Non-Invasive Tools in Perioperative Stroke Risk Assessment for Asymptomatic Carotid Artery Stenosis with a Focus on the Circle of Willis.

This review aims to explore advancements in perioperative ischemic stroke risk estimation for asymptomatic patients with significant carotid artery stenosis, focusing on Circle of Willis (CoW) morphology based on the CTA or MR diagnostic imaging in the current preoperative diagnostic algorithm. Functional transcranial Doppler (fTCD), near-infrared spectroscopy (NIRS), and optical coherence tomography angiography (OCTA) are discussed in the context of evaluating cerebrovascular reserve capacity and collateral vascular systems, particularly the CoW. These non-invasive diagnostic tools provide additional valuable insights into the cerebral perfusion status. They support biomedical modeling as the gold standard for the prediction of the potential impact of carotid artery stenosis on the hemodynamic changes of cerebral perfusion. Intraoperative risk assessment strategies, including selective shunting, are explored with a focus on CoW variations and their implications for perioperative ischemic stroke and cognitive function decline. By synthesizing these insights, this review underscores the potential of non-invasive diagnostic methods to support clinical decision making and improve asymptomatic patient outcomes by reducing the risk of perioperative ischemic neurological events and preventing further cognitive decline.

Impaired cerebrovascular reactivity correlates with reduced retinal vessel density in patients with carotid artery stenosis: Cross-sectional, single center study.

BACKGROUND: The cerebral and retinal circulation systems are developmentally, anatomically, and physiologically interconnected. Thus, we hypothesized that hypoperfusion due to atherosclerotic stenosis of the internal carotid artery (ICA) can result in disturbances of both cerebral and retinal microcirculations. We aimed to characterize parameters indicating cerebrovascular reactivity (CVR) and retinal microvascular density in patients with ICA stenosis, and assess if there is correlation between them. METHODS: In this cross-sectional study the middle cerebral artery (MCA) blood flow velocity was measured by transcranial Doppler (TCD) and, simultaneously, continuous non-invasive arterial blood pressure measurement was performed on the radial artery by applanation tonometry. CVR was assessed based on the response to the common carotid artery compression (CCC) test. The transient hyperemic response ratio (THRR) and cerebral arterial resistance transient hyperemic response ratio (CAR-THRR) were calculated. Optical coherence tomography angiography (OCTA) was used to determine vessel density (VD) on the papilla whole image for all (VDP-WIall) and for small vessels (VDP-WIsmall). The same was done in the peripapillary region: all (VDPPall), and small (VDPPsmall) vessels. The VD of superficial (VDMspf) and deep (VDMdeep) macula was also determined. Significance was accepted when p<0.05. RESULTS: Twenty-four ICA stenotic patients were evaluated. Both CVR and retinal VD were characterized. There was a significant, negative correlation between CAR-THRR (median = -0.40) and VDPPsmall vessels (median = 52%), as well as between VDPPall vessels (median = 58%), and similar correlation between CAR-THRR and VDP-WIsmall (median = 49.5%) and between VDP-WIall (median = 55%). CONCLUSION: The significant correlation between impaired cerebrovascular reactivity and retinal vessel density in patients with ICA stenosis suggests a common mechanism of action. We propose that the combined use of these diagnostic tools (TCD and OCTA) helps to better identify patients with increased ischemic or other cerebrovascular risks.

The Effect of Circle of Willis Morphology on Retinal Blood Flow in Patients with Carotid Stenosis Measured by Optical Coherence Tomography Angiography.

