Pseudoxanthoma elasticum and retinitis pigmentosa in a patient with a novel mutation in the ABCC6 gene.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is an autosomal recessive condition caused by mutations in the ABCC6 gene. Ocular features include angioid streaks, peau d'orange fundus, and drusen. We report a novel ABCC6 mutation causing PXE in a patient with a mixed phenotype of PXE and retinitis pigmentosa (RP). CASE: A 37-year-old female presented with decreased peripheral vision and nyctalopia. Ocular imaging revealed angioid streaks emanating from the optic nerve as well as peripheral pigmentary changes and bone spicules. Genetic testing revealed two mutations in ABCC6 in trans. No other mutation was identified. CONCLUSION: We present a rare case with ocular findings of PXE and RP in a patient with a novel ABCC6 mutation. The patient presented both with peripheral pigmentary changes and angioid streaks. Further investigation into this novel mutation would be beneficial to determine if the mutation is involved in the RP phenotype.

LONG-TERM PROGNOSIS OF CHOROIDAL NEOVASCULARIZATION COMPLICATING ANGIOID STREAKS.

PURPOSE: To report the very long-term visual prognosis of choroidal neovascularization complicating angioid streaks in the antivascular endothelial growth factor era. METHODS: Retrospective monocentric study aimed at analyzing patients' demographics, choroidal neovascularization features, angioid streak-associated conditions, and previous and current therapies for choroidal neovascularization. The main outcome measures were the quantitative measurement of central retinal pigment epithelial atrophy enlargement by comparing the ratio of pixels involved on automated infrared images acquired by spectral-domain optical coherence tomography and the changes in best-corrected visual acuity. The secondary outcome measures were the number of intravitreal injections and the changes in central choroidal thickness and central retinal thickness. Subgroup analyzes were performed to compare macular atrophy extent between eyes of patients with or without proven pseudoxanthoma elasticum ("PXE" or "no PXE") and between eyes previously treated or not with photodynamic therapy ("PDT" or "no PDT"). RESULTS: Thirty-three eyes of 23 patients were included. The mean best-corrected visual acuity decreased significantly from 66 ± 19 Early Treatment Diabetic Retinopathy Study letters at the time of the first antivascular endothelial growth factor injection to 52 ± 23 Early Treatment Diabetic Retinopathy Study letters at the end of the follow-up (mean follow-up duration: 109 ± 42 months, range: 47-175 months). The ratio of central retinal pigment epithelial atrophy enlargement was 201%, 110%, 240%, and 111% in the PXE, no PXE, PDT, and no PDT groups, respectively. CONCLUSION: Despite the use of antivascular endothelial growth factor agents, the very long-term prognosis appeared relatively poor, especially in patients with PXE. This study also suggests that PDT should be used with caution in the management of choroidal neovascularization in eyes with angioid streaks.

HYPERREFLECTIVE FOCI PRECEDE MACULAR NEOVASCULARIZATION FORMATION IN ANGIOID STREAKS.

PURPOSE: To describe the steps leading to the development and progression of macular neovascularization (MNV) in angioid streaks. METHODS: The study was designed as retrospective, longitudinal case series. Patients with angioid streaks were investigated by means of multimodal imaging, including fundus autofluorescence and structural optical coherence tomography. Main outcome measures were hyperreflective foci and MNV progression steps. RESULTS: Overall, 40 eyes (20 patients) affected by angioid streaks were evaluated. Over the follow-up, five eyes of five patients developed MNV. The mean follow-up was of 1.6 years. The mean number of anti-vascular endothelial growth factor injections was 4.35 ± 1.4. Mean best-corrected visual acuity was 0.53 ± 0.38 LogMAR at the MNV onset, improving to 0.42 ± 0.40 LogMAR at the end of the follow-up ( P > 0.05). Intraretinal hyperreflective foci onset and coalescence represented the first alterations occurring before the onset of the MNV. Anti-vascular endothelial growth factor treatment was associated with exudation relapsing and remitting, with still present intraretinal hyperreflective foci and pigment accumulation. The longitudinal analysis of our cohort of eyes outlined the event timeline: 1.2 months to find concentrated hyperreflective foci, 4.5 months to observe pigment organization through the outer nuclear layer, and 1.5 years to detect MNV. CONCLUSION: Hyperreflective foci formation, concentration, and migration represent early alterations occurring before the onset of the MNV in angioid streaks.

