Macular microhole and foveal red spot syndrome: a critical review of the literature.

PURPOSE: The purpose of this article is to review the literature on nomenclature, natural history, clinical features, diagnosis, management, and prognosis of both macular microhole (MMH) and foveal red spot syndrome (FRS). METHODS: A PubMed primary literature search (February 1, 2020) utilizing the terms macular microhole, foveal red spot syndrome, and outer retinal hole was conducted. All chosen articles were case reports or case series. Articles qualified for inclusion if they documented symptoms, imaging findings, or followed patients longitudinally. RESULTS: A total of 14 studies from 1988 to 2019 that evaluated either MMH, FRS, or both were included in the review. No comparative study between the two defects was found. Studies often used the terms FRS and MMH interchangeably to reference both partial- and full-thickness lesions of the macula. Spectral-domain optical coherence tomography (SD-OCT) was most frequently able to identify these lesions and revealed an absence of all neural retinal layers from the inner limiting membrane (ILM) to the retinal pigment epithelium (RPE) in the full-thickness lesions while the partial-thickness lesions most often involved the photoreceptor layer (PRL) and less frequently the external limiting membrane (ELM). OCT revealed that vitreomacular traction (VMT) was involved in the natural history of both FRS and MMH for a significant subset of patients. CONCLUSION: The terms MMH and FRS have been used interchangeably in the literature. Advances in OCT have revealed that MMHs and FRSs are distinct but sometimes overlapping entities. We suggest that MMH and FRS are similar entities defined as one or more sharply defined lesions in the fovea of the eye < 150 µm in size. MMHs are a full-thickness defect of the entire neuroretina at the center of the foveola while FRSs are partial-thickness lesions. Current literature suggests that there may be subtle differences in the pathogenesis, clinical features, and diagnosis between MMH and FRS; however, prognosis and management for both are favorable. Lastly, we suggest that the terms outer lamellar macular microholes and full-thickness macular microholes may be the more appropriate terminologies to refer to FRS and MMH, respectively.

[Closure of Persisting Full Thickness Macular Holes by Subretinal Fluid Application: Technical Approach and Surgical Considerations]. / Verschluss von persistierenden Makulalöchern durch subretinale Flüssigkeitsapplikation: technisches Vorgehen und chirurgische Überlegungen.

INTRODUCTION: Firm adhesions between the retina and adjacent retinal pigment epithelium (RPE) may prevent the closure of macular holes (MH) after chromovitrectomy. Controlled application of subretinal (SR) fluid with BSS may release these adhesions leading to closure of the retracted retina in large and or refractory macular holes. METHODS: For a standardized procedure, it is recommended to exclude residues of epiretinal membranes on the retinal surface preoperatively at OCT or intraoperatively by means of vital dyes. Intraoperatively, a perfluorocarbon (PFO) bubble is placed above the MH and lowers the infusion bottle of 20 mmHg. Subsequently, SR-fluid blebs are applied in the upper, temporal and inferior quadrants with a subretinal 41-gauge cannula. After removing decalin bubble, the SR-detachment is enlarged toward the foveal center. This is essential to achieve a complete detachment of the outer macular edges from the RPE. The MH can be closed by a temporary gas endotamponade. RESULTS: With a standardized procedure, the operation can be carried out safely and with minimal effort. Additional measures, such as care for bubble-free SR-fluid sands or machine assistance, were added. In a pilot study, experienced VR surgeons performed the SR-fluid application safely and without complications. The preoperative diameter of the MH was 1150 µm (651 - 2350 µm). The secondary closure rate for our PMH was 80.9%. CONCLUSION: SR-adhesions seem to have a previously unnoticed component in persistent macular holes. An SR-fluid application can be carried out quickly, safely and with minimal material effort. The initial results show a high secondary closure rate.

Increased serum cortisol is associated with alterations in cross-sectional and topographic OCT parameters in diabetic retinopathy: a preliminary study.

PURPOSE: Cortisol, a steroid hormone, plays an essential role in metabolic processes of diabetes mellitus. This study for the first time evaluated the association of serum cortisol with spectral domain optical coherence tomography (SD-OCT)-based cross-sectional and topographic parameters with severity of diabetic retinopathy (DR). METHODS: A tertiary care center-based preliminary study was undertaken. Fourteen consecutive cases of DR and fifteen healthy controls were included. Cases were graded according to ETDRS classification: non-proliferative DR (NPDR, n = 8) and proliferative DR (PDR, n = 6). All study subjects underwent complete ophthalmological evaluation. Serum cortisol was analyzed using chemiluminescence microparticle assay method. Central subfield thickness (CST), cube average thickness (CAT), cube volume (CV), retinal nerve fiber layer (RNFL) thickness, disorganization of inner retinal layers (DRIL), grade of retinal photoreceptor ellipsoid zone (EZ) disruption and grade of retinal pigment epithelium (RPE) alterations were evaluated using SD-OCT. Statistical analysis was done using ANOVA and Pearson's correlation analysis. RESULTS: Mean serum cortisol levels (µg/dL) were NPDR = 11.59 ± 0.42, PDR = 14.50 ± 0.26 and controls = 8.22 ± 0.77. With increasing severity of DR, mean CST, CAT, CV showed positive correlation, whereas mean RNFL thickness showed negative correlation with serum cortisol levels (p < 0.01). DRIL, EZ disruption and RPE alterations showed positive correlation with serum cortisol levels (p < 0.001). CONCLUSION: Serum cortisol levels are significantly associated with severity of DR and correlate positively with CST, CAT, CV, DRIL, EZ disruption and RPE alterations and negatively with RNFL thickness.

Application of subretinal fluid to close refractory full thickness macular holes: treatment strategies and primary outcome: APOSTEL study.

INTRODUCTION: Persisting macular holes (PMH) after surgical release of any epiretinal traction of the vitreous and adjacent membrane may rely on secondary firm adhesions between the retracted retina and adjacent retinal pigment epithelium. Secondary application of subretinal (SR)-fluid may release these adhesions followed by an anatomical closure. METHODS: Twelve surgeons applied in a consecutive case series SR-fluid in 41 eyes with PMH and reported retrospectively their initial surgical, anatomical and functional experience with this approach. RESULTS: The mean duration of the MH prior to SR-fluid application was 17 months (6-96 months). The mean age of the patients at the time of surgery was 72 years (54-88). The mean preoperative aperture diameter of the opening was 1212 µm (239-4344 µm), base diameter 649 µm (SD 320 µm). The mean preoperative BCVA prior to surgery was 0.1 (0.01-0.3). All patients (41/41) complained about reduced BCVA and a significant central scotoma (negative scotoma) in their central field of vision. The secondary closure rate for our PMH was 85.36% (35 out of 41 eyes) at 6 weeks after surgery. The postoperative BCVA improved to 0.22 (0.02-0.5). The application of SR-fluid was not associated with major intraoperative adverse effects. CONCLUSION: Remaining SR-adhesions may inhibit PMH closure. Their release by application of SR-fluid will lead to a fast and immediate anatomical closure in many cases without serious adverse events.

Predictive factors for functional improvement following intravitreal bevacizumab injections after central retinal vein occlusion.

PURPOSE: Vision loss in central retinal vein occlusion (CRVO) is mostly caused by macular edema (ME) and can be treated with intravitreal bevacizumab injections. The goal of this study was to identify predictive factors for improvement in visual acuity. METHODS: Three hundred and sixteen eyes of six centres having received intravitreal bevacizumab for ME due to CRVO were enrolled in this multicentre, retrospective, interventional case series. The follow-up time was 24 to 48 weeks. Investigated patient characteristics were pretreatment, duration of CRVO prior to the first injection, initial best-corrected visual acuity (BCVA), baseline central retinal thickness as measured by optical coherence tomography, gender, eye, age, comorbidity with glaucoma, systemic hypertension, or diabetes mellitus. RESULTS: Multiple regression analysis confirmed the following baseline predictive factors for an increase in visual acuity: low BCVA (p < 0.001), high CRT (p < 0.02), and treatment naïve patients (p = 0.03). None of the other investigated patient characteristics could be identified as prognostic factors for increase in visual acuity (p > 0.1). CONCLUSIONS: Intravitreal injections of bevacizumab in a routine clinical setting effectively improved and stabilized BCVA in CRVO. Our large multicenter study identified initial BCVA, baseline CRT, and pre-treatment as prognostic factors for visual improvement.

INCREASED SERUM LEVELS OF UREA AND CREATININE ARE SURROGATE MARKERS FOR DISRUPTION OF RETINAL PHOTORECEPTOR EXTERNAL LIMITING MEMBRANE AND INNER SEGMENT ELLIPSOID ZONE IN TYPE 2 DIABETES MELLITUS.

PURPOSE: To evaluate the role of serum urea and creatinine as surrogate markers for disruption of retinal photoreceptor external limiting membrane (ELM) and inner segment ellipsoid zone (EZ) in Type 2 diabetic retinopathy (DR) using spectral-domain optical coherence tomography, for the first time. METHODS: One hundred and seventeen consecutive cases of Type 2 diabetes mellitus (diabetes without retinopathy [No DR; n = 39], nonproliferative diabetic retinopathy [NPDR; n = 39], proliferative diabetic retinopathy [PDR; n = 39]) and 40 healthy control subjects were included. Serum levels of urea and creatinine were assessed using standard protocol. Spectral-domain optical coherence tomography was used to grade the disruption of ELM and EZ as follows: Grade 0, no disruption of ELM and EZ; Grade 1, ELM disrupted, EZ intact; Grade 2, ELM and EZ disrupted. Data were analyzed statistically. RESULTS: Increase in serum levels of urea (F = 22.93) and creatinine (F = 15.82) and increased grades of disruption of ELM and EZ (γ = 116.3) were observed with increased severity of DR (P < 0.001). Increase in serum levels of urea (F = 10.45) and creatinine (F = 6.89) was observed with increased grades of disruption of ELM and EZ (P = 0.001). CONCLUSION: Serum levels of urea and creatinine are surrogate markers for disruption of retinal photoreceptor ELM and EZ on spectral-domain optical coherence tomography in DR.

IMPACT OF VITREORETINAL INTERFACE ARCHITECTURE ON SUCCESSFUL VITREOMACULAR TRACTION RESOLUTION IN EYES SCHEDULED FOR INTRAVITREAL OCRIPLASMIN THERAPY.

PURPOSE: To evaluate the impact of the vitreoretinal interface architecture, in specific the angle between the posterior vitreous cortex and the internal limiting membrane, on vitreomacular traction (VMT) resolution in eyes treated with intravitreally injected ocriplasmin (Jetrea). METHODS: Retrospective, multicenter cohort study and exploratory data analysis. Spectral domain optical coherence tomography assessments were performed before scheduled ocriplasmin injections. General (age and sex) as well as ocular variables (lens status, presence of epiretinal membrane formations, horizontal diameter of VMT, central retinal thickness, and in particular various prespecified angles between the posterior vitreous cortex and internal limiting membrane) were analyzed to evaluate their impact on successful VMT resolution. RESULTS: Fifty-nine eyes of 59 patients were included. Univariate analysis of age (odds ratio [OR]: 0.881; 95% CI: [0.812-0.955]; P = 0.0022) and lens status (OR: 11.03; 95% CI: [2.23-54.57]; P = 0.0033) had a significant impact on successful VMT resolution, whereas sex (OR: 0.668; 95% CI: [0.126-2.065]; P = 0.4906), epiretinal membrane formation (OR: 0.581; 95% CI: [0.168-2.006]; P = 0.3903), horizontal diameter of VMT (OR: 0.99930; 95% CI: [0.99825-1.00035]; P = 0.1886), and central retinal thickness (OR: 0.9985; 95% CI: [0.9934-1.00436]; P = 0.56) failed. The angle at 500 µm apart from the fovea centralis, irrespective if measured nasally (OR: 1.135; 95% CI: [1.013-1.272]; P = 0.0289) or temporally (OR: 1.099; 95% CI: [1.001-1.208]; P = 0.0485), showed a significant correlation with VMT resolution. CONCLUSION: The angle between the posterior vitreous cortex and the internal limiting membrane 500 µm apart from the fovea centralis correlates with VMT resolution and may be a clinically useful marker for selection of patients to be treated with ocriplasmin. This observation needs to be proven in a prospective confirmatory investigation.

[Laser Iridotomy - In Cases of Acute Angle Closure Only?] / Laseriridotomie ­ nur bei akuter Engwinkelsituation?

The narrowing of the chamber angle-as a result of anatomic predispositions like high hyperopia or increasing lens thickness-poses the greatest risk for acute angle closure. A laser iridotomy counts as a standard procedure in cases of acute angle closure, whereas there are no coherent recommendations or guidelines for a prophylactic therapy. Modern imaging techniques, such as anterior segment optical coherence tomography or Scheimpflug photography, can give valuable information for the planning of treatment. This review presents traditional and modern imaging techniques and summarises recommendations for action in relation to recent publications.

Increased serum level of homocysteine correlates with retinal nerve fiber layer thinning in diabetic retinopathy.

PURPOSE: To study the correlation between serum levels of vitamin B12, folic acid, and homocysteine and the severity of diabetic retinopathy and the correlation with retinal nerve fiber layer (RNFL) thinning on spectral domain optical coherence tomography (SD-OCT). METHODS: In a tertiary care center-based prospective cross-sectional study, 60 consecutive cases and 20 healthy controls in the age group of 40-65 years were included. The eyes of the cases were divided into three groups according to Early Treatment Diabetic Retinopathy Study (ETDRS) classification: diabetes mellitus without retinopathy (n = 20), non-proliferative diabetic retinopathy with macular edema (n = 20), and proliferative diabetic retinopathy with macular edema (n = 20). The serum levels of vitamin B12 and folic acid were measured using a standard protocol. The serum homocysteine assay was performed using an enzyme-linked immunosorbent assay (ELISA) kit. Average RNFL thickness was measured using SD-OCT. Statistical analysis was used to assess the correlations between the study variables. RESULTS: Increased severity of diabetic retinopathy was found to correlate with an increase in the serum levels of homocysteine (F = 53.79; p<0.001). The mean serum levels of vitamin B12 and folic acid were found to be within the normal reference range. A positive correlation was found between retinal nerve fiber layer thinning and serum levels of homocysteine (p<0.001). CONCLUSIONS: This study, for the first time, demonstrated a correlation between increased homocysteine with a decrease in RNFL thickness and increased severity of diabetic retinopathy.

INTRAVITREAL INJECTIONS OF ZIV-AFLIBERCEPT FOR DIABETIC MACULAR EDEMA: A Pilot Study.

PURPOSE: Diabetic macular edema is the leading cause of blindness in young adults in developed countries. Beyond metabolic control, several therapies have been studied such as laser treatment and intravitreal injections of corticosteroids or anti-vascular endothelial growth factor drugs. In terms of public health the long-term treatment with the current available drugs is very expensive and new therapies with the same or better effect should be investigated. This study sought to evaluate the efficacy and safety of intravitreal injections of ziv-aflibercept for the treatment of diabetic macular edema. METHODS: Seven consecutive patients with diabetic macular edema were enrolled. A complete examination, including full-field electroretinography, visual acuity, central retinal thickness, and evaluation of systemic and ocular complications, was performed before and at 24 weeks after intravitreal injections of ziv-aflibercept. The seven patients were submitted to six consecutive intravitreal injections of ziv-aflibercept with a 4-week interval. RESULTS: No significant differences were found in the amplitude or implicit time of any electroretinography component after intravitreal injections of ziv-aflibercept, and no systemic or ocular complication was observed. The improvement of visual acuity was significant at 24 weeks (P < 0.05). The central retinal thickness significantly decreased during the course of 24 weeks. CONCLUSION: Intravitreal injections of ziv-aflibercept seem to be a safe and effective treatment option for diabetic macular edema.

Influence of ocular volume and lens status on pharmacokinetics and duration of action of intravitreal vascular endothelial growth factor inhibitors.

PURPOSE: To assess the effects of ocular axial length, refraction, and lens status on pharmacokinetics and duration of action of the vascular endothelial growth factor (VEGF) inhibitors ranibizumab and bevacizumab after intravitreal injection in humans. METHODS: In 119 eyes of 119 patients, aqueous humor was sampled at different time points after intravitreal injection of ranibizumab or bevacizumab, and either drug or VEGF concentrations were measured by enzyme-linked immunosorbent assays and Luminex multiplex bead technology, respectively. Relative deviation of the measured drug concentrations from the time-corrected mean values was calculated (n = 41). Repetitive VEGF measurements were preformed to identify the duration of complete suppression of ocular VEGF activity for individual eyes (n = 78). In addition, axial length, spherical equivalent refraction, and lens status were determined. RESULTS: For neither ranibizumab nor bevacizumab, a correlation between ocular pharmacokinetics (as measured by relative deviation of drug concentration from the mean) and axial length was detected in phakic eyes (Spearman's correlation coefficient, r = 0.084; P = 0.600). Similarly, the duration of action of intravitreal ranibizumab (as measured by VEGF suppression time) did not correlate with spherical equivalent refraction in phakic eyes (Spearman's correlation coefficient, r = 0.164; P = 0.301) and was not different between phakic and pseudophakic eyes (P = 0.694; Mann-Whitney U test). CONCLUSION: The results indicate that ocular volume and lens status have no relevant impact on ocular pharmacokinetics and duration of action of VEGF-inhibitory drugs and may, thus, be excluded as factors accounting for the high interindividual variability in morphologic and functional responses to intravitreal anti-VEGF therapy.

Nitric oxide and oxidative stress is associated with severity of diabetic retinopathy and retinal structural alterations.

BACKGROUND: The aim of the study was to determine plasma nitric oxide (NO) and lipid peroxide (LPO) levels in diabetic retinopathy and its association with severity of disease. DESIGN: Prospective observational study. PARTICIPANTS: A total of 60 consecutive cases and 20 healthy controls were included. METHODS: Severity of retinopathy was graded according to early treatment diabetic retinopathy study (ETDRS) classification. Photoreceptor inner segment ellipsoid band (ISel) disruption and retinal pigment epithelium (RPE) alteration were graded using spectral domain optical coherence tomography. Data were statistically analyzed. MAIN OUTCOME MEASURES: Plasma thiobarbituric acid reactive substances, NO assay and reduced glutathione (GSH) were measured using standard protocol. RESULTS: Increased severity of diabetic retinopathy was significantly associated with increase in plasma levels of LPO (P < 0.05), NO (P < 0.001) and decrease in plasma levels of GSH (P < 0.0001), ISel disruption (P < 0.001) and RPE topographic alteration (P < 0.01). CONCLUSION: Increased plasma NO levels are associated with increased severity of diabetic retinopathy. For the first time, it has been demonstrated that increased plasma LPO, NO and decreased GSH levels are associated with in vivo structural changes in inner segment ellipsoid and RPE.

Testing the effects of the dye acid violet-17 on retinal function for an intraocular application in vitreo-retinal surgery.

PURPOSE: To facilitate epiretinal or inner limiting membrane peeling, dyes like Indocyanine Green (ICG) as well as Trypan Blue (TB) were used so far. However, toxic effects on the retina were described for both dyes. The aim of our study was to investigate the effects of a novel vital dye Acid violet-17 (AV-17) on retinal histology and function to assess a possible application in vitreo-retinal surgery. METHODS: AV-17 was dissolved in a solvent with heavy water. An electroretinogram was recorded on perfused bovine retina. After reaching stable b-wave amplitudes, AV-17 (0.125-0.5 mg/ml) or the solvent was applied epiretinally for 30-300 seconds. The b-wave amplitudes were recorded before, during, and after treatment. Cultures of bovine retina were incubated for 30 or 300 seconds with the dye or solvent and processed for live/dead staining, immunohistochemistry, and immunoblotting. RESULTS: Reductions of the b-wave amplitudes were observed directly after the exposure to AV-17, which were rapidly and completely reversible within the recovery period for all exposure times at the concentrations of 0.125 and 0.25 mg/ml as opposed to the partial recovery after exposure to 0.5 mg/ml. A high degree of damage in the ganglion cell layer (GCL) and glial reactivity were detected at the concentrations of 0.25 and 0.5 mg/ml but not after exposure to lower concentrations or the solvent. CONCLUSION: Application of AV-17 at a concentration of up to 0.125 mg/ml was well tolerated in terms of retinal function, survival in the GCL, and glial reactivity whereas higher concentrations are not recommended.

Geometry, penetration force, and cutting profile of different 23-gauge trocars systems for pars plana vitrectomy.

BACKGROUND: To investigate the geometry, penetration force, and cutting profile of 23-gauge trocar systems for pars plana vitrectomy based on their grinding methods in a standardized laboratory setting. METHODS: In this experimental study, Eleven different commercially available 23-gauge sclerotomy trocar systems were divided into 4 groups according to their needle grinding and deburring: "back" bevel, "spear" bevel, "lancet" bevel, and "spatula" bevel. The normative geometrical data of the trocar systems were systematically analyzed according to nomenclature ISO 7864 and ISO 9626. Force to penetrate a 0.4-mm thick polyurethane foil was measured by a Penetrometer, when the trocar needle was piercing, cutting, and sliding through the foil at different defined loading phases and plotted as a load-displacement diagram. Magnified images of the consecutive cut were taken under a microscope after the entire penetration through the foil. Three physicians used all trocar systems in a masked fashion on human sclera to evaluate the manual penetration force in 30° and 90°. RESULTS: The mean outer diameter of the trocar systems was 0.630 ± 0.009 mm, and the mean outer diameter of the trocars was 0.750 ± 0.013 mm. The mean point length was 3.11 ± 0.49 mm, and the mean length of the bevel was 1.46 ± 0.23 mm. The primary bevel angle was 10.75 ± 0.41°, and the secondary bevel angle was 65.9 ± 42.56°. The piercing forces of the back bevel and spear-pointed trocars/needles were at the same level (0.087 ± 0.028 N). The lancet-pointed needle had remarkable low piercing and cutting forces with 0.41 N (range, 0.35-0.47 N). The spatula bevel tip showed the highest penetration piercing force with 1.6 N (range, 1.59-1.73 N). The back bevel systems induced frequently triangular-shaped incisions, with two nearly rectangular cuts of short length. The spear bevels produced a regular characteristic linear cut. Especially, the lancet blade created straight cut with a linear wound apposition. Spatula trocar systems caused usually an arched accurate incision. The manual force to penetrate the human sclera in an angled and rectangular angle appeared in the surgeons hand lower with a back bevel, lancet, or spear tip, whereas higher with spatula bevel systems. CONCLUSION: Lancet and back bevel systems show less penetration force of inner needles than the spatula systems. The results of the penetration force experiments correlated well with the manual force on sclera.

Off-label use of intravitreal bevacizumab: A global conundrum.

Bevacizumab is a monoclonal, humanized, full-length antibody targeting vascular endothelial growth factor(VEGF-A), known for its anti-angiogenic properties. The off-label use of bevacizumab has stirred legal, financial, industrial, and ethical complexities. With its potential to treat diverse ocular conditions, this commentary delves into the multifaceted dimensions of bevacizumab's off-label utilization, encompassing clinical trials, regulatory frameworks, safety considerations, comparative effectiveness, and economic implications.

Fundus Autofluorescence in Posterior and Panuveitis-An Under-Estimated Imaging Technique: A Review and Case Series.

Fundus autofluorescence (FAF) is a prompt and non-invasive imaging modality helpful in detecting pathological abnormalities within the retina and the choroid. This narrative review and case series provides an overview on the current application of FAF in posterior and panuveitis. The literature was reviewed for articles on lesion characteristics on FAF of specific posterior and panuveitis entities as well as benefits and limitations of FAF for diagnosing and monitoring disease. FAF characteristics are described for non-infectious and infectious uveitis forms as well as masquerade syndromes. Dependent on the uveitis entity, FAF is of diagnostic value in detecting disease and following the clinical course. Currently available FAF modalities which differ in excitation wavelengths can provide different pathological insights depending on disease entity and activity. Further studies on the comparison of FAF modalities and their individual value for uveitis diagnosis and monitoring are warranted.