The Circle of Willis (CoW) is the main collateral system, and its morphological variants are more common in patients who have severe carotid artery stenosis. Earlier data suggest that optical coherence tomography angiography (OCTA) may help to assess the changes in cerebral vascular perfusion by imaging the retinal blood flow. In this single-center prospective clinical study, patients scheduled for carotid endarterectomy (CEA) underwent preoperative computed tomography angiography (CTA) of the extra- and intracranial cerebral circulation. OCTA imaging was performed one week before surgery and postoperatively one month later. The patients were divided into two subgroups based on CTA evaluation of CoW: compromised CoW or non-compromised CoW (containing hypoplastic and normal segments). The effect of the patient's age, OCTA scan quality (SQ), CoW morphology, laterality, and surgery on superficial capillary vessel density (VD) in the macula were assessed in multivariable regression models using linear mixed models. We found that VD significantly decreased with aging (-0.12%; 95%CI: -0.07--0.15; p < 0.001) and was significantly higher in patients with non-compromised CoW morphology (by 0.87% 95%CI (0.26-1.50); p = 0.005). After CEA, retinal blood flow significantly improved by 0.71% (95%CI: 0.18-1.25; p = 0.01). These results suggest that in the case of carotid artery occlusion, patients with non-compromised CoW have more preserved ocular blood flow than subjects with compromised CoW due to remodeling of the intra-orbital blood flow. Measuring the retinal blood flow might be used as a relevant and sensitive indicator of collateral cerebrovascular circulation.

Assessment of Visual Quality Improvement as a Result of Spectacle Personalization.

Personalized spectacles customized according to an individual's facial anatomy were developed to provide enhanced visual performance and overall comfort when compared to standard spectacles. In this comparative crossover trial, each subject was randomly assigned to wear either personalized spectacles or standard spectacles for two weeks and then tried the second pair for another two weeks. Visual acuity and reading speed were measured, and visual quality and comfort were assessed using specific questionnaires. The correlation of the wearing parameters with the subjects' satisfaction was calculated. According to our results, the subjects wearing personalized glasses reported significantly less experience of swaying and significantly higher overall satisfaction compared to those wearing the control spectacles. At the end of the study, 62% of subjects preferred the personalized spectacles, and visual quality was the primary reason for their spectacle preference followed by wearing comfort. The difference from the ideal cornea-vertex distance was significantly lower when wearing the personalized spectacles compared to the control frames. In addition, the absolute value of the difference from the ideal cornea-vertex distance was significantly correlated with patient satisfaction. These results suggest that personalized spectacles, customized according to an individual's facial anatomy for the ideal wearing parameters, result in both visual and comfort advantages for wearers.

Intraocular neutralizing antibodies against aflibercept in patients with age related macular degeneration.

PURPOSE: To detect immunoglobulins in aqueous humour of AMD patients after repeated administration of intravitreal aflibercept. PATIENTS AND METHODS: Twenty-one patients (age: 77.85 ± 9.21 years) previously treated with intravitreal aflibercept due to wet type age-related macular degeneration (AMD group) and 18 age-matched control subjects (age: 69.75 ± 12.67 years) were included in this study. Patients in the AMD group received a mean of 5 intravitreal injections (min: 1 max: 17) prior to the cataract surgery. Samples of aqueous humour (50 µl) were obtained by anterior chamber paracentesis as the first step of routine cataract surgery. The IgG content of the samples was analysed by an in-house developed ELISA system. RESULTS: A significant increase in nonspecific IgG levels in the AMD group was detected compared to the control group (13.37 ± 6.65 vs. 9.44 ± 6.55 µg/ml; p = 0.03). In 11 patients, intraocular anti-aflibercept immunoglobulins could be detected (0.05 ± 0.01 µg/ml) which was significantly higher than the limit of detection for anti-aflibercept (0.04 µg/ml; p = 0.001). No correlation was found between the number of injections or the type of CNV and the aqueous level of anti-aflibercept (r = 0.02; p = 0.95). CONCLUSION: According to our results, penetration of non-specific systemic antibodies through the impaired blood-retinal barrier is higher in patients with neovascular AMD than in subjects with an intact structural barrier. Evaluation of neutralizing antibodies to anti-VEGF agents in the aqueous humour can lead us to understanding tachyphylaxis and changes in intraocular immune mechanisms due to AMD.

Presence of SARS-CoV-2 on the conjunctival mucosa in patients hospitalized due to COVID-19: Pathophysiological considerations and therapeutic implications.

