Diagnostic Challenges in Inflammatory Choroidal Neovascularization.

Inflammation plays a key role in the induction of choroidal neovascularization (CNV). Inflammatory choroidal neovascularization (iCNV) is a severe but uncommon complication of both infectious and non-infectious uveitides. It is hypothesized that its pathogenesis is similar to that of wet age-related macular degeneration (AMD), and involves hypoxia as well as the release of vascular endothelial growth factor, stromal cell-derived factor 1-alpha, and other mediators. Inflammatory CNV develops when inflammation or infection directly involves the retinal pigment epithelium (RPE)-Bruch's membrane complex. Inflammation itself can compromise perfusion, generating a gradient of retinal-choroidal hypoxia that additionally promotes the formation of choroidal neovascularization in the course of uveitis. The development of choroidal neovascularization may be a complication, especially in conditions such as punctate inner choroidopathy, multifocal choroiditis, serpiginous choroiditis, and presumed ocular histoplasmosis syndrome. Although the majority of iCNV cases are well defined and appear as the "classic" type (type 2 lesion) on fluorescein angiography, the diagnosis of iCNV is challenging due to difficulties in differentiating between inflammatory choroiditis lesions and choroidal neovascularization. Modern multimodal imaging, particularly the recently introduced technology of optical coherence tomography (OCT) and OCT angiography (noninvasive and rapid imaging modalities), can reveal additional features that aid the diagnosis of iCNV. However, more studies are needed to establish their role in the diagnosis and evaluation of iCNV activity.

The multimodal imaging features and outcomes of multifocal choroiditis/punctate inner choroidopathy lesion with multiple evanescent white dot syndrome-like features: a retrospective study.

BACKGROUND: Multiple evanescent white dot syndrome (MEWDS)-like features is a rare condition triggered by a macular disease or iatrogenic injury, exhibiting MEWDS changes in the fundus. This study aims to describe the multimodal imaging features and outcomes of multifocal choroiditis/punctate inner choroidopathy (MFC/PIC) lesions with MEWDS-like features. METHODS: Six cases were studied retrospectively. All cases were given regional and oral corticosteroids. RESULTS: All cases showed an isolated juxtafoveal yellowish-white MFC/PIC lesion with disruption of RPE-Bruch's membrane-choriocapillaris complex (RPE-BM-CC), subretinal hyperreflective materials and choroidal thickening on optical coherence tomography. Two weeks after presentation, the grayish-white dots disappeared spontaneously and the corticosteroids were given. After four weeks, the ellipsoid zone (EZ) around the lesion and hyper-autofluorescence resolved. After 13 weeks, five cases showed shrinkage of the juxtafoveal lesion and restoration of foveal EZ. After six months, the juxtafoveal lesion became pigmented. Only one case developed type 2 choroidal neovascularization. CONCLUSIONS: The clinical course of MEWDS-like manifestations is still evanescent in our cases. The yellowish-white juxtafoveal MFC/PIC lesions with disruption of RPE-BM-CC and choroidal thickening showed a well-controlled prognosis after corticosteroid treatment.

A case of tubulointerstitial nephritis and uveitis syndrome accompanied by subclinical choroiditis.

BACKGROUND: Tubulointerstitial nephritis and uveitis (TINU) syndrome is an uveits characterized by complications of idiopathic acute tubulointerstitial nephritis, and most cases present only anterior uveitis. We report a case of TINU syndrome in which the presence of choroiditis was revealed by multimodal imaging. CASE PRESENTATION: A 12-year-old male visited our hospital with a 6-day history of ocular pain and hyperemia. Conjunctival and ciliary injections, 1 + flare and 3 + cells of anterior chamber inflammation with mutton fat keratic precipitates were observed in both eyes (OU), together with redness and swelling of the optic disc OU. Laboratory tests showed slightly high levels of soluble IL-2R and serum ß2 microglobulin and markedly high levels of urinary ß2 microglobulin. The diagnosis of probable TINU syndrome was established on the basis of bilateral uveitis and urinalysis results in accordance with a clinical criteria of tubulointerstitial nephritis. With treatment with oral prednisolone (PSL) at 20 mg/day, ocular findings improved, and the dose of PSL was gradually reduced and withdrawn 6 months later. However, 1 month later from the withdrawal, ocular inflammation recurred with the presence of retinal exudates and snowball vitreous opacities in the peripheral retina OU. Fluorescein angiography showed leakages from peripheral retinal vessels and staining corresponding to retinal exudates. Indocyanine green angiography showed hypofluorescent dots scattered over the ocular fundus. Optical coherence tomography revealed the presence of choroidal thickening. Laser speckle flowgraphy color map showed a relatively cooler color. Findings from these multimodal images indicated the presence of subclinical choroiditis; therefore, oral PSL was administered again, and ocular inflammatory findings were improved. CONCLUSIONS: TINU syndrome can exhibit subclinical choroiditis detected with multimodal imaging. Further studies are necessary to determine the frequency of subclinical choroiditis in TINU syndrome.

