Optical coherence tomography angiography in diabetic retinopathy: A major review.

Diabetic retinopathy (DR) is characterized by retinal vasculopathy and is a leading cause of visual impairment. Optical coherence tomography angiography (OCTA) is an innovative imaging technology that can detect various pathologies and quantifiable changes in retinal microvasculature. We briefly describe its functional principles and advantages over fluorescein angiography and perform a comprehensive review on its clinical applications in the screening or management of people with prediabetes, diabetes without clinical retinopathy (NDR), nonproliferative DR (NPDR), proliferative DR (PDR), and diabetic macular edema (DME). OCTA reveals early microvascular alterations in prediabetic and NDR eyes, which may coexist with sub-clinical neuroretinal dysfunction. Its applications in NPDR include measuring ischemia, detecting retinal neovascularization, and timing of early treatment through predicting the risk of retinopathy worsening or development of DME. In PDR, OCTA helps characterize the flow within neovascular complexes and evaluate their progression or regression in response to treatment. In eyes with DME, OCTA perfusion parameters may be of predictive value regarding the visual and anatomical gains associated with treatment. We further discussed the limitations of OCTA and the benefits of its incorporation into an updated DR severity scale.

The effect of combination therapy with intravitreal bevacizumab and topical timolol-dorzolamide eye drops on diabetic macular edema: a double-blind randomized controlled trial.

BACKGROUND: The mainstay of treatment in diabetic macular edema (DME) is intravitreal administration of anti-vascular endothelial growth factors (anti-VEGFs). Aqueous depressants may enhance the effects of anti-VEGF agents by prolonging their clearance via aqueous outflow. PURPOSE: To compare the anatomical and functional outcomes of treatment with intravitreal bevacizumab (IVB) and topical timolol-dorzolamide versus IVB alone. METHOD: In this randomized placebo-controlled clinical trial, patients with center-involving DME (ci-DME) and best corrected visual acuity (BCVA) of 20/30 or less were enrolled and randomly allocated to two treatment arms. One group received three monthly IVB injections and timolol-dorzolamide eye drops twice a day (IVB + TD group); the other group received three monthly IVB injections and artificial tear drops as placebo (IVB group). Patients underwent ophthalmic evaluations and macular optical coherence tomography scans at baseline and 1 month after the third injection. RESULT: Forty-six eyes from 46 patients with ci-DME were recruited. There was no intergroup difference regarding age, gender distribution, diabetic retinopathy stage, glycemic indices, BCVA, central macular thickness (CMT), or intraocular pressure at baseline. BCVA was significantly improved in the IVB + TD group (0.46 ± 0.18 to 0.36 ± 0.18 logarithm of the minimum angle of resolution [logMAR], p = 0.002), in contrast to IVB group (0.40 ± 0.17 to 0.35 ± 0.22 logMAR, p = 0.113). Similarly, the IVB + TD group showed a significant reduction in CMT (p < 0.001), unlike the IVB group (p = 0.086); and the CMT change in the former was greater than in the latter (- 0.57 ± 57.67 vs. - 25.52 ± 68.02 µm, p = 0.033). CONCLUSION: Our findings support the short-term effectiveness of topical timolol-dorzolamide as adjunctive therapy to IVB injections in managing center-involving DME in terms of anatomical and visual outcomes. TRIAL REGISTRATION: Clinicaltrials.gov NCT05083689 (October 19, 2021).

Corneal Epithelial Thickness Mapping: A Major Review.

The corneal epithelium (CE) is the outermost layer of the cornea with constant turnover, relative stability, remarkable plasticity, and compensatory properties to mask alterations in the underlying stroma. The advent of quantitative imaging modalities capable of producing epithelial thickness mapping (ETM) has made it possible to characterize better the different patterns of epithelial remodeling. In this comprehensive synthesis, we reviewed all available data on ETM with different methods, including very high-frequency ultrasound (VHF-US) and spectral-domain optical coherence tomography (SD-OCT) in normal individuals, corneal or systemic diseases, and corneal surgical scenarios. We excluded OCT studies that manually measured the corneal epithelial thickness (CET) (e.g., by digital calipers) or the CE (e.g., by confocal scanning or handheld pachymeters). A comparison of different CET measuring technologies and devices capable of producing thickness maps is provided. Normative data on CET and the possible effects of gender, aging, diurnal changes, refraction, and intraocular pressure are discussed. We also reviewed ETM data in several corneal disorders, including keratoconus, corneal dystrophies, recurrent epithelial erosion, herpes keratitis, keratoplasty, bullous keratopathy, carcinoma in situ, pterygium, and limbal stem cell deficiency. The available data on the potential role of ETM in indicating refractive surgeries, planning the procedure, and assessing postoperative changes are reviewed. Alterations in ETM in systemic and ocular conditions such as eyelid abnormalities and dry eye disease and the effects of contact lenses, topical medications, and cataract surgery on the ETM profile are discussed.