Introduction: Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in a worldwide pandemic, due to its great capacity to invade the human body. Previous studies have shown that the primary route of invasion of this virus is the human respiratory tract via the co-expression of ACE2 receptor and TMPRSS2, a serine protease on the cellular surface. Interestingly, this condition is present not only on the respiratory epithelium but on the conjunctival mucosa, as well. Thus, we hypothesized that SARS-CoV-2 is present on the conjunctival mucosa. Aim: To prove that SARS-CoV-2 can be detected in the conjunctiva. Methods: Previously nasopharyngeal swab-sample based real-time polymerase chain reaction (PCR) positive COVID-19 infected patients were selected at the COVID Care Centers of Semmelweis University, Budapest, Hungary. The study was approved by the ethical committee of Semmelweis University. During their recovery, both nasopharyngeal and conjunctival swab-samples were taken and PCR method was used to detect the presence of SARS-CoV-2 RNA. Appropriate statistical analysis was performed. Results: The study population consisted of 97 patients, 49 females (50.5%) and 48 males (49.5%), with a mean age of 67.2 ± 11.9 years. During recovery, with nasopharyngeal swabs, the PCR test was positive in 55 cases (56.70%), whereas with conjunctival swabs it was positive in 8 cases (8.25%). Both tests were positive in 5 cases (5.15%). In some patients, ocular symptoms were observed as well. The rest of the patients (29 cases) had negative nasopharyngeal PCR tests during recovery. Conclusions: Although only in few cases, the data of the present study provides a proof of concept that SARS-CoV-2 can be present on the conjunctival mucosa even in nasopharyngeal negative patients, a finding, which can have clinical importance. Also, on the basis of these findings one can hypothesize that - in addition to the respiratory tract - the conjunctiva can be an entrance route for SARS-CoV-2 to the human body. Thus, in high-risk conditions, in addition to covering the mouth and nose with mask, the protection of the eyes is also strongly recommended.

Microbiota mitochondria disorders as hubs for early age-related macular degeneration.

Age-related macular degeneration (AMD) is a progressive neurodegenerative disease affecting the central area (macula lutea) of the retina. Research on the pathogenic mechanism of AMD showed complex cellular contribution governed by such risk factors as aging, genetic predisposition, diet, and lifestyle. Recent studies suggested that microbiota is a transducer and a modifier of risk factors for neurodegenerative diseases, and mitochondria may be one of the intracellular targets of microbial signaling molecules. This review explores studies supporting a new concept on the contribution of microbiota-mitochondria disorders to AMD. We discuss metabolic, vascular, immune, and neuronal mechanism in AMD as well as key alterations of photoreceptor cells, retinal pigment epithelium (RPE), Bruch's membrane, choriocapillaris endothelial, immune, and neuronal cells. Special attention was paid to alterations of mitochondria contact sites (MCSs), an organelle network of mitochondria, endoplasmic reticulum, lipid droplets (LDs), and peroxisomes being documented based on our own electron microscopic findings from surgically removed human eyes. Morphometry of Bruch's membrane lipids and proteoglycans has also been performed in early AMD and aged controls. Microbial metabolites (short-chain fatty acids, polyphenols, and secondary bile acids) and microbial compounds (lipopolysaccharide, peptidoglycan, and bacterial DNA)-now called postbiotics-in addition to local effects on resident microbiota and mucous membrane, regulate systemic metabolic, vascular, immune, and neuronal mechanisms in normal conditions and in various common diseases. We also discuss their antioxidant, anti-inflammatory, and metabolic effects as well as experimental and clinical observations on regulating the main processes of photoreceptor renewal, mitophagy, and autophagy in early AMD. These findings support an emerging concept that microbiota-mitochondria disorders may be a crucial pathogenic mechanism of early AMD; and similarly, to other age-related neurodegenerative diseases, new treatment approaches should be targeted at these disorders.

The effect of systemic factors on retinal blood flow in patients with carotid stenosis: an optical coherence tomography angiography study.

