Multimodal Imaging of Dark Without Pressure Lesions in Pediatric Retinal Vasculitis

Multimodal Imaging of Dark Without Pressure Lesions in Pediatric Retinal Vasculitis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Multimodal Imaging of Dark Without Pressure Lesions in Pediatric Retinal Vasculitis Quan Dong Nguyen, Cigdem Yasar, Hashem Ghoraba, Muhammad Hassan, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4283639/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 19 Jul, 2025 Read the published version in Eye → Version 1 posted 10 You are reading this latest preprint version Abstract Purpose : A unique form of retinopathy-plausibly dark without pressure (DWP) was identified during the management of pediatric patients with retinal vasculitis (RV) and described in the index case series. Methods: Forty-three consecutive pediatric uveitis patients presented to tertiary care-unit were evaluated. We assessed DWP-like lesions in pediatric patients with RV. Wide angle fundus photographs (WAFP), fundus autofluorescence (FAF), and optical coherence tomography (OCT) images were analyzed to identify potential retinopathy. Incidence of DWP in pediatric RV patients was also analyzed. WAFP were evaluated using image-J software to measure retinopathy area (RA). Results: Twenty-six of 43 patients were diagnosed with RV and were treated. Retinopathy was detected in 20 patients (30 eyes/76.9%) during treatment. Mean age was 12.8±3.36 years; 40% were female. On WAFP, the lesions appeared as dark areas that were diffuse, mid-peripheral or peripheral. All 20 patients (30 eyes) showed hypo-autofluorescence on FAF at the same locations as the WAFP. Twelve patients (17 eyes) who had OCT images of the RA demonstrated ellipsoid zone disruption. Progression of the retinopathy overtime was analyzed in 28 eyes; all eyes showed improvement of RV with therapy. Mean RA significantly decreased from 394.67 mm2 (time of retinopathy detection) to 365.88 mm2 (last follow-up) (p=0.03). Conclusions: Pediatric RV may be associated with a retinopathy pattern described as DWP previously. Improvement in the RA may be related to improvement of disease activity, but further studies are needed to understand the underlying pathophysiology. Such findings might serve as a marker of previous/ongoing RV in pediatric patients. Health sciences/Medical research/Outcomes research Health sciences/Diseases/Eye diseases/Uveal diseases dark without pressure pediatric retinal vasculitis retinopathy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Retinal vasculitis is a sight-threatening disease defined as inflammation of the retinal vessels and may be accompanied by retinal vascular sheathing, leakage, occlusion, or neovascularization. 1,2 In a study of 1867 pediatric idiopathic uveitis patients with normal ophthalmoscopy, 81.2% of the patients demonstrated retinal vasculitis, diagnosed using fluorescein angiography (FA), supporting the notion that retinal vasculitis may be a common manifestation of pediatric uveitis. The authors also indicated that uveitic eyes with retinal vasculitis are more likely to have band keratopathy, posterior or anterior synechia, and macular edema. 2 Despite being a prognostic indicator, it is often difficult to detect the presence of vasculitis in the pediatric population. Such challenge is because FA is not commonly performed in this population due to the invasive nature of the test and the uncooperative nature of the pediatric patient population. 1,3-6 Therefore, an alternate imaging biomarker on the fundus examination and photography may be needed to detect retinal vasculitis without FA, in the absence of other clinical signs such as vascular sheathing and retinal hemorrhage. Dark without pressure (DWP) retinopathy was first described by Nagpal et al. in 1975 in patients with hemoglobinopathies. 7 Fawzi et al. published a case series of 8 patients with dark without pressure lesions on fundus photographic images, which corresponds to hypo-autofluorescence on fundus autofluorescence (FAF) and ellipsoid zone (EZ) disruption on optical coherence tomography (OCT). 8 The etiology is unclear, but it was suggested to represent a congenital, benign, and incidental lesion that requires no further evaluations. 8-13 Two cohort studies on Ebola virus survivors reported dark without pressure lesions in some patients, which may be related to viral disease. 14,15 Herein, we report multimodal imaging findings in pediatric retinal vasculitis patients who demonstrated DWP. To the best of our knowledge, the index case series is the first to associate this unique retinopathy with pediatric retinal vasculitis. Methods Study Design and Population We conducted a retrospective evaluation of consecutive pediatric uveitis patients who were evaluated between November 2017 and December 2020 in the Uveitis Clinic at the Byers Eye Institute, Stanford University. Prior to the commencement of the research, institutional review board (IRB) approval was obtained from the Stanford IRB, ensuring compliance with ethical standards (IRB-41266). All participants were provided with detailed information about the study procedures, risks, and benefits, and a signed consent form was obtained from all participants. The study adhered to the principles outlined in the Declaration of Helsinki. Dark Without Pressure Retinopathy The DWP appears as an area of dark retinal discoloration that can be visualized on clinical examination and wide-angle fundus photograph (WA-FP). The pattern can be patchy or diffuse, and the latter may extend to the peripheral fundus (Supplemental Material 1A-C). There is a distinct well-defined demarcation between the abnormal and normal retina. The area of retinopathy appears as a well demarcated area of hypo-autofluorescence (Figure 1B) on wide angle fundus autofluorescence (WA-FAF) that corresponds to the changes on the WA-FP (Figure 1A). An optical coherence tomography (OCT) scan through the area of retinopathy demonstrates ellipsoid zone disruption with a clear distinctive edge between normal and abnormal retina corresponding to other imaging modalities (Figure 1C). Infrared image also demonstrates corresponding hypo reflectivity in the area of the DWP (Figure 1C). All these changes were observed in association with retinal vasculitis on wide angle fluorescein angiography (WA-FA) (Figure 1D). Supplemental Material 1: Wide-angle fundus photograph of three different patients demonstrating DWP (dark without pressure) localized to peripheral, mid-peripheral and diffuse retinal area. A: DWP localized to mid-peripheral and peripheral fundus of the right eye (white dash lines). B: DWP localized to mid-peripheral fundus of the left eye (white dash lines). C: DWP localized to diffuse retinal area of the right eye (outside the white dash lines). Figure 1: Multimodal imaging of the dark without pressure (DWP) r etinopathy in the left eye of a pediatric patient with retinal vasculitis. A: Color fundus photo demonstrating DWP localized to the mid-peripheral fundus of the left eye (blue dashes). B: Hypo - autofluorescence corresponding to the DWP (white arrows). C: Ellipsoid zone disruption at the area of DWP on optical coherence tomography. D: Retinal vasculitis of the left eye with diffuse vascular leakage on the wide-angle fluoresceine angiography. Inclusion and Exclusion Criteria We included pediatric patients aged 18 years or younger who were diagnosed with DWP in the setting of retinal vasculitis. Retinal vasculitis was diagnosed through clinical examination (perivascular sheathing and exudates), WA-FA (perivascular leakage), or both. Other inclusion criteria included the availability of good quality WA-FP and WA-FA images at baseline. Patients who lacked WA-FP or WA-FAF images of sufficient quality were excluded from the study. Data Collection and Analysis Demographics and clinical data were collected including underlying systemic disease, ocular examination, and treatment history. Imaging data included WA-FP (Optos, Dunfermline, United Kingdom), WA-FAF (Optos, Dunfermline, United Kingdom), WA-FA (Optos, Dunfermline, United Kingdom), and OCT (SD-OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany)). All the data were collected at the initial presentation as well as follow-up visits. We performed both cross-sectional and longitudinal analyses. The latter was performed to examine the evolution of the area of retinopathy. WA-FP images from both initial and follow-up visits were registered using an image registration software. The boundaries of the lesions were identified and annotated using an imaging tool. Image-J software (1.53k/Java 1.8) was utilized to assess the progression of the lesion area over time (Supplemental Material 2). The OCT images were utilized to evaluate the integrity of EZ in the area of retinopathy with a special focus on the lesion edges as the disease progressed over the course of treatment. Supplemental Material 2 : Utilizing image registration using Image J software for quantification of the dark without pressure (DWP) retinopathy area. A: DWP at baseline (blue arrows). B: Image registration at baseline. C: DWP at the last follow-up (1 year later) D: Image registration at the last follow-up. Statistical Methods The data obtained were analyzed using descriptive statistics. The correlation evaluations were conducted using parametric statistical analyses. SPSS was utilized to perform statistical analyses. Study Design and Population We conducted a retrospective evaluation of consecutive pediatric uveitis patients who were evaluated between November 2017 and December 2020 in the Uveitis Clinic at the Byers Eye Institute, Stanford University. Prior to the commencement of the research, institutional review board (IRB) approval was obtained from the Stanford IRB, ensuring compliance with ethical standards (IRB-41266). All participants were provided with detailed information about the study procedures, risks, and benefits, and a signed consent form was obtained from all participants. The study adhered to the principles outlined in the Declaration of Helsinki. Dark Without Pressure Retinopathy The DWP appears as an area of dark retinal discoloration that can be visualized on clinical examination and wide-angle fundus photograph (WA-FP). The pattern can be patchy or diffuse, and the latter may extend to the peripheral fundus (Supplemental Material 1A-C). There is a distinct well-defined demarcation between the abnormal and normal retina. The area of retinopathy appears as a well demarcated area of hypo-autofluorescence (Figure 1B) on wide angle fundus autofluorescence (WA-FAF) that corresponds to the changes on the WA-FP (Figure 1A). An optical coherence tomography (OCT) scan through the area of retinopathy demonstrates ellipsoid zone disruption with a clear distinctive edge between normal and abnormal retina corresponding to other imaging modalities (Figure 1C). Infrared image also demonstrates corresponding hypo reflectivity in the area of the DWP (Figure 1C). All these changes were observed in association with retinal vasculitis on wide angle fluorescein angiography (WA-FA) (Figure 1D). Supplemental Material 1: Wide-angle fundus photograph of three different patients demonstrating DWP (dark without pressure) localized to peripheral, mid-peripheral and diffuse retinal area. A: DWP localized to mid-peripheral and peripheral fundus of the right eye (white dash lines). B: DWP localized to mid-peripheral fundus of the left eye (white dash lines). C: DWP localized to diffuse retinal area of the right eye (outside the white dash lines). Figure 1: Multimodal imaging of the dark without pressure (DWP) r etinopathy in the left eye of a pediatric patient with retinal vasculitis. A: Color fundus photo demonstrating DWP localized to the mid-peripheral fundus of the left eye (blue dashes). B: Hypo - autofluorescence corresponding to the DWP (white arrows). C: Ellipsoid zone disruption at the area of DWP on optical coherence tomography. D: Retinal vasculitis of the left eye with diffuse vascular leakage on the wide-angle fluoresceine angiography. Inclusion and Exclusion Criteria We included pediatric patients aged 18 years or younger who were diagnosed with DWP in the setting of retinal vasculitis. Retinal vasculitis was diagnosed through clinical examination (perivascular sheathing and exudates), WA-FA (perivascular leakage), or both. Other inclusion criteria included the availability of good quality WA-FP and WA-FA images at baseline. Patients who lacked WA-FP or WA-FAF images of sufficient quality were excluded from the