Incidence and Risk Factors of Visual Impairment in Patients with Angioid Streaks and Macular Neovascularization.

OBJECTIVE: To estimate the incidence and risk factors of visual impairment and complications in eyes with macular neovascularization (MNV) because of angioid streaks (ASs). DESIGN: Longitudinal multicenter retrospective cohort study. SUBJECTS: Patients with AS-associated MNV treated with anti-VEGF agents and a follow-up of > 3 months. METHODS: Clinical and MNV characteristics were collected at baseline. Visual acuity (VA) values and the presence of atrophy or fibrosis were collected at each visit. MAIN OUTCOME MEASURES: Rate of VA change over time and associated factors; the incidence rate of moderate-to-severe visual impairment (MSVI) and blindness and hazard ratio (HR) of candidate risk factors for MSVI; the incidence rate of fibrosis and macular atrophy. RESULTS: Overall, 84 eyes of 66 patients (39 men, 58%) with a mean (standard deviation) age of 55.7 (13.8) years were followed for a mean (standard deviation) of 67.7 (48.5) months. The median number of anti-VEGF doses per eye was 13. The average rate (95% confidence interval [CI]) of visual loss was +0.04 (0.02-0.06) logarithm of the minimum angle of resolution/year (P < 0.001); the visual loss was faster in nonnaive eyes (P = 0.007) and those with better baseline VA (P < 0.001); it was slower in eyes with pattern dystrophy-like features (P = 0.04). The incidence rates (95% CI) of MSVI and blindness were 10.4 (6.88-15)/100-eye-years and 2.33 (1.12-4.29)/100-eye-years. A higher number of injections (HR [95% CI] = 0.45 [0.19-0.94] for receiving ≥ 13 injections vs. < 13; P = 0.03) was protective against MSVI. The incidence rates (95% CI) of fibrosis and macular atrophy were 24.1 (17.5-32.3)/100-eye-years and 14.3 (10.1-19.6)/100-eye-years. CONCLUSIONS: Eyes with MNV-related AS had a high rate of visual impairment and propensity to macular fibrosis and atrophy. A higher number of injections yielded better chances of maintaining good VA, suggesting the need for intensive treatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Systemic disease associations with angioid streaks in a large healthcare claims database.

BACKGROUND/OBJECTIVES: To assess systemic associations of angioid streaks (AS) using a large US healthcare database. SUBJECTS/METHODS: A retrospective cross-sectional study was conducted of patients diagnosed with AS in a large, national US insurer from 2000-2019. Cases were matched 1:5 to controls. The prevalence rates of established associated disease states and other systemic diseases were calculated and compared using logistic regression. Additionally, the rate of anti-VEGF treatment was assessed as a proxy for the incidence of choroidal neovascularization (CNV). RESULTS: One thousand eight hundred fifty-two cases of AS and 9028 matched controls were included. The rates of association between AS and the well-characterized conditions included: Pseudoxanthoma elasticum (PXE)-228 patients (12.3%), Ehlers-Danlos syndrome-18 patients (1.0%), Paget's disease-6 patients (0.3%), hemoglobinopathies-30 patients (1.6%), and idiopathic-1573 patients (84.9%). There was a statistically higher prevalence of the following less classically associated diseases among patients with AS compared to controls: hereditary spherocytosis (1.7% vs. 0.6%, p < 0.001), connective tissue disease (1.0% vs 0.3%, p < 0.001) and non-exudative age-related macular degeneration (33.9% vs 10.6%, p < 0.001). Among 1442 eligible cases analyzed, 427 (29.6%) received at least 1 anti-VEGF injection with 338 (23.4%) patients having the injection after their AS diagnosis. CONCLUSIONS: In the largest collection of AS patients to date, the classical teaching of systemic disease associations occur at rates far, far lower than previously reported. The association of AS with other less reported diseases highlights new potential associations and may contribute to the understanding of AS formation.

Central serous chorioretinopathy and angioid streaks: coincidental?

