The relationship of diabetic retinopathy severity scales with frequency and surface area of diabetic retinopathy lesions.

PURPOSE: To assess the relationship between qualitative diabetic retinopathy (DR) scales with the precise numbers and surface area of DR lesions within the Early Treatment Diabetic Retinopathy Study (ETDRS) standard seven field (S7F) region on ultrawide-field (UWF) color fundus images. METHODS: In this study, we collected UWF images from adult patients with diabetes. Poor-quality images and eyes with any pathology precluding assessment of DR severity were excluded. The DR lesions were manually segmented. DR severity was graded according to the International Clinical Diabetic Retinopathy (ICDR) and AA protocol by two masked graders within the ETDRS S7F. These lesions' numbers and surface area were computed and correlated against the DR scores using the Kruskal-Wallis H test. Cohen's Kappa was performed to determine the agreement between two graders. RESULTS: One thousand five hundred and twenty eyes of 869 patients (294 females, 756 right eyes) with a mean age of 58.7 years were included. 47.4% were graded as no DR, 2.2% as mild non-proliferative DR (NPDR), 24.0% as moderate NPDR, 6.3% as severe NPDR, and 20.1% as proliferative DR (PDR). The area and number of DR lesions generally increased as the ICDR level increased up to severe NPDR, but decreased from severe NPDR to PDR. There was perfect intergrader agreement on the DR severity. CONCLUSION: A quantitative approach reveals that DR lesions' number and area generally correlate with ICDR-based categorical DR severity levels with an increasing trend in the number and area of DR lesions from mild to severe NPDR and a decrease from severe NPDR to PDR.

Practical applications of vitreous imaging for the treatment of vitreous opacities with YAG vitreolysis.

PURPOSE: To demonstrate the methodology and efficacy of using scanning laser ophthalmoscopy (SLO) and dynamic optical coherence tomography (OCT) to identify and treat symptomatic vitreous floaters using yttrium-aluminum garnet laser vitreolysis (YLV). METHODS: This is a case series highlighted from a cross sectional retrospective study conducted at the Vitreous Retina Macula Specialists of Toronto. Forty eyes from thirty-five patients were treated with YLV between November 2018 and December 2020 for symptomatic floaters and imaged with SLO and dynamic OCT. Patients were re-treated with YLV if they reported ongoing significant vision symptoms during follow-up which correlated to visible opacities on exam and or imaging. Three cases will be highlighted to present the practical applications of SLO and dynamic OCT imaging for YLV treatment. RESULTS: Forty treated eyes were enrolled in this study, with twenty-six eyes (65%) requiring at least one repeat YLV treatment following the first treatment due to ongoing symptomatic floaters. Following the first YLV, there was a significant improvement in overall mean best corrected visual acuity compared to before treatment (0.11 ± 0.20 LogMAR units vs. 0.14 ± 0.20 LogMAR units, p = 0.02 (paired t test)). Case 1 demonstrates a dense, solitary vitreous opacity that has been localized with dynamic OCT imaging to track its movements and retinal shadowing with the patient's eye movements. Case 2 shows the utility of adjusting the fixation target to monitor the movement of vitreous opacities in real-time. Case 3 exhibits an association between decreased symptom burden and vitreous opacity density after YLV. CONCLUSION: Image-guided YLV facilitates the localization and confirmation of vitreous opacities. SLO and dynamic OCT of the vitreous can provide a real-time evaluation of floater size, movement, and morphology, to help clinicians target treatment and monitoring of symptomatic floaters.

Anesthesia for ophthalmic surgery: an educational review.

PURPOSE: Selecting an anesthetic agent for ophthalmic surgery has crucial implications for the surgeon, anesthesiologist, and patient. This educational review explores the common classes of anesthesia used in ophthalmology. Additionally, we discuss the considerations unique to cataract, glaucoma, strabismus, orbital, oculoplastic, and ocular trauma surgeries. METHODS: A comprehensive Embase search was performed using combinations of the subject headings "anesthesia", "eye surgery", "ophthalmology" and "cataract extraction", "glaucoma", "strabismus", "vitreoretinal surgery", "retina surgery", "eye injury", and "eyelid reconstruction". RESULTS: Topical anesthetics are the most commonly used form of ocular anesthesia, used in both an office and surgical setting, and carry a minimal side effect profile. Notably, topical anesthetics offer analgesia, but do not provide akinesia or amnesia. Regional blocks, such as are sub-Tenon's, peribulbar, and retrobulbar blocks, are used when akinesia is required in addition to analgesia. Recently, sub-Tenon's blocks have recently gained popularity due to their improved safety profile compared to other regional blocks. General anesthesia is considered for long, complex surgery, surgery in patients with multiple comorbidities, surgery in young pediatric patients, or surgery in patients intolerant to local or regional anesthetic. CONCLUSION: Anesthetizing the eye has rapidly evolved in recent years, supporting the safety, efficacy and comfort of ocular surgery. Since there are many viable options of anesthetics available for ophthalmic surgery, a robust understanding of the patients needs, the skill of the surgical team, and surgery-specific factors ought to be considered when creating an anesthetic plan for surgery.

A proof of concept study to evaluate the treatment response of aflibercept in wARMD using OCT-A (Canada study).

PURPOSE: To Utilize OCT-A to measure the change in size (mm2) and density (flow index) of choroidal neovascular membranes (CNVMs) from baseline to week 52 of treatment-naïve wet age-related macular degeneration (wARMD) patients receiving intravitreal aflibercept injections (IAI). METHODS: Patients were treated with IAI at baseline, month 1 and month 2 and then every other month for a total of 12 months. Along with clinical examination and best corrected visual acuity (BCVA), OCT-A 6- and 3-mm scans were acquired at every visit between May 2017 and January 2019. Data from baseline, week 12 and week 52 were analyzed prospectively and included in the final analysis. RESULTS: Twenty-five eyes from 23 patients were included in the study. The mean BCVA at baseline and week 52 increased from 20/125 to 20/80, respectively (p < 0.001). The mean CST at baseline and week 52 decreased from 330.48 to 222.40 µm, respectively (p < 0.001). 1Seventeen patients (18 eyes) completed all protocol-based 6 × 6 mm and 3 × 3 mm OCT-A scans. In this subgroup, 6-mm OCT-A scans revealed that the mean size of the CNVM before and after IAI was 1.21 mm2 and 0.56 mm2, respectively (p < 0.001), while the 3-mm OCT-A scans at baseline and week 52 demonstrated a decrease in mean size of the CNVM from 0.89 to 0.37 mm2, respectively (p < 0.001). The 6-mm perfusion density map revealed no difference at either time points. CONCLUSIONS: OCT-A provides a useful approach for monitoring and evaluating the treatment of intravitreal aflibercept for CNVMs. Mean size of CNVMs can be identified by 3- or 6-mm scans, but without machine learning, it requires extensive segmentation. While reproducibility and clear delineation of CNVMs in wARMD using OCT-A is challenging, OCT-A does offer the ability to monitor CNVM size changes during treatment and may offer another biomarker to assist in assessing treatment response.

Feasibility of peripheral OCT imaging using a novel integrated SLO ultra-widefield imaging swept-source OCT device.

PURPOSE: To describe the feasibility of peripheral OCT imaging in retinal diseases using a novel full-field device. METHODS: A total of 134 consecutive eyes were referred and imaged on the Optos Silverstone swept-source OCT (SS-OCT) (Optos PLC; Dunfermline, UK). Scanning laser ophthalmoscope (SLO) images and the associated SS-OCT images were obtained in the posterior pole, mid-periphery or far periphery based on the nature of the referral and on new areas of interest observed in the optomap images at the time of imaging. RESULTS: A total of 134 eyes (96 patients) were enrolled in the study. One hundred and twenty-five eyes (91 patients) with 38 retinal pathologies were prospectively assessed and 9 eyes (5 patients) were excluded due to incomplete image acquisition. The average age of the subjects was 54 years (range 21-92 years). Thirty-nine out of 125 eyes (31%) had macular pathologies. Eighty-six out of 125 eyes (69%) had peripheral only pathologies, an area which cannot be visualized by standard OCT devices with a 50 degree field-of-view. CONCLUSIONS: The ability to capture peripheral pathologies using an integrated SLO-UWF imaging with full-field swept-source provided high-grade anatomical insight that confirmed the medical and surgical management in a majority of cases. Its use in the mid- and far periphery provides a holistic clinical picture, which can potentially aid in the understanding of various retinal pathologies.

Focal Scleral Nodule: A New Name for Solitary Idiopathic Choroiditis and Unifocal Helioid Choroiditis.

PURPOSE: To evaluate multimodal imaging findings of solitary idiopathic choroiditis (SIC; also known as unifocal helioid choroiditis) to clarify its origin, anatomic location, and natural course. DESIGN: Multicenter retrospective observational case series. PARTICIPANTS: Sixty-three patients with SIC in 1 eye. METHODS: Demographic and clinical data were collected. Multimodal imaging included color fundus photography, OCT (including swept-source OCT), OCT angiography (OCTA), fundus autofluorescence, fluorescein and indocyanine green angiography, and B-scan ultrasonography. MAIN OUTCOME MEASURES: Standardized grading of imaging features. RESULTS: Mean age at presentation was 56 ± 15 years (range, 12-83 years). Mean follow-up duration in 39 patients was 39 ± 55 months (range, 1 month-25 years). The lesions measured a mean of 2.4 × 2.1 mm in basal diameter, were located inferior (64%) or nasal to the optic disc, and appeared yellow (53%). No systemic associations were found. The lesions all appeared as an elevated subretinal mass, with OCT demonstrating all lesions to be confined to the sclera, not the choroid. On OCT, the deep lesion margin was visible in 12 eyes with a mean lesion thickness of 0.6 mm. Overlying choroidal thinning or absence was seen in 95% (mean choroidal thickness, 28 ± 35 µm). Mild subretinal fluid was observed overlying the lesions in 9 patients (14%). Retinal pigment epithelial disruption and overlying retinal thinning was observed in 56% and 57%, respectively. OCT angiography was performed in 13 eyes and demonstrated associated choroidal and lesional flow voids. Four lesions (6%) were identified at the macula, leading to visual loss in 1 patient. One lesion demonstrated growth and another lesion showed spontaneous resolution. CONCLUSIONS: In this largest series to date, multimodal imaging of SIC demonstrated a scleral location in all patients. The yellow and white clinical appearance may be related to scleral unmasking resulting from atrophy of overlying tissues. Additional associated features included documentation of deep margin on swept-source OCT, trace subretinal fluid in a few patients, and OCTA evidence of lesional flow voids. Because of the scleral location of this lesion in every patient, a new name, focal scleral nodule, is proposed.

The future of retinal imaging.

PURPOSE OF REVIEW: This article reviews emerging technologies in retinal imaging, including their scientific background, clinical implications and future directions. RECENT FINDINGS: Fluorescence lifetime imaging ophthalmoscopy is a technology that will reveal biochemical and metabolic changes of the retina at the cellular level. Optical coherence tomography is evolving exponentially toward higher resolution, faster speed, increased portability and more cost effective. Adaptive optics scanning laser ophthalmoscopy fluorescein angiography will provide unprecedented detail of the retinal vasculature down to the level of capillaries, enabling earlier and more sensitive detection of retinal vascular diseases. SUMMARY: Continued developments in retinal imaging focus on improved resolution, faster speed and noninvasiveness, while providing new information on the structure-function relationship of the retina inclusive of metabolic activity at the cellular level.

VASOPROLIFERATIVE TUMORS IN INTERMEDIATE UVEITIS.

PURPOSE: To describe patients with intermediate uveitis complicated by vasoproliferative tumors (VPTs). METHODS: Data were collected at seven Uveitis/Ocular Oncology centers on demographic, ophthalmic findings at baseline and at follow-up, and on imaging. The therapeutic intervention, final visual acuity, and duration of follow-up were recorded. RESULTS: A total of 36 eyes from 34 patients (12 men, 22 women; mean age 35.3 ± 14.2 years) were included in this study. Visual acuity at presentation ranged from 20/40 to counting fingers. At the time of VPT diagnosis, intermediate uveitis was active in all eyes. The mean VPT thickness was 3.06 ± 0.86 mm. Local treatment to the VPT was provide in 22 eyes (61.1%) and no local treatment to the VPT in 14 eyes (38.9%). After the VPT was detected, systemic or local treatment for the inflammation was initiated and on follow-up FAs 94.4% of the eyes showed resolution of the vascular leakage. During follow-up of 35.8 months, the 22 VPTs treated locally had a reduction in the tumor thickness to 1.25 mm, whereas the 14 VPTs untreated remained stable (final mean tumor thickness 2.65 mm). CONCLUSION: The presence of active intermediate uveitis accompanied by VPTs suggests the need for an aggressive uveitis treatment.

DOME-SHAPED MACULA IN MYOPIC EYES: Twelve-Month Follow-up.

PURPOSE: To study the long-term clinical course of dome-shaped macula in myopic eyes and to evaluate treatment efficacy for subretinal fluid (SRF) as a related complication. METHODS: A retrospective, single-center consecutive case series study was conducted. The authors analyzed myopic eyes with dome-shaped macula in patients who presented for evaluation of decreased vision. Dome-shaped macula was defined as a convexity of the retina-choroidal macular complex seen on spectral domain optical coherence tomography images. All patients were followed for at least 12 months (mean, 25 months). Fluorescein angiography and/or indocyanine green angiography were performed in cases with SRF to rule out choroidal neovascularization. RESULTS: A total of 56 dome-shaped macula eyes from 36 patients were included in the study (bilateral in 55% of patients). Mean patient age was 56.9 ± 13.1 years. The mean spherical equivalent was -9.1 ± 6.0 diopters; 53% of eyes were considered highly myopic (>-6 diopters) and 47% of eyes were mildly myopic. In most cases (37 eyes; 66.1%), the dome-shaped macula was detected on vertical spectral domain optical coherence tomography scan patterns. No significant changes (P ≥ 0.1) were observed in mean best-corrected visual acuity or mean central foveal thickness from baseline to final follow-up. Subretinal fluid was present in 29 eyes (51.8%) at baseline, with no differences in best-corrected visual acuity in eyes with and without SRF (P ≥ 0.05). Nineteen of the 29 SRF eyes were treated: 8 underwent low-fluence photodynamic therapy, whereas 7 received bevacizumab, and 4 ranibizumab. No significant differences were found between treated and untreated SRF eyes in best-corrected visual acuity improvement (P ≥ 0.1), or complete resolution of SRF (P ≥ 0.1). Likewise, photodynamic therapy did not yield any significant benefit versus untreated eyes in best-corrected visual acuity or improvement of SRF. CONCLUSION: Dome-shaped macula is a condition associated with myopic eyes that seems to remain stable over time in terms of vision and macular profiles. It is often associated with chronic SRF, for which no effective treatment is current available. However, SRF does not seem to be a significant cause of visual impairment.

Ultra-Widefield Steering-Based Spectral-Domain Optical Coherence Tomography Imaging of the Retinal Periphery.

PURPOSE: To describe the spectral-domain optical coherence tomography (SD OCT) features of peripheral retinal findings using an ultra-widefield (UWF) steering technique to image the retinal periphery. DESIGN: Observational study. PARTICIPANTS: A total of 68 patients (68 eyes) with 19 peripheral retinal features. MAIN OUTCOME MEASURES: Spectral-domain OCT-based structural features. METHODS: Nineteen peripheral retinal features, including vortex vein, congenital hypertrophy of the retinal pigment epithelium, pars plana, ora serrata pearl, typical cystoid degeneration (TCD), cystic retinal tuft, meridional fold, lattice and cobblestone degeneration, retinal hole, retinal tear, rhegmatogenous retinal detachment, typical degenerative senile retinoschisis, peripheral laser coagulation scars, ora tooth, cryopexy scars (retinal tear and treated retinoblastoma scar), bone spicules, white without pressure, and peripheral drusen, were identified by peripheral clinical examination. Near-infrared scanning laser ophthalmoscopy images and SD OCT of these entities were registered to UWF color photographs. RESULTS: Spectral-domain OCT resolved structural features of all peripheral findings. Dilated hyporeflective tubular structures within the choroid were observed in the vortex vein. Loss of retinal lamination, neural retinal attenuation, retinal pigment epithelium loss, or hypertrophy was seen in several entities, including congenital hypertrophy of the retinal pigment epithelium, ora serrata pearl, TCD, cystic retinal tuft, meridional fold, lattice, and cobblestone degenerations. Hyporeflective intