Correlation of retinal vascular characteristics with laboratory and ocular findings in Fabry disease: exploring ocular diagnostic biomarkers.

BACKGROUND: The goal of this study was to evaluate macular microvascular changes in patients with Fabry disease (FD) using optical coherence tomography angiography (OCTA) and to explore their correlation with laboratory and ocular findings. METHODS: A total of 76 eyes (38 patients) and 48 eyes of 24 healthy controls were enrolled in this prospective study. Vessel Area Density (VAD) and Foveal Avascular Zone (FAZ) area were calculated on 2.9 × 2.9 mm OCTA images scanned with the Heidelberg Spectralis II (Heidelberg, Germany). VAD was measured in three layers: Superficial Vascular Plexus (SVP), Intermediate Capillary Plexus (ICP), and Deep Capillary Plexus (DCP). All scans were analyzed with the EA-Tool (Version 1.0), which was coded in MATLAB (The MathWorks Inc, R2017b). FAZ area was manually measured in full-thickness, SVP, ICP and DCP scans. RESULTS: Average VAD in SVP, ICP and DCP was higher in Fabry disease patients than in controls (49.4 ± 11.0 vs. 26.5 ± 6.2, 29.6 ± 7.4 vs. 20.2 ± 4.4, 32.3 ± 8.8 vs. 21.7 ± 5.1 respectively, p < 0.001). Patients with cornea verticillata (CV) had a higher VAD in ICP and DCP compared to patients without CV (p < 0.01). Patients with increased lysoGb3 concentration had a higher VAD in DCP when compared to patients with normal lysoGb3 concentration (p < 0.04). There was no difference in VAD in patients with and without vascular tortuosity. However, a significantly higher VAD was observed in patients with vascular tortuosity compared to controls (p < 0.03). CONCLUSIONS: Increased lysoGb3 and VAD in DCP could be reliable biomarkers of disease activity. Cornea verticillata could be adopted as a predictive biomarker for VAD changes and disease progression. The combination of cornea verticillata and increased VAD may serve as a diagnostic biomarker for Fabry disease, however due to the discrepancies in VAD values in various studies, further research has to be done to address this claim.

Characterization and Classification of Postoperative Cysts After Strabismus Surgery: Clinical, Histological, and Anterior Segment OCT Analysis in a Large German Cohort.

INTRODUCTION: In this work, we provide a detailed characterization of a rare complication-subconjunctival cyst formation after strabismus surgery-in a large German cohort. METHODS: We conducted a retrospective analysis of 822 consecutive patients who underwent strabismus surgery between 2015 and 2022. The patients received comprehensive eye and orthoptic examinations preoperatively, at 1 day, and at 3 months postoperatively. Cysts were analyzed with slit-lamp examination, anterior segment optical coherence tomography (AS-OCT), and histopathological subsumption. RESULTS: Nineteen cases of postoperative cysts were observed (2.3%), 12 of which underwent surgical revision. Clinical evaluation including slit-lamp and AS-OCT as well as histological analysis resulted in a classification of three types of cysts: type 1, which is a single hyporeflective cyst, type 2, which is a multilobular hyporeflective cyst, and type 3, a dense hyperreflective granulomatous-like cyst. Eta (η) correlation ratio analysis could show a correlation between time of clinical appearance and type of cyst (Eta = 0.63). Most cysts developed within 20 days after surgery. Not only did cysts more frequently affect the medial rectus muscle, which in most cases underwent a shortening procedure (11/19 tucks, 4/19 resections) for intermittent exotropia (X(T)), but the cyst also formed earlier than in the lateral rectus muscle (Eta = 0.45). No correlation could be shown between the type of surgical procedure and time of cyst occurrence (Eta = 0.1). Patient age and cyst type correlated strongly (Eta = 0.47). The underlying type of strabismus did not correlate with the type of cyst observed. CONCLUSIONS: Our cases showed a strong positive correlation to the type of strabismus (X(T)), age (young patients), and the procedure (tuck/resection). We introduce a grading system for postoperative cysts after strabismus surgery, complementing histopathology and slit-lamp aspects with AS-OCT information.

Investigation of OCTA Biomarkers in Fabry Disease: A Long Term Follow-Up of Macular Vessel Area Density and Foveal Avascular Zone Metrics.

INTRODUCTION: Retinal microvasculature is known to be altered in patients with Fabry disease (FD). We aimed to investigate the long-term changes in macular microvasculature and explore a reliable retinal biomarker for treatment monitoring in FD. METHODS: Prospective study of 26 eyes with FD followed up to 48 months (mean 24, range 8-48). OCT angiography (OCTA) images (2.9 × 2.9 mm) were obtained using Heidelberg Spectralis II at baseline and follow-up. Macular vessel area density (VAD, %) was measured in three layers: superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) in three peri-macular circular sectors (c1, c2, c3). Additionally, foveal avascular zone (FAZ) area (mm2) and horizontal and vertical diameters (µm) were assessed. RESULTS: VAD decreased over time in SVP, ICP (in sectors c2 and c3) and DCP (all sectors) (p < 0.04). VAD reduction was predominantly seen in treated FD patients. FAZ and horizontal diameters increased at follow-up in FD patients compared to baseline (p ≤ 0.025). Correlation analysis showed a moderate to strong negative correlation between VAD of SVP and DCP in the innermost circle and FAZ in treated patients (r = - 0.6; p < 0.0001). CONCLUSIONS: This is the first long-term follow-up OCTA study in FD to our knowledge. A decrease in VAD, pronounced in the peripheral circle and deeper layers, as well as an enlargement of the FAZ could be observed over time. These changes reflect the vascular remodelling during the course of the disease. Interestingly, the reduction of VAD was more pronounced in treated patients. This could be a result of enzyme replacement therapy and could be potentially used as a reliable biomarker for monitoring the treatment of the disease. A baseline examination of VAD and FAZ before treatment initiation is meaningful. Larger studies are needed to establish the use of VAD and FAZ as biomarkers for treatment monitoring.

Current Practice in the Treatment of Epithelial and Melanocytic Tumours with Interferon-α2b: A Survey of Tertiary Eye Centres in Germany.

PURPOSE: To evaluate the standard of care, in particular the use of topical or subconjunctival interferon-α2b, in treating ocular surface squamous neoplasia or melanocytic tumours in tertiary eye centres in Germany. METHODS: A survey containing 14 questions was sent to 43 tertiary eye centres in Germany. The questions addressed the surgical and medical management of ocular surface squamous neoplasia and melanocytic tumours (primary acquired melanosis and malignant melanoma), as well as the clinical experiences and difficulties in prescribing off-label interferon-α2b eye drops and subconjunctival injections. RESULTS: Twenty-four tertiary eye centres responded to the survey. Eighty-three percent of centres had used interferon-α2b in their clinical practice and 25% prescribed it as the first-line cytostatic agent following surgical excision of ocular surface squamous neoplasia, while 10% would do so for melanocytic tumours. Correspondingly, the majority of respondents selected mitomycin C as their first-line agent. Side effects were uncommon with topical interferon-α2b eye drops but were more frequently reported after subconjunctival interferon-α2b injections. In total, eight centres had experience with interferon-α2b injections. The most significant obstacles perceived by ophthalmologists when prescribing interferon-α2b were its high cost and the reimbursement thereof. CONCLUSION: Off-label mitomycin C was the preferred adjuvant therapy for epithelial and melanocytic tumours, with interferon-α2b being the standard second-line option. Interferon-α2b has predominantly been used to treat ocular surface squamous neoplasia and, to a lesser extent, melanocytic tumours at German tertiary eye centres. Following its market withdrawal, supply shortages of interferon-α2b are likely to have a profound impact on patient care and their quality of life.

Investigation of Structural Alterations in Inherited Retinal Diseases: A Quantitative SD-OCT-Analysis of Retinal Layer Thicknesses in Light of Underlying Genetic Mutations.