BACKGROUND: To report an unusual case of central serous chorioretinopathy in a patient with angioid streaks. CASE PRESENTATION: The authors describe a case report of a 26-year old male patient presenting acute scotoma and metamorphopsia in OD. He had been diagnosed with angioid streaks complicated with choroidal neovascularization and referred to us for treatment. The patient presented an ETDRS score of 85 letters (20/20) in OD and in OS. The anterior segment examination was unremarkable. Fundoscopy revealed bilateral angioid streaks (AS) and peau d'orange, as well as a small neurosensory retinal detachment in the macula of OD. A multimodal retinal analysis, including fundus photography, infra-red and fundus autofluorescence imaging, spectral-domain optical coherence tomography, optical coherence tomography angiography, fluorescein and indocyanine green angiography was performed. The diagnosis of central serous chorioretinopathy was made in the absence of any identifiable choroidal neovascularization. He was submitted to half-dose photodynamic therapy with verteporfin. One month later, he reported no visual complaints, his vision was 85 letters (20/20) in OD and a complete resolution of the sub-retinal fluid was registered. No signs of choroidal neovascularization were detected on the optical coherence tomography angiography (OCTA). A complete medical workup evaluation was made to exclude systemic diseases usually associated with AS. CONCLUSIONS: To the authors' knowledge, this is the second reported case of CSC associated with angioid streaks. The focal abnormalities in the Bruch's membrane and the irregular vascular choriocapillary network associated with AS might predispose to CSC.

Seeing through the cracks.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive multisystem disorder showing phenotypic heterogeneity giving rise to complex comorbidities. The most 'visible' signs are dermatological; however, these may be subtle and hidden from the view of an affected individual. Ophthalmic signs can be easily missed, and here we highlight the importance of a multisystem assessment. We report a patient who developed advanced sight loss due to maculopathy whose underlying PXE aetiology went unnoticed until subtle skin signs were noticed on the lateral aspect of his neck. He was aware of the skin changes. Careful review of his previous retinal imaging showed the presence of 'angioid streaks' and anatomic alteration at the outer retina-Bruch membrane associated with his prior history of choroidal neovascularisation. The diagnosis was subsequently confirmed by skin biopsy and genetic testing. This case highlights the subtlety of both dermatological and ophthalmic signs in PXE.

Irregular vascular network identified with OCT-A in angioid streaks: A probable predictor of active choroidal neovascularization (case series).

PURPOSE: To evaluate the risk of active choroidal neovascularization (CNV) in presence of deep irregular vascular network (IVN) in eyes with angioid streaks (AS). METHODS: Observational case series including three treatment-naive eyes with angioid streaks and IVN, without CNV. Patients were followed-up during 18 months with multimodal imaging including structural optical coherence tomography (OCT) and OCT Angiography (OCT-A) to detect possible neovascular complication. RESULTS: On OCT-A, IVN was detected as a peripapillary and/or macular high-flow lesion, filling the spaces between the angioid streaks in the outer retina slab. Repeated OCT-A could detect an active CNV emerging from the IVN, as a high-flow rich anastomotic vascular network with a perilesional dark halo. Patient was treated with intravitreal injections of Bevacizumab on a Pro Re Nata regimen, with a decreased CNV area and lower vascular density on control OCT-A. CONCLUSION: OCT-A shown to be helpful in detecting the presence of IVN in asymptomatic eyes with AS during a routine examination. In our series, the IVN seems to be predictor of active CNV, needing a close surveillance and frequent follow-up to allow early treatment upon CNV activation.

The identification of activity of choroidal neovascularization complicating angioid streaks.