HHV-6B- and HHV-7-associated choroiditis secondary to acute myelogenous leukemia: a case report.

We report a case of human herpes virus 6 (HHV-6)- and human herpes virus 7 (HHV-7)-associated choroiditis in an immunocompromised woman. A 42-year-old Chinese woman with a history of acute myelogenous leukemia presented with blurred vision and black floaters in her right eye. Anterior segment examination findings were normal. Ophthalmoscopic examination revealed a subretinal lesion in the superonasal peripapillary region with several punctate hemorrhages. Optical coherence tomography showed a crater-like choroidal protuberance, associated with retinal pigment epithelium rupture and full-thickness retinal edema in the involved area. Indocyanine green angiography demonstrated a broad hypofluorescent lesion in the choroid. The patient was diagnosed with choroiditis. Subsequently, metagenomic next-generation sequencing revealed HHV-6B and HHV-7 DNA in the aqueous humor. Therefore, antiviral therapy was initiated. The patient experienced resolution of all symptoms and signs after treatment with intravenous foscarnet and oral acyclovir. The findings in this case indicate that HHV-6 and HHV-7 can cause ocular infection, particularly in immunocompromised patients.

Polypoidal choroidal vasculopathy 20 years after resolution of tubercular choroiditis.

We report the case of a 72-year-old white woman with blurring of vision in both eyes of 15 days' duration. She had a history of treatment for bilateral tuberculosis choroiditis 20 years before. She was diagnosed with polypoidal choroidal vasculopathy in the right eye and inflammatory choroidal neovascular membrane in the left eye, based on multimodal imaging, including optical coherence tomography, fundus fluorescein angiography, and indocyanine green angiography. The right eye received 3 intravitreal injections of aflibercept and showed complete resolution. The left eye was treated with a single intravitreal injection of aflibercept.

Punctate inner choroidopathy in common variable immunodeficiency associated with a pathogenic variant in the tumour necrosis factor receptor superfamily 13b (TNFRSF13B) gene - Case report and review of the literature.

BACKGROUND: Common variable immunodeficiency (CVID) has been recognised as the most common primary immunodeficiency in adulthood, and is characterised by increased susceptibility to infection, autoimmunity and increased risk of malignancies. Although ocular manifestations are not common in CVID, rare associated inflammatory eye conditions have been reported including submacular choroiditis. OBJECTIVE: To report a case of punctate inner choroidopathy in a patient with common variable immunodeficiency. CASE PRESENTATION: A 40-year-old lady with CVID and associated autoimmune thrombocytopenia, who was treated with immunoglobulin replacement and Eltrombopag, experienced gradually deteriorating right eye vision. Fundal examination and optical coherence tomography (OCT) revealed right multifocal retinal choroidal lesions consistent with a diagnosis of unilateral punctate inner choroidopathy (PIC) with secondary choroidal neovascularisation (CNV). Anti-VEGF injections led to stabilised fundal appearances. Genetic testing revealed a heterozygous sequence change c.260 T > Ap.(IIe87Asn), pathogenic variant in the Tumour Necrosis Factor Superfamily 13B (TNFRSF13B) gene, which is reported as being associated with ∼10% of CVID cases. CONCLUSION: Autoimmunity may be the dominant clinical presenting feature of CVID. Punctuate inner choroidopathy is an idiopathic inflammatory chorioretinopathy, and to the best of our knowledge, has not been previously reported in CVID. A better understanding of the molecular bases of autoimmune diseases in CVID may provide novel therapeutic targets for autoimmune diseases in this patient population.

Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis.

Importance: Idiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients. Objective: To identify the genes and pathways associated with idiopathic MFC. Design, Setting, and Participants: This was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022. Main outcomes and measures: Genetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients. Results: This study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10-9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 × 10-8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H-related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10-3) and proteins involved in platelet activation and the complement cascade. Conclusions and relevance: Results suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.

[Acute posterior multifocal placoid pigment epitheliopathy, serpiginous choroiditis and related diseases]. / Épithéliopathie en plaque, choroïdite serpigineuse et leurs formes frontières.

Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE) and serpiginous choroiditis are two diseases classified as "white spot syndromes." Both are inflammatory/autoimmune diseases with suspected primary involvement of the choriocapillaris. The former usually has an excellent prognosis, while the latter can rapidly induce legal blindness. Whereas these diseases are well defined and well known, other entities (such as persistent placoid maculopathy or ampiginous choroiditis) with features of both APMPPE and serpiginous choroiditis have been described more recently. This review aims to describe demographic characteristics and multimodal imaging features to help differentiate between these four diseases.

Choroidal lesions in varicella zoster virus uveitis.

Purpose: To evaluate choroidal lesions with spectral domain optical coherence tomography (SD-OCT) scan in varicella zoster virus (VZV) uveitis. Methods: VZV-uveitis cases which underwent OCT scan for choroidal lesions were studied. SD-OCT scan passing through these lesions was studied in detail. Subfoveal choroidal thickness (SFCT) during active and resolved stages was studied. Angiogaphic features were studied where available. Results: Thirteen out of 15 cases had same-sided herpes zoster ophthalmicus skin rashes. All except three patients had old or active kerato-uveitis. All eyes demonstrated clear vitreous and a single or multiple hypopigmented orangish-yellow choroidal lesions. The number of lesions remained unchanged during the follow-up on clinical examination. SD-OCT over lesions (n = 11) showed choroidal thinning (n = 5), hyporeflective choroidal elevation during active inflammation (n = 3), transmission effects (n = 4), and ellipsoid zone disruption (n = 7). The mean change in SFCT (n = 9) after resolution of the inflammation was 26.3 µm (range: 3-90 µm). Fundus fluorescein angiography showed iso-fluorescence over lesions in all (n = 5), but indocyanine green angiography (n = 3) showed hypofluorescence at lesions. Mean follow-up was 1.38 years (range: 3 months-7 years). De-novo appearance of choroidal lesion during the first relapse of VZV-uveitis was captured in one case. Conclusion: VZV-uveitis can cause focal or multifocal hypopigmented choroidal lesions with thickening or scarring of choroidal tissue, depending on the disease activity.

THE CHRYSANTHEMUM PHENOTYPE OF IDIOPATHIC MULTIFOCAL CHOROIDITIS.

PURPOSE: To describe the clinical characteristics and multimodal imaging features of a distinctive subtype of active idiopathic multifocal choroiditis (iMFC) lesions with grey-yellow chorioretinal lesions surrounded by smaller satellite dots, a presentation referred to as "chrysanthemum lesions." METHODS: Retrospective, observational, multicenter case series of eyes with active iMFC and chrysanthemum lesions. Multimodal imaging features were reviewed and presented. RESULTS: Twenty-five eyes from 20 patients (12 women and 8 men), with a mean age of 35.8 ± 17.0 years (range, 7-78 years) were included. Chrysanthemum lesions were equally located in the macula (48.0%) or the mid/far periphery (52.0%). The number of lesions per eye varied from 1 (16.0%) to more than 20 (56.0%). On optical coherence tomography, chrysanthemum lesions showed typical features of iMFC, including subretinal hyperreflective material splitting the retinal pigment epithelium/Bruch membrane. Chrysanthemum lesions were hypoautofluorescent on fundus autofluorescence imaging, hyperfluorescent on fluorescein angiography, hypofluorescent on indocyanine green angiography, and associated with choriocapillaris flow signal deficit on optical coherence tomography angiography. CONCLUSION: Active iMFC may present with findings resembling chrysanthemum lesions. The distinctive lesion morphology on ophthalmoscopic examination, the large number of lesions, and the high prevalence of exclusive midperipheral and far peripheral involvement may represent a distinctive phenotype of iMFC.

Exploring Imaging Characteristics Associated With Disease Activity in Idiopathic Multifocal Choroiditis: A Multimodal Imaging Approach.