study. Data Collection and Analysis Demographics and clinical data were collected including underlying systemic disease, ocular examination, and treatment history. Imaging data included WA-FP (Optos, Dunfermline, United Kingdom), WA-FAF (Optos, Dunfermline, United Kingdom), WA-FA (Optos, Dunfermline, United Kingdom), and OCT (SD-OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany)). All the data were collected at the initial presentation as well as follow-up visits. We performed both cross-sectional and longitudinal analyses. The latter was performed to examine the evolution of the area of retinopathy. WA-FP images from both initial and follow-up visits were registered using an image registration software. The boundaries of the lesions were identified and annotated using an imaging tool. Image-J software (1.53k/Java 1.8) was utilized to assess the progression of the lesion area over time (Supplemental Material 2). The OCT images were utilized to evaluate the integrity of EZ in the area of retinopathy with a special focus on the lesion edges as the disease progressed over the course of treatment. Supplemental Material 2 : Utilizing image registration using Image J software for quantification of the dark without pressure (DWP) retinopathy area. A: DWP at baseline (blue arrows). B: Image registration at baseline. C: DWP at the last follow-up (1 year later) D: Image registration at the last follow-up. Statistical Methods The data obtained were analyzed using descriptive statistics. The correlation evaluations were conducted using parametric statistical analyses. SPSS was utilized to perform statistical analyses. Results Patient Characteristics Forty-three pediatric patients with a confirmed diagnosis of anterior, intermediate, and posterior pediatric uveitis were identified. Among these, 26 patients (40 eyes) fulfilled the eligibility criteria and were included in the study. The diagnoses and treatment of these patients have been highlighted in table 1 (Supplemental Material 3-4). Retinopathy of Interest Among the 26 patients with retinal vasculitis, retinopathy was detected in 20 (76.9%) patients (30 eyes, 75%). The mean age was 12.8 (±3.36) years and 40% were female. The mean duration of follow-up was 27.2 (±13.7) months. Six patients (10 eyes) had mild peripheral retinal vasculitis on WA-FA and did not demonstrate the DWP retinopathy on various imaging modalities and were excluded. The remaining 17 patients with uveitis, but without vasculitis did not demonstrate DWP retinopathy and therefore were excluded (Supplemental Material 3). Among the patients who demonstrated DWP on imaging modalities, 12 patients (60%) (19 eyes) had visible DWP retinopathy at the time of diagnosis of retinal vasculitis at their baseline visit. Eight patients (11 eyes) had no demonstrable DWP at the time of initial diagnosis of vasculitis but developed it later along the disease course and after initiation of treatment. In this subgroup, the mean interval between the time of diagnosis of vasculitis and the appearance DWP was 2.6 (±1.2) months. Muli-modal Imaging Modality Analysis All patients (20 patients; 30 eyes) who demonstrated DWP had similar findings of dark discoloration on WA-FP with a corresponding area of hypo autofluorescence on WA-FAF. OCT data was available for only eleven patients (17 eyes) and demonstrated EZ disruption within area of retinopathy with a sharp transition to normal retina at the edges of the retinopathy. Macular sparing was also noted on OCT of all the study patients. Nineteen (19) patients (28 eyes) had adequate imaging information available at the follow up visits and were included in the longitudinal analysis. Amongst these, 18 patients demonstrated regression/progression (19 (67.8%) eyes/8 (28.5%) eyes) of the retinopathy lesion while in one patient (1 eye), the retinopathy area remained diffuse and stable. The change in the DWP retinopathy area over time was analyzed in 19 patients (28 eyes), with 2 patients (2 eyes) excluded due to inadequate image quality. Mean retinopathy area for these patients decreased from 394.67 mm 2 (at time of retinopathy detection) to 365.88 mm 2 (last follow-up), which was statistically significant (p=0.03). All patients showed either improvement or resolution of vasculitis with treatment. Amongst patients with complete resolution of vascular leakage on FA (9 patients; 11 eyes), the DWP retinopathy lesions were still visible in all patients. However, 5 patients (7 eyes) showed improvement in their area of DWP, while 4 patients (4 eyes) showed progression in DWP. Among the 14 patients (17 eyes) with improvement to very mild leakage but without complete resolution of retinal vasculitis, the area of retinopathy improved in 9 patients (12 eyes) and 3 patients (4 eyes) showed progression. Whereas there was no change in retinopathy area in 1 patient (1 eye). (Table 1). Regression of the retinopathy area showed EZ recovery on the OCT follow up images (Figure 2). Figure 2: Optic coherence tomography (OCT) follow-up images of 2 patients (A&B). Dark without pressure (DWP) area can be seen as hypo-reflectance area (between red arrows) on the infrared (IR) with a corresponding ellipsoid zone (EZ) disruption (between white arrows) on OCT (A1-A2). Follow up image (A1) after 2 years showed recovery of the EZ compared to prior OCT image (A2). The OCT images of the second patient showed DWP as hypo-reflectance area (between red arrows) on IR with a corresponding ellipsoid zone (EZ) disruption (between white arrows) (B1-B2). Follow up image (B1) after 2 years showed recovery of the EZ compared to prior OCT image (B2). Case Presentations CASE 1 An early adolescence female presented with blurry vision and floaters in both eyes (OU). There were 2+ cells and 1.5+ flare in the anterior chamber OU, and fundus examination revealed 1+ vitritis and no lesions OU. WA-FA showed severe retinal vasculitis OU, cystoid macular edema in the left eye (OS), and subretinal fluid OS, and optic disc inflammation, OU. The patient was also diagnosed with Sunflower syndrome. At baseline, the fundus photo and WA-FAF did not show signs of DWP as previously described. The patient was treated with infliximab 7.5 mg/kg/day and IV methylprednisolone 750 mg for 3 days each month. After 3 months of treatment, FA showed resolution of leakage and WA-FP and WA-FAF showed the DWP at the midperipheral retina OU. While the retinal vasculitis was inactive at 1 year follow up, the lesion was reshaped (regressed in some parts and progressed in some other areas). OCT of the lesion showed EZ disruption (Figure 3). Figure 3: Wide angle fundus photo (WA-FP) (A1, B1) and Wide-angle fundus autofluorescence (WA-FAF) (A2, B2) images for both eyes at the first visit did not demonstrate any dark without pressure retinopathy (DWP). Wide angle fluorescein angiography (WA-FA) (A3, B3) images of both eyes showed diffuse vascular leakage and macular optical coherence tomography (OCT) image in the left eye showed cystoid macular edema and subretinal fluid (B3). After 1 year of treatment, the DWP was seen as dark retinal areas on WA-FP (C1, D1) that correlated with hypo-autofluorescence on WA-FAF (C2, D2). At the 1-year visit, WA-FA (C3, D3) image showed resolution of the leakage in both eyes. OCT images (F1, F2) through the retinopathy in both eyes showed ellipsoid zone disruption. CASE 2 An early adolescence male with pan uveitis in the OS was referred to the Uveitis Clinic. Anterior segment examination showed 0.5+ cells and 1+ flare in the anterior chamber of both eyes (OU), and dilated fundus examination showed 1+ vitreous cell in the right eye (OD) and 3+ vitreous cell OS. FA showed significant, diffuse retinal vascular leakage in OS and no vasculitis OD. The patient was diagnosed with pan-uveitis in OU. Given the pan-uveitis in OU and severe retinal vasculitis in OS, the patient was treated with infliximab 5 mg/kg monthly and methylprednisolone 750 mg for 3 days monthly. At the baseline visit, there was a diffuse DWP which was barely visible, making it difficult to recognize. After treatment, the novel retinopathy became more prominent on both WA-FP and WA-FAF images (Supplemental Material 5). Supplemental Material 5: Wide angle fundus photo (WA-FP) (A1), wide angle fundus autofluorescence (WA-FAF) (A2) images at the first visit did not demonstrate any retinopathy findings and wide-angle fluorescein angiography (WA-FA) (A3) images showed diffuse vascular leakage. Macular optical coherence tomography (OCT) image in the left eye showed cystoid macular edema (CME) (C1). After 2 months of treatment, the retinopathy could be seen as dark retinal areas on WA-FP (B1) and hypo-autofluorescence on WA-FAF (B2). WA-FA (B3) images showed near complete improvement of vascular leakage and CME is resolved (C2). OCT images (C3) through the retinopathy showed ellipsoid zone disruption along the section. CASE 3 An early adolescence male was referred to the Uveitis Clinic for acute retinal necrosis in OD. Evaluations for infectious etiologies were negative. The patient was diagnosed with Philadelphia chromosome negative pre-B-cell acute lymphoblastic leukemia and started chemotherapy by the Oncology Service. WA-FA showed diffuse leakage in OD and normal findings in OS. At the first visit, there was perivascular sheathing and diffuse DWP noted on WA-FP that was difficult to recognize. With treatment, retinal vasculitis improved, and the retinopathy area was more delineated. At the last visit, the retinal vasculitis improved, and the novel retinopathy was localized and improved. (Figure 4). Figure 4: Baseline wide angle fluorescein angiography(A) showed diffuse leakage in the right eye and follow up WA-FA after 1 year (B) showed resolution of the leakage. Baseline wide angle fundus photo (WA-FP) (C) image showing the novel retinopathy as areas of diffuse dark retina. 3 months later, WA-FP image (D) showed a small healthy retinal area inside the white dash line. 6 months later (E) retinopathy became smaller with more healthy retinal area inside the white dash line and 9 months later (F) more healthy area can be seen inside the white dash lines. Discussion Vascular inflammation is a common finding in patients diagnosed with pediatric uveitis and is associated with a higher incidence of chronic complications. Despite being a prognostic indicator of the disease status, it is challenging to diagnose vasculitis and follow response to treatment in pediatric patients. The challenge is secondary to difficulties associated with FA testing due to its invasive nature and difficult examination. In this study, we described a retinopathy akin to DWP with characteristic dark areas on WA-FP, hypo autofluorescence on FAF, and EZ disruption on OCT, which may be associated with pediatric retinal vasculitis. DWP was the term coined by Nagpal et al. in 1975 7 They identified flat dark lesions in midperipheral retina that were similar in shape to white without pressure in patients with hemoglobinopathies. These lesions were reported to be transient, change shape, and occasionally disappear over weeks. Their hypothesis was that these lesions probably were altered reflex at the level of either retinal pigment epithelium or internal limiting membrane. Condon and Serjeant also noted similar lesions in Jamaican patients, 10% of which had sickle cell haemoglobinopathies. 10,11 More recently, another study found a higher prevalence of DWP lesions (25%) in sickle cell disease patients. 16 In 2014, Fawzi et al. utilized multimodal imaging to analyze lesions of white without pressure and DWP in 10 patients between the age of 12-37. 