The RAP study, report 4: morphological and topographical characteristics of multifocal macular neovascularization type 3.

PURPOSE: To report on the morphological characteristics and regional distribution of multifocal macular neovascularization type 3 (mMNV3). METHODS: Twenty-two consecutive eyes of 21 patients with mMNV3 were included using multimodal imaging. The count and stage of lesions of all MNV types and the existence of exudate and hemorrhage were determined. Also, we addressed the regional distribution of MNV3 lesions between the superior-inferior and the nasal-temporal halves of the macula, and the range of the distance of the lesions from the central fovea. Furthermore, we explored the number of feeding vessels including the cilioretinal artery. RESULTS: We found 51 lesions in 22 eyes of 21 patients. They were bifocal in 16 (73%) eyes, trifocal in 5 (23%), and quadrifocal in one (4%). No lesion of MNV1 or 2 was found. Fifteen (68%), 2 (9%), and 16 (73%) eyes were associated with retinal hard exudate, subretinal pigment epithelium exudate, and intraretinal hemorrhage, respectively. Thirty (59%) lesions were located in the temporal half of the macula, whereas 21 (41%) were located nasally (p = 0.07). One (2%) lesion was closer than 500 µm, 49 (96%) between 500 and 1500 µm, and one (2%) between 1500 and 3000 µm. The lesions were supplied by one arteriole in one (4%) eye, two arterioles in 16 (73%) eyes, and 3 arterioles in 5 (23%) eyes. The CRA contributed as a feeding vessel in 5 (23%) eyes. CONCLUSION: The multifocal variant of MNV3 has specific morphological and topographical characteristics. Multimodal imaging allows the understanding of the pathomorphological condition in more detail.

THE RAP STUDY, REPORT 5: REDISCOVERING MACULAR NEOVASCULARIZATION TYPE 3: Multimodal Imaging of Fellow Eyes over 24 months.

PURPOSE: To explore the condition of fellow eyes of patients with macular neovascularization Type 3 (MNV3) and to verify whether the retinal-choroidal anastomosis (RCA) develops equally in all MNV types. METHODS: The contralateral eyes of 94 patients with MNV3, 96 patients with MNV1, and 96 patients with MNV2 were included. Multimodal imaging was performed. The MNV3 stage including the development of fibrosis and RCA over 24 months was determined. RESULTS: In the contralateral eyes of patients of the solitary (one lesion) MNV3 group, 32 eyes (42.1%) showed early/intermediate age-related macular degeneration, 25 eyes (33%) showed MNV3, and 11 eyes (14.5%) experienced fibrosis, of which 4 eyes (5.2%) had a RCA, 7 eyes (9.2%) had atrophy after resolved MNV3, and 1 eye (1.3%) developed MNV1. In the multifocal (more than one lesion) MNV3 group, 2 eyes (11.1%) showed early/intermediate age-related macular degeneration, 9 eyes (50%) showed 15 MNV3 lesions, and 4 eyes (22.2%) showed fibrosis, of which 2 eyes (11.1%) manifested with a RCA and 3 eyes (16.7%) showed atrophy after resolved MNV3. The number of eyes with a RCA accounted for 40% of all eyes with fibrosis. The count of simultaneous bilateral multifocal MNV3 was 5 (55.6%). In the MNV1 and MNV2 groups, no eye developed a RCA. The incidence of RCAs in the scarred eyes in MNV3 was significantly higher (P < 0.0001). CONCLUSION: Retinal-choroidal anastomosis is an exclusive clinical feature of MNV3. The development of the multifocal MNV3 is usually bilateral and simultaneous. The occurrence of fibrosis in MNV3 has decreased dramatically after the introduction of the antiangiogenic therapy.

THE IMPACT OF THE VITREOMACULAR INTERFACE ON FUNCTIONAL AND ANATOMICAL OUTCOMES IN DIABETIC MACULAR EDEMA TREATED WITH THREE DIFFERENT ANTI-VEGF AGENTS: Post Hoc Analysis of The Protocol T Study.

