Punctate Inner Choroiditis

Introduction

Punctate inner choroiditis (PIC) is an uncommon inflammatory disorder in the group of white dot syndromes, originally reported by Watzke and colleagues in 1984. 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.¹ 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, 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.^2,3 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 multifocal choroiditis(MFC)/PIC lesions.⁴ 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 percent of reported cases were in women, 97 percent of patients were Caucasian, and the median age was 30 years.⁵ 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 16-64 years) and 93 percent of patients were female.⁶

Bilateral PIC lesions have been reported in 49-57 percent of patients.^6–10 A strong association exists between PIC and high myopia, with 80-90 percent of patients with PIC with associated myopia. ^7,8,10 In previous studies, the mean refractive error has ranged between −4.6 diopters to −7.00 diopters in each eye.^5,6,10 In contrast, emmetropia and hyperopia can be found in 16 % of cases.⁶ A separate study characterizing patients with chorioretinal inflammatory disorders, including multifocal choroiditis 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.¹¹

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.¹² 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%^5,13,14 In a study of genetic markers in patients with multifocal choroiditis with panuveitis (MFCPU) and PIC, both groups demonstrated connections to particular regions associated with tumor necrosis factor(TNF) loci and interleukin(IL)-10 haplotypes, compared to a control group of healthy individuals.¹³ These genetic markers have been previously known to be linked to non-infectious uveitis.^13,15 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%.¹³ Complement factor H (CFH) polymorphisms and PIC/MFC exhibited a high correlation, indicating abnormal regulation of the alternative complement pathway.^16,17 The findings imply that coagulation and complement cascades are important components of the underlying pathophysiology of PIC/MFC.¹⁶

Susceptibility to PIC may be influenced by genetic predisposition and triggered by an environmental stressor such as infection or immunization.³ 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.¹⁸ 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 choroidal neovascularization (CNV), a different study examining light and electron microscopy findings in two eyes revealed lymphocytes at the inner choroid and macrophages at Bruch’s membrane.¹⁹ Furthermore, the areas of CNV displayed persistent pericytes, which may be a driving force behind the choroidal inflammation.¹⁹ In another study of six 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.²⁰ 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.^21,22

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” facilitate immune activity and neovascularization.¹ 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%).⁵ 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 micrometers), 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.²³ Additionally, other causes of choroiditis, including syphilis, tuberculosis, or sarcoidosis should be ruled out.²³ However, controversies exist in terms of differentiating PIC and idiopathic multifocal choroiditis(MFC) as the same disease spectrum or different entity.²⁴ Many reports suggest that they are part of the same disease spectrum.^6,18,25 However, the SUN group has established the diagnostic criteria of MFC which include the presence of large (size > 125 micrometers), 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.²⁶

Multimodal Imaging

Optical Coherence Tomography (OCT)

Zhang et al. classified OCT staging of PIC into 5 stages.²⁷ 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.²⁷

Fig. 1.

Spectral-domain OCT of punctate inner choroiditis lesions.

(A). OCT shows stage III PIC lesion breaking through the RPE with moderate hyperreflectivity beneath the outer plexiform layer (OPL).

(B). OCT demonstrates stage IV PIC lesion displayed a V-shaped herniation of the OPL and inner retina into the choroid due to tissue loss from the photoreceptor layer and inner choroid.

Zarranz Ventura et al. using enhanced depth imaging optical coherence tomography (EDI-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.²⁸ Choroidal thickness was variable as choroidal thinning was associated with myopia in PIC patients.²⁸ However, focal choroidal thickening can be found beneath active PIC lesions.²⁵ 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.²⁹ There were reports of OCT findings that revealed hypo-reflective back shadowing in the choroid beneath the PIC lesions represented CNV lesions in PIC.^30–32 20% of eyes with PIC/MFC had focal choroidal excavation, which can lead to CNV development.^29,33

Gan et al. 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).³⁴ OCT has become an immensely helpful tool in the diagnosis and monitoring of disease progression.

Fundus Autofluorescence (FAF)

Short-wavelength (SW) and near-infrared (NIR) fundus autofluorescence (FAF) imaging show naturally occurring fluorophores of lipofuscin from retinal pigment epithelium (RPE) and melanin from choroid, respectively. Li et al. 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 were 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.^{35 36} 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 lesions³⁷ and appeared to be slower to respond to corticosteroid treatment in comparison to active inflammatory spots³⁸.

Fig. 2.

Color fundus photograph and fundus autofluorescence (FAF) of PIC lesions. (A). The color fundus photograph shows multiple small discrete whitish lesions consistent with PIC. (B). FAF shows hypoautofluorescent spots with hyperautofluorescent borders corresponding to active PIC lesions (red arrows). The green arrow shows hypoautofluorescent spot without hyperautofluorescent border representing inactive PIC lesion.