Addressing inter-device variations in optical coherence tomography angiography: will image-to-image translation systems help?

BACKGROUND: Optical coherence tomography angiography (OCTA) is an innovative technology providing visual and quantitative data on retinal microvasculature in a non-invasive manner. MAIN BODY: Due to variations in the technical specifications of different OCTA devices, there are significant inter-device differences in OCTA data, which can limit their comparability and generalizability. These variations can also result in a domain shift problem that may interfere with applicability of machine learning models on data obtained from different OCTA machines. One possible approach to address this issue may be unsupervised deep image-to-image translation leveraging systems such as Cycle-Consistent Generative Adversarial Networks (Cycle-GANs) and Denoising Diffusion Probabilistic Models (DDPMs). Through training on unpaired images from different device domains, Cycle-GANs and DDPMs may enable cross-domain translation of images. They have been successfully applied in various medical imaging tasks, including segmentation, denoising, and cross-modality image-to-image translation. In this commentary, we briefly describe how Cycle-GANs and DDPMs operate, and review the recent experiments with these models on medical and ocular imaging data. We then discuss the benefits of applying such techniques for inter-device translation of OCTA data and the potential challenges ahead. CONCLUSION: Retinal imaging technologies and deep learning-based domain adaptation techniques are rapidly evolving. We suggest exploring the potential of image-to-image translation methods in improving the comparability of OCTA data from different centers or devices. This may facilitate more efficient analysis of heterogeneous data and broader applicability of machine learning models trained on limited datasets in this field.

Intravitreal Injections and Face Masks: Endophthalmitis Risk Before and During the COVID-19 Pandemic.

Purpose: To assess the added risk of acute endophthalmitis after intravitreal injections associated with the widespread use of face masks during the COVID-19 pandemic. Methods: In this retrospective, single-center study, records of patients with acute endophthalmitis following intravitreal bevacizumab (IVB) injections during the pre-COVID era-that is, March 1st, 2013 to October 31st, 2019 -and the COVID-19 era-that is, March 1st, 2020 to April 1st, 2021 -were reviewed and compared. Results: A total of 28,085 IVB injections were performed during the pre-COVID era; nine eyes of nine patients developed acute post-IVB endophthalmitis in this era, giving an overall incidence of 0.032% (3.2 in 10,000 injections). In the COVID era, 10,717 IVB injections were performed; four eyes of four patients developed acute post-IVB endophthalmitis in this era, giving an overall incidence of 0.037% (3.7 in 10,000 injections). The incidences of post-IVB endophthalmitis during these two eras were not statistically significantly different (P = 0.779). Conclusion: Face masking protocols seem unlikely to impose any additional risk of post-IVB endophthalmitis.

Are inner nuclear layer ischemic lesions hidden indicators of retinal vein occlusion risk? A case-control study.

PURPOSE: To investigate the association between retinal vein occlusion (RVO) and evidence of previous, unnoticed inner nuclear layer (INL) infarction in the fellow eye. METHODS: This prospective case-control study compared the prevalence of INL lesions in the fellow eye of consecutive people with hypertension (PwHTN) with unilateral RVO versus a randomly chosen eye of an age-matched control group of PwHTN without RVO. En face slabs above the outer plexiform layer (OPL) were generated from 6 × 6 fovea-centered optical coherence tomography scans. Cross-sectional scans and en face slabs were surveyed for evidence of active/resolved ischemic INL lesions. RESULTS: 69 PwHTN were included and assigned to two groups, i.e., the RVO group (n = 37; 22 BRVO and 15 CRVO) and the control group (n = 32). There was no inter-group difference regarding age, gender distribution, and background diseases. Resolved INL lesions were more frequent in the RVO group (n = 26) than in the control group (n = 4) (70.3% vs. 12.5%, p < 0.001). BRVO and CRVO cases had similar prevalence of INL lesions in their fellow eyes. Unlike diabetes, ischemic heart disease, and gender, INL lesions were associated with RVO (in the fellow eye) with an odds ratio of 15.7 (95%CI: 4.17-76.73, p < 0.001). CONCLUSION: We identified a substantially higher prevalence of INL lesions in PwHTN with RVO compared to PwHTN without RVO. The atrophic appearance of lesions suggests they may serve as early markers of increased RVO risk in individuals with systemic or cardiovascular predisposing factors.