Carotid artery stenosis (CAS) is among the leading causes of mortality and permanent disabilities in the Western world. CAS is a consequence of systemic atherosclerotic disease affecting the majority of the aging population. Optical coherence tomography angiography (OCTA) is a novel imaging technique for visualizing retinal blood flow. It is a noninvasive, fast method for qualitative and quantitative assessment of the microcirculation. Cerebral and retinal circulation share similar anatomy, physiology, and embryology; thus, retinal microvasculature provides a unique opportunity to study the pathogenesis of cerebral small vessel disease in vivo. In this study, we aimed to analyze the effect of systemic risk factors on retinal blood flow in the eyes of patients with significant carotid artery stenosis using OCT angiography. A total of 112 eyes of 56 patients with significant carotid stenosis were included in the study. We found that several systemic factors, such as decreased estimated glomerular filtration rate (eGFR), hypertension, and carotid occlusion have a significant negative effect on retinal blood flow, while statin use and carotid surgery substantially improve ocular microcirculation. Neither diabetes, clopidogrel or acetylsalicylic acid use, BMI, serum lipid level, nor thrombocyte count showed a significant effect on ocular blood flow. Our results demonstrate that a systematic connection does exist between certain systemic risk factors and retinal blood flow in this patient population. OCTA could help in the assessment of cerebral circulation of patients with CAS due to its ability to detect subtle changes in retinal microcirculation that is considered to represent changes in intracranial blood flow.

Imaging retinal microvascular manifestations of carotid artery disease in older adults: from diagnosis of ocular complications to understanding microvascular contributions to cognitive impairment.

Carotid artery stenosis (CAS) is a consequence of systemic atherosclerotic disease affecting the aging populations of the Western world. CAS is frequently associated with cognitive impairment. However, the mechanisms contributing to the development of vascular cognitive impairment (VCI) associated with CAS are multifaceted and not fully understood. In addition to embolization and decreased blood flow due to the atherosclerotic lesion in the carotid artery, microcirculatory dysfunction in the cerebral circulation also plays a critical role in CAS-related VCI. To better understand the microvascular contributions to cognitive decline associated with CAS and evaluate microvascular protective effects of therapeutic interventions, it is essential to examine the structural and functional changes of the microvessels in the central nervous system (CNS). However, there are some limitations of in vivo brain vascular imaging modalities. The retinal microvasculature provides a unique opportunity to study pathogenesis of cerebral small vessel disease and VCI, because the cerebral circulation and the retinal circulation share similar anatomy, physiology and embryology. Similar microvascular pathologies may manifest in the brain and the retina, thus ocular examination can be used as a noninvasive screening tool to investigate pathological changes in the CNS associated with CAS. In this review, ocular signs of CAS and the retinal manifestations of CAS-associated microvascular dysfunction are discussed. The advantages and limitation of methods that are capable of imaging the ocular circulation (including funduscopy, fluorescein angiography, Doppler sonography, optical coherence tomography [OCT] and optical coherence tomography angiography [OCTA]) are discussed. The potential use of dynamic retinal vessel analysis (DVA), which allows for direct visualization of neurovascular coupling responses in the CNS, for understanding microvascular contributions to cognitive decline in CAS patients is also considered.

Differences in guidelines for patients with carotid artery stenosis in some European countries / A nyaki veroér-szukületes betegek ellátási irányelveinek különbségei Európa különbözo országaiban.

