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Transdifferentiation and Intrachoroidal Migration of Melanotic Retinal Pigment Epithelium in Punctate Inner Choroiditis

Bijon, Jacques; Freund, K Bailey
PURPOSE/OBJECTIVE:To report the multimodal imaging features of hyperpigmented chorioretinal lesions originating from the retinal pigment epithelium (RPE) within punched-out lesions of punctate inner choroidopathy (PIC). METHODS:Retrospective case report. Multimodal imaging findings including fundus photography, optical coherence tomography (OCT), and OCT-angiography (OCTA) were analyzed. RESULTS:A 49-year-old female with myopic degeneration developed progressive lesions of PIC requiring immunosuppressive therapy with adalimumab. Within areas of punched-out chorioretinal atrophic lesions, the occurrence of hyperpigmented lesions were observed which enlarged and extended into the choroid over a multiyear follow-up. CONCLUSION/CONCLUSIONS:This case illustrates the development of pigmented choroidal lesions appearing to originate from the RPE through transdifferentiation following previous chorioretinal inflammatory lesions. The introduction of adalimumab treatment may have activated the cellular migration of the RPE. To the best of our knowledge, this is the first report of intrachoroidal RPE migration in PIC.
PMID: 37973041
ISSN: 1937-1578
CID: 5610412

MULTIZONAL OUTER RETINOPATHY AND RETINAL PIGMENT EPITHELIOPATHY (MORR): A Newly Recognized Entity or an Unusual Variant of AZOOR?

Ramtohul, Prithvi; Marchese, Alessandro; Introini, Ugo; Goldstein, Debra A; Freund, K Bailey; Jampol, Lee M; Yannuzzi, Lawrence A
PURPOSE:To describe specific clinical, multimodal imaging, and natural history features of an unusual variant of acute zonal occult outer retinopathy. METHODS:Retrospective, observational, longitudinal, multicenter case series. Patients exhibiting this unusual clinical condition among cases previously diagnosed with acute zonal occult outer retinopathy were included. Multimodal imaging, laboratory evaluations, and genetic testing for inherited retinal diseases were reviewed. RESULTS:Twenty eyes from 10 patients (8 females and 2 males) with a mean age of 54.1 ± 13.3 years (range, 38-71 years) were included. The mean follow-up duration was 13.1 ± 5.3 years (range, 8-23 years). Presenting symptoms were bilateral in 7 patients (85% of eyes) and included scotomata and photopsia. All patients had bilateral lesions at presentation involving the peripapillary and far peripheral retina. Baseline optical coherence tomography showed alteration of the retinal pigment epithelium and photoreceptor layers corresponding to zonal areas of fundus autofluorescence abnormalities. Centrifugal and centripetal progression of the peripapillary and far-peripheral lesions, respectively, occurred over the follow-up, resulting in areas of complete outer retinal and retinal pigment epithelium atrophy. CONCLUSION:Initial alteration of photoreceptors and retinal pigment epithelium and a stereotypical natural course that includes involvement of the far retinal periphery, characterize this unusual condition. It may represent a variant of acute zonal occult outer retinopathy or may be a new entity. We suggest to call it multizonal outer retinopathy and retinal pigment epitheliopathy .
PMCID:10589432
PMID: 37748093
ISSN: 1539-2864
CID: 5614102

PUNCTATE INNER PACHYCHOROIDOPATHY: Demographic and Clinical Features of Inner Choroidal Inflammation in Eyes with Pachychoroid Disease