PURPOSE: To identify characteristics on multimodal imaging (MMI) in idiopathic multifocal choroiditis (MFC) that can identify inflammatory activity and distinguish choroidal neovascularization (CNV) activity from inflammatory activity. DESIGN: Prospective cohort study. METHODS: MMI consisted of spectral-domain optical coherence tomography (angiography) (SD-OCT(A)), fundus autofluorescence, fundus photography, infrared imaging, fluorescein angiography (FA), and indocyanine green angiography (ICGA). MMI characteristics obtained during active and inactive disease were compared within the same lesion. Secondly, MMI characteristics were compared between active inflammatory lesions with and without CNV activity. RESULTS: Fifty patients (110 lesions) were included. In 96 lesions without CNV activity, the mean focal choroidal thickness was increased during the active disease (205 µm) compared to the inactive disease (180 µm) (P ≤ .001). Lesions with inflammatory activity typically demonstrated moderately reflective material located in the sub-retinal pigment epithelium (RPE) and/or in the outer retina with disruption of the ellipsoid zone. During the inactive stage of the disease, the material disappeared or became hyperreflective and indistinguishable from the RPE. During the active stage of the disease, the area of hypoperfusion in the choriocapillaris significantly increased as visualized on both ICGA and SD-OCTA. CNV activity in 14 lesions was associated with subretinal material with a mixed reflectivity and hypotransmission of light to the choroid on SD-OCT and leakage on FA. SD-OCTA identified vascular structures in all active CNV lesions and in 24% of lesions without CNV activity (showing old, quiescent CNV membranes). CONCLUSION: Inflammatory activity in idiopathic MFC was associated with several MMI characteristics, including focally increased choroidal thickness. These characteristics can guide clinicians in the challenging process of the evaluation of disease activity in idiopathic MFC patients.

PRIMARY MULTIPLE EVANESCENT WHITE DOT SYNDROME AND MULTIPLE EVANESCENT WHITE DOT SYNDROME SECONDARY TO MULTIFOCAL CHOROIDITIS/PUNCTATE INNER CHOROIDOPATHY: A Comparative Study.

PURPOSE: To present and compare the clinical features and multimodal imaging (MMI) findings of the primary form of multiple evanescent white dot syndrome (MEWDS) and MEWDS secondary to multifocal choroiditis/punctate inner choroidopathy (MFC/PIC). METHODS: A prospective case series. Thirty eyes of 30 MEWDS patients were included and divided into the primary MEWDS group and MEWDS secondary to MFC/PIC group. Demographic, epidemiologic, and clinical characteristics and MEWDS-related MMI findings of the two groups were compared. RESULTS: Seventeen eyes from 17 patients with primary MEWDS and 13 eyes from 13 patients with MEWDS secondary to MFC/PIC were evaluated. Patients with MEWDS secondary to MFC/PIC tended to have a higher degree of myopia than those with primary MEWDS. No other significant differences in demographic, epidemiologic, and clinical characteristics and MMI findings were found between the two groups. CONCLUSION: "MEWDS-like reaction" hypothesis seems to be correct for MEWDS secondary to MFC/PIC, and the authors highlight the importance of MMI examinations in MEWDS. Further research is needed to confirm whether the hypothesis is applicable to other forms of secondary MEWDS.

Bilateral Ampiginous Choroiditis following Confirmed SARS-CoV-2 Infection.

INTRODUCTION: Ampiginous Choroiditis is a rare posterior uveitis that combines clinical features of Acute Multifocal Posterior Placoid Pigment Epitheliopathy and Serpiginous Chorioretinitis. Its pathophysiology is poorly understood and further studies are necessary to understand which mechanisms start the immunologic reaction. CASE REPORT: The purpose of this article is to report a well-documented case of Ampiginous Choroiditis following in seven days a RT-PCR confirmed SARS-CoV-2 infection, suggesting that the infection might have contributed as a trigger. CONCLUSION: Timely diagnosis and correct treatment are paramount to improve the visual outcomes, and the patient had successful response to systemic steroids.

Recurrence of tubercular choroiditis following anti-SARS-CoV-2 vaccination.

PURPOSE: To report recurrence of tubercular choroiditis following anti-SARS-CoV-2 vaccination in two patients with quiescent disease activity for more than a year. METHODS: Retrospective observational case reports. RESULTS: Two patients (one female and one male) under follow-up for posterior uveitis having stable course with absence of ocular inflammation for more than a year presented with recurrence of choroiditis lesions 2-6 weeks following anti-SARS-CoV-2 vaccination. Both the patients were managed with intravitreal dexamethasone implant (Ozurdex®, Allergan, Inc., Irvine, CA, USA) and showed resolution of choroiditis lesions upon follow-up. CONCLUSIONS: Acute onset recurrence of inflammation, in absence of any change in health status or treatment suggests the potential role of vaccination being the trigger of this reactivation. Given large-scale vaccination against novel coronavirus- SARS-CoV-2, careful vigilance is warranted to pick up the disease recurrence in patients with posterior uveitis.

Multifocal choroiditis and choroidal tuberculoma: Signs of presumed ocular tuberculosis.