Fluorescein Angiography (FA) and Indocyanine Green Angiography (ICGA)

On FA, active PIC lesions usually showed hypofluorescence in the early phase and then appeared hyperfluorescent with late leakage and staining in the late phase. The leakage was more apparent if the RPE displayed a dehiscence. On the other hand, inactive PIC lesions appeared hyperfluorescent throughout all the phases as a result of RPE window defects. In the presence of secondary CNV, FA revealed early hyperfluorescence with late leakage.^25,39,40

On ICGA, both active and inactive PIC lesions demonstrated hypocyanescent spots that became more noticeable in the late phase of ICGA.^25,40

Optical Coherence Tomography Angiography (OCTA)

In active PIC lesions, OCTA demonstrated a demarcated region of flow void at the choriocapillaris level correlating to the area of RPE elevation with subretinal hyperreflective material on OCT. One study reported the post-treatment choriocapillaris (CC) flow void was reduced compared to the pre-treatment CC flow void.⁴¹ Therefore, the utility of OCTA can be used to monitor treatment response in PIC. However, it is difficult to distinguish between an active inflammatory lesion and subsequent CNV in PIC; multimodal imaging is essential to reach an accurate diagnosis. However, some CNV in PIC may not be precisely detected solely by FA and ICG. OCTA, a non-invasive technique, with no dye injected into the systemic circulation, showed comparatively high sensitivity (89.47%) and specificity (98.46%) in the detection of CNV, which may be beneficial in making a diagnosis of CNV in PIC.^42,43 On en-face slabs, OCTA shows a lacy network of vessels in the outer retina, and comparable B-scans show a blood flow signal. The presence of a neovascular network may not always indicate disease activity, because it frequently continues throughout periods of quiescence.⁴⁴ Despite the benefit of using OCTA for CNV identification and subsequent tools for treatment, caution must be taken when interpreting OCTA results because of the potential for numerous artifacts, including segmentation, motion, and projection artifacts.

Special imaging characteristics of PIC

Solitary punctate chorioretinitis (SPC)

The clinical features of the PIC subtype were described by Gan et al. in 12 patients who had a single lesion in the macular region that had multimodal imaging characteristics similar to those of conventional PIC lesions. Moreover, focal choroidal excavation and CNV may occur and recurrences of SPC mostly occurred at the original lesion location.⁴⁵

Punctate inner pachychoroidopathy

Using unsupervised machine learning and cluster analysis, Ramtohul et al. reported the subtype of PIC with pachychoroid characteristics in 102 eyes from 82 patients. This revealed two clusters: patients in cluster 1 had higher myopia, older age, multiple lesions, thin choroids, and a higher risk of developing patchy chorioretinal atrophy. Patients in cluster 2 classified as punctate inner pachychoroidopathy had lower myopia or emmetropia, mostly a single lesion, thick choroids, choroidal vascular hyperpermeability on ICGA, and a high prevalence of focal choroidal excavation.⁴⁶

Treatment

At present, no consensus on standard treatment of PIC has been established. In patients who do not have visually significant symptoms or CNV, ophthalmologists may consider observation without treatment and close monitoring for signs of disease progression. In cases of presentation with CNV, visual disturbances, or progression of the disease, treatment options include systemic or local corticosteroids, steroid-sparing immunomodulatory drugs, or anti-VEGF therapy.⁴⁷

Corticosteroids

Systemic corticosteroids have played an important role in controlling active inflammatory lesions in PIC. Previous reports demonstrated that corticosteroid therapy, either systemic or local, decreased the occurrence of CNV in patients with PIC/MFC.^48,49 One study showed that systemic corticosteroid therapy within 6 months following diagnosis of PIC/MFC could lower the risk of developing CNV than the group that was not being treated.⁴⁸ Flaxel et al. determined that systemic corticosteroid treatment could potentially help with visual improvement and control of CNV activity.⁴⁹

Immunomodulatory therapy (IMT)

Immunomodulatory drugs have been used in patients who cannot taper steroids lower than 7.5 milligrams per day or are intolerant of the adverse effects of systemic corticosteroids. Antimetabolites including methotrexate (MTX), mycophenolate mofetil (MMF), and azathioprine (AZA) are the most common medications used as steroid-sparing IMT.⁵⁰ Small case series reported the use of mycophenolate mofetil in recurrent PIC with a decrease in attack frequency of PIC.⁵¹ De Groot et al. reported that immunosuppressive treatment (MTX, MMF, AZA) in PIC/MFC showed good efficacy in terms of decreased total number of recurrences per year and increased steroid-free remission.⁴⁷ A report showed promising results in reducing the risk of CNV in patients treated with IMT.¹⁰

Biologics

Shmueli et al. reported the use of adalimumab in 7 patients with refractory PIC and MFC enabled a significant steroid-sparing effect, decreased disease flare-up, and preserved vision with a mean follow-up of 17.8 months.⁵² One larger prospective observational cohort study in the Netherlands demonstrated that immunosuppressive monotherapy is insufficient to establish long-term steroid-free remission in over one-third of the patients with PIC/MFC.⁵³ Biologic treatment appears to be beneficial in this patient population, despite the limited research available from small case series.^52,54