Összefoglaló. A tudomány jelenlegi állása szerint - csoportok összehasonlítására épülo matematikai-statisztikai eszközökkel - a leginkább hatékonynak és hatásosnak vélt kezelési módszerek szisztematikus elemzése mentén, a bizonyítékokon alapuló irányelveken nyugvó gyógyító munkát tekintjük követendonek. A nyaki veroérszukület ellátása esetén az utóbbi években elkészült mind a hazai, mind az európai irányelv, mindemellett a társszakmák irányelveiben is megjelentek kezelési javaslatok. Közleményünkben összehasonlítottuk a témában publikált magyar, angol, német és olasz nyelvu, valamint az európai társaságok által kiadott irányelveket. Az irányelvek alapelveikben hasonlóak, formailag és tartalmilag azonban jelentos (idonként egymásnak ellentmondani látszó) különbségeket találhatunk. Az ellentmondások három leggyakoribb oka: 1) az egyes irányelvek által kituzött célok különbözosége, 2) az aszimptomatikus és szimptomatikus betegcsoport definíciói, valamint 3) az eltéro evidenciaszintek. Az irányelvek összevetése alapján a tünetes, szignifikáns nyaki veroérszukületek sebészi ellátása evidenciának tekintheto. A szimptomatikus nyaki veroérszukület a definíció szerint ellenoldali cerebralis ischaemia okozta, tranziens vagy definitív plegia, paresis, aphasia és az azonos oldali arteria centralis retinae embolisatiója miatti amaurosis fugax. A tünetmentes nyaki veroérszukületek ellátása tekintetében az európai és a nemzeti irányelvek nem azonosak, ezen esetek terápiás döntése egyéni mérlegelést igényel. Tünetmentes, 70%-os stenosis esetén vascularteam-konzílium javasolt. Orv Hetil. 2020; 161(51): 2139-2145. Summary. The correct practice is the one that is proven to be the most effective based on systematic statistical analyses of different treatment methods, and is applied according to evidence-based principles. In recent years, not only has the European Society of Vascular Surgery created a guideline about the management of supra-aortic steno-occlusive disease, but some nations' vascular surgical societies and related disciplines have also developed their own guidance. In this paper, the guidelines by the European societies on the clinical care of patients with carotid artery luminal narrowing is compared to national guidelines published in Hungarian, English, German, and Italian. Although the fundamental points of the guidelines are similar, there are some important differences among them both in presentation and in content; as a result, they sometimes appear to be contradictory. The three main sources of inconsistency are the various goals, the discrepancy in the definition of symptomatic and asymptomatic carotid artery stenosis, and the bias arising from the use of distinct evidence levels. A comparison of guidelines suggests that the treatment of symptomatic significant carotid artery stenosis with surgery can be considered evidence. Symptomatic carotid artery stenosis is defined as transient or definite plegia, paresis, aphasia due to cerebral ischemia, and monocular blindness caused by embolism in the central retinal artery. However, in the case of asymptomatic 70% or greater carotid artery stenosis, the guidelines are quite heterogeneous, and these patients require individual consideration and a vascular team decision is recommended. Orv Hetil. 2020; 161(51): 2139-2145.

Retinal biomarkers for Alzheimer's disease and vascular cognitive impairment and dementia (VCID): implication for early diagnosis and prognosis.

Cognitive impairment and dementia are major medical, social, and economic public health issues worldwide with significant implications for life quality in older adults. The leading causes are Alzheimer's disease (AD) and vascular cognitive impairment/dementia (VCID). In both conditions, pathological alterations of the cerebral microcirculation play a critical pathogenic role. Currently, the main pathological biomarkers of AD-ß-amyloid peptide and hyperphosphorylated tau proteins-are detected either through cerebrospinal fluid (CSF) or PET examination. Nevertheless, given that they are invasive and expensive procedures, their availability is limited. Being part of the central nervous system, the retina offers a unique and easy method to study both neurodegenerative disorders and cerebral small vessel diseases in vivo. Over the past few decades, a number of novel approaches in retinal imaging have been developed that may allow physicians and researchers to gain insights into the genesis and progression of cerebromicrovascular pathologies. Optical coherence tomography (OCT), OCT angiography, fundus photography, and dynamic vessel analyzer (DVA) are new imaging methods providing quantitative assessment of retinal structural and vascular indicators-such as thickness of the inner retinal layers, retinal vessel density, foveal avascular zone area, tortuosity and fractal dimension of retinal vessels, and microvascular dysfunction-for cognitive impairment and dementia. Should further studies need to be conducted, these retinal alterations may prove to be useful biomarkers for screening and monitoring dementia progression in clinical routine. In this review, we seek to highlight recent findings and current knowledge regarding the application of retinal biomarkers in dementia assessment.

The Impact of Deterministic Signal Loss on OCT Angiography Measurements.