The diagnosis of OTB (Ocular tuberculosis) is usually difficult to make. Definitive diagnosis requires the identification of M. tuberculosis organisms in ocular tissues or fluids, but samples are often difficult to obtain, and biopsy may be hard to justify. We describe a 50-years-old Maghreb male, who presented a multifocal choroiditis associated with a choroidal tuberculoma on the left eye. Based on positive QuantiFERON-TB-Gold test and suggestive clinical and radiographic findings, a diagnosis of presumed ocular tuberculosis was made. Serial swept-source optical coherence tomography (SS-OCT) and widefield fundus retinographies during subsequent follow-up visits demonstrated the characterization of the atypical tuberculosis presentation and allowed the assessment of response to antitubercular therapy and oral steroids.

Primary Sjögren's syndrome-related Choroiditis in a Newly Diagnosed Older Adult.

PURPOSE: To report a case of secondary bilateral choroiditis in a patient with primary Sjögren's syndrome(pSS). STUDY DESIGN: Case report. RESULTS: A 69-year-old woman visited our hospital for consultation due to decreased visual acuity in both eyes for 1 month. At the first visit, best corrected visual acuity (BCVA) was 0.2 and 0.3 in her right and left eyes, respectively. Intraocular pressure values were 15 mmHg and 16 mmHg in her right and left eyes, respectively. Examination revealed edema of the eyelids and conjunctiva,and corneal fluorescence staining was positive. No inflammation in the anterior chamber or vitreous opacities were observed. Bilateral multiple retinal detachments were observed on the posterior fundus, and optical coherence tomography revealed bilateral multiple areas of retinal neuroepithelial detachment, choroidal thickening, and choroidal folds. No abnormal fluorescence leakage was observed on fundus fluorescein angiography or indocyanine green angiography. In addition, systematic manifestations included recurrent bilateral parotid gland enlargement. Labial gland biopsy revealed dilated glandular ducts, scattered interstitial glands, and lymphocytic foci. Salivary gland scintigraphy revealed severe impairment of glandular excretory function. Moreover, blood tests for anti-Ro/SSA and anti-La/SSBantibodies were positive. The patient was diagnosed with primary Sjögren's syndrome. After 2 months treatment with oral prednisolone acetate combined with hydroxychloroquine, her BCVAimproved to 0.8 and 1.0 in the right and left eyes, respectively. The fundus also recovered to normal, and no recurrence was observed during the 1-year follow-up period. CONCLUSIONS: The current case highlights that pSS, which usually manifests with dry eye and keratoconjunctivitis, may manifest with chronic choroiditis in both eyes as well. Based on our experience with this case, patients with clinically suspected bilateral choroiditis should be evaluated for pSS.

PUNCTATE INNER CHOROIDOPATHY-LIKE REACTIONS IN UNRELATED RETINAL DISEASES.

PURPOSE: To report a cohort of patients with a punctate inner choroidopathy (PIC)-like reaction in concurrent, unrelated, chorioretinal disorders. METHODS: This was a retrospective observational study of patients seen at two referral centers with lesions consistent with PIC on multimodal imaging; patients with lesions resembling idiopathic multifocal choroiditis were also included. Active PIC-like lesions appeared as focal hyperreflective lesions splitting the retinal pigment epithelium/Bruch membrane (RPE/BrM) complex on optical coherence tomography. Chronic PIC-like lesions included subretinal fibrosis, multifocal punched-out chorioretinal atrophy, and curvilinear streaks. Patients' demographics, additional imaging features, and treatment responses were collected and summarized. RESULTS: Twenty-two eyes of 16 patients with a PIC-like reaction were included (75% females; median age 40 years). Underlying diagnoses included hereditary retinal conditions (10 patients, 63%) and acquired etiologies, all characterized by the RPE/BrM or outer retinal disruption. Fifteen eyes (68%) had active PIC-like lesions; seven eyes (32%) had chronic PIC-like lesions. Active PIC-like lesions regressed with time and responded to systemic steroids. Subretinal fibrosis (3 eyes, 20%), macular atrophy (3 eyes, 20%), and concomitant subretinal fibrosis and macular atrophy (5 eyes, 33%) developed on follow-up. Recurrences occurred in five eyes (23%). CONCLUSION: RPE/BrM or outer retina disruption may trigger a PIC-like reaction in susceptible patients, presumably because of the loss of immune privilege. A PIC-like reaction may influence the clinical progression and the visual prognosis of the primary chorioretinal disease.