIC/MFC [ ].
Susceptibility to PIC may be influenced by genetic predisposition and triggered by an environmental stressor such as infection or immunization [ ]. Multiple genes are involved in immunoregulation, and this combined polygenic effect may contribute to an increased propensity of autoimmune disease in general and may be seen in PIC. This predisposition along with an environmental stressor can induce an autoimmune response in the retina or choroid and lead to the development of PIC. The immune system’s inability to regulate and control inflammation effectively may play a role as well [ ]. Dysregulation of the immune response could lead to chronic inflammation in the choroid, contributing to the formation of the characteristic lesions of PIC.
The choroid plays a crucial role in supplying oxygen and nutrients to the outer retina. Inflammation appears to be a central feature in the pathophysiology of PIC. In PIC, the choroidal vasculature is affected, leading to the formation of characteristic yellow–white lesions at the inner choroid and retinal pigment epithelium (RPE). Over time, the lesions scar and leave an area of punched-out depigmentation. When looking at the areas of CNV, a different study examining light and electron microscopy findings in 2 eyes revealed lymphocytes at the inner choroid and macrophages at Bruch’s membrane [ ]. Furthermore, the areas of CNV displayed persistent pericytes, which may be a driving force behind the choroidal inflammation [ ]. In another study of 6 eyes with PIC, areas of CNV were found between the neurosensory retina and the RPE layer. The pathology assessment found pericytes, fibrocytes, and inflammatory cell aggregates; however, in this study, the inflammatory cells consisted of lymphocytes and plasma cells, with no macrophages [ ]. The presence of lymphocytes, plasma cells, or macrophages supports the idea of an immune-mediated process. The release of inflammatory mediators, such as cytokines and chemokines, likely contributes to the recruitment and activation of immune cells in the choroid [ , ].
A theory of the pathophysiology of PIC involves the fact that a significant percentage of patients with PIC have high degrees of myopia. In myopic eyes, the RPE and Bruch’s membrane display progressive thinning, weakness, and instability that may lead to small “cracks” that may facilitate immune activity and neovascularization [ ]. Further studies are needed to determine whether the pathophysiology of myopia is truly involved in PIC disease pathogenesis.
While there are many possibilities for the specific causes of initial inflammation and mechanisms of progression, this initial framework provides a better understanding of the disease and its presentation.
Clinical features and diagnosis
The most common presenting symptoms in PIC were scotomata (91%), blurred vision (86%), photopsia (73%), floaters (69%), photophobia (69%), metamorphopsia (65%), and loss of peripheral vision (26%) [ ]. Most patients with PIC had visual acuity at presentation better than 20/40. PIC usually is a clinical diagnosis with the aid of multimodal imaging. The Standardization of Uveitis Nomenclature (SUN) working group utilized machine learning to establish diagnostic criteria for PIC including the presence of small (size <250 μm), punctate, multifocal choroidal inflammatory lesions in the posterior pole, with or without the involvement of the mid-periphery, and minimal or absent anterior chamber and vitreous inflammation [ ]. Additionally, other causes of choroiditis, including syphilis, tuberculosis, or sarcoidosis, should be ruled out [ ]. However, controversies exist in terms of differentiating PIC and idiopathic MFC as the same disease spectrum or different entity [ ]. Many reports suggest that they are part of the same disease spectrum [ , , ]. However, the SUN group has established the diagnostic criteria of MFC which include the presence of large (size >125 μm), oval or round-shaped, multifocal choroidal inflammatory lesions with punched-out atrophic chorioretinal scars that show signs of vitreous inflammation and are located in the mid- or far-periphery. The posterior pole may or may not be involved. Syphilis, tuberculosis, and sarcoidosis should be excluded [ ].
Multimodal imaging
Optical coherence tomography
Zhang and colleagues classified OCT staging of PIC into 5 stages [ ]. Stage I showed minute irregularities in the outer nuclear layer. Stage II revealed a focal elevation of RPE with corresponding disruption of the inner and outer segments of the photoreceptor interface. Stage III lesion broke through the RPE, forming a hump-shaped chorioretinal nodule with moderate reflectivity beneath the outer plexiform layer (OPL), subsequently with disruption of Bruch’s membrane. Stage IV lesion showed a V-shaped herniation of the OPL and inner retina into the choroid due to tissue loss from the photoreceptor layer and inner choroid ( Fig. 1 ). In stage V, the photoreceptors surrounding the lesion were eventually eliminated, accompanied by RPE proliferation [ ].
Zarranz-Ventura and colleagues using enhanced depth imaging OCT to demonstrate quantitative and qualitative analyses of retinal and choroidal morphology in patients with PIC found that focal hyperreflective dots in Sattler’s medium vessel layer beneath or adjacent to PIC lesions were seen in 68.5% of 35 patients [ ]. Choroidal thickness was variable as choroidal thinning was associated with myopia in PIC patients [ ]. However, focal choroidal thickening can be found beneath active PIC lesions [ ]. In addition, focal choroidal excavation (FCE) can be found in PIC which is associated with choroidal scarring, defined as hyperreflective choroidal tissue under the excavation on OCT. It was thought that choroidal scarring was the cause of the pathophysiology of FCE in PIC [ ]. There were reports of OCT findings that revealed hyporeflective back shadowing in the choroid beneath the PIC lesions represented CNV lesions in PIC [ ]. Twenty percent of eyes with PIC/MFC had FCE, which can lead to CNV development [ , ].
Gan and colleagues reported intraretinal cystoid space may be a suggestive sign of regression of PIC lesion that should be differentiated from active CNV to avoid unnecessary treatment with anti-vascular endothelial growth factor (anti-VEGF) [ ]. OCT has become an immensely helpful tool in the diagnosis and monitoring of disease progression.
Fundus autofluorescence
Short-wavelength (SW) and near-infrared (NIR) fundus autofluorescence (FAF) imaging show naturally occurring fluorophores of lipofuscin from RPE and melanin from choroid, respectively. Li and colleagues classified FAF in PIC lesions into 3 categories: (1) Hypoautofluorescent spot with hyperautofluorescent border which was usually presented in active lesions and was more pronounced by SW-FAF. (2) Hypoautofluorescent spot without hyperautofluorescent border appeared in 2 different circumstances. Initially, hypoautofluorescent spots could be observed in most atrophic PIC lesions corresponding to the RPE hyperproliferation in the fundus examination ( Fig. 2 ). Secondly, hypoautofluorescent spots could be similarly seen in subclinical PIC lesions, appearing normal or minor discoloration on fundus examination was more noticeable on NIR-FAF contrasted to SW-FAF. (3) Hypoautofluorescent spot coexisting with hyperautofluorescent patch which was found more numerous in SW-FAF, matched the dispersed yellowish spots observed during fundus examination and ellipsoid zone discontinuity on OCT [ , ]. Nevertheless, FAF appeared to show more extensive active PIC lesions than the spots seen on the fundus examination and had an advantage in diagnosis and monitoring PIC lesions. Furthermore, hyperautofluorescent patches on FAF could be a predictive factor of recurrence of PIC lesions [ ] and appeared to be slower to respond to corticosteroid treatment in comparison to active inflammatory spots [ ].
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