Purpose: In this study, we aimed at investigating the impact of deterministic signal loss on image quality and, thus, on optical coherence tomography angiography (OCTA) measurements performed by the RTVue-XR Avanti System. Methods: Absorptive filters with different optical densities (ODs) were used to simulate signal loss in a controlled way in 30 eyes from 15 healthy subjects. Scan Quality (SQ), provided by the AngioVue software, was applied as a measure of image quality. Results: Assessing the effect of decreased light transmittance on SQ values as well as that of attenuated image quality on OCTA parameters revealed a strong systematic dependence between these quantities. Attenuated image quality was associated with significantly decreased macular and peripapillary vessel density (VD) values, and we calculated a correction factor of 2.27% to 3.97% for a one-unit change in SQ for the different VD parameters. Conclusions: Our findings suggest that the influence of systematic changes in image quality on OCTA parameters needs to be considered during patient follow-up in order to make valid assessment of progression. Translational Relevance: For accurate evaluation of longitudinal changes in OCTA parameters, equal scan quality or using a correction factor is suggested.

The effect of image quality on the reliability of OCT angiography measurements in patients with diabetes.

BACKGROUND: This study aimed to determine the relationship between image quality and measurement repeatability of optical coherence tomography angiography (OCTA) parameters in patients with non-proliferative diabetic retinopathy. METHODS: A total of 100 eyes of 50 patients were included in the study. Three OCTA images were obtained consecutively during one session of imaging in all patients using the RTVue AngioVue OCTA device. We applied the signal strength index (SSI) provided by the RTVue system to define scan quality. Superficial vessel density (VD) in the central 3 × 3 mm macular and in the perifoveal region, as well as foveal avascular zone (FAZ) area were evaluated by the AngioAnalytics software for each scan from three consecutive measurements, whereby measurement repeatability of the OCTA parameters were calculated. The effect of SSI value on OCTA parameters, as well as on measurement errors was assessed. RESULTS: Values of SSI ranged from 30 to 85 with an overall mean of 61.79 ± 10.38. Mean SSI values showed significant positive correlation with the mean retinal capillary vessel density values, but not with non-flow area. Repeatability of OCTA parameters was generally improved with higher SSI values. We calculated a mean correction factor of 0.22% (95% CI 0.20-0.24 µm; p < 0.001) for VD at the 3 × 3 mm macular scan, 0.23% (95% CI 0.21-0.26%; p < 0.001) for perifoveal VD and - 0.001 mm2 (95% CI - 0.001 to 0.002; p = 0.001) for the non-flow area for each unit increase in SSI for the comparison of images with different SSI values. CONCLUSIONS: The influence of image quality on OCTA metrics should be considered for image comparisons during follow-up to avoid misinterpretation of small changes in OCTA parameters in patients with diabetes.

Inhibition of epidermal growth factor receptor improves antitumor efficacy of vemurafenib in BRAF-mutant human melanoma in preclinical model.

Oncogenic activation of the epidermal growth factor receptor (EGFR) signaling pathway occurs in a variety of tumor types, albeit in human melanoma, the contribution of EGFR is still unclear. The potential role of EGFR was analyzed in four BRAF-mutant, one NRAS-mutant and one wild-type NRAS-BRAF-carrying human melanoma cell lines. We have tested clinically available reversible tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, irreversible EGFR-TKI pelitinib and a reversible experimental compound PD153035 on in-vitro proliferation, apoptosis, migration as well as in-vivo metastatic colonization in a spleen-liver model. The presence of the intracellular domain of EGFR protein and its constitutive activity were demonstrated in all cell lines. Efficacies of EGFR-TKIs showed significant differences, and irreversible inhibition had the strongest antitumor potential. Compared with BRAF-mutant cells, wild-type BRAF was associated with relative resistance against gefitinib. In combination with gefitinib, selective mutant BRAF-inhibitor vemurafenib showed additive effect in all BRAF-mutant cell lines. Treatment of BRAF-mutant cells with gefitinib or pelitinib attenuated in-vitro cell migration and in-vivo colonization. Our preclinical data suggest that EGFR is a potential target in the therapy of BRAF-mutant malignant melanoma; however, more benefits could be expected from irreversible EGFR-TKIs and combined treatment settings.