OBJECTIVES: To inspect the inter-reader agreement of different diagnostic modalities in identifying choroidal neovascularization (CNV) activity secondary to angioid streaks (AS) and to analyze the prevalence of subretinal hyper-reflective material (SHRM) in active CNV. METHODS: Retrospective study of patients with AS with active CNV; optical coherence tomography (OCT), OCT angiography (OCTA), fundus fluorescein angiography (FFA), and indocyanine green angiography (ICGA) from each patient were collected. Agreement between two readers using different diagnostic modalities is presented as free-marginal kappa (k) and 95% confidence interval (CI). RESULTS: This study included 19 eyes of 12 patients with active CNV (5 naive and 14 previously treated). Agreement among readers on CNV activity was excellent for OCT (k =0.88; 95% CI 0.71-1.00), good for FFA (k = 0.70; 95% CI 0.46-0.94) and ICGA (k = 0.58; 95% CI 0.31-0.84), and poor using OCTA (k = 0.39; 95% CI 0.11-0.68). SHRM was the most common OCT finding associated with active CNV (100%); fuzzy borders were present in 53% of SHRM cases at baseline. CONCLUSIONS: Identification of CNV activity in AS is challenging; OCT was the best modality to inspect active CNV. The identification of SHRM contributed to recognizing active CNV. Further studies are needed to assess the role of SHRM in anticipating prognosis and guiding treatment of CNV secondary to AS.

Prevalence of Dark without Pressure and Angioid Streaks in Sickle Cell Disease.

BACKGROUND AND OBJECTIVES: To investigate the prevalence of areas of dark without pressure (DWOP) and angioid streaks (AS) in patients with sickle cell disease (SCD). PATIENTS AND METHODS: This was a consecutive series of 77 adults with SCD. RESULTS: DWOP appeared as multiple patches in 35 of the affected eyes and as a single lesion in 3 eyes. OCT finding demonstrated the ellipsoid layer was hyporeflective in DWOP. AS were identified in six cases (3.9%) and were bilateral in five cases. The prevalence of AS was higher with increasing age, being 67% in the patients older than age 45 years. CONCLUSION: The prevalence of DWOP in adults with SCD is 25% in this study, which is higher than previously reported, and the prevalence of AS is around 4%, which is midway between prior estimates. Recognition of the clinical examination and imaging features of DWOP reduce the need for additional investigation. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:620-622.].

A case report: pseudoxanthoma elasticum diagnosed based on ocular angioid streaks and the curative effect of Conbercept treatment.

BACKGROUND: This article is a case report of pseudoxanthoma elasticum (PXE) which was diagnosed based on significant angioid streaks (AS) with choroidal neovascularization (CNV) and regain normal visual function by intravitreal injection with Conbercept. CASE PRESENTATION: A 51-year-old woman was referred to the Ophthalmology Department of Qingdao Municipal Hospital (Qingdao, China) on September 14, 2020 for metamorphopsia and loss of vision in the left eye in the preceding three days. Past history: high myopia for more than 30 years, best corrected visual acuity (BCVA) of both eyes was 1.0 (5 m Standard Logarithm Visual Acuity chart in decimal notations), hypertension for six years, and cerebral infarction two years ago, no history of ocular trauma or surgeries or similar patients in family was documented. We used methods for observation, including fundus examination, optical coherence tomography (OCT), fluorescein angiography combined with indocyanine green angiography (FFA + ICGA). Due to her symptoms and manifestations, along with the appearance of her neck skin, which resembled 'chicken skin', we speculated that she should be further examined at the Department of Dermatology by tissue paraffin section and molecular pathology analyses, and the diagnosis of PXE was then confirmed. After intravitreal injection with Conbercept (10 mg/ml, 0.2 ml, Chengdu Kanghong Biotechnologies Co., Ltd.; Chengdu, Sichuan, China) she regained her BCVA. CONCLUSIONS: This patient regained her best corrected visual acuity through intravitreal injection with Conbercept. To the best of our knowledge, no publications are available on cases in which a vision loss and the normal visual function can be reverted by intravitreal injection with Conbercept. Although PXE is a disease with low incidence and thus no effective cure established, targeted symptomatic treatment can effectively retard the disease progression and improve visual function, such as intravitreal injection with Conbercept.

Clinical Characterization of Korean Patients with Pseudoxanthoma Elasticum and Angioid Streaks.