8 Their study was the first to establish that DWP lesions seen in 8 patients had changes in the outer retinal layers and were not related to vitreoretinal interface abnormalities or alteration of retinal pigment epithelium (RPE). On the OCT scans they noted an abrupt transition to hypo reflectivity at the level of the ellipsoid zone and outer photoreceptor segments in the DWP areas. Although the lesions reported by Fawzi et al. have similarities to those seen in our population, unlike our patients with a clear fluorescein angiography-based diagnosis of retinal vasculitis, most of their population had no ocular disease except 3 patients who were diagnosed with multi evanescent white dot syndrome, HLA-B27 anterior and intermediate uveitis, and astrocytic hamartoma. Interestingly, 6 of 8 patients with DWP lesions were of dark fundus pigmentation like previously reported studies. One patient with HLA-B27 and intermediate uveitis and DWP lesions had light fundus pigmentation. However, the authors did not perform FA on any of the included patients to evaluate for signs of vasculitis. The FAF imaging in their study showed hypo-autofluorescence in areas of the DWP similar to our study. However, they reported hypo-autofluorescence in areas of white without pressure lesions as well even though their OCT findings were that of increased reflectivity of EZ and interdigitation zone unlike DWP. Fawzi et al. proposed that the fundus pigmentation may play a more important role in the clinician’s ability to see these lesions against a darker background rather than being a factor in development of these lesions. Visual field testing was performed in one of the patients in the area of DWP showed no changes leading to thought that these lesions had mainly anatomical changes with little functional significance. Similar to Fawzi et al., Pimentel et al. reported DWP lesions without any ocular pathology in a pediatric population ranging from 3-13 years. Their OCT and FAF findings also showed hypo-reflectivity in areas of the lesions. 12 In contrast to previous reports, various studies have correlated the DWP lesions to infectious and inflammatory etiologies. A cohort study of 14 Ebola virus survivors showed 141 Ebola virus retinal lesion in 22 of 27 eyes and 88.7% of these retinal lesions had perilesional DWP lesions with OCT characteristics of disrupted ellipsoid zone and interdigitation zone. 14 Another cohort on same population of Ebola survivors obtained sequential WA-FP and OCT images of these DWP lesions. 15 . Similar to our study, they also reported that some of these lesions evolve over time with non-uniform expansion and retraction across various borders. However, unlike our study, they did not report any vasculitis in their patient population, although, no FA was performed in their study to confirm a clear absence of vasculitis. They also showed that the higher density of Ebola retinal lesions was associated with larger area of the DWP lesions and DWP lesions can circumferentially involve 360 degrees of the retina while sparing the macula. Such findings were also seen in our study where more extensive vasculitis was associated with larger DWP lesions which sometimes involved the entire retina with macular sparing. Another case report of a patient with ocular toxoplasmosis also demonstrated perilesional DWP lesions which resolved as the lesion became inactive. 17 However, on a follow up with another reactivation showing satellite lesions and perivascular infiltrates, there were no initial signs of DWP lesions. However, as the patient was started on appropriate treatment including prednisolone, the patient developed DWP lesions. Such findings were seen in some of our patients as well where DWP lesions were initially absent but developed on follow-up visits after initiation of treatment. DWP lesion sizes are improved or progressed after resolution of the leakage on FA. Progression of DWP lesions after resolution of the leakage may be related to the disease severity or duration. The pathophysiology of the DWP is not clearly understood and several mechanisms have been proposed to explain these lesions. Fawzi et al. suggested that these changes are secondary to the presence of different photopigments in the photoreceptors in these areas that have different spectral range and reflectance compared to normal photopigment i.e., mainly lipofuscin. 8 They supported the hypothesis with reflectivity changes seen in photoreceptor outer segments in patients with Mizuo-Nakamura phenomenon, particularly the similarity between dark-adapted state of fundus in this phenomenon and DWP lesions. The different photopigment spectral range in these areas could be a reason for the hypo-autofluorescence seen on FAF in these areas despite normal underlying RPE. It has been shown that different fluorophores have different excitation and emission spectrums and there are even differences in the autofluorescence spectrums recorded by our commercially used machines. 18 Although Fawzi et al. suggested that these areas may be associated with photoreceptor dysfunction but because of their localized and circumscribed appearance, they are of little clinical significance. 8 Pimentel et al. also thought that these lesions are not clinically significant and may represent acquired developmental changes. 12 On other hand in cases where these lesions have been associated with infections such as Ebola, the proposed mechanism for these DWP lesions was changes in the metabolic state of mitochondria which make the up the EZ of the photoreceptors observed on the OCT. 19 The mitochondria serve as powerhouse of the photoreceptors but are very sensitive to cellular energy requirements and their environmental stimuli such as oxidative stress caused by the inflammation. 20-22 The mitochondria change their morphology by mechanisms such as fusion and expanding their matrix in these stress states. 20,23,24 These morphological changes have been shown to change the optical parameters such as light scattering and refractivity of the mitochondria. 20,21,25,26 In studies using zebrafish, it has also been shown that chronic stress causes mitochondrial movement from EZ towards muller cells which play a role in photoreceptor and mitochondrial turnover. 27 Additionally, these changes in mitochondria in response to oxidative also affect the energy production required for photoreceptor function. Therefore, it has been shown in studies that EZ integrity correlated with the photoreceptor layer health and in turn visual acuity in cases where the damage involves the fovea. 28-31 The changes in the mitochondrial function and structure in response to inflammatory stress and resultant alterations in photoreceptor health could also be a contributing for the hypo autofluorescence seen in these DWP areas due to decreased lipofuscin turnover. 32 The fluorophores responsible for autofluorescence are dependent on the metabolic activity in the area and are also very susceptible to oxidative damage which may change their excitation and emission spectrums resulting in hypo-fluorescence in DWP areas despite presence of structurally normal RPE. 33,34 In addition to changes in the mitochondrial activity, the inflammatory cytokines can also cause direct damage to the photoreceptors. 29,35 Based on the studies that have documented DWP lesions, it can be deduced that multiple factors are at play which can contribute to these lesions and these lesions in turn can be a similar phenotypic appearance of various underlying phenomenon. Our study supports an active inflammatory pathogenesis of these DWP lesions. The resultant phenotypic appearance could be secondary to interplay of the various mechanisms including mitochondrial changes, photoreceptor damage as well as changes in the photopigment production or structure in the area. We observed that they can be present at time of disease detection in more extensive vasculitis or can develop after exposure to leakage in moderate vascular leakage or may even be absent in cases with only mild peripheral leakage. Whatever the timeline, in case the lesions are observed, they are associated with EZ disruption and or hypo reflectivity in areas of the lesion. We believe that after treatment and with resolution of the leakage, retinopathy can improve with the recovery of EZ disruption in less severe or more acute disease cases. However, if the damage is severe and or chronic with significant persistent leakage, EZ disruption may be irreversible. Our study, however, has certain limitations. First, this is a retrospective cohort of a relatively small sample size. Second, longer follow up of the patients is needed to further document the evolution of the lesions and to determine their functional and clinical significance. Lastly, size calculations in the peripheral lesions on widefield imaging may be less accurate due to wrapping of images. Conclusion Pediatric retinal vasculitis may be associated with dark without pressure retinopathy. These lesions can change in size over time after resolution of the vasculitis. DWP may be a helpful finding should pediatric retinal vasculitis be suspected and may serve as a useful imaging biomarker. Future studies should be conducted employing additional imaging technologies such as adaptive optics, electrophysiology, and visual field to better understand the functional changes in the DWP retinopathy as well as its relationship with retinal vasculitis. Declarations Acknowledgement None Conflict of Interest None Funding An unrestricted grant from Research to Prevent Blindness, National Eye Institute, P30-Ey026877. Precis: We identified a novel link between pediatric retinal vasculitis and a retinopathy pattern termed dark without pressure retinopathy (DWP). DWP changes in post-vasculitis resolution can serve as a valuable biomarker in diagnosing and monitoring pediatric retinal vasculitis, providing insights to ophthalmology clinicians. Competing Interests Statement: No competing interest for any of the authors References Abu El-Asrar AM, Herbort CP, Tabbara KF. Retinal vasculitis. Ocul Immunol Inflamm. Dec 2005;13(6):415-433. Yang P, Zhong Z, Su G, et al. Retinal Vasculitis, a Common Manifestation of Idiopathic Pediatric Uveitis? Retina. Mar 1 2021;41(3):610-619. Agarwal A, Afridi R, Agrawal R, Do DV, Gupta V, Nguyen QD. Multimodal Imaging in Retinal Vasculitis. Ocul Immunol Inflamm. Jun 2017;25(3):424-433. 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Condon PI, Serjeant GR. Ocular findings in homozygous sickle cell anemia in Jamaica. Am J Ophthalmol. Apr 1972;73(4):533-543. Flores Pimentel MA, Duncan JL, de Alba Campomanes AG, Moore A. Dark without pressure retinal changes in a paediatric age group. Eye (Lond). Apr 2021;35(4):1221-1227. Sherman T, Palileo BM, Adam CR, Abrams GW. Dark Without Pressure In A Case Of Choroidal Osteoma. Retin Cases Brief Rep. Jun 8 2020. Steptoe PJ, Momorie F, Fornah AD, et al. Multimodal Imaging and Spatial Analysis of Ebola Retinal Lesions in 14 Survivors of Ebola Virus Disease. JAMA Ophthalmol. Jun 1 2018;136(6):689-693. Steptoe PJ, Momorie F, Fornah AD, et al. Evolving Longitudinal Retinal Observations in a Cohort of Survivors of Ebola Virus Disease. JAMA Ophthalmol. Apr 1 2020;138(4):395-403. Lott PW, McKibbin M. Prevalence of Dark without Pressure and Angioid Streaks in Sickle Cell Disease. Ophthalmic Surg Lasers Imaging Retina. Nov 2021;52(11):620-622. P JS, Guly CM, Dick AD. Ocular Toxoplasmosis Associated Dark Without Pressure. Ocul Immunol Inflamm. May 2 2022:1-3. Bittencourt MG, Hassan M, Halim MS, et al. Blue light versus green light fundus autofluorescence in normal subjects and in patients with retinochoroidopathy secondary to retinal and uveitic diseases. J Ophthalmic Inflamm Infect. Jan 8 2019;9(1):1. Cuenca N, Ortuno-Lizaran I, Pinilla I. Cellular Characterization of OCT and Outer Retinal Bands Using Specific Immunohistochemistry Markers and Clinical Implications. Ophthalmology. Mar 2018;125(3):407-422. Litts KM, Zhang Y, Freund KB, Curcio CA. Optical Coherence Tomography and Histology of Age-Related Macular Degeneration Support Mitochondria as Reflectivity Sources. Retina. Mar 2018;38(3):445-461. Tychinsky V. The metabolic component of cellular refractivity and its importance for optical cytometry. J Biophotonics. Sep 2009;2(8-9):494-504. Wilson JD, Bigelow CE, Calkins DJ, Foster TH. Light scattering from intact cells reports oxidative-stress-induced mitochondrial swelling. Biophys J. Apr 2005;88(4):2929-2938. Mirra S, Marfany G. Mitochondrial Gymnastics in Retinal Cells: A Resilience Mechanism Against Oxidative Stress and Neurodegeneration. Adv Exp Med Biol. 2019;1185:513-517. Shutt T, Geoffrion M, Milne R, McBride HM. The intracellular redox state is a core determinant of mitochondrial fusion. EMBO Rep. Oct 2012;13(10):909-915. Zheng JY, Tsai YC, Kadimcherla P, et al. The C-terminal transmembrane domain of Bcl-xL mediates changes in mitochondrial morphology. Biophys J. Jan 1 2008;94(1):286-297. Tychinsky V, Kretushev A, Vyshenskaja T. Mitochondria optical parameters are dependent on their energy state: a new electrooptical effect? Eur Biophys J. Dec 2004;33(8):700-705. Rutter KM, Hutto RA, Brockerhoff SE. Photoreceptor mitochondria can be transferred and turned over by Müller glia. Investigative Ophthalmology & Visual Science. 