Inherited retinal diseases can result from various genetic defects and are one of the leading causes for blindness in the working-age population. The present study aims to provide a comprehensive description of changes in retinal structure associated with phenotypic disease entities and underlying genetic mutations. Full macular spectral domain optical coherence tomography scans were obtained and manually segmented in 16 patients with retinitis pigmentosa, 7 patients with cone−rod dystrophy, and 7 patients with Stargardt disease, as well as 23 age- and sex-matched controls without retinal disease, to assess retinal layer thicknesses. As indicated by generalized least squares models, all IRDs were associated with retinal thinning (p < 0.001), especially of the outer nuclear layer (ONL, p < 0.001). Except for the retinal nerve fiber layer, such thinning was associated with a reduced visual acuity (p < 0.001). These advances in our understanding of ultrastructural retinal changes are important for the development of gene-, cell-, and optogenetic therapy. Longitudinal studies are warranted to describe the temporal component of those changes.

Development of a Patient-Oriented Organizational Management System for Intravitreal Injection Therapy in a Standardized "Treat-and-Extend" Regime at a University Eye Clinic. / Entwicklung eines patientennahen Organisationsmanagements für die intravitreale Injektionstherapie in einem standardisierten "Treat-and-Extend"-Regime an einer Universitäts-Augenklinik.

BACKGROUND: The treatment of macular edema with intravitreal injections has revolutionized the treatment of associated diseases in ophthalmology. However, with a few exceptions, this is a chronic treatment where patients require many injections and usually need to stay in treatment for years. Patient adherence and control of patient flow are critical to treatment success. In this manuscript, we describe the development of a patient-oriented organization management for intravitreal injections in a university hospital. MATERIAL AND METHODS: In 2015, the intravitreal treatment in our clinic was switched to the treat-and-extend regime. At the same time, the optimization of the previous organizational processes in perioperative management was evaluated. For the period 2015 to 2018, we analyzed and gradually optimized the procedures of our intravitreal injection therapy in a survey with a specialized service provider. RESULTS: Through the analysis of the original processes, the patient appointment was optimized, work processes were summarized, spatially reorganized and there was only a slight increase in the number of staff involved compared with the significant increase in the number of injections. Through these measures, the total in-hospital-time of the patients could be drastically reduced and at the same time the number of patients on one operation day could be multiplied. CONCLUSION: In the context of chronic treatment with intravitreal injections, the care of an increased number of patients is a logistical challenge. By optimizing processes, existing resources can be better used to meet the increased demands. An optimized system offers the patient greater adherence and a better visual outcome largely independent of the medication used.

Clinical Heterogeneity in Autosomal Recessive Bestrophinopathy with Biallelic Mutations in the BEST1 Gene.

Autosomal recessive bestrophinopathy (ARB) has been reported as clinically heterogeneous. Eighteen patients (mean age: 22.5 years; 15 unrelated families) underwent ophthalmological examination, fundus photography, fundus autofluorescence, and optical coherence tomography (OCT). Molecular genetic testing of the BEST1 gene was conducted by the chain-terminating dideoxynucleotide Sanger methodology. Onset of symptoms (3 to 50 years of age) and best-corrected visual acuity (0.02-1.0) were highly variable. Ophthalmoscopic and retinal imaging defined five phenotypes. Phenotype I presented with single or confluent yellow lesions at the posterior pole and midperiphery, serous retinal detachment, and intraretinal cystoid spaces. In phenotype II fleck-like lesions were smaller and extended to the far periphery. Phenotype III showed a widespread continuous lesion with sharp peripheral demarcation. Single (phenotype IV) or multifocal (phenotype V) vitelliform macular dystrophy-like lesions were observed as well. Phenotypes varied within families and in two eyes of one patient. In addition, OCT detected hyperreflective foci (13/36 eyes) and choroidal excavation (11/36). Biallelic mutations were identified in each patient, six of which have not been reported so far [c.454C>T/p.(Pro152Ser), c.620T>A/p.(Leu207His), c.287_298del/p.(Gln96_Asn99del), c.199_200del/p.(Leu67Valfs*164), c.524del/p.(Ser175Thrfs*19), c.590_615del/p.(Leu197Profs*26)]. BEST1-associated ARB presents with a variable age of onset and clinical findings, that can be categorized in 5 clinical phenotypes. Hyperreflective foci and choroidal excavation frequently develop as secondary manifestations.