This study aimed to characterize Korean patients with pseudoxanthoma elasticum (PXE) presenting with angioid streaks. Retinal phenotypes were longitudinally evaluated by multimodal ophthalmic imaging, and targeted gene panel sequencing for inherited retinal diseases was conducted. Seven subjects from unrelated families (median age, 51.2 years) were enrolled and followed for a median of 3.2 years. Four asymptomatic patients were significantly younger than three symptomatic patients with decreased visual acuity at presentation (mean age; 38.1 vs. 61.5 years, p = 0.020). The asymptomatic patients maintained good vision (20/32 or better) and had no choroidal neovascularization (CNV) over the observation period. The symptomatic patients showed additional reduction in visual acuity and bilateral CNV occurrence during the longitudinal follow-up. Pathogenic ABCC6 variants were identified in all patients, leading to a diagnosis of PXE. Heterozygous monoallelic variants were identified in four patients and compound heterozygous variants were detected in three patients. Nine ABCC6 variants were identified, including one novel variant, c.2035G>T [p.Glu679Ter]. This is the first genetic study of Korean patients with PXE.

Case Report: Alagille Syndrome Presenting with Angioid Streaks.

SIGNIFICANCE: Alagille syndrome is rare genetic disease, which affects liver and heart function. Cases are frequently diagnosed late, and a complete ocular examination aids in the diagnosis. Although ophthalmic manifestations are usually benign, occasionally, sight-threatening complications occur. PURPOSE: The case presented herein highlights a rare condition, which usually can be diagnosed by the ophthalmological findings. However, in this particular case report, the complication of angioid streaks and choroidal neovascularization is reported for the first time in Alagille syndrome. CASE REPORT: Α 32-year-old woman diagnosed with Alagille syndrome presented with diminution of vision in the left eye. The cause was choroidal neovascularization related to angioid streaks. She was treated with intravitreal injections of ranibizumab but developed an extensive macular scar. A few years later, she developed the same complication in the right eye and was treated similarly. CONCLUSIONS: Alagille syndrome has many ophthalmic manifestations, most of them benign with minimal threat to vision. Herein for the first time, we present a case of Alagille syndrome with angioid streak-related choroidal neovascularization, which resulted in severe vision loss.

Contribution of OCT angiography in angioid streaks.

PURPOSE: To study the appearance of angioid streaks (AS) in swept source optical coherence tomography angiography. METHODS: Retrospective observational study of 16 patients (31 eyes) with various stages of AS. All included patients underwent complete ophthalmologic examinations including best-corrected visual acuity (BCVA), slit-lamp examination, indirect ophthalmoscopy and fundus photography. Swept source optical coherence tomography (SS-OCT), OCT angiography (OCT-A) and fluorescein angiography were also performed. RESULTS: En face OCT detected hyper-reflective points in 65% of cases, with a choriocapillaris (CC) shadow on the corresponding OCT-A. Diffuse CC rarefaction was detected in 94%. In eyes without neovascular complications, streaks were visible as a hyposignal in the outer retina. An irregular vascular network (IVN) was detected in 80% of eyes. It filled the spaces between the AS and corresponded to flat elevation of the retinal pigmentary epithelium. Twenty-four eyes had choroidal neovascularization (CNV). CNV was type 1 in 8%, type 2 in 43%, mixed in 20% and unclassified in 29% because of a large scar. We found multiple sites of CNV in 8% of cases. CNV shape was tangled in 66% and in 2 eyes with newly diagnosed CNV. OCT-A showed a perilesional halo around new CNV. The morphology and configuration of neovascular network follow the IVN and the path of the AS and arises in proximity to sites of BM disruption. CONCLUSION: OCT-A allows early detection and monitoring of AS and their neovascular complications. It shows CC rarefaction, IVN and a predominantly tangled shape of CNV. However, there are some limitations associated with difficulty in characterizing signs of CNV activity.

Angioid streaks and obstructive sleep apnea syndrome: are they related?