2022;63(7):2579 – F0462-2579 – F0462. Saxena S, Meyer CH, Akduman L. External limiting membrane and ellipsoid zone structural integrity in diabetic macular edema. Eur J Ophthalmol. Jun 16 2021:11206721211026106. Sinha S, Saxena S, Prasad S, et al. Association of serum levels of anti-myeloperoxidase antibody with retinal photoreceptor ellipsoid zone disruption in diabetic retinopathy. J Diabetes Complications. May 2017;31(5):864-868. Mori Y, Suzuma K, Uji A, et al. Restoration of foveal photoreceptors after intravitreal ranibizumab injections for diabetic macular edema. Sci Rep. Dec 14 2016;6:39161. De S, Saxena S, Kaur A, et al. Sequential restoration of external limiting membrane and ellipsoid zone after intravitreal anti-VEGF therapy in diabetic macular oedema. Eye (Lond). May 2021;35(5):1490-1495. Sparrow JR, Boulton M. RPE lipofuscin and its role in retinal pathobiology. Exp Eye Res. May 2005;80(5):595-606. Vives-Bauza C, Anand M, Shiraz AK, et al. The age lipid A2E and mitochondrial dysfunction synergistically impair phagocytosis by retinal pigment epithelial cells. J Biol Chem. Sep 5 2008;283(36):24770-24780. Ben-Shabat S, Itagaki Y, Jockusch S, Sparrow JR, Turro NJ, Nakanishi K. Formation of a nonaoxirane from A2E, a lipofuscin fluorophore related to macular degeneration, and evidence of singlet oxygen involvement. Angew Chem Int Ed Engl. Mar 1 2002;41(5):814-817. Eskandarpour M, Nunn MA, Weston-Davies W, Calder VL. Immune-Mediated Retinal Vasculitis in Posterior Uveitis and Experimental Models: The Leukotriene (LT)B4-VEGF Axis. Cells. Feb 15 2021;10(2). Table Table 1. Characteristics of Patients and Retinopathy Changes over the Disease Course Patient Eye Anatomical Diagnosis Vasculitis Status at Last Visit Retinopathy Status Change in Area of Retinopathy 1 OD Panuveitis Very mild activity at peripheral Mid-peripheral Regression 2 OD Panuveitis Mild activity at peripheral Diffuse Regression 2 OS Panuveitis Mild activity at peripheral Diffuse Regression 3 OD Anterior uveitis Mild activity Diffuse Regression 3 OS Anterior uveitis Very mild activity Peripheral Progression 5 OD Posterior uveitis Mild activity Mid- Peripheral Progression 5 OS Posterior uveitis Mild activity Mid- Peripheral Progression 6 OS Panuveitis Mild activity Diffuse Stable 7 OD Anterior uveitis Very mild activity Diffuse Regression 7 OS Anterior uveitis Very mild activity Diffuse Regression 8 OS Panuveitis İnactive Diffuse Progression 9 OD Panuveitis Very mild activity Diffuse Regression 10 OD Anterior uveitis Mild activity Peripheral Regression 11 OD Anterior uveitis İnactive Diffuse Regression 11 OS Anterior uveitis Very mild activity Peripheral Regression 12 OS Panuveitis İnactive Mid-Peripheral Progression 13 OD Posterior uveitis İnactive Diffuse Progression 13 OS Posterior uveitis Active Diffuse Progression 14 OD Intermediate uveitis İnactive Peripheral Regression 14 OS Intermediate uveitis İnactive Peripheral Regression 15 OD Anterior uveitis Very mild activity Diffuse Regression 15 OS Anterior uveitis İnactive Diffuse Progression 16 OS Panuveitis Very mild activity at peripheral Mid-peripheral Regression 17 OD Anterior uveitis Very Mild activity Diffuse Regression 18 OD Panuveitis İnactive Diffuse Regression 18 OS Panuveitis İnactive Diffuse Regression 19 OS Anterior uveitis İnactive Peripheral Regression 20 OS Posterior uveitis İnactive Mid-peripheral Regression Additional Declarations There is no conflict of interest Supplementary Files SupplementalMaterial1.png SupplementalMaterial2.png SupplementalMaterial3.docx SupplementalMaterial41.docx SupplementalMaterial5.jpg Cite Share Download PDF Status: Published Journal Publication published 19 Jul, 2025 Read the published version in Eye → Version 1 posted Editorial decision: revise 19 Nov, 2024 Reviewer # 3 agreed at journal 18 Oct, 2024 Review # 2 received at journal 22 Jul, 2024 Review # 1 received at journal 08 Jul, 2024 Reviewer # 2 agreed at journal 26 Jun, 2024 Reviewer # 1 agreed at journal 22 Jun, 2024 Reviewers invited by journal 19 Jun, 2024 Editor assigned by journal 18 Jun, 2024 Submission checks completed at journal 18 Apr, 2024 First submitted to journal 17 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4283639","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":316243657,"identity":"28cc300a-cec4-4683-bf4d-c69615ef4bf1","order_by":0,"name":"Quan Dong 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18:50:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4283639/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4283639/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41433-025-03882-3","type":"published","date":"2025-07-19T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60432729,"identity":"896c6378-89c5-414d-a8cd-b2d4a9525fb2","added_by":"auto","created_at":"2024-07-16 16:54:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":798247,"visible":true,"origin":"","legend":"\u003cp\u003eMultimodal imaging of the dark without pressure (DWP) \u003cu\u003er\u003c/u\u003eetinopathy in the left eye of a pediatric patient with retinal vasculitis. A: Color fundus photo demonstrating DWP localized to the mid-peripheral fundus of the left eye (blue dashes). B: Hypo\u003cu\u003e-\u003c/u\u003eautofluorescence corresponding to the DWP (white arrows). C: Ellipsoid zone disruption at the area of DWP on optical coherence tomography. D: Retinal vasculitis of the left eye with diffuse vascular leakage on the wide-angle fluoresceine angiography.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4283639/v1/b79903a529a34c14385d040e.png"},{"id":60432733,"identity":"ee424925-13b3-42fe-9af4-c7820608d6d4","added_by":"auto","created_at":"2024-07-16 16:54:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":631366,"visible":true,"origin":"","legend":"\u003cp\u003eOptic coherence tomography (OCT) follow-up images of 2 patients (A\u0026amp;B). Dark without pressure (DWP) area can be seen as hypo-reflectance area (between red arrows) on the infrared (IR) with a corresponding ellipsoid zone (EZ) disruption (between white arrows) on OCT (A1-A2). Follow up image (A1) after 2 years showed recovery of the EZ compared to prior OCT image (A2). The OCT images of the second patient showed DWP as hypo-reflectance area (between red arrows) on IR with a corresponding ellipsoid zone (EZ) disruption (between white arrows) (B1-B2). Follow up image (B1) after 2 years showed recovery of the EZ compared to prior OCT image (B2).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4283639/v1/5a4ce93e6f1c2a287aa1083a.png"},{"id":60432730,"identity":"124d092b-e1e0-448e-be1f-1a0c74ccc42e","added_by":"auto","created_at":"2024-07-16 16:54:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":905133,"visible":true,"origin":"","legend":"\u003cp\u003eWide angle fundus photo (WA-FP) (A1, B1) and Wide-angle fundus autofluorescence (WA-FAF) (A2, B2) images for both eyes at the first visit did not demonstrate any dark without pressure retinopathy (DWP). Wide angle fluorescein angiography (WA-FA) (A3, B3) images of both eyes showed diffuse vascular leakage and macular optical coherence tomography (OCT)image in the left eye showed cystoid macular edema and subretinal fluid (B3). After 1 year of treatment, the DWP was seen as dark retinal areas on WA-FP (C1, D1) that correlated with hypo-autofluorescence on WA-FAF (C2, D2). At the 1-year visit, WA-FA (C3, D3) image showed resolution of the leakage in both eyes. OCT images (F1, F2) through the retinopathy in both eyes showed ellipsoid zone disruption.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4283639/v1/f100154a8f291565a053e1ff.png"},{"id":60433883,"identity":"3f3bffde-8c8d-475b-9959-4392617cb766","added_by":"auto","created_at":"2024-07-16 17:02:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":623909,"visible":true,"origin":"","legend":"\u003cp\u003eBaseline wide angle fluorescein angiography(A) showed diffuse leakage in the right eye and follow up WA-FA after 1 year (B) showed resolution of the leakage. Baseline wide angle fundus photo (WA-FP) (C) image showing the novel retinopathy as areas of diffuse dark retina. 3 months later, WA-FP image (D) showed a small healthy retinal area inside the white dash line. 6 months later (E) retinopathy became smaller with more healthy retinal area inside the white dash line and 9 months later (F) more healthy area can be seen inside the white dash lines.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4283639/v1/f9fcd9c8cc7558d65dda2fb7.png"},{"id":88506038,"identity":"42d75428-c3e5-4b19-9936-e6a2e8517b60","added_by":"auto","created_at":"2025-08-07 07:29:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4877270,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4283639/v1/4e681bb8-12a1-497b-bf12-933de765087d.pdf"},{"id":60432737,"identity":"099a8790-a003-4150-8f82-2ed1b4099423","added_by":"auto","created_at":"2024-07-16 16:54:34","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":355860,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalMaterial1.png","url":"https://assets-eu.researchsquare.com/files/rs-4283639/v1/9d38f75fb013089324ad9c7c.png"},{"id":60432732,"identity":"1ee7ff0a-62ea-4b6b-b082-62440d95b9c8","added_by":"auto","created_at":"2024-07-16 16:54:34","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1008550,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalMaterial2.png","url":"https://assets-eu.researchsquare.com/files/rs-4283639/v1/1e604c685573a234b56818a8.png"},{"id":60433884,"identity":"51c458d4-5f4f-4609-865f-bacb9cf98b63","added_by":"auto","created_at":"2024-07-16 17:02:34","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":33564,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalMaterial3.docx","url":"https://assets-eu.researchsquare.com/files/rs-4283639/v1/81adfa9bc2a621606c82b687.docx"},{"id":60432734,"identity":"b74c1357-9138-438c-bdd2-b7babfde9dc6","added_by":"auto","created_at":"2024-07-16 16:54:34","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":52131,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalMaterial41.docx","url":"https://assets-eu.researchsquare.com/files/rs-4283639/v1/6e8fcb81e2338c679f1c1961.docx"},{"id":60432736,"identity":"a36a45a4-27fc-41aa-b373-c00fb33da887","added_by":"auto","created_at":"2024-07-16 16:54:34","extension":"jpg","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":129106,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalMaterial5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4283639/v1/9cfafd22cb3e50ab3a2fb53d.jpg"}],"financialInterests":"There is no conflict of interest","formattedTitle":"Multimodal Imaging of Dark Without Pressure Lesions in Pediatric Retinal Vasculitis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRetinal vasculitis is a sight-threatening disease defined as inflammation of the retinal vessels and may be accompanied by retinal vascular sheathing, leakage, occlusion, or neovascularization.\u003csup\u003e1,2\u003c/sup\u003e In a study of 1867 pediatric idiopathic uveitis patients with normal ophthalmoscopy, 81.2% of the patients demonstrated retinal vasculitis, diagnosed using fluorescein angiography (FA), supporting the notion that retinal vasculitis may be a common manifestation of pediatric uveitis. The authors also indicated that uveitic eyes with retinal vasculitis are more likely to have band keratopathy, posterior or anterior synechia, and macular edema.\u003csup\u003e2\u003c/sup\u003e Despite being a prognostic indicator, it is often difficult to detect the presence of vasculitis in the pediatric population. Such challenge is because FA is not commonly performed in this population due to the invasive nature of the test and the uncooperative nature of the pediatric patient population. \u003csup\u003e1,3-6\u003c/sup\u003e Therefore, an alternate imaging biomarker on the fundus examination and photography may be needed to detect retinal vasculitis without FA, in the absence of other clinical signs such as vascular sheathing and retinal hemorrhage.\u003c/p\u003e\n\u003cp\u003eDark without pressure (DWP) retinopathy was first described by Nagpal et al. in 1975 in patients with hemoglobinopathies. \u003csup\u003e7\u003c/sup\u003e Fawzi et al. published a case series of 8 patients with dark without pressure lesions on fundus photographic images, which corresponds to hypo-autofluorescence on fundus autofluorescence (FAF) and ellipsoid zone (EZ) disruption on optical coherence tomography (OCT).\u003csup\u003e8\u003c/sup\u003e The etiology is unclear, but it was suggested to represent a congenital, benign, and incidental lesion that requires no further evaluations.\u003csup\u003e8-13\u003c/sup\u003e Two cohort studies on Ebola virus survivors reported dark without pressure lesions in some patients, which may be related to viral disease.