PURPOSE: To investigate the impact of baseline vitreomacular interface status on treatment outcomes in patients treated with three different anti-vascular endothelial growth factors for diabetic macular edema. METHODS: Post hoc analysis from patients enrolled in the DRCR.net Protocol T study. Optical coherence tomography images were analyzed at baseline and at the end of follow-up to identify the presence of complete vitreomacular adhesion, partial vitreomacular adhesion, vitreomacular traction syndrome, and complete posterior vitreous detachment. RESULTS: Six hundred and twenty-nine eyes were eligible for the study based on the study criteria. Complete adhesion eyes gained on average +3.7 more ETDRS letters compared with the complete posterior vitreous detachment group at the end of the 12 months follow-up ( P < 0.001). Baseline vitreomacular interface status had no significant influence on central subfield thickness at 12 months ( P = 0.144). There was no difference between the treatment arms based on effect of baseline vitreomacular interface status on best-corrected visual acuity gain. CONCLUSION: This study provides evidence that vitreomacular interface status affects functional outcomes in diabetic macular edema patients treated with anti-vascular endothelial growth factor injections. The presence of complete or partial vitreomacular adhesion at baseline may be associated with a larger treatment benefit than those with complete posterior vitreous detachment.

THE RAP STUDY, REPORT TWO: The Regional Distribution of Macular Neovascularization Type 3, a Novel Insight Into Its Etiology.

PURPOSE: To explore the regional distribution of macular neovascularization type 3 (MNV3). METHODS: Seventy-eight eyes of 78 patients were reviewed. We defined the location of each lesion after applying a modified ETDRS grid and the incidence of simultaneous MNV1 or 2. Also, we investigated the distribution of MNV3 at the outline of the foveal avascular zone and when the diameter of foveal avascular zone was less than 325 µm. RESULTS: The distribution of MNV3 was 4 lesions (5%) from the center to 500 µm, 72 (92%) from 500 µm to 1500 µm, and 2 (3%) from 1,500 µm to 3000 µm. The distribution in respect of the ETDRS fields was 7 (9%) nasal, 16 (20%) superior, 32 (40%) temporal, and 23 (31%) inferior. No additional MNV1 or 2 were found elsewhere. Most lesions tended to distribute along straight bands radiating from the perifoveal area, mainly in the temporal half (72%). None of the cases had MNV3 at the boundary of the foveal avascular zone. Only five cases had foveal avascular zone diameter of less than 325 µm, the closest lesion was 425 µm away from the center. CONCLUSION: MNV3 lesions are most likely neither symmetrical nor uniformly distributed. They have a higher affinity to distribute radially in the temporal perifoveal area.

Management of recurrent aphthous ulcers using low-level lasers: A systematic review.

BACKGROUND AND OBJECTIVE: The exact etiology of recurrent aphthous ulcers (RAS) is unknown. The management of RAS is not always straightforward. The aim of this review is to critically analyze and summarize the clinical literature focusing on the management of aphthous ulcers using low-level lasers. MATERIALS AND METHODS: The Medline (PubMed), Web of Knowledge (ISI), Cochrane Central Register of Controlled Trials (CENTRAL) and Embase databases were searched electronically for studies published in last 20 years (1995-2015) using the keywords "recurrent aphthous stomatitis," "aphthous ulcers," and "laser." RESULTS: A total of 85 articles were found during the initial search; 76 studies were excluded for not fulfilling the criteria whereas nine studies were deemed suitable for this review. Among the included studies, two articles were case reports and seven were randomized clinical trials. Study design, sample size, type of intervention and control of each study were critically analyzed and summarized according to the CONSORT protocol. In majority of the patients, immediate pain relief and accelerated ulcer healing was observed following irradiation with lasers. CONCLUSIONS: Although various types of lasers have succeeded in providing immediate pain relief to patients, carbon dioxide (CO2) lasers have the unique advantage of requiring a short exposure time (5-10s). In order to ascertain the efficacy of laser for treating ulcers in the clinical setting, more clinical trials are required.