Ramtohul, Prithvi; Freund, K Bailey; Parodi, Maurizio Battaglia; Introini, Ugo; Bandello, Francesco; Miserocchi, Elisabetta; Cicinelli, Maria Vittoria
PURPOSE:To perform an unsupervised machine learning clustering of patients with punctate inner choroidopathy (PIC) and provide new insights into the significance of pachychoroid disease features in PIC eyes. METHODS:Retrospective multicenter study, including 102 eyes from 82 patients diagnosed with PIC. Demographics, clinical data, and multimodal imaging, including fundus photography, optical coherence tomography, and indocyanine green angiography, were collected. Clusters of eyes were identified, and multilevel logistic regression analysis was performed to compare between-group differences. RESULTS:Using 17 clinical features, two distinct clusters of patients with PIC were identified. Cluster 1 patients were characterized by older age, high myopia, myopic maculopathy features, thin choroids, multiple lesions, and a higher likelihood of developing patchy chorioretinal atrophy. Cluster 2 consisted of younger age, emmetropia or low myopia, thick choroids, choroidal vascular hyperpermeability on late-phase indocyanine green angiography, and high prevalence of focal choroidal excavation. These features exhibited significant differences ( P < 0.05) between the two clusters. CONCLUSION:While PIC typically affects young myopic female patients with thin choroids, a subset of patients with PIC exhibits features associated with pachychoroid disease. Considering the potential influence of choroidal venous insufficiency on PIC manifestations and secondary complications, we propose the term "punctate inner pachychoroidopathy" to characterize this distinct subtype of PIC.
PMID: 37657077
ISSN: 1539-2864
CID: 5614042

INFLAMMATORY CELL ACTIVITY IN TREATED NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Histologic Case Study [Case Report]

Berlin, Andreas; Messinger, Jeffrey D; Ramtohul, Prithvi; Balaratnasingam, Chandrakumar; Mendis, Randev; Ferrara, Daniela; Freund, K Bailey; Curcio, Christine A
BACKGROUND:Imaging indicators of macular neovascularization risk can help determine patient eligibility for new treatments for geographic atrophy secondary to age-related macular degeneration. Because type 1 macular neovascularization includes inflammation, we assessed by histology the distribution of cells with inflammatory potential in two fellow eyes with age-related macular degeneration. METHODS:Two eyes of a White woman in her 90's with type 3 macular neovascularization treated with antivascular endothelial growth factor were prepared for high-resolution histology. Eye-tracked spectral domain optical coherence tomography applied to the preserved donor eyes linked in vivo imaging to histology. Cells were enumerated in the intraretinal, subretinal, and subretinal retinal pigment epithelium (RPE)-basal lamina compartments on 199 glass slides. Cells with numerous organelles were considered to RPE-derived; cells with sparse RPE organelles were considered non-RPE phagocytes. RESULTS:Both eyes had soft drusen and abundant subretinal drusenoid deposit. In the retina and subretinal space, RPE-derived cells, including hyperreflective foci, were common (n = 125 and 73, respectively). Non-RPE phagocytes were infrequent (n = 5 in both). Over drusen, RPE morphology transitioned smoothly from the age-normal layer toward the top, suggesting transdifferentiation. The sub-RPE-basal lamina space had RPE-derived cells (n = 87) and non-RPE phagocytes (n = 49), including macrophages and giant cells. CONCLUSION:Numerous sub-RPE-basal lamina cells of several types are consistent with the documented presence of proinflammatory lipids in drusen and aged Bruch's membrane. The relatively compartmentalized abundance of infiltrating cells suggests that drusen contents are more inflammatory than subretinal drusenoid deposit, perhaps reflecting their environments. Ectopic RPE occurs frequently. Some manifest as hyperreflective foci. More cells may be visible as optical coherence tomography technologies evolve.
PMID: 37871271
ISSN: 1539-2864
CID: 5611612

Imaging Histology Correlations of Intraretinal Fluid in Neovascular Age-Related Macular Degeneration