\u003csup\u003e14,15\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eHerein, we report multimodal imaging findings in pediatric retinal vasculitis patients who demonstrated DWP. To the best of our knowledge, the index case series is the first to associate this unique retinopathy with pediatric retinal vasculitis. \u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eStudy Design and Population\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a retrospective evaluation of consecutive\u0026nbsp;pediatric uveitis patients who were evaluated\u0026nbsp;between November 2017 and December 2020 in the Uveitis Clinic at the Byers Eye Institute, Stanford University. Prior to the commencement of the research, institutional review board (IRB) approval was obtained from the Stanford IRB, ensuring compliance with ethical standards (IRB-41266). All participants were provided with detailed information about the study procedures, risks, and benefits, and a signed consent form was obtained from all participants. The study adhered to the principles outlined in the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDark Without Pressure Retinopathy\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe DWP appears as an area of dark retinal discoloration that can be visualized on clinical examination and wide-angle fundus photograph (WA-FP). The pattern can be patchy or diffuse, and the latter may extend to the peripheral fundus (Supplemental Material 1A-C). There is a distinct well-defined demarcation between the abnormal and normal retina. The area of retinopathy appears as a well demarcated area of hypo-autofluorescence (Figure 1B) on wide angle fundus autofluorescence (WA-FAF) that corresponds to the changes on the WA-FP (Figure 1A). An optical coherence tomography (OCT) scan through the area of retinopathy demonstrates ellipsoid zone disruption with a clear distinctive edge between normal and abnormal retina corresponding to other imaging modalities (Figure 1C). Infrared image also demonstrates corresponding hypo reflectivity in the area of the DWP (Figure 1C). All these changes were observed in association with retinal vasculitis on wide angle fluorescein angiography (WA-FA) (Figure 1D).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplemental Material 1:\u0026nbsp;\u003c/strong\u003eWide-angle fundus photograph of three different patients demonstrating DWP (dark without pressure) localized to peripheral, mid-peripheral and diffuse retinal area. A: DWP localized to mid-peripheral and peripheral fundus of the right eye (white dash lines). B: DWP localized to mid-peripheral fundus of the left eye (white dash lines). C: DWP localized to diffuse retinal area of the right eye (outside the white dash lines).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1:\u003c/strong\u003e Multimodal imaging of the dark without pressure (DWP) \u003cu\u003er\u003c/u\u003eetinopathy in the left eye of a pediatric patient with retinal vasculitis. A: Color fundus photo demonstrating DWP localized to the mid-peripheral fundus of the left eye (blue dashes). B: Hypo\u003cu\u003e-\u003c/u\u003eautofluorescence corresponding to the DWP (white arrows). C: Ellipsoid zone disruption at the area of DWP on optical coherence tomography. D: Retinal vasculitis of the left eye with diffuse vascular leakage on the wide-angle fluoresceine angiography.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInclusion and Exclusion Criteria\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe included pediatric patients aged 18 years or younger who were diagnosed with DWP in the setting of retinal vasculitis. Retinal vasculitis was diagnosed through clinical examination (perivascular sheathing and exudates), WA-FA (perivascular leakage), or both. Other inclusion criteria included the availability of good quality WA-FP and WA-FA images at baseline. Patients who lacked WA-FP or WA-FAF images of sufficient quality were excluded from the study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData Collection and Analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDemographics and clinical data were collected including underlying systemic disease, ocular examination, and treatment history. Imaging data included WA-FP (Optos, Dunfermline, United Kingdom), WA-FAF (Optos, Dunfermline, United Kingdom), WA-FA (Optos, Dunfermline, United Kingdom), and OCT (SD-OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany)). All the data were collected at the initial presentation as well as follow-up visits. We performed both cross-sectional and longitudinal analyses. The latter was performed to examine the evolution of the area of retinopathy. WA-FP images from both initial and follow-up visits were registered using an image registration software. The boundaries of the lesions were identified and annotated using an imaging tool. Image-J software (1.53k/Java 1.8) was utilized to assess the progression of the lesion area over time (Supplemental Material 2). The OCT images were utilized to evaluate the integrity of EZ in the area of retinopathy with a special focus on the lesion edges as the disease progressed over the course of treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplemental Material 2\u003c/strong\u003e:\u0026nbsp;Utilizing image registration using Image J software for quantification of the dark without pressure (DWP) retinopathy area. A: DWP at baseline (blue arrows). B: Image registration at baseline. C: DWP at the last follow-up (1 year later)\u003cem\u003e\u0026nbsp;\u003c/em\u003eD: Image registration at the last follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical Methods\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe data obtained were analyzed using descriptive statistics. The correlation evaluations were conducted using parametric statistical analyses. SPSS was utilized to perform statistical analyses.\u003c/p\u003e\u003cp\u003e\u003cem\u003eStudy Design and Population\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a retrospective evaluation of consecutive\u0026nbsp;pediatric uveitis patients who were evaluated\u0026nbsp;between November 2017 and December 2020 in the Uveitis Clinic at the Byers Eye Institute, Stanford University. Prior to the commencement of the research, institutional review board (IRB) approval was obtained from the Stanford IRB, ensuring compliance with ethical standards (IRB-41266). All participants were provided with detailed information about the study procedures, risks, and benefits, and a signed consent form was obtained from all participants. The study adhered to the principles outlined in the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDark Without Pressure Retinopathy\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe DWP appears as an area of dark retinal discoloration that can be visualized on clinical examination and wide-angle fundus photograph (WA-FP). The pattern can be patchy or diffuse, and the latter may extend to the peripheral fundus (Supplemental Material 1A-C). There is a distinct well-defined demarcation between the abnormal and normal retina. The area of retinopathy appears as a well demarcated area of hypo-autofluorescence (Figure 1B) on wide angle fundus autofluorescence (WA-FAF) that corresponds to the changes on the WA-FP (Figure 1A). An optical coherence tomography (OCT) scan through the area of retinopathy demonstrates ellipsoid zone disruption with a clear distinctive edge between normal and abnormal retina corresponding to other imaging modalities (Figure 1C). Infrared image also demonstrates corresponding hypo reflectivity in the area of the DWP (Figure 1C). All these changes were observed in association with retinal vasculitis on wide angle fluorescein angiography (WA-FA) (Figure 1D).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplemental Material 1:\u0026nbsp;\u003c/strong\u003eWide-angle fundus photograph of three different patients demonstrating DWP (dark without pressure) localized to peripheral, mid-peripheral and diffuse retinal area. A: DWP localized to mid-peripheral and peripheral fundus of the right eye (white dash lines). B: DWP localized to mid-peripheral fundus of the left eye (white dash lines). C: DWP localized to diffuse retinal area of the right eye (outside the white dash lines).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1:\u003c/strong\u003e Multimodal imaging of the dark without pressure (DWP) \u003cu\u003er\u003c/u\u003eetinopathy in the left eye of a pediatric patient with retinal vasculitis. A: Color fundus photo demonstrating DWP localized to the mid-peripheral fundus of the left eye (blue dashes). B: Hypo\u003cu\u003e-\u003c/u\u003eautofluorescence corresponding to the DWP (white arrows). C: Ellipsoid zone disruption at the area of DWP on optical coherence tomography. D: Retinal vasculitis of the left eye with diffuse vascular leakage on the wide-angle fluoresceine angiography.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInclusion and Exclusion Criteria\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe included pediatric patients aged 18 years or younger who were diagnosed with DWP in the setting of retinal vasculitis. Retinal vasculitis was diagnosed through clinical examination (perivascular sheathing and exudates), WA-FA (perivascular leakage), or both. Other inclusion criteria included the availability of good quality WA-FP and WA-FA images at baseline. Patients who lacked WA-FP or WA-FAF images of sufficient quality were excluded from the study.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData Collection and Analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDemographics and clinical data were collected including underlying systemic disease, ocular examination, and treatment history. Imaging data included WA-FP (Optos, Dunfermline, United Kingdom), WA-FAF (Optos, Dunfermline, United Kingdom), WA-FA (Optos, Dunfermline, United Kingdom), and OCT (SD-OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany)). All the data were collected at the initial presentation as well as follow-up visits. We performed both cross-sectional and longitudinal analyses. The latter was performed to examine the evolution of the area of retinopathy. WA-FP images from both initial and follow-up visits were registered using an image registration software. The boundaries of the lesions were identified and annotated using an imaging tool. Image-J software (1.53k/Java 1.8) was utilized to assess the progression of the lesion area over time (Supplemental Material 2). The OCT images were utilized to evaluate the integrity of EZ in the area of retinopathy with a special focus on the lesion edges as the disease progressed over the course of treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplemental Material 2\u003c/strong\u003e:\u0026nbsp;Utilizing image registration using Image J software for quantification of the dark without pressure (DWP) retinopathy area. A: DWP at baseline (blue arrows). B: Image registration at baseline. C: DWP at the last follow-up (1 year later)\u003cem\u003e\u0026nbsp;\u003c/em\u003eD: Image registration at the last follow-up.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical Methods\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe data obtained were analyzed using descriptive statistics. The correlation evaluations were conducted using parametric statistical analyses. SPSS was utilized to perform statistical analyses.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cem\u003ePatient Characteristics\u003c/em\u003e \u003c/p\u003e\n\u003cp\u003eForty-three pediatric patients with a confirmed diagnosis of anterior, intermediate, and posterior pediatric uveitis were identified. Among these, 26 patients (40 eyes) fulfilled the eligibility criteria and were included in the study. The diagnoses and treatment of these patients have been highlighted in table 1 (Supplemental Material 3-4).