Inverted ILM Flap Technique in Optic Disc Pit Maculopathy.

Purpose: To present the outcome of optic disc pit maculopathy (ODPM) managed successfully with an inverted internal limiting membrane (ILM) flap over the optic disc. A narrative review of ODPM pathogenesis and surgical management techniques are also provided. Case Report: This prospective interventional case series included three eyes of three adult patients (25-39 years old) with unilateral ODPM and a mean duration of unilaterally decreased visual acuity of 7.33 ± 2.40 months (4-12 months). The pars plana vitrectomy with posterior vitreous detachment induction was performed on eyes, followed by an inverted ILM flap insertion over the optic disc and gas tamponade. Patients were followed for 7-16 weeks postoperatively; best-corrected visual acuity (BCVA) improved dramatically in one patient from 2/200 to 20/25. BCVA in other patients improved two and three lines - to 20/50 and 20/30, respectively. A significant anatomical improvement was achieved in all three eyes, and no complication was detected throughout the follow-up period. Conclusion: Vitrectomy with inverted ILM flap insertion over the optic disc is safe and can yield favorable anatomical improvement in patients with ODPM.

Ziv-aflibercept in Diabetic Macular Edema: Relation of Subfoveal Choroidal Thickness with Visual and Anatomical Outcomes.

Purpose: To evaluate the effects of intravitreal ziv-aflibercept injections (IVZ) on subfoveal choroidal thickness (SCT) as well as on central macular thickness (CMT) and on best corrected visual acuity (BCVA) changes in eyes with center-involved diabetic macular edema (CI-DME). Methods: Fifty-seven eyes of 36 patients with CI-DME were included in this prospective interventional case series. Structural optical coherence tomography (OCT) and enhanced depth imaging OCT were performed at baseline followed by three monthly 1.25 mg IVZ injections. Changes of SCT, CMT, and BCVA at each follow-up session were assessed. The association between baseline SCT and its monthly changes with final visual and anatomical outcomes were also assessed. Results: CMT at baseline, and at the first, second, and third month follow-up sessions were 396 ± 119, 344 ± 115, 305 ± 89, and 296 ± 101 µm, respectively (P-value < 0.001). SCT at baseline, and at months one, two, and three were 236 ± 47, 245 ± 56, 254 ± 54, and 241 ± 54 µm, respectively (P-value > 0.99). Corresponding figures for BCVA were 0.58 ± 0.29, 0.47 ± 0.31, 0.4 ± 0.24, and 0.37 ± 0.23 LogMAR, respectively (P-value < 0.001). There was a statistically significant positive correlation between BCVA and CMT changes following IVZ injections (P-value < 0.001). However, there were no significant correlations between SCT changes and visual acuity (VA) and CMT changes following IVZ injections. Conclusion: IVZ improved visual outcomes and macular thickness profiles in patients with CI-DME. However, IVZ had no significant effect on SCT. Baseline SCT and its monthly changes had no association with visual and anatomical outcomes.

Headache-a challenge across medical students' life: a systematic review and meta-analysis.

BACKGROUND: Headache is a disabling disease that affects psychosocial factors. Medical students are recognized to be more susceptible to psychological stress than other. Quantitative summaries of prevalence studies on this subject are limited. The aim of this study was to quantify and comprehend the variance in prevalence at the global and regional levels. METHODS: We used a comprehensive search approach to find studies on headaches prevalence in the medical literature published between November 1990 and May 5, 2022. Database searched were PubMed, Scopus, EMBASE, and Google Scholar. Studies that reported headaches (unspecified, migraine, or tension-type headache (TTH)) in medical students were included. Subgroup analysis and meta-regression were applied to investigate heterogeneity, with the risk of bias tool employed to assess study quality. PROSPERO number CRD42022321556 was assigned to the study protocol. RESULTS: Out of 1561 studies, 79 were included. The pooled prevalence estimates of unspecified headache, migraine, and TTH were 70.44% (95% CI: 63.32-77.57), 18.9% (95% CI: 15.7-22.0), and 39.53% (95% CI: 31.17-47.90), respectively. TTH and migraine were more prevalent in Eastern Mediterranean and American region. TTH and migraine were less prevalent in higher income countries. CONCLUSION: Although the prevalence of headaches among medical students varies in different countries, it is higher than the general population of the same age. Higher stressors and overwork in these students may contribute to this condition. The well-being of medical students should be a priority for the relevant authorities.

RONA Technique: A Novel ILM Peeling Method for Treatment of Large Full-Thickness Macular Holes.

