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.

Can intravitreal injections with higher volume cause higher intraocular eye pressure? Considerations for anti-complement injections in normal and glaucomatous eyes.

The approval of Syfovre® (pegcetacoplan) and Iverzay® (avacincaptad pegol) for the treatment of geographic atrophy (GA) marks a significant advancement in retinal disease therapy, offering both complement 3 and complement 5 inhibitors. With this breakthrough, an increase in intravitreal injections (IVI) is expected to treat GA, raising questions about potential effects on intraocular pressure (IOP). This concern is exacerbated by the larger injection volume required for GA treatment, potentially impacting IOP. Previous studies have shown that IVI can lead to a temporary increase in IOP with a 0.05 ml injection. This transient elevation is challenging to manage with glaucoma drops, and a preventive approach, such as paracentesis immediately before IVIs, may be more effective. Despite concerns, clinical significance and long-term effects of IOP changes with a 0.05 ml injection remain uncertain. To address these concerns, routine evaluations including macular optical coherence tomography (OCT), fundus autofluorescence, IOP measurements, and retinal nerve fiber layer OCT before the first IVI with avacincaptad pegol and pegcetacoplan are recommended to detect potential changes early. Further research is needed to determine the extent to which IOP changes impact GA patients and whether cumulative effects occur with repeated IVIs, especially in those with additional eye conditions.

Surgical classification for large macular hole: based on different surgical techniques results: the CLOSE study group.

BACKGROUND: The CLOSE study group proposes an updated surgical classification for large macular holes based on a systematic review of new treatments. Recently, many new techniques have been introduced to treat large full-thickness macular holes (FTMH); although the indications are not clear. An updated surgical classification is needed to help surgical decision-making. METHODS: We gathered published series by the CLOSE Study Group members and from literature search until June 2021. Techniques included: internal limiting membrane peeling (ILM peeling), ILM flaps, macular hydrodissection (macular hydro), human amniotic membrane graft (hAM), and autologous retinal transplantation (ART). Within each technique, chi-square test assessed association between the minimal linear diameter (MLD) (in µm) and closure rate; the postoperative best-corrected visual acuity (BCVA) gains were compared among groups. RESULTS: Data extraction included 31 published articles: total of 1135 eyes. Eyes were divided into the following groups: ILM peel (n: 683), ILM Flap (n: 233), macular hydrodissection (n: 64), hAM (n: 59), and ART (n: 96). The initial BCVA and size were heterogenous between the groups. ILM peel showed the best results in large FTMH ≤ 535 µm (closure rate 96.8%); adjusted mean BCVA: 0.49 (LogMAR) with a statistical difference among groups. Large FTMH between 535 and 799 µm: ILM flap technique showed better results (closure rate 99.0%); adjusted mean BCVA: 0.67(LogMAR); also with a statistical difference. For large FTMH ≥ 800 µm more invasive techniques are required. Use of hAM, macular hydrodissection and ART showed higher closure rates for this category (100%, 83.3% and 90.5% respectively), and adjusted mean BCVA varied from 0.76 to 0.89. Although there was no statistical difference between those techniques for this group due to the smaller number of cases. CONCLUSIONS: The CLOSE study group demonstrated the potential usefulness of a new surgical classification for large FTMHs and propose OCT biomarkers for use in clinical practice and future research. This new classification demonstrated that Large (400-550 µm) and X-Large (550-800 µm) holes can be treated highly successfully with ILM peel and ILM flap techniques, respectively. Further studies are necessary for the larger FTMHs (XX-Large and Giant), using the CLOSE classification, in order to determine which technique is better suited for each hole size and characteristics.

Anti-Vegf therapy leads to an improvement in grade of retinal pigment epithelium alterations on single layer retinal pigment epithelium map in diabetic macular edema.

PURPOSE: In bovine retinal pigment epithelium (RPE) cells, increased secretion of vascular endothelial growth factor (VEGF) has a positive linear association with proliferation of RPE. Spectral domain optical coherence tomography (SD-OCT) based improvement in grades of topographic retinal pigment epithelium alterations (RPE-A), were evaluated after intravitreal anti-VEGF therapy, in diabetic macular edema (DME), for the first time. METHODS: A tertiary care center-based, prospective study. Forty-four consecutive patients, 40-65 years of age with type 2 diabetes mellitus (DM) with DME, were administered three doses of anti-VEGF therapy at monthly intervals. Pre- and post-intervention SD-OCT was done and central sub field thickness (CST), cube average thickness (CAT) and topographic grades of RPE-A were assessed using single layer RPE map (SL-RPE) as; Grade 0: No alterations, Grade 1: Alteration in two quadrants, Grade 2: Alteration in more than two quadrants. RESULTS: CST decreased from 354.2 ± 16.0 µm pre-intervention to 233.2 ± 7.9 µm post-intervention. CAT reduced from 340.6 ± 6.5 µm pre-intervention to 274.1 ± 5.1 µm post-intervention. Significant improvement in grades of RPE-A pre- v/s post-intervention were observed. (Grade 0: 0 v/s 39; Grade 1: 17 v/s 3; Grade 2: 27 v/s 2) (p < 0.001). CONCLUSION: Anti-VEGF therapy is associated with an improvement in grades of RPE-A in DME.The study was registered with the Clinical Trial Registry of India (CTRI/2019/03/018135).