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRetinopathy of Interest\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 26 patients with retinal vasculitis, retinopathy was detected in 20 (76.9%) patients (30 eyes, 75%). The mean age was 12.8 (\u0026plusmn;3.36) years and 40% were female. The mean duration of follow-up was 27.2 (\u0026plusmn;13.7) months. Six patients (10 eyes) had mild peripheral retinal vasculitis on WA-FA and did not demonstrate the DWP retinopathy on various imaging modalities and were excluded. The remaining 17 patients with uveitis, but without vasculitis did not demonstrate DWP retinopathy and therefore were excluded (Supplemental Material 3). \u003c/p\u003e\n\u003cp\u003eAmong the patients who demonstrated DWP on imaging modalities, 12 patients (60%) (19 eyes) had visible DWP retinopathy at the time of diagnosis of retinal vasculitis at their baseline visit. Eight patients (11 eyes) had no demonstrable DWP at the time of initial diagnosis of vasculitis but developed it later along the disease course and after initiation of treatment. In this subgroup, the mean interval between the time of diagnosis of vasculitis and the appearance DWP was 2.6 (\u0026plusmn;1.2) months. \u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMuli-modal Imaging Modality Analysis \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll patients (20 patients; 30 eyes) who demonstrated DWP had similar findings of dark discoloration on WA-FP with a corresponding area of hypo autofluorescence on WA-FAF. OCT data was available for only eleven patients (17 eyes) and demonstrated EZ disruption within area of retinopathy with a sharp transition to normal retina at the edges of the retinopathy. Macular sparing was also noted on OCT of all the study patients. Nineteen (19) patients (28 eyes) had adequate imaging information available at the follow up visits and were included in the longitudinal analysis. Amongst these, 18 patients demonstrated regression/progression (19 (67.8%) eyes/8 (28.5%) eyes) of the retinopathy lesion while in one patient (1 eye), the retinopathy area remained diffuse and stable. The change in the DWP retinopathy area over time was analyzed in 19 patients (28 eyes), with 2 patients (2 eyes) excluded due to inadequate image quality. Mean retinopathy area for these patients decreased from 394.67 mm\u003csup\u003e2\u003c/sup\u003e (at time of retinopathy detection) to 365.88 mm\u003csup\u003e2\u003c/sup\u003e (last follow-up), which was statistically significant (p=0.03).\u003c/p\u003e\n\u003cp\u003eAll patients showed either improvement or resolution of vasculitis with treatment. Amongst patients with complete resolution of vascular leakage on FA (9 patients; 11 eyes), the DWP retinopathy lesions were still visible in all patients. However, 5 patients (7 eyes) showed improvement in their area of DWP, while 4 patients (4 eyes) showed progression in DWP.\u003c/p\u003e\n\u003cp\u003eAmong the 14 patients (17 eyes) with improvement to very mild leakage but without complete resolution of retinal vasculitis, the area of retinopathy improved in 9 patients (12 eyes) and 3 patients (4 eyes) showed progression. Whereas there was no change in retinopathy area in 1 patient (1 eye). (Table 1). Regression of the retinopathy area showed EZ recovery on the OCT follow up images (Figure 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2:\u003c/strong\u003e Optic coherence tomography (OCT) follow-up images of 2 patients (A\u0026amp;B). Dark without pressure (DWP) area can be seen as hypo-reflectance area (between red arrows) on the infrared (IR) with a corresponding ellipsoid zone (EZ) disruption (between white arrows) on OCT (A1-A2). Follow up image (A1) after 2 years showed recovery of the EZ compared to prior OCT image (A2). The OCT images of the second patient showed DWP as hypo-reflectance area (between red arrows) on IR with a corresponding ellipsoid zone (EZ) disruption (between white arrows) (B1-B2). Follow up image (B1) after 2 years showed recovery of the EZ compared to prior OCT image (B2).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCase Presentations\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCASE 1 \u003c/p\u003e\n\u003cp\u003eAn early adolescence female presented with blurry vision and floaters in both eyes (OU). There were 2+ cells and 1.5+ flare in the anterior chamber OU, and fundus examination revealed 1+ vitritis and no lesions OU. WA-FA showed severe retinal vasculitis OU, cystoid macular edema in the left eye (OS), and subretinal fluid OS, and optic disc inflammation, OU. The patient was also diagnosed with Sunflower syndrome. At baseline, the fundus photo and WA-FAF did not show signs of DWP as previously described. The patient was treated with infliximab 7.5 mg/kg/day and IV methylprednisolone 750 mg for 3 days each month. After 3 months of treatment, FA showed resolution of leakage and WA-FP and WA-FAF showed the DWP at the midperipheral retina OU. While the retinal vasculitis was inactive at 1 year follow up, the lesion was reshaped (regressed in some parts and progressed in some other areas). OCT of the lesion showed EZ disruption (Figure 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 3: \u003c/strong\u003eWide angle fundus photo (WA-FP) (A1, B1) and Wide-angle fundus autofluorescence (WA-FAF) (A2, B2) images for both eyes at the first visit did not demonstrate any dark without pressure retinopathy (DWP). Wide angle fluorescein angiography (WA-FA) (A3, B3) images of both eyes showed diffuse vascular leakage and macular optical coherence tomography (OCT) image in the left eye showed cystoid macular edema and subretinal fluid (B3). After 1 year of treatment, the DWP was seen as dark retinal areas on WA-FP (C1, D1) that correlated with hypo-autofluorescence on WA-FAF (C2, D2). At the 1-year visit, WA-FA (C3, D3) image showed resolution of the leakage in both eyes. OCT images (F1, F2) through the retinopathy in both eyes showed ellipsoid zone disruption.\u003c/p\u003e\n\u003cp\u003eCASE 2\u003c/p\u003e\n\u003cp\u003eAn early adolescence male with pan uveitis in the OS was referred to the Uveitis Clinic. Anterior segment examination showed 0.5+ cells and 1+ flare in the anterior chamber of both eyes (OU), and dilated fundus examination showed 1+ vitreous cell in the right eye (OD) and 3+ vitreous cell OS. FA showed significant, diffuse retinal vascular leakage in OS and no vasculitis OD. The patient was diagnosed with pan-uveitis in OU. Given the pan-uveitis in OU and severe retinal vasculitis in OS, the patient was treated with infliximab 5 mg/kg monthly and methylprednisolone 750 mg for 3 days monthly. At the baseline visit, there was a diffuse DWP which was barely visible, making it difficult to recognize. After treatment, the novel retinopathy became more prominent on both WA-FP and WA-FAF images (Supplemental Material 5). \u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e \u003cstrong\u003eSupplemental Material 5:\u003c/strong\u003e Wide angle fundus photo (WA-FP) (A1), wide angle fundus autofluorescence (WA-FAF) (A2) images at the first visit did not demonstrate any retinopathy findings and wide-angle fluorescein angiography (WA-FA) (A3) images showed diffuse vascular leakage. Macular optical coherence tomography (OCT) image in the left eye showed cystoid macular edema (CME) (C1). After 2 months of treatment, the retinopathy could be seen as dark retinal areas on WA-FP (B1) and hypo-autofluorescence on WA-FAF (B2). WA-FA (B3) images showed near complete improvement of vascular leakage and CME is resolved (C2). OCT\u003cs\u003e \u003c/s\u003eimages (C3) through the retinopathy showed ellipsoid zone disruption along the section.\u003c/p\u003e\n\u003cp\u003eCASE 3\u003c/p\u003e\n\u003cp\u003eAn early adolescence male was referred to the Uveitis Clinic for acute retinal necrosis in OD. Evaluations for infectious etiologies were negative. The patient was diagnosed with Philadelphia chromosome negative pre-B-cell acute lymphoblastic leukemia and started chemotherapy by the Oncology Service. WA-FA showed diffuse leakage in OD and normal findings in OS. At the first visit, there was perivascular sheathing and diffuse DWP noted on WA-FP that was difficult to recognize. With treatment, retinal vasculitis improved, and the retinopathy area was more delineated. At the last visit, the retinal vasculitis improved, and the novel retinopathy was localized and improved. (Figure 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 4:\u003c/strong\u003e Baseline wide angle fluorescein angiography(A) showed diffuse leakage in the right eye and follow up WA-FA after 1 year (B) showed resolution of the leakage. Baseline wide angle fundus photo (WA-FP) (C) image showing the novel retinopathy as areas of diffuse dark retina. 3 months later, WA-FP image (D) showed a small healthy retinal area inside the white dash line. 6 months later (E) retinopathy became smaller with more healthy retinal area inside the white dash line and 9 months later (F) more healthy area can be seen inside the white dash lines.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eVascular inflammation is a common finding in patients diagnosed with pediatric uveitis and is associated with a higher incidence of chronic complications. Despite being a prognostic indicator of the disease status, it is challenging to diagnose vasculitis and follow response to treatment in pediatric patients. The challenge is secondary to difficulties associated with FA testing due to its invasive nature and difficult examination. In this study, we described a retinopathy akin to DWP with characteristic dark areas on WA-FP, hypo autofluorescence on FAF, and EZ disruption on OCT, which may be associated with pediatric retinal vasculitis. \u003c/p\u003e\n\u003cp\u003eDWP was the term coined by Nagpal et al. in 1975 \u003csup\u003e7\u003c/sup\u003e They identified flat dark lesions in midperipheral retina that were similar in shape to white without pressure in patients with hemoglobinopathies. These lesions were reported to be transient, change shape, and occasionally disappear over weeks. Their hypothesis was that these lesions probably were altered reflex at the level of either retinal pigment epithelium or internal limiting membrane. Condon and Serjeant also noted similar lesions in Jamaican patients, 10% of which had sickle cell haemoglobinopathies.\u003csup\u003e10,11\u003c/sup\u003e More recently, another study found a higher prevalence of DWP lesions (25%) in sickle cell disease patients.\u003csup\u003e16\u003c/sup\u003e In 2014, Fawzi et al. utilized multimodal imaging to analyze lesions of white without pressure and DWP in 10 patients between the age of 12-37.\u003csup\u003e8\u003c/sup\u003e Their study was the first to establish that DWP lesions seen in 8 patients had changes in the outer retinal layers and were not related to vitreoretinal interface abnormalities or alteration of retinal pigment epithelium (RPE). On the OCT scans they noted an abrupt transition to hypo reflectivity at the level of the ellipsoid zone and outer photoreceptor segments in the DWP areas. Although the lesions reported by Fawzi et al. have similarities to those seen in our population, unlike our patients with a clear fluorescein angiography-based diagnosis of retinal vasculitis, most of their population had no ocular disease except 3 patients who were diagnosed with multi evanescent white dot syndrome, HLA-B27 anterior and intermediate uveitis, and astrocytic hamartoma. Interestingly, 6 of 8 patients with DWP lesions were of dark fundus pigmentation like previously reported studies. One patient with HLA-B27 and intermediate uveitis and DWP lesions had light fundus pigmentation. However, the authors did not perform FA on any of the included patients to evaluate for signs of vasculitis. The FAF imaging in their study showed hypo-autofluorescence in areas of the DWP similar to our study. However, they reported hypo-autofluorescence in areas of white without pressure lesions as well even though their OCT findings were that of increased reflectivity of EZ and interdigitation zone unlike DWP. Fawzi et al. proposed that the fundus pigmentation may play a more important role in the clinician\u0026rsquo;s ability to see these lesions against a darker background rather than being a factor in development of these lesions. Visual field testing was performed in one of the patients in the area of DWP showed no changes leading to thought that these lesions had mainly anatomical changes with little functional significance. Similar to Fawzi et al., Pimentel et al. reported DWP lesions without any ocular pathology in a pediatric population ranging from 3-13 years. Their OCT and FAF findings also showed hypo-reflectivity in areas of the lesions.\u003csup\u003e12\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn contrast to previous reports, various studies have correlated the DWP lesions to infectious and inflammatory etiologies. A cohort study of 14 Ebola virus survivors showed 141 Ebola virus retinal lesion in 22 of 27 eyes and 88.7% of these retinal lesions had perilesional DWP lesions with OCT characteristics of disrupted ellipsoid zone and interdigitation zone.