PURPOSE: To present a new technique, RONA, for internal limiting membrane peeling and show its comparable success rate in closure of large full-thickness macular holes (FTMHs). METHODS: This prospective interventional case series was implemented from January 2018 to November 2019. Consecutive cases with large FTMH with an aperture size of more than 500 µ m were included. The RONA technique was used to make consecutive flaps; the central border of which remained adherent to the FTMH edge. The emphasis is that the central border of all flaps should remain adherent to the FTMH edge, letting the flaps remain there spontaneously. RESULTS: Seventeen eyes of 17 patients (4 males and 13 females; age 62.3 ± 7.8 years) were included. The mean size of opening and base of FTMH were 651.1 ± 141.1 µ m (range: 501-950) and 964.6 ± 383.8 µ m (range: 527-2098), respectively. One week after the surgery, complete closure of all FTMHs occurred with no hole reopening until the end of 12 months. The mean best-corrected visual acuity at baseline and 12 months after surgery were 1.57 ± 0.30 and 0.75 ± 0.028 logarithm of the minimum angle of resolution, respectively, with statistically significant improvement ( P < 0.001). CONCLUSION: The first advantage of this efficacious technique is that there is no need to manipulate FTMH edge or underneath tissues. Another and of course, the most important advantage is that there is no need to care about flap unfolding during the exchange stage.

Smoking and environmental tobacco smoke exposure: implications in ocular disorders.

PURPOSE: This article aims to gather and review the available knowledge on several implications of smoking and environmental tobacco smoke (ETS) exposure in ocular disorders and provides pathomechanistic insights where applicable. MATERIALS AND METHODS: PubMed and Scopus databases were searched for relevant studies on the association of smoking and ETS exposure with various ocular disorders. Studies with different evidence levels, e.g., in-vivo, case-control, cohort, and meta-analysis, were included. RESULTS: Smoking is an established, modifiable risk factor in several ocular diseases, including cataract, age-related macular degeneration, and Graves' ophthalmopathy; smokers are subject to more severe disease courses and less favorable treatment outcomes. Uveitis is twice as likely in smokers; smoking may also delay its resolution. Smoking and ETS exposure are major risk factors for diseases of other organs, with associated ocular complications as well, such as diabetes mellitus. ETS exposure is also associated with ocular surface pathologies, including dry eye syndrome. In children, early-life ETS exposure and maternal smoking during pregnancy are strongly associated with refractive errors and strabismus. Currently, available data on potential risks attributable to ETS exposure regarding ocular diseases are scarce and, in some instances, controversial. CONCLUSION: In addition to smoking, ETS exposure is also a significant public health concern with possible links to several ocular diseases. However, the level of education of at-risk populations in this regard does not match the strength of the evidence.

Retinal ischemic cascade: New insights into the pathophysiology and imaging findings.

Retinal ischemia gives rise to a complex spectrum in which the cumulative profile of ischemia of the middle and inner retina can be highly variable. We reviewed the current knowledge on paracentral acute middle maculopathy (PAMM) pathophysiology and accompanying risk factors, the middle and inner retinal vasculature and blood flow, and the vulnerability of the middle retina in vaso-occlusive disorders. The inner nuclear layer (INL) is easily affected by slight degrees of retinal hypoperfusion and ischemia. INL infarction starts at perivenular sites, manifesting as skip PAMM lesions and a fern-like appearance in cross-sectional and en face views, respectively. With horizontal progression, INL infarction may develop into diffuse globular PAMM. If vertical progression occurs, the entire middle and inner portions of the retina can be affected. Transmural infarction of the middle and inner retina would be at the end of this spectrum. This gradient of ischemic progression resembles an ischemic cascade. We review the evidence supporting the term "retinal ischemic cascade," which encompasses a broad continuum of manifestations with roots in middle retinal infarction. With this terminology, variations in spatial and temporal progression and resolution of ischemia can also be delivered; it further enables addressing the possible associations between the middle and inner retinal ischemic patterns.

Erratum: Inverted ILM Flap Technique in Optic Disc Pit Maculopathy.

[This corrects the article DOI: 10.18502/jovr.v18i2.13189.].

Central Serous Chorioretinopathy Risk Factors in An Iranian Cohort: A Case-control Study.