BACKGROUND: Sleep apnea syndrome (OSAS) has been associated with different ocular manifestations including glaucoma, floppy eye syndrome, punctate keratitis, keratoconus, and optic neuropathy. Angioid streaks are mainly associated with pseudoxanthoma elasticum (PXE) although they can appear in other systemic conditions affecting the elastic fibers. METHODS: This is a prospective, cross-sectional study. A complete ophthalmic examination was performed in 92 patients undergoing overnight polysomnography for suspicion of OSAS. Diagnosis and classification of OSAS were made based on apnea-hypopnea index (AHI). Stereoscopic optic disc photographs were taken in all patients and independently evaluated by two ophthalmologists. Patients with angioid streaks were referred to a dermatologist for axillary skin biopsy in order to rule out pseudoxanthoma elasticum or other skin abnormalities. RESULTS: Bilateral angioid streaks were observed in three patients who had been diagnosed with severe OSAS (AHI > 30/h). No clinical features characteristic of pseudoxanthoma elasticum or other pathological skin signs were observed. Skin biopsies were normal for all three patients, supporting the diagnosis of idiopathic angioid streaks. One of the patients developed bilateral choroidal neovascularization secondary to the angioid streaks over subsequent years. CONCLUSIONS: In view of the low prevalence of idiopathic angioid streaks in the general population, the finding of angioid streaks in patients with severe OSAS suggests OSAS as a possible risk factor for its development. The hypothesis of a connective tissue abnormality that could explain an association between both entities deserves further elucidation.

MULTIMODAL IMAGING OF FOCAL CHOROIDAL EXCAVATION COMPLICATED BY CHOROIDAL NEOVASCULARIZATION IN A PATIENT WITH ANGIOID STREAKS AND PSEUDOXANTHOMA ELASTICUM.

PURPOSE: To describe a case of focal choroidal excavation (FCE) complicated with Type-2 choroidal neovascularization (CNV) in a patient with angioid streaks secondary to pseudoxanthoma elasticum before and after treatment with bevacizumab. METHODS: Fundus photography, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, spectral-domain optical coherence tomography (SD-OCT) and SD-OCT angiography were performed in a 60-year-old white woman with angioid streaks and bilateral FCE. Spectral domain OCT images were taken before and after three-monthly intravitreal injections of bevacizumab. Histopathological analysis of the dermis established the diagnosis of pseudoxanthoma elasticum. RESULTS: Multimodal imaging revealed bilateral FCE and CNV. Spectral domain OCT diagnosed bilateral FCE and Type-1 and Type-2 CNV in the right eye, and irregular vascular network, along macular streak, in both eyes, which were not observed on fluorescein neither on indocyanine green angiography, but only on SD-OCT angiography. Patient presented good anatomical and functional response to intravitreal injections of bevacizumab. CONCLUSION: Focal choroidal excavation is a rare condition detected mainly by SD-OCT, which may be associated with angioid streaks secondary to pseudoxanthoma elasticum and complicated by CNV. Multimodal imaging is important for diagnosis and follow-up of such patients, even in the absence of signs of CNV, and anatomical and functional response to anti-vascular endothelial growth factor therapy is good.

PSEUDOXANTHOMA ELASTICUM: SUCCESSFUL LONG-TERM MANAGEMENT OF CHOROIDAL NEOVASCULARIZATION SECONDARY TO ANGIOID STREAKS WITH PRO RE NATA INTRAVITREAL BEVACIZUMAB INJECTIONS.

PURPOSE: To demonstrate how a patient with recurrent episodes of choroidal neovascularization (CNV), secondary to angioid streaks, can be managed successfully with a pro re nata regime of intravitreal bevacizumab injection over an eight-year period. METHOD: A 32-year-old white woman with pseudoxanthoma elasticum has been followed up over an eight-year period for management of recurrent episodes of CNV in both eyes. She was educated to recognize the early signs and symptoms of CNV. Physical examination including visual acuity and slit-lamp examination as well as investigations such as macula optical coherence tomography and optical coherence tomography angiography were performed. Bevacizumab injections were given to her when she was diagnosed with CNV. RESULTS: Multiple episodes of CNV were successfully treated with pro re nata regimes of intravitreal bevacizumab injections. The patient was able to maintain excellent visual acuity of 0 logarithm of the minimum angle of resolution even after suffering recurrent episodes of CNV. CONCLUSION: This case report supports that a pro re nata regime of intravitreal bevacizumab injection therapy can be used successfully to treat recurrent episodes of CNV in a patient with pseudoxanthoma elasticum over an eight-year period. Early diagnosis through patient education and the use of appropriate diagnostic tools such as optical coherence tomography angiography have enabled us to deliver early treatment, resulting in an excellent outcome for this patient.