Monitoring of central corneal thickness after phacoemulsification-comparison of statical and rotating Scheimpflug pachymetry, and spectral-domain OCT.

AIM: To explore the possibility of deploying three contactless devices (static and rotating Scheimpflug technology, spectral domain optical coherence tomography) for measuring central corneal thickness (CCT) in preoperative and postoperative examinations of cataract patients. METHODS: Totally 72 patients who had undergone surgery without complications were selected. The CCT was measured prior to the operation, as well as on the first, 5th-7th and 28th day following the operation using the Nidek NT 530-P, Sirius®, and Topcon OCT-2000 devices. RESULTS: A significant postoperative increase and subsequent decrease in CCT was identified with all three devices. The correlations were highly significant and thus reflect a very good degree of comparability at all times with the exception of the rotating Scheimpflug camera. The postoperative results from the latter differed significantly from the other devices. The correlations were Sirius/Topcon (P=0.010) and Sirius/Nidek (P<0.0005). No statistically significant difference could be identified in the comparison between Topcon and Nidek (P=0.056). CONCLUSION: All three devices are suitable for postoperative monitoring of CCT. The measurement results are only comparable to a limited extent and not interchangeable in the course of treating a single patient. This is due to the different imaging technology used in the devices and the resulting modalities for conducting the measurements.

External limiting membrane and ellipsoid zone structural integrity in diabetic macular edema.

The external limiting membrane (ELM) and ellipsoid zone (EZ) can be observed exquisitely by SD-OCT. In diabetic macular edema (DME), dysfunction of mitochondria, represented by the EZ in the foveal photoreceptors results in reduced visual acuity (VA). An increase in VEGF was found to correlate with increased severity of DR, increased central subfield thickness (CST), and sequential disruption of ELM and EZ. The mechanism of ELM and EZ restoration after anti-VEGF therapy in DME has been discovered. The ELM restores first followed by EZ restoration. Thus, authors have discovered and established ELM as a novel retinal structural barrier.

Vitrectomy in full thickness macular holes on top of a pigment epithelial detachment in age-related macular degeneration (AMD). Surgical consideration and review of the literature.

PURPOSE: To present the surgical treatment of a full thickness macular hole (MH) caused by a vitreomacular traction (VMT) on top of an adjacent subfoveal pigment epithelial detachment (PED) in age-related macular degeneration (AMD). OBSERVATION: A 77-year-old female with a subfoveal PED receiving consecutive intravitreal injections noticed a sudden decreased visual acuity (VA) due to the development an occult MH in her right eye after 19 repeated intravitreal anti vascular endothelial growth factor (VEGF)-injections. Her initial VA declined from 20/50 to 20/400. The firm VMT induced a rupture of the multi-layered retina and may progress to an RPE-tear or possible to a subretinal haemorrhage. We discussed with the patient the risks of the natural progression and explained possible treatment options: We continued her anti-VEGF combined with air bubble injections to induce a posterior vitreous detachment, to stabilise the retinal architecture, reduce the subretinal fluid and avoid possible intraoperative bleeding. As injections did release the VMT, vitrectomy released the posterior vitreous from the optic nerve and trimmed it towards the central retina. Peeling with brilliant blue removed the internal limiting membrane without any signs of bleeding, rupture of the PED or enlargement of the MH, prior to the installation of 10% SF6 gas. The postoperative optical coherence tomography (OCT) on day 5 confirmed a closed MH, while the size, shape and pattern of the PED remained unchanged. Her VA increased from 20/400 to 20/50 (equal to her previous VA prior to the MH-formation). To avoid a potential progression of the PED, we maintained her retreatment intervals at 5 weeks for the next 6 months. A literature review presents similar intraoperative approaches and postoperative outcomes in 8 out of the 9 published cases. CONCLUSIONS AND IMPORTANCE: VMT can induce an occult MH on top of a PED, causing a significant loss of vision. When gas injections are not successful, surgery may release the traction, restore the retinal architecture, and significantly improve and maintain the VA over a documented long-term observation. The epiretinal procedure should be assisted under regular anti-VEGF injections to maintain the subretinal architecture.

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.

External limiting membrane: retinal structural barrier in diabetic macular edema.

Advances in spectral-domain optical coherence tomography (SD-OCT) technology have enhanced the understanding of external limiting membrane (ELM) and ellipsoid zone (EZ) in diabetic macular edema. An increase in VEGF has been demonstrated to be associated with sequential ELM and EZ disruption on SD-OCT. An intact ELM is a prerequisite for an intact EZ in DME. Anti-VEGF therapy leads to restoration of barrier effect of ELM. The ELM restores first followed by EZ restoration.

[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.