Berlin, Andreas; Messinger, Jeffrey D; Balaratnasingam, Chandrakumar; Mendis, Randev; Ferrara, Daniela; Freund, K Bailey; Curcio, Christine A
PURPOSE/UNASSIGNED:Fluid presence and dynamism is central to the diagnosis and management of neovascular age-related macular degeneration. On optical coherence tomography (OCT), some hyporeflective spaces arise through vascular permeability (exudation) and others arise through degeneration (transudation). Herein we determined whether the histological appearance of fluid manifested this heterogeneity. METHODS/UNASSIGNED:Two eyes of a White woman in her 90s with anti-vascular endothelial growth factor treated bilateral type 3 neovascularization secondary to age-related macular degeneration were osmicated, prepared for submicrometer epoxy resin sections, and correlated to eye-tracked spectral domain OCT. Examples of intraretinal tissue fluid were sought among similarly prepared donor eyes with fibrovascular scars, in a web-based age-related macular degeneration histopathology resource. Fluid stain intensity was quantified in reference to Bruch's membrane and the empty glass slide. RESULTS/UNASSIGNED:Exudative fluid by OCT was slightly reflective and dynamically responded to anti-vascular endothelial growth factor. On histology, this fluid stained moderately, possessed a smooth and homogenous texture, and contained blood cells and fibrin. Nonexudative fluid in degenerative cysts and in outer retinal tubulation was minimally reflective on OCT and did not respond to anti-vascular endothelial growth factor. By histology, this fluid stained lightly, possessed a finely granular texture, and contained mainly tissue debris. Quantification supported the qualitative impressions of fluid stain density. Cells containing retinal pigment epithelium organelles localized to both fluid types. CONCLUSIONS/UNASSIGNED:High-resolution histology of osmicated tissue can distinguish between exudative and nonexudative fluid, some of which is transudative. TRANSLATIONAL RELEVANCE/UNASSIGNED:OCT and histological features of different fluid types can inform clinical decision-making and assist in the interpretation of newly available automated fluid detection algorithms.
PMCID:10637202
PMID: 37943552
ISSN: 2164-2591
CID: 5609862

Variability in Capillary Perfusion Is Increased in Regions of Retinal Ischemia Due to Branch Retinal Vein Occlusion

Hein, Martin; Mehnert, Andrew; Freund, K Bailey; Yu, Dao-Yi; Balaratnasingam, Chandrakumar
PURPOSE:To investigate alterations in macular perfusion variability due to branch retinal vein occlusion (BRVO) using a novel approach based on optical coherence tomography angiography (OCTA) coefficient of variation (CoV) analysis. METHODS:Thirteen eyes of 13 patients with macular ischemia due to BRVO were studied. Multiple consecutive en face OCTA images were acquired. Bias field correction, spatial alignment, and normalization of intensities across the images were performed followed by pixelwise computation of standard deviation divided by the mean to generate a CoV map. Region of interest-based CoV values, derived from this map, for arterioles, venules, and the microvasculature were compared between regions with macular ischemia and control areas of the same eye. Control areas were regions of the same macula that were not affected by the BRVO and had normal retinal vascular structure as seen on multimodal imaging and normal retinal vascular density measurements as quantified using OCTA. RESULTS:CoV increased by a mean value of 17.6% within the microvasculature of ischemic regions compared to the control microvasculature (P < 0.0001). CoV measurements of microvasculature were consistently greater in the ischemic area of all 13 eyes compared to control. There were no differences in CoV measurements between ischemic and control areas for arterioles (P = 0.13) and venules (P = 1.0). CONCLUSIONS:Greater variability in microvasculature perfusion occurs at sites of macular ischemia due to BRVO. We report a novel way for quantifying macular perfusion variability using OCTA. This technique may have applicability for studying the pathophysiology of other retinal vascular diseases.
PMCID:10615145
PMID: 37856113
ISSN: 1552-5783
CID: 5614242

Histology, dimensions, and fluorescein staining characteristics of nodular and cuticular drusen in age-related macular degeneration

Evers, Charles D; Chen, Ling; Messinger, Jeffrey D; Killingsworth, Murray; Freund, K Bailey; Curcio, Christine A
PURPOSE/OBJECTIVE:To enable in vivo analysis of drusen composition and lifecycle, we assessed macular nodular and cuticular drusen using histology. METHODS:Median and interquartile range (IQR) of base widths of single (non-confluent) nodular drusen in 3 sources were determined histologically: 43 eyes of 43 clinically undocumented donors, in an online resource; one eye with punctate hyperfluorescence in fluorescein angiography (FA); and two eyes of one patient with bilateral "starry sky" cuticular drusen. All tissues were processed for high-resolution epoxy-resin histology and for cuticular drusen, transmission electron microscopy. RESULTS:All drusen localized between the retinal pigment epithelium basal lamina and inner collagenous layer of Bruch's membrane. They were solid, globular, homogeneously stained with toluidine blue, and uncovered by basal laminar deposit and basal mounds. Median base widths were 13.0 µm (Source 1, N=128 drusen, IQR 7.7, 20.0 µm), 15.3 µm (Source 2, N=87, IQR 10.6, 20.5 µm), and 7.3 µm (Source 3, N=78, IQR 3.9, 14.1 µm). CONCLUSIONS:In three samples, >90% of solitary nodular drusen were <30 µm, the visibility threshold in color fundus photography; these drusen are hyperfluorescent in FA. Whether these progress to soft drusen, known as high-risk from epidemiology studies and hypofluorescent, may be determinable from multimodal imaging datasets that include FA.
PMID: 37399252
ISSN: 1539-2864
CID: 5539052

Histology of Type 3 Macular Neovascularization and Microvascular Anomalies in Treated Age-Related Macular Degeneration: A Case Study

Berlin, Andreas; Cabral, Diogo; Chen, Ling; Messinger, Jeffrey D.; Balaratnasingam, Chandrakumar; Mendis, Randev; Ferrara, Daniela; Freund, K. Bailey; Curcio, Christine A.
Purpose: To investigate intraretinal neovascularization and microvascular anomalies by correlating in vivo multimodal imaging with corresponding ex vivo histology in a single patient. Design: A case study comprising clinical imaging from a community-based practice, and histologic analysis at a university-based research laboratory (clinicopathologic correlation). Participants: A White woman in her 90s treated with numerous intravitreal anti-VEGF injections for bilateral type 3 macular neovascularization (MNV) secondary to age-related macular degeneration (AMD). Methods: Clinical imaging comprised serial infrared reflectance, eye-tracked spectral-domain OCT, OCT angiography, and fluorescein angiography. Eye tracking, applied to the 2 preserved donor eyes, enabled the correlation of clinical imaging signatures with high-resolution histology and transmission electron microscopy. Main Outcome Measures: Histologic/ultrastructural descriptions and diameters of vessels seen in clinical imaging. Results: Six vascular lesions were histologically confirmed (type 3 MNV, n = 3; deep retinal age-related microvascular anomalies [DRAMAs], n = 3). Pyramidal (n = 2) or tangled (n = 1) morphologies of type 3 MNV originated at the deep capillary plexus (DCP) and extended posteriorly to approach without penetrating persistent basal laminar deposit. They did not enter the subretinal pigment epithelium (RPE)"“basal laminar space or cross the Bruch membrane. Choroidal contributions were not found. The neovascular complexes included pericytes and nonfenestrated endothelial cells, within a collagenous sheath covered by dysmorphic RPE cells. Deep retinal age-related microvascular anomaly lesions extended posteriorly from the DCP into the Henle fiber and the outer nuclear layers without evidence of atrophy, exudation, or anti-VEGF responsiveness. Two DRAMAs lacked collagenous sheaths. External and internal diameters of type 3 MNV and DRAMA vessels were larger than comparison vessels in the index eyes and in aged normal and intermediate AMD eyes. Conclusions: Type 3 MNV vessels reflect specializations of source capillaries and persist during anti-VEGF therapy. The collagenous sheath of type 3 MNV lesions may provide structural stabilization. If so, vascular characteristics may be useful in disease monitoring in addition to fluid and flow signal detection. Further investigation with longitudinal imaging before exudation onset will help determine if DRAMAs are part of the type 3 MNV progression sequence. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.
SCOPUS:85150961252
ISSN: 2666-9145
CID: 5460022