The potential key role of choroidal non-perfusion and rod degeneration in the pathogenesis of macular neovascularization type 3.

Macular neovascularization type 3 (MNV3) is a multifactorial disease with distinct epidemiological, clinical, pathomorphological and topographical characteristics. This review of the literature discusses the latest experimental and clinical outcomes that could explain the pathogenesis of retinal neovascularization. Although patients with MNV3 are usually older than those with MNV1 or 2, their lesions do not coexist with, precede, or follow other types in the same eye. The regional distribution of MNV3 lesions is characterized as confined to the parafoveal macula without any involvement of the rod-free foveal area. Focal outer retinal atrophy and choroidal non-perfusion are the main structural features that occur prior to the development of retinal neovascularization. Also, histological and experimental studies of MNV3 and other non-neovascular age-related macular degeneration diseases complicated with MNV3-like lesions strongly suggest rod degeneration contributes to the pathogenesis. Therefore, the retinal neovascularization in MNV3 has a different pathogenesis from the choroidal neovascularization in MNV1 and 2 and emerging evidence indicates that choroidal non-prefusion and rod degeneration play a key role in the pathogenesis of MNV3. Accordingly, we suggest a sequence of pathological events that start with choroidal non-perfusion due to advanced age followed by hypoxia of the outer retina at the parafoveal area. This induces a remarkable degeneration of rods that triggers the growth of retinal neovascularization due to the imbalance of the angiogenic factors in the outer retina.

An Automated Comparative Analysis of the Exudative Biomarkers in Neovascular Age-Related Macular Degeneration, The RAP Study: Report 6.

PURPOSE: To investigate differences in volume and distribution of the main exudative biomarkers across all types and subtypes of macular neovascularization (MNV) using artificial intelligence (AI). DESIGN: Cross-sectional study. METHODS: An AI-based analysis was conducted on 34,528 OCT B-scans consisting of 281 (250 unifocal, 31 multifocal) MNV3, 55 MNV2, and 121 (30 polypoidal, 91 non-polypoidal) MNV1 treatment-naive eyes. Means (SDs), medians and heat maps of cystic intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachments (PED), and hyperreflective foci (HRF) volumes, as well as retinal thickness (RT) were compared among MNV types and subtypes. RESULTS: MNV3 had the highest mean IRF with 291 (290) nL, RT with 357 (49) µm, and HRF with 80 (70) nL, P ≤ .05. MNV1 showed the greatest mean SRF with 492 (586) nL, whereas MNV3 exhibited the lowest with 218 (382) nL, P ≤ .05. Heat maps showed IRF confined to the center, whereas SRF was scattered in all types. SRF, HRF, and PED were more distributed in the temporal macular half in MNV3. Means of IRF, HRF, and PED were higher in the multifocal than in the unifocal MNV3 with 416 (309) nL,114 (95) nL, and 810 (850) nL, P ≤ .05. Compared to the non-polypoidal subtype, the polypoidal subtype had greater means of SRF with 695 (718) nL, HRF 69 (63) nL, RT 357 (45) µm, and PED 1115 (1170) nL, P ≤ .05. CONCLUSIONS: This novel quantitative AI analysis shows that SRF is a biomarker of choroidal origin in MNV1, whereas IRF, HRF, and RT are retinal biomarkers in MNV3. Polypoidal MNV1 and multifocal MNV3 present with higher exudation compared to other subtypes.

Do patients with unilateral macular neovascularization type 3 need AREDS supplements to slow the progression to advanced age-related macular degeneration?

Given the wide spectrum of unique characteristics of macular neovascularization type 3 (MNV3) compared with types 1 and 2, we suggest regrading the colour photography assessment of the AREDS study to verify the impact of AREDS supplements on eyes with MNV3.

Twist Technique to Stop Fluid Leakage and Fixate the Eye During Bimanual Cortex Removal in Phacoemulsification.

Leakage of fluid through the side port during aspiration of the cortex leads to instability of the anterior chamber. In addition, eye movement may cause an unintended pulling of the irrigation probe out of the corneal wound resulting in collapsing of the anterior chamber. Both situations could pose a challenge to the surgeon and increase the risk of serious intraoperative complications. Therefore, we describe a simple effective maneuver to avoid these conditions during bimanual cortex removal and viscoelastic washout. In Khaled technique, rotating the irrigation probe outwards causes complete occlusion of the lumen of the side port and a simultaneous stabilization of the anterior chamber. Twisting the incision by the irrigation probe also offers better fixation of the eye at the edge of the side port and a subsequent reduction of eye movement.

Segmentation of macular neovascularization and leakage in fluorescein angiography images in neovascular age-related macular degeneration using deep learning.

BACKGROUND/OBJECTIVES: We aim to develop an objective fully automated Artificial intelligence (AI) algorithm for MNV lesion size and leakage area segmentation on fluorescein angiography (FA) in patients with neovascular age-related macular degeneration (nAMD). SUBJECTS/METHODS: Two FA image datasets collected form large prospective multicentre trials consisting of 4710 images from 513 patients and 4558 images from 514 patients were used to develop and evaluate a deep learning-based algorithm to detect CNV lesion size and leakage area automatically. Manual segmentation of was performed by certified FA graders of the Vienna Reading Center. Precision, Recall and F1 score between AI predictions and manual annotations were computed. In addition, two masked retina experts conducted a clinical-applicability evaluation, comparing the quality of AI based and manual segmentations. RESULTS: For CNV lesion size and leakage area segmentation, we obtained F1 scores of 0.73 and 0.65, respectively. Expert review resulted in a slight preference for the automated segmentations in both datasets. The quality of automated segmentations was slightly more often judged as good compared to manual annotations. CONCLUSIONS: CNV lesion size and leakage area can be segmented by our automated model at human-level performance, its output being well-accepted during clinical applicability testing. The results provide proof-of-concept that an automated deep learning approach can improve efficacy of objective biomarker analysis in FA images and will be well-suited for clinical application.

The RAP study, report 3: Discoloration of the macular region in patients with macular neovascularization type 3.

BACKGROUND/AIMS: To explore whether the existence and pattern of distribution of macular haemorrhage or exudate can be valuable diagnostic markers for macular neovascularization type 3 (MNV3) in patients with neovascular age-related macular degeneration. METHODS: Eighty-three eyes of 83 consecutive treatment naïve patients with stage 3 MNV3 were enrolled. The diagnosis was based on fluorescein angiography (FA) and optical coherence tomography (OCT). Subretinal and intraretinal haemorrhage and dense exudates were evaluated on colour fundus photography. Fluorescein angiography (FA) images and OCT scans were used to identify the axial location of the haemorrhage. 83 patients with MNV1 and 83 with MNV2 were included as two control groups. RESULTS: In the MNV3 group, 62 (75%) eyes had intraretinal haemorrhage and 52 (63%) had dense exudates. 73 (88%) eyes had intraretinal haemorrhage and/or dense exudates. 41 (49%) had both pathologies. The intraretinal haemorrhage was flame shaped over the lesion and punctate or semi-punctate further away from it and directed to the fovea. No subretinal haemorrhage was noticed. In the MNV1 and MNV2 groups, 11 (13%) and 24 (29%) eyes had subretinal haemorrhage or dense exudates, respectively. No intraretinal haemorrhage was seen in the two control groups. The prevalence of exudates and haemorrhage (irrespective of its location) was greater in MNV3 than in MNV1 or 2 (p < 0.0001). CONCLUSION: The existence and pattern of distribution of intraretinal haemorrhage is pathognomonic of MNV3. It makes (alone or with dense exudates) the diagnose MNV3 possible using fundoscopy or colour fundus photo and without further diagnostic expenditure.

Automated quantification of macular fluid in retinal diseases and their response to anti-VEGF therapy.

AIM: To objectively assess disease activity and treatment response in patients with retinal vein occlusion (RVO), neovascular age-related macular degeneration (nAMD) and centre-involved diabetic macular oedema (DME), using artificial intelligence-based fluid quantification. METHODS: Posthoc analysis of 2311 patients (11 151 spectral-domain optical coherence tomography volumes) from five clinical, multicentre trials, who received a flexible antivascular endothelial growth factor (anti-VEGF) therapy over a 12-month period. Fluid volumes were measured with a deep learning algorithm at baseline/months 1, 2, 3 and 12, for three concentric circles with diameters of 1, 3 and 6 mm (fovea, paracentral ring and pericentral ring), as well as four sectors surrounding the fovea (superior, nasal, inferior and temporal). RESULTS: In each disease, at every timepoint, most intraretinal fluid (IRF) per square millimetre was present at the fovea, followed by the paracentral ring and pericentral ring (p<0.0001). While this was also the case for subretinal fluid (SRF) in RVO/DME (p<0.0001), patients with nAMD showed more SRF in the paracentral ring than at the fovea up to month 3 (p<0.0001). Between sectors, patients with RVO/DME showed the highest IRF volumes temporally (p<0.001/p<0.0001). In each disease, more SRF was consistently found inferiorly than superiorly (p<0.02). At month 1/12, we measured the following median reductions of initial fluid volumes. For IRF: RVO, 95.9%/97.7%; nAMD, 91.3%/92.8%; DME, 37.3%/69.9%. For SRF: RVO, 94.7%/97.5%; nAMD, 98.4%/99.8%; DME, 86.3%/97.5%. CONCLUSION: Fully automated localisation and quantification of IRF/SRF over time shed light on the fluid dynamics in each disease. There is a specific anatomical response of IRF/SRF to anti-VEGF therapy in all diseases studied.

RAP study, report 1: novel subtype of macular neovascularisation type III, cilioretinal MNV3.

PURPOSE: To report on patients with macular neovascularisation type III (MNV3) arising from cilioretinal arteries (CRAs) (cilioretinal macular neovascularisation type III (cMNV3)). METHODS: We reviewed baseline examinations of patients with neovascular age-related macular degeneration using multimodal imaging. We determined the type and distribution of MNV lesions in each cMNV3 case, the range of distances from the fovea, existence of exudative maculopathy, intraretinal haemorrhage and other morphological characteristics. 50 consecutive eyes with usual MNV3 without CRA were included as a control group. RESULTS: 102 eyes of 102 patients were identified with MNV3 lesions. Among these, we found 12 eyes (12%) with cMNV3, 84 eyes (82%) with usual MNV3 without CRA and 6 eyes (6%) with usual MNV3 with CRA. Ten cases of cMNV3 had one lesion, and two cases had two lesions. The lesions were distributed equally between the superior and inferior halves of the macula, whereas in the nasal and temporal halves, there were 8 (57%) and 6 (43%) lesions, respectively. All cMNV3 lesions were located between 500 and 1500 µm from the central fovea except one, which was located between 1500 and 3000 µm. None of the lesions had macular neovascularisation type I (MNV1) or macular neovascularisation type II (MNV2) elsewhere in both groups. Exudative maculopathy and intraretinal haemorrhage were found in seven (88%) and five (63%) of the eight pure cMNV3 cases, respectively. CONCLUSION: cMNV3 can be solitary or multiple, isolated or accompanied with usual MNV3 lesions, but not with concurrent MNV1 or MNV2. It is frequently associated with extensive exudative maculopathy, intraretinal haemorrhage and subretinal fluid.

Neuroretinal atrophy following resolution of macular oedema in retinal vein occlusion.

BACKGROUND/AIMS: To characterise neuroretinal atrophy in retinal vein occlusion (RVO). METHODS: We included patients with central/branch RVO (CRVO=196, BRVO=107) who received ranibizumab according to a standardised protocol for 6 months. Retinal atrophy was defined as the presence of an area of retinal thickness (RT) <260 µm outside the foveal centre. Moreover, the thickness of three distinct retinal layer compartments was computed as follows: (1) retinal nerve fibre layer to ganglion cell layer, (2) inner plexiform layer (IPL) to outer nuclear layer (ONL) and (3) inner segment/outer segment junction to retinal pigment epithelium. To characterise atrophy further, we assessed perfusion status on fluorescein angiography and best-corrected visual acuity (BCVA), and compared these between eyes with/without atrophy. RESULTS: 23 patients with CRVO and 11 patients with BRVO demonstrated retinal atrophy, presenting as sharply demarcated retinal thinning confined to a macular quadrant. The mean RT in the atrophic quadrant at month 6 was 249±26 µm (CRVO) and 244±29 µm (BRVO). Individual layer analysis revealed pronounced thinning in the IPL to ONL compartment. Change in BCVA at 6 months was similar between the groups (BRVO, +15 vs +18 letters; CRVO, +14 vs +18 letters). CONCLUSIONS: In this exploratory analysis, we describe the characteristics of neuroretinal atrophy in RVO eyes with resolved macular oedema after ranibizumab therapy. Our analysis shows significant, predominantly retinal thinning in the IPL to ONL compartment in focal macular areas in 11% of patients with RVO. Eyes with retinal atrophy did not show poorer BCVA outcomes.

The Distribution of Leakage on Fluorescein Angiography in Diabetic Macular Edema: A New Approach to Its Etiology.

Purpose: To determine the distribution of leakage on fluorescein angiography (FA) and explore the clinically protective role of astrocytes against damage to the inner blood retinal barrier (iBRB) in diabetic macular edema (DME). Methods: A consecutive case series of 87 eyes of 87 patients with DME was included. We measured the leakage area in each field of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid on late-phase FA images. The normative thickness of the nerve fiber layer (NFL), in which the astrocytes are confined, was derived from a previous work using spectral-domain optical coherence tomography. We explored the difference in leakage areas in every two fields. Moreover, we investigated the correlation between the mean of the leakage area and the mean of thickness of the NFL in each ETDRS field. Results: The leakage areas in the nasal, inferior, superior, and temporal fields were 2.34 mm2, 2.84 mm2, 3.03 mm2, and 3.96 mm2. The difference in leakage area between each two fields was significant in all cases (P < 0.05) except between the inferior and superior fields (P = 0.65). The temporal field was the only field that showed leakage in all 87 cases. The correlation between the leakage area and the thickness of the NFL in the ETDRS fields was negative and highly significant: r = -0.96 (95% confidence interval -0.99 to -0.02). Conclusion: The distribution of leakage correlates inversely and statistically significantly with the thickness of the NFL, suggesting astrocytes in the NFL play a pivotal role in preventing damage to the iBRB and subsequent evolution of microaneurysms in DME. Moreover, fluid extravasation due to damage to the iBRB is expressed earlier in the temporal than in the other three fields.

Potential of Electrospun Nanofibers for Biomedical and Dental Applications.

Electrospinning is a versatile technique that has gained popularity for various biomedical applications in recent years. Electrospinning is being used for fabricating nanofibers for various biomedical and dental applications such as tooth regeneration, wound healing and prevention of dental caries. Electrospun materials have the benefits of unique properties for instance, high surface area to volume ratio, enhanced cellular interactions, protein absorption to facilitate binding sites for cell receptors. Extensive research has been conducted to explore the potential of electrospun nanofibers for repair and regeneration of various dental and oral tissues including dental pulp, dentin, periodontal tissues, oral mucosa and skeletal tissues. However, there are a few limitations of electrospinning hindering the progress of these materials to practical or clinical applications. In terms of biomaterials aspects, the better understanding of controlled fabrication, properties and functioning of electrospun materials is required to overcome the limitations. More in vivo studies are definitely required to evaluate the biocompatibility of electrospun scaffolds. Furthermore, mechanical properties of such scaffolds should be enhanced so that they resist mechanical stresses during tissue regeneration applications. The objective of this article is to review the current progress of electrospun nanofibers for biomedical and dental applications. In addition, various aspects of electrospun materials in relation to potential dental applications have been discussed.