Ipsilateral transient amaurosis, mydriasis and light reflex absence after subconjunctival local anesthesia with mepivacaine in three patients with refractory glaucoma - a case report.

BACKGROUND: The subconjunctival anesthesia with local anesthetics is considered as a low-risk procedure allowing ocular surgery without serious complications typical for retro- or parabulbar anesthesia, especially in patients with preexisting Optic Nerve damage. We report development of ipsilateral transient amaurosis accompanied with mydriasis and both, direct and consensual light response absence. CASE PRESENTATION: Three patients with advanced refractory glaucoma undergoing laser cyclophotocoagulation (CPC) for intraocular pressure lowering experienced these adverse effects just few minutes after subconjunctival injection of mepivacaine 2% solution (Scandicaine® 2%, without vasoconstrictor supplementation). The vision was completely recovered to usual values in up to 20 h after mepivacaine application. Extensive ophthalmological examination, including cranial magnetic resonance imaging (MRI), revealed no further ocular abnormalities, especially no vascular constriction or thrombotic signs as well as no retinal detachment. The oculomotor function remained intact. The blockade of ipsilateral ciliary ganglion parasympathetic fibers by mepivacaine may be the responsible mechanism. Systemic pathways as drug-drug interactions seem to be unlikely involved. Importantly, all three patients tolerated the same procedure previously or at a later date without any complication. Overall, our thoroughly elaborated risk management could not determine the causative factor explaining the observed ocular complications just in the current occasion and not at other time points. CONCLUSIONS: Doctors should be aware and patients should be informed about such rare complications after subconjunctival local anesthetics administration. Adequate risk management should insure patients' safety.

Classification and characterization of acute macular neuroretinopathy with spectral domain optical coherence tomography.

PURPOSE: To classify and characterize AMN lesions with SD-OCT during a follow-up as long as 5 years. METHODS: Retrospective study of 14 patients (18 eyes) with special focus on SD-OCT. We measured thickness of inner nuclear layer (INL), outer retinal layer (ONL), and hyperreflective band at baseline and during follow-up. AMN lesions were classified as type 1 and type 2. RESULTS: Of 14 patients (six males, eight females, mean age 29.7 years), three patients (four eyes) had type 1 and nine (12 eyes) had type 2. Two patients did not meet the criteria for AMN type 1 or 2 and were therefore classified as new subtype of AMN. In all patients, statistically significant thinning of ONL and INL was observable. Mean ONL of all patients was 90.2 ± 7.81 and 72.3 ± 15.64 µm (p < 0.05) during follow-up; mean INL was 54.4 ± 10.71 and 37.5 ± 6.18 µm (p < 0.05) in the course. In the subgroup analysis in AMN type 2, the thinning of both ONL and INL was also statistically significant (mean ONL: 87.4 ± 6.02 and 71.6 ± 12.7 µm (p < 0.05); mean INL: 48.5 ± 5.04 and 38.5 ± 5.6 µm (p < 0.05)) in the course. CONCLUSION: SD-OCT allows for classification, characterization, and further understanding of AMN lesions. Up to now, this is one of the largest AMN case series differentiating into different subtypes and following up for up to 5 years. Furthermore, we describe a new AMN subtype characterized by initially clinically visible yellowish parafoveal lesions, subtle pigmentary changes at late stage, lack of classic dark appearance on IR reflectance, involvement of RPE/Bruch's complex, and disruption of ellipsoid zone and interdigitation zone. The patients suffered from a prolonged visual impairment and paracentral scotomata. We propose the term AMN type 3 or "paracentral acute outer maculopathy."

[Conjunctival amyloidosis]. / Konjunktivale Amyloidose.