Stellate Multiform Amelanotic Choroidopathy (SMACH). Clinical and Multimodal Imaging Features

Ramtohul, Prithvi; Pellegrini, Marco; Pichi, Francesco; Preziosa, Chiara; Marchese, Alessandro; Cicinelli, Maria Vittoria; Miserocchi, Elisabetta; Mundae, Rusdeep; Mrejen, Sarah; Rofagha, Soraya; Mein, Calvin E; Mein, Luke; Ober, Michael D; Cunha de Souza, Eduardo; Cohen, Salomon Yves; van Dijk, Elon H C; Jampol, Lee; Boon, Camiel J F; Freund, K Bailey
PURPOSE/OBJECTIVE:To describe the clinical and multimodal imaging features of stellate multiform amelanotic choroidopathy (SMACH; also known as serous maculopathy due to aspecific choroidopathy). METHODS:Retrospective observational case series of eyes presenting with SMACH. Multimodal imaging including fundus photography, optical coherence tomography (OCT), OCT-angiography (OCTA), and indocyanine green angiography (ICGA) was analyzed. RESULTS:Eighteen eyes from 18 patients (mean age: 28±19 years) were included. The mean follow-up duration was 9 years. Ophthalmoscopy showed a yellowish-orange, dendriform choroidal lesion. At presentation, subretinal fluid (SRF) was seen in 10/18 cases (56%). Eight patients (44%) showed no evidence of SRF during a mean follow-up of 6 years. Cross-sectional OCT showed hyperreflective fibrous-like changes within the inner choroid with choriocapillaris flow preservation on OCTA. En face OCT showed a hyperreflective choroidal lesion with finger-like projections oriented in a stellate configuration. On ICGA, SMACH showed early and late hypofluorescence. None of the cases showed lesion growth. CONCLUSIONS:SMACH appears to be a unilateral choroidopathy characterized by distinctive multimodal imaging features. As SRF was absent in some cases, while a dendriform pattern was a consistent finding in all eyes, we propose renaming this entity "stellate multiform amelanotic choroidopathy", a name which retains its prior abbreviation "SMACH".
PMID: 37127025
ISSN: 1539-2864
CID: 5544792

Characterisation of the vascular anterior surface of type 1 macular neovascularisation after anti-VEGF therapy

Corvi, Federico; Bacci, Tommaso; Corradetti, Giulia; Staurenghi, Giovanni; Sarraf, David; Freund, K Bailey; Sadda, SriniVas
BACKGROUND:To evaluate whether the status of vasculature at the top of type 1 macular neovascularisation (MNV) could function as mediator of the observed protective effect against the development of complete retinal pigment epithelial and outer retinal atrophy (cRORA). METHODS:In consecutive treatment-naïve patients, the vasculature at the anterior surface of the MNV was isolated using a slab designed to extract the most superficial vascular portion of the MNV lesion showing a choriocapillaris (CC)-like structure which we termed the 'neo-CC'. The ratio between the neo-CC area (isolated using this custom slab) and the MNV area (isolated using the standard outer retina-CC slab) at baseline and at last follow-up was evaluated. RESULTS:Forty-four eyes from 44 patients were included. 20 showed cRORA by the final follow-up (median 23 months), whereas 24 did not progress to atrophy (median 23.5 months). The proportion of MNV with neo-CC at the anterior surface was significantly lower in eyes which progressed to cRORA compared with those which did not. The multivariate regression showed that a lower proportion of neo-CC coverage over the MNV was associated with an increased odds for cRORA development. CONCLUSIONS:More extensive coverage of neo-CC is associated with a lower likelihood of development of macular atrophy in eyes receiving antivascular endothelial growth factor therapy, suggesting the protective effect of a type 1 MNV may be mediated by the development of a neo-CC and may provide insights into the biological significance of MNV as a response mechanism in eyes with age-related macular degeneration.
PMID: 35537801
ISSN: 1468-2079
CID: 5214342