Sequential restoration of external limiting membrane and ellipsoid zone after intravitreal anti-VEGF therapy in diabetic macular oedema.

BACKGROUND/OBJECTIVES: To study the mechanism of restoration of retinal photoreceptor ellipsoid zone (EZ), after intravitreal bevacizumab (IVB) therapy, in diabetic macular oedema (DMO). SUBJECTS/METHODS: Forty-four consecutive patients aged 40-65 years having type 2 diabetes mellitus (DM) with DMO were prospectively recruited for IVB therapy. It comprised of three doses (1.25 mg in 0.05 ml) of IVB at monthly intervals. Patients with other ocular and systemic diseases affecting retinal vessels and earlier ophthalmological interventions were excluded. Visual acuity (logMAR VA) was recorded. Spectral domain optical coherence tomography (SD-OCT) was performed pre and post intervention. Central sub-foveal thickness (CST) and grades of disorganization of retinal inner layers (DRIL), external limiting membrane (ELM) and EZ were assessed. Data were statistically analysed on SPSS software. Clinical trials registry: CTRI/2019/03/018135. RESULTS: Mean logMAR VA decreased after IVB therapy from 1.78 ± 0.07 pre-intervention to 0.42 ± 0.05 post intervention (p < 0.001). Similarly, CST reduced from 354.23 ± 15.0 µm pre-intervention to 233.18 ± 7.88 µm post intervention (p < 0.001). Among qualitative variables, DRIL decreased from 93.2% pre-intervention to 13.6% post intervention. Likewise, global ELM disruption reduced from 81.8 to 9.1% and global EZ disruption reduced from 79.5 to 11.4%. ELM restoration preceded EZ restoration. CONCLUSION: Anti-VEGF therapy restores the barrier effect of ELM. It causes ELM to restore first followed by EZ restoration in DMO.

Critical analysis of techniques and materials used in devices, syringes, and needles used for intravitreal injections.

Intravitreal injections have become the most commonly performed intraocular treatments worldwide. Because intravitreal injections may induce severe adverse events, such as infectious and noninfectious endophthalmitis, cataract, ocular hypertension, vitreous hemorrhage, or retinal detachment, appropriate awareness of the materials and techniques used are essential to reduce these sight-threatening complications. This review provides insights into the needles, syringes, silicone oil coating, sterilization methods, devices to assist intravitreal injections, scleral piercing techniques using needles, syringe handling, anesthesia, and safety issues related to materials and techniques. It is paramount that physicians be aware of every step involved in intravitreal injections and consider the roles and implications of all materials and techniques used. The ability to understand the theoretical and practical circumstances may definitely lead to state-of-the-art treatments delivered to patients. The most important practical recommendations are: choosing syringes with as little silicone oil as possible, or, preferably, none; avoiding agitation of syringes; awareness that most biologics (e.g., antiangiogenic proteins) are susceptible to changes in molecular properties under some conditions, such as agitation and temperature variation; understanding that improper materials and techniques may lead to complications after intravitreal injections, e.g., inflammation; and recognizing that some devices may contribute to an enhanced, safer, and faster intravitreal injection technique.

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.

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.

Serum vitamin D is a biomolecular biomarker for proliferative diabetic retinopathy.

BACKGROUND: Vitamin D is a multi-functional fat-soluble metabolite essential for a vast number of physiological processes. Non-classical functions are gaining attention because of the close association of vitamin D deficiency with diabetes, and its complications. The present study was undertaken to evaluate the role of vitamin D as a biomarker for proliferative diabetic retinopathy. METHODS: A tertiary care center based cross-sectional study was undertaken. Seventy-two consecutive cases of type 2 diabetes mellitus were included. Diagnosis of diabetes mellitus was made using American Diabetes Association guidelines. Study subjects included: diabetes mellitus with no retinopathy (No DR) (n = 24); non-proliferative diabetic retinopathy (n = 24); and proliferative diabetic retinopathy (n = 24) and healthy controls (n = 24). All of the study subjects underwent complete ophthalmological evaluation. Best Corrected Visual Acuity (BCVA) was measured on the logarithm of the minimum angle of resolution (logMAR) scale. Serum 25-OH Vitamin D assay was done using chemiluminescent microparticle immunoassay technology. Diagnostic accuracy of vitamin D was assessed using receiver operating characteristics curve analysis and area under curve (AUC) was determined for the first time. RESULTS: ANOVA revealed a significant decrease in serum vitamin D levels with severity of diabetic retinopathy (F = 8.95, p < 0.001). LogMAR BCVA was found to increase significantly with the severity of DR (F = 112.64, p < 0.001). On AUC analysis, a cut off value of 18.6 ng/mL for Vitamin D was found to be significantly associated with proliferative diabetic retinopathy [sensitivity = 86.36% (95% CI 65.1-96.9); specificity = 81.82% (95% CI 59.7-94.7); AUC = 0.91 (excellent); and Z value = 8.17]. CONCLUSIONS: Serum vitamin D levels of ≤ 18.6 ng/mL serve as sensitive and specific indicator for proliferative disease, among patients of DR.