As PIC often affects young women, some considerations for treatment in patients of child-bearing potential are needed. Treating women who are pregnant or breastfeeding with systemic IMT should be undertaken with caution and with coordination with the obstetrician. De Groot et al. reported that pregnant patients with PIC receiving corticosteroids, azathioprine, or intravitreal anti-VEGF injections did not generally experience any significant maternal, obstetrical, or fetal complications; however, one patient experienced intrahepatic cholestasis of pregnancy (ICP) while receiving azathioprine.⁵⁵

Prognosis

In general, the visual prognosis in PIC is favorable with most patients maintaining good visual acuity. Best corrected visual acuities of better than 20/40 have been reported in 66-82.5 % of patients.^2,6,9 According to a report by Leung et al, the incidence rates of visual impairment to 20/50 or worse were 0.06 per eye-year (EY), and visual loss up to 20/200 or worse were 0.006/EY.¹⁴ Depending on where the secondary CNV is located, visual loss may result. Risk factors for increased relapsed rate of PIC were related to a history of secondary CNV and high myopia (greater than −6 diopters).⁵³ Additionally, there was a report of a relatively high relapse rate (44%) in pregnant patients with PIC; however, the best corrected visual acuity remained stable.⁵⁵

Complications

CNV is the most common complication found in PIC and can cause moderate to severe visual loss depending on the location and severity. The rate of CNV in PIC varied from 22-75%^6–8,10 with an initial presentation of CNV in 30-47.8% of PIC patients.^9,10 The explanation of secondary CNV that appeared to be more common in idiopathic MFC and PIC than in other types of uveitis was the susceptibility to ischemia and hypoperfusion of choriocapillaris in myopic eyes.⁵³ The presence of CNV lesions in the fellow eye, the recurrence of PIC lesions³⁷, and previous corticosteroid treatment were associated with an increased risk of developing CNV.¹⁰ The characteristic “pitchfork sign” of inflammatory CNV on the OCT can aid in diagnosis.⁵⁶ The use of OCTA can help differentiate active inflammatory lesions from secondary CNV by the presence of the neovascular network in outer retina segmentation. However, to determine the activity of CNV, the presence of subretinal fluid or intraretinal fluid on OCT might be considered carefully in conjunction with OCTA.

Currently, the treatment of CNV includes the use of intravitreal anti-VEGF and control of underlying inflammation. A lot of reports exist supporting the treatment of inflammatory CNV with intravitreal anti-VEGF including bevacizumab, ranibizumab, and aflibercept.^33,57–61 Wu et al. showed that combined corticosteroid treatment with ranibizumab appeared to control the recurrence of CNV and reduced new PIC lesions compared to intravitreal ranibizumab alone.⁵⁷ Pohlmann et al demonstrated combination of systemic immunosuppressive therapy, and anti-VEGF appeared to decrease the size of CNV and fluid retention on OCTA compared to anti-VEGF alone.⁵⁸ A small case series reported that combined intravitreal anti-VEGF with adjunctive intravitreal dexamethasone for the treatment of CNV associated with PIC with encouraging outcomes.⁶²

Summary

PIC is a rare ocular inflammatory disorder that typically affects young myopic female patients. Multimodal imaging is essential in diagnosis, monitoring of disease activity, and early detection of CNV. Treatment of PIC is variable and clear guidelines are lacking. However, corticosteroids and steroid-sparing IMT may be helpful for patients who experience a relapse of PIC, visually significant symptoms, or the development of CNV. Prompt anti-VEGF treatment after early CNV identification can maintain desired visual outcomes.

KEY POINTS.

• 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.

• Combining multimodal imaging is crucial in the diagnosis and monitoring progression of the disease.

• No consensus exists on the standard treatment of PIC; corticosteroids and immunosuppressive drugs play an important role in controlling inflammation and preventing subsequent complications.

• The most common vision-threatening complication is secondary choroidal neovascularization (CNV), which can be treated with anti-vascular endothelial growth factor (VEGF) medications and control of active inflammation with corticosteroids and/or immunosuppressive therapy.

• The visual prognosis in PIC generally is favorable. Most patients with this condition maintain good visual outcomes.

CLINICS CARE POINTS.

• Multimodal imaging is important to help in the diagnosis of PIC and monitoring the disease progression.

• Treatment with immunosuppressive therapy including corticosteroids, immunomodulatory drugs, or biologic agents may be necessary depending on the location of PIC lesions, and vision impairment.

• CNV is the most common complication associated with PIC which can be treated with anti-VEGF with promising results.

• Regular follow-up is essential to help monitor the progression of PIC lesions and early detection of visually threatening complications related to CNV.

SYNOPSIS.

Punctate inner choroiditis is a group of white dot syndromes that occurs predominately in young, myopic, female patients. This review provides an update on diagnostic criteria by Standard Uveitis Nomenclature (SUN) 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 (CNV). Secondary CNV, which is the most common complication, can cause significant visual deterioration if left untreated. Treatment of secondary CNV with anti-VEGF has been used extensively with promising results. Longterm follow-up in patients with PIC is necessary for early detection of PIC recurrence or the emergence of secondary CNV to avoid severe vision loss and preserve favorable visual outcomes.