BACKGROUND: This article reports a case of primary localized conjunctival λ light-chain (AL) amyloidosis. METHODS: Case report. RESULTS: A 73-year-old woman presented with a 1-year history of a painless growth in the conjunctiva of the left eye. A yellow-salmon pink diffuse mass of tissue was identified in the inferomedial bulbar conjunctiva and inferior fornix. An incisional biopsy was performed. The histopathological and immunohistochemical examinations revealed interstitial and vascular amyloid deposits of λ light chains. The diagnosis was amyloidosis of the conjunctiva. The systemic evaluation revealed normal findings and systemic amyloidosis was excluded. Nevertheless, due to an unexplained cardiac insufficiency and after consultation with the treating hematologist a treatment with three cycles of systemic chemotherapy with melphalan and prednisolone was initiated but 6 months later the conjunctival mass in the inferior fornix showed persistence and complete excision was performed. At 16, 24 and 44 months of follow-up no evidence of recurrence was seen on clinical examination. The magnetic resonance imaging (MRI) at 16 and 24 months of follow-up showed no associated cranial or orbital infiltration. CONCLUSION: Conjunctival AL amyloidosis is a rare clinical entity. Because of the heterogeneity of amyloidosis in clinical presentation, pattern of amyloid-related organ toxicity, association with lymphoproliferative diseases and rate of disease progression, identification of amyloid deposits is essential and systemic involvement has to be excluded.

Visual and morphological outcomes of bevacizumab (Avastin®) versus ranibizumab (Lucentis®) treatment for retinal angiomatous proliferation.

Retinal angiomatous proliferation (RAP) is a variant of exudative age-related macular degeneration with particularly bad prognosis. The purpose of this work is to describe the long-term functional and morphological outcome of patients treated with intravitreal bevacizumab and ranibizumab. Retrospective case series of 16 eyes treated with bevacizumab and 19 eyes treated with ranibizumab. All patients received initially three intravitreal injections of bevacizumab (1.25 mg/0.05 ml) or ranibizumab (0.5 mg/0.05 ml) every 4 weeks. Follow-up ranged from 1 to 7 months after the third injection. Complete ophthalmologic examination including best-corrected visual acuity (VA), optical coherence tomography, fluorescein angiography, and in selected cases, indocyanine green angiography was performed. Triple intravitreal injections resulted in improvement of VA in bevacizumab-treated as well as in ranibizumab-treated patients; logarithm of the minimal angle of resolution (logMAR) 0.84 before treatment and 0.67 at month 9, and logMAR 0.75 before treatment and 0.59 at month 9, respectively. Central macular thickness (CMT) in the bevacizumab group improved from 363.67 ± 47.4 µm at baseline to 328 ± 49.77 µm at month 6 (p = 0.03) and 301 ± 129.69 at month 9 (p = 0.35). CMT in the ranibizumab group improved from 545.62 ± 167.39 µm at baseline to 395.88 ± 169.37 µm at month 6 and 411.83 ± 212.41 µm at month 9 (p = 0.03, p = 0.05, respectively). Patients with RAP might benefit from both intravitreal bevacizumab and ranibizumab treatments with stabilization of VA over a longer period of time. Close follow-up should nevertheless be performed in this special subgroup because of the high recurrence rate.

Acute visual loss after preoperative embolization of an ethmoidal metastasis.

An unintentional embolization of retinal arteries is rare and has been documented as a complication after embolization of arteries supplying head and neck tumors. However, occlusion of the central retinal artery with severe loss of vision has never been reported to be a complication from embolization of tumor-supplying ethmoidal branches of the ophthalmic artery. A 40 year-old male patient with a history of right nephrectomy for renal cell carcinoma underwent preoperative radiological embolization of an ethmoidal metastasis after having experienced a life-threatening sinus bleeding. Repeated probing of the ophthalmic artery with an endovascular microcatheter for particle embolization of the tumor-supplying arteries was performed under anticoagulation with heparin. Postoperatively, a standard ophthalmological examination including extended vascular evaluation by angiography was performed. After extended probing of the ophthalmic artery a marked reduction in its blood flow occurred. Despite post-interventional imaging showing persisting perfusion of the central retinal and ciliary arteries, the patient developed complete loss of vision on this side four days later. At this time fundoscopy and fluorescein angiography revealed a recanalized central artery occlusion, while indocyanin angiography showed infarctions of the choroid. Radiological intervention via the ophthalmic artery can result in complete loss of vision, even after limited and transient obstruction of the vessel.