Purpose: This study aimed to investigate the possible risk factors of central serous chorioretinopathy (CSCR) in an Iranian cohort. Methods: We recruited 39 consecutive CSCR cases and 80 age-matched controls with no ocular pathology from the same medical center from March 2019 to March 2021. Enrolled patients underwent complete ophthalmological examination and extensive history taking in a referral setting. Logistic regression analysis was performed to detect any possible association of potential risk factors with CSCR. Results: The mean age of CSCR patients was 40.69±7.71 years. The male-to-female ratio in cases and controls was 1:1.79 and 1.22:1, respectively. Logistic regression analysis revealed that alcohol consumption (odds ratio, OR: 62.0, P<0.001), smoking (OR: 4.0, 95% CI: 1.47-10.85, P<0.006), corticosteroid use (OR: 6.95, 95% CI: 2.64-18.28, P<0.001), and high psychological stress (OR: 13.34, 95% CI: 4.68-38.02, P<0.01) were significant risk factors for developing CSCR. Ischemic heart disease (P=0.550), hypertension (P=0.750), and hyperopia (P=0.467) were not associated with the risk of CSCR. The most common form of steroid use was oral in both groups. No pregnant female was present in the study sample, precluding the assessment of its potential association with CSCR. Conclusion: CSCR often affects individuals of productive working ages; thus, identifying its preventable risk factors is highly encouraged. Our results suggested that alcohol consumption, smoking, and high levels of psychological stress are independent, preventable risk factors for CSCR.

The First Reported Case of Ocular Syphilis in an Iranian Patient.

Purpose: To report the first case of ocular syphilis in an Iranian patient and discuss its diagnostic challenges. Case Report: A man in his mid-70s presented with progressive bilateral visual and auditory decline. He had previously lived in a Southeast Asian country for 10 years. Prior steroid therapies entailed no inflammation subsidence. His visual acuity at presentation was light perception OU. Funduscopic findings included severe vitritis, severe optic atrophy, diffuse retinal vascular occlusion, and diffuse retinal atrophy OU. Angiography demonstrated diffuse areas of retinal and choriocapillaris atrophy with no active choroiditis. Scaly cutaneous lesions were noted on his palms and soles - atypical findings of secondary syphilis. Serum analysis revealed an underlying syphilis infection. The cerebrospinal fluid sample was reactive to anti-syphilis antibodies, securing a neurosyphilis diagnosis. Two weeks of antibiotic therapy resulted in cutaneous lesions resolution and relative visual improvement despite extensive baseline retinal atrophic damage. Conclusion: Ocular syphilis can mimic numerous ocular inflammatory scenarios. In cases of ocular inflammation that is unresponsive to steroids, reconsidering alternative diagnoses, especially infections with the highest clinical relevance, is necessary. We stress the importance of acquiring patients' sexual history, regardless of cultural barriers and the rarity of the entity in some regions.

The effect of vitamin D supplementation on the outcome of treatment with bevacizumab in diabetic macular edema: a randomized clinical trial.

PURPOSE: Concomitant vitamin D deficiency (VDD) is speculated to aggravate diabetic macular edema (DME). We aimed to determine the effect of hypovitaminosis D correction on the outcome of treatment with intravitreal bevacizumab (IVB) in DME eyes. METHODS: In this randomized clinical trial, 83 eyes of 83 patients with DME were recruited and divided into three groups: normal vitamin D levels + IVB administration (Group 1), vitamin D insufficient/deficient + IVB administration (Group 2), and vitamin D insufficient/deficient + IVB administration + oral vitamin D supplementation (Group 3). Participants were followed for 6 months after the intervention. Visual (corrected distance visual acuity, CDVA) and anatomical (central macular thickness, CMT) outcomes of intervention were evaluated 1, 3, and 6 months after three monthly loading doses of IVB were given. Serum vitamin D levels were measured 1 and 6 months after the third IVB administration. RESULTS: A total of 29, 26, and 28 eyes were enrolled in groups 1, 2, and 3, respectively. In months 1, 3, and 6, after the three basic loading doses of IVB, visual acuity and CMT improved in all three groups, but improvements (both functional and anatomical) in groups 1 and 3 in month 6 were more significant than in group 2 (mean CDVA LogMAR changes: - 0.18 ± 0.03, - 0.14 ± 0.05, and - 0.2 ± 0.06; mean CMT reductions: - 82.24 ± 11.43, - 66.62 ± 14.34, and - 86.14 ± 18.36, in groups 1, 2, and 3, respectively; p < 0.001). The mean number of IVB injections during follow-up was 5.33 (range 4-7), which did not differ between the groups. CONCLUSION: Correction of vitamin D deficiency in DME patients with type 2 diabetes and vitamin D deficiency, in addition to IVB injections, may play a role in improving CDVA and CMT. However, this beneficial effect seems to be delayed by several months. TRIAL REGISTRATION: Iranian Registry of Clinical Trials (IRCT), IRCT20200407046978N1, registered on April 11, 2020, retrospectively registered ( https://en.irct.ir/trial/46999 ).