\u003csup\u003e14\u003c/sup\u003e Another cohort on same population of Ebola survivors obtained sequential WA-FP and OCT images of these DWP lesions.\u003csup\u003e15\u003c/sup\u003e . Similar to our study, they also reported that some of these lesions evolve over time with non-uniform expansion and retraction across various borders. However, unlike our study, they did not report any vasculitis in their patient population, although, no FA was performed in their study to confirm a clear absence of vasculitis. They also showed that the higher density of Ebola retinal lesions was associated with larger area of the DWP lesions and DWP lesions can circumferentially involve 360 degrees of the retina while sparing the macula. Such findings were also seen in our study where more extensive vasculitis was associated with larger DWP lesions which sometimes involved the entire retina with macular sparing. Another case report of a patient with ocular toxoplasmosis also demonstrated perilesional DWP lesions which resolved as the lesion became inactive.\u003csup\u003e17\u003c/sup\u003e However, on a follow up with another reactivation showing satellite lesions and perivascular infiltrates, there were no initial signs of DWP lesions. However, as the patient was started on appropriate treatment including prednisolone, the patient developed DWP lesions. Such findings were seen in some of our patients as well where DWP lesions were initially absent but developed on follow-up visits after initiation of treatment. DWP lesion sizes are improved or progressed after resolution of the leakage on FA. Progression of DWP lesions after resolution of the leakage may be related to the disease severity or duration.\u003c/p\u003e\n\u003cp\u003eThe pathophysiology of the DWP is not clearly understood and several mechanisms have been proposed to explain these lesions. Fawzi et al. suggested that these changes are secondary to the presence of different \u003cem\u003ephotopigments\u003c/em\u003e in the photoreceptors in these areas that have different spectral range and reflectance compared to normal photopigment i.e., mainly lipofuscin.\u003csup\u003e8\u003c/sup\u003e They supported the hypothesis with reflectivity changes seen in photoreceptor outer segments in patients with Mizuo-Nakamura phenomenon, particularly the similarity between dark-adapted state of fundus in this phenomenon and DWP lesions. The different photopigment spectral range in these areas could be a reason for the hypo-autofluorescence seen on FAF in these areas despite normal underlying RPE. It has been shown that different fluorophores have different excitation and emission spectrums and there are even differences in the autofluorescence spectrums recorded by our commercially used machines.\u003csup\u003e18\u003c/sup\u003e Although Fawzi et al. suggested that these areas may be associated with photoreceptor dysfunction but because of their localized and circumscribed appearance, they are of little clinical significance.\u003csup\u003e8\u003c/sup\u003e Pimentel et al. also thought that these lesions are not clinically significant and may represent acquired developmental changes.\u003csup\u003e12\u003c/sup\u003e \u003c/p\u003e\n\u003cp\u003eOn other hand in cases where these lesions have been associated with infections such as Ebola, the proposed mechanism for these DWP lesions was changes in the metabolic state of mitochondria which make the up the EZ of the photoreceptors observed on the OCT.\u003csup\u003e19\u003c/sup\u003e The mitochondria serve as powerhouse of the photoreceptors but are very sensitive to cellular energy requirements and their environmental stimuli such as oxidative stress caused by the inflammation.\u003csup\u003e20-22\u003c/sup\u003e The mitochondria change their morphology by mechanisms such as fusion and expanding their matrix in these stress states.\u003csup\u003e20,23,24\u003c/sup\u003e These morphological changes have been shown to change the optical parameters such as light scattering and refractivity of the mitochondria.\u003csup\u003e20,21,25,26\u003c/sup\u003e In studies using zebrafish, it has also been shown that chronic stress causes mitochondrial movement from EZ towards muller cells which play a role in photoreceptor and mitochondrial turnover.\u003csup\u003e27\u003c/sup\u003e Additionally, these changes in mitochondria in response to oxidative also affect the energy production required for photoreceptor function. Therefore, it has been shown in studies that EZ integrity correlated with the photoreceptor layer health and in turn visual acuity in cases where the damage involves the fovea.\u003csup\u003e28-31\u003c/sup\u003e The changes in the mitochondrial function and structure in response to inflammatory stress and resultant alterations in photoreceptor health could also be a contributing for the hypo autofluorescence seen in these DWP areas due to decreased lipofuscin turnover.\u003csup\u003e32\u003c/sup\u003e The fluorophores responsible for autofluorescence are dependent on the metabolic activity in the area and are also very susceptible to oxidative damage which may change their excitation and emission spectrums resulting in hypo-fluorescence in DWP areas despite presence of structurally normal RPE.\u003csup\u003e33,34\u003c/sup\u003e In addition to changes in the mitochondrial activity, the inflammatory cytokines can also cause direct damage to the photoreceptors. \u003csup\u003e29,35\u003c/sup\u003e \u003c/p\u003e\n\u003cp\u003eBased on the studies that have documented DWP lesions, it can be deduced that multiple factors are at play which can contribute to these lesions and these lesions in turn can be a similar phenotypic appearance of various underlying phenomenon. Our study supports an active inflammatory pathogenesis of these DWP lesions. The resultant phenotypic appearance could be secondary to interplay of the various mechanisms including mitochondrial changes, photoreceptor damage as well as changes in the photopigment production or structure in the area. We observed that they can be present at time of disease detection in more extensive vasculitis \u003cem\u003eor\u003c/em\u003e can develop after exposure to leakage in moderate vascular leakage \u003cem\u003eor\u003c/em\u003e may even be absent in cases with only mild peripheral leakage. Whatever the timeline, in case the lesions are observed, they are associated with EZ disruption and or hypo reflectivity in areas of the lesion. We believe that after treatment and with resolution of the leakage, retinopathy can improve with the recovery of EZ disruption in less severe or more acute disease cases. However, if the damage is severe and or chronic with significant persistent leakage, EZ disruption may be irreversible.\u003c/p\u003e\n\u003cp\u003eOur study, however, has certain limitations. First, this is a retrospective cohort of a relatively small sample size. Second, longer follow up of the patients is needed to further document the evolution of the lesions and to determine their functional and clinical significance. Lastly, size calculations in the peripheral lesions on widefield imaging may be less accurate due to wrapping of images. \u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePediatric retinal vasculitis may be associated with dark without pressure retinopathy. These lesions can change in size over time after resolution of the vasculitis. DWP may be a helpful finding should pediatric retinal vasculitis be suspected and may serve as a useful imaging biomarker. Future studies should be conducted employing additional imaging technologies such as adaptive optics, electrophysiology, and visual field to better understand the functional changes in the DWP retinopathy as well as its relationship with retinal vasculitis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAn unrestricted grant from Research to Prevent Blindness, National Eye Institute, P30-Ey026877.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrecis:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe identified a novel link between pediatric retinal vasculitis and a retinopathy pattern termed dark without pressure retinopathy (DWP). DWP changes in post-vasculitis resolution can serve as a valuable biomarker in diagnosing and monitoring pediatric retinal vasculitis, providing insights to ophthalmology clinicians.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests Statement:\u0026nbsp;\u003c/strong\u003eNo competing interest for any of the authors\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAbu El-Asrar AM, Herbort CP, Tabbara KF. Retinal vasculitis. \u003cem\u003eOcul Immunol Inflamm. \u003c/em\u003eDec 2005;13(6):415-433.\u003c/li\u003e\n\u003cli\u003eYang P, Zhong Z, Su G, et al. Retinal Vasculitis, a Common Manifestation of Idiopathic Pediatric Uveitis? \u003cem\u003eRetina. \u003c/em\u003eMar 1 2021;41(3):610-619.\u003c/li\u003e\n\u003cli\u003eAgarwal A, Afridi R, Agrawal R, Do DV, Gupta V, Nguyen QD. Multimodal Imaging in Retinal Vasculitis. \u003cem\u003eOcul Immunol Inflamm. \u003c/em\u003eJun 2017;25(3):424-433.\u003c/li\u003e\n\u003cli\u003eEl-Asrar AM, Herbort CP, Tabbara KF. A clinical approach to the diagnosis of retinal vasculitis. \u003cem\u003eInt Ophthalmol. \u003c/em\u003eApr 2010;30(2):149-173.\u003c/li\u003e\n\u003cli\u003eShrestha JK, Khadka D, Lamichhane G, Khanal S. Retinal vasculitis. \u003cem\u003eNepal J Ophthalmol. \u003c/em\u003eJan-Jun 2009;1(1):66-71.\u003c/li\u003e\n\u003cli\u003eDiala FGI, McCarthy K, Chen JL, Tsui E. Multimodal imaging in pediatric uveitis. \u003cem\u003eTher Adv Ophthalmol. \u003c/em\u003eJan-Dec 2021;13:25158414211059244.\u003c/li\u003e\n\u003cli\u003eNagpal KC, Goldberg MF, Asdourian G, Goldbaum M, Huamonte F. Dark-without-pressure fundus lesions. \u003cem\u003eBr J Ophthalmol. \u003c/em\u003eSep 1975;59(9):476-479.\u003c/li\u003e\n\u003cli\u003eFawzi AA, Nielsen JS, Mateo-Montoya A, et al. 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Dark without pressure retinal changes in a paediatric age group. \u003cem\u003eEye (Lond). \u003c/em\u003eApr 2021;35(4):1221-1227.\u003c/li\u003e\n\u003cli\u003eSherman T, Palileo BM, Adam CR, Abrams GW. Dark Without Pressure In A Case Of Choroidal Osteoma. \u003cem\u003eRetin Cases Brief Rep. \u003c/em\u003eJun 8 2020.\u003c/li\u003e\n\u003cli\u003eSteptoe PJ, Momorie F, Fornah AD, et al. Multimodal Imaging and Spatial Analysis of Ebola Retinal Lesions in 14 Survivors of Ebola Virus Disease. \u003cem\u003eJAMA Ophthalmol. \u003c/em\u003eJun 1 2018;136(6):689-693.\u003c/li\u003e\n\u003cli\u003eSteptoe PJ, Momorie F, Fornah AD, et al. Evolving Longitudinal Retinal Observations in a Cohort of Survivors of Ebola Virus Disease. \u003cem\u003eJAMA Ophthalmol. \u003c/em\u003eApr 1 2020;138(4):395-403.\u003c/li\u003e\n\u003cli\u003eLott PW, McKibbin M. Prevalence of Dark without Pressure and Angioid Streaks in Sickle Cell Disease. \u003cem\u003eOphthalmic Surg Lasers Imaging Retina. \u003c/em\u003eNov 2021;52(11):620-622.\u003c/li\u003e\n\u003cli\u003eP JS, Guly CM, Dick AD. Ocular Toxoplasmosis Associated Dark Without Pressure. \u003cem\u003eOcul Immunol Inflamm. \u003c/em\u003eMay 2 2022:1-3.\u003c/li\u003e\n\u003cli\u003eBittencourt MG, Hassan M, Halim MS, et al. Blue light versus green light fundus autofluorescence in normal subjects and in patients with retinochoroidopathy secondary to retinal and uveitic diseases. \u003cem\u003eJ Ophthalmic Inflamm Infect. \u003c/em\u003eJan 8 2019;9(1):1.\u003c/li\u003e\n\u003cli\u003eCuenca N, Ortuno-Lizaran I, Pinilla I. Cellular Characterization of OCT and Outer Retinal Bands Using Specific Immunohistochemistry Markers and Clinical Implications. \u003cem\u003eOphthalmology. \u003c/em\u003eMar 2018;125(3):407-422.\u003c/li\u003e\n\u003cli\u003eLitts KM, Zhang Y, Freund KB, Curcio CA. 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The intracellular redox state is a core determinant of mitochondrial fusion. \u003cem\u003eEMBO Rep. \u003c/em\u003eOct 2012;13(10):909-915.\u003c/li\u003e\n\u003cli\u003eZheng JY, Tsai YC, Kadimcherla P, et al. The C-terminal transmembrane domain of Bcl-xL mediates changes in mitochondrial morphology. \u003cem\u003eBiophys J. \u003c/em\u003eJan 1 2008;94(1):286-297.\u003c/li\u003e\n\u003cli\u003eTychinsky V, Kretushev A, Vyshenskaja T. Mitochondria optical parameters are dependent on their energy state: a new electrooptical effect? \u003cem\u003eEur Biophys J. \u003c/em\u003eDec 2004;33(8):700-705.\u003c/li\u003e\n\u003cli\u003eRutter KM, Hutto RA, Brockerhoff SE. Photoreceptor mitochondria can be transferred and turned over by M\u0026uuml;ller glia. \u003cem\u003eInvestigative Ophthalmology \u0026amp; Visual Science. \u003c/em\u003e2022;63(7):2579 \u0026ndash; F0462-2579 \u0026ndash; F0462.\u003c/li\u003e\n\u003cli\u003eSaxena S, Meyer CH, Akduman L. External limiting membrane and ellipsoid zone structural integrity in diabetic macular edema. \u003cem\u003eEur J Ophthalmol. \u003c/em\u003eJun 16 2021:11206721211026106.\u003c/li\u003e\n\u003cli\u003eSinha S, Saxena S, Prasad S, et al. Association of serum levels of anti-myeloperoxidase antibody with retinal photoreceptor ellipsoid zone disruption in diabetic retinopathy. \u003cem\u003eJ Diabetes Complications. \u003c/em\u003eMay 2017;31(5):864-868.\u003c/li\u003e\n\u003cli\u003eMori Y, Suzuma K, Uji A, et al. Restoration of foveal photoreceptors after intravitreal ranibizumab injections for diabetic macular edema. \u003cem\u003eSci Rep. \u003c/em\u003eDec 14 2016;6:39161.\u003c/li\u003e\n\u003cli\u003eDe S, Saxena S, Kaur A, et al. Sequential restoration of external limiting membrane and ellipsoid zone after intravitreal anti-VEGF therapy in diabetic macular oedema. \u003cem\u003eEye (Lond). \u003c/em\u003eMay 2021;35(5):1490-1495.\u003c/li\u003e\n\u003cli\u003eSparrow JR, Boulton M. RPE lipofuscin and its role in retinal pathobiology. \u003cem\u003eExp Eye Res. \u003c/em\u003eMay 2005;80(5):595-606.\u003c/li\u003e\n\u003cli\u003eVives-Bauza C, Anand M, Shiraz AK, et al. The age lipid A2E and mitochondrial dysfunction synergistically impair phagocytosis by retinal pigment epithelial cells. \u003cem\u003eJ Biol Chem. \u003c/em\u003eSep 5 2008;283(36):24770-24780.\u003c/li\u003e\n\u003cli\u003eBen-Shabat S, Itagaki Y, Jockusch S, Sparrow JR, Turro NJ, Nakanishi K. Formation of a nonaoxirane from A2E, a lipofuscin fluorophore related to macular degeneration, and evidence of singlet oxygen involvement. \u003cem\u003eAngew Chem Int Ed Engl. \u003c/em\u003eMar 1 2002;41(5):814-817.\u003c/li\u003e\n\u003cli\u003eEskandarpour M, Nunn MA, Weston-Davies W, Calder VL. Immune-Mediated Retinal Vasculitis in Posterior Uveitis and Experimental Models: The Leukotriene (LT)B4-VEGF Axis. \u003cem\u003eCells. \u003c/em\u003eFeb 15 2021;10(2).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Characteristics of Patients and Retinopathy Changes over the Disease Course\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"618\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatient\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEye\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnatomical Diagnosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVasculitis Status at Last Visit\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRetinopathy Status\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eChange in Area of Retinopathy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePanuveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eVery mild activity at peripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eMid-peripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePanuveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eMild activity at peripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePanuveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eMild activity at peripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003eAnterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eMild activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003eAnterior uveitis\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eVery mild activity\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003ePeripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePosterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eMild activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eMid-\u0026nbsp;Peripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePosterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eMild activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eMid-\u0026nbsp;Peripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePanuveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eMild activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eStable\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003eAnterior uveitis\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eVery mild activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003eAnterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eVery mild activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePanuveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eİnactive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePanuveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eVery mild activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003eAnterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eMild activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003ePeripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003eAnterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eİnactive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003eAnterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eVery mild activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003ePeripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePanuveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eİnactive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eMid-Peripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePosterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eİnactive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePosterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eActive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003eIntermediate uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eİnactive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003ePeripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003eIntermediate uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eİnactive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003ePeripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003eAnterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eVery mild activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003eAnterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eİnactive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eProgression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePanuveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eVery mild activity at peripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eMid-peripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003eAnterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eVery Mild activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePanuveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eİnactive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePanuveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eİnactive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eDiffuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003eAnterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eİnactive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003ePeripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.766990291262136%\" valign=\"top\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.796116504854369%\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.33009708737864%\"\u003e\n \u003cp\u003ePosterior uveitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.24271844660194%\"\u003e\n \u003cp\u003eİnactive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.68284789644013%\"\u003e\n \u003cp\u003eMid-peripheral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.181229773462782%\"\u003e\n \u003cp\u003eRegression\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"eye","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"eye","sideBox":"Learn more about [Eye](http://www.nature.com/eye/)","snPcode":"41433","submissionUrl":"https://mts-eye.nature.com/cgi-bin/main.plex","title":"Eye","twitterHandle":"@eye_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"dark without pressure, pediatric retinal vasculitis, retinopathy ","lastPublishedDoi":"10.21203/rs.3.rs-4283639/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4283639/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e: A unique form of retinopathy-plausibly dark without pressure (DWP) was identified during the management of pediatric patients with retinal vasculitis (RV) and described in the index case series.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003eForty-three consecutive pediatric uveitis patients presented to tertiary care-unit were evaluated. We assessed DWP-like lesions in pediatric patients with RV. Wide angle fundus photographs (WAFP), fundus autofluorescence (FAF), and optical coherence tomography (OCT) images were analyzed to identify potential retinopathy. Incidence of DWP in pediatric RV patients was also analyzed. WAFP were evaluated using image-J software to measure retinopathy area (RA).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003eTwenty-six of 43 patients were diagnosed with RV and were treated. Retinopathy was detected in 20 patients (30 eyes/76.9%) during treatment. Mean age was 12.8±3.36 years; 40% were female. On WAFP, the lesions appeared as dark areas that were diffuse, mid-peripheral or peripheral. All 20 patients (30 eyes) showed hypo-autofluorescence on FAF at the same locations as the WAFP. Twelve patients (17 eyes) who had OCT images of the RA demonstrated ellipsoid zone disruption. Progression of the retinopathy overtime was analyzed in 28 eyes; all eyes showed improvement of RV with therapy. Mean RA significantly decreased from 394.67 mm2 (time of retinopathy detection) to 365.88 mm2 (last follow-up) (p=0.03).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003ePediatric RV may be associated with a retinopathy pattern described as DWP previously. Improvement in the RA may be related to improvement of disease activity, but further studies are needed to understand the underlying pathophysiology. Such findings might serve as a marker of previous/ongoing RV in pediatric patients.\u003c/p\u003e","manuscriptTitle":"Multimodal Imaging of Dark Without Pressure Lesions in Pediatric Retinal Vasculitis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-16 16:54:29","doi":"10.21203/rs.3.rs-4283639/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2024-11-19T16:10:12+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-10-18T11:54:24+00:00","index":3,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-07-22T07:52:27+00:00","index":2,"fulltext":"This content is not available."},{"type":"editorInvitedReview","content":"This content is not available.","date":"2024-07-08T07:02:41+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-26T08:02:32+00:00","index":2,"fulltext":"This content is not available."},{"type":"reviewerAgreed","content":"This content is not available.","date":"2024-06-22T09:18:01+00:00","index":1,"fulltext":"This content is not available."},{"type":"reviewersInvited","content":"","date":"2024-06-19T06:51:25+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-18T12:16:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-18T09:24:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"Eye","date":"2024-04-17T18:49:24+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"eye","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"eye","sideBox":"Learn more about [Eye](http://www.nature.com/eye/)","snPcode":"41433","submissionUrl":"https://mts-eye.nature.com/cgi-bin/main.plex","title":"Eye","twitterHandle":"@eye_journal","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"145f0dad-5988-40f4-9625-778c7d0732fb","owner":[],"postedDate":"July 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":33441281,"name":"Health sciences/Medical research/Outcomes research"},{"id":33441282,"name":"Health sciences/Diseases/Eye diseases/Uveal diseases"}],"tags":[],"updatedAt":"2025-08-07T07:11:39+00:00","versionOfRecord":{"articleIdentity":"rs-4283639","link":"https://doi.org/10.1038/s41433-025-03882-3","journal":{"identity":"eye","isVorOnly":false,"title":"Eye"},"publishedOn":"2025-07-19 04:00:00","publishedOnDateReadable":"July 19th, 2025"},"versionCreatedAt":"2024-07-16 16:54:29","video":"","vorDoi":"10.1038/s41433-025-03882-3","vorDoiUrl":"https://doi.org/10.1038/s41433-025-03882-3","workflowStages":[]},"version":"v1","identity":"rs-4283639","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4283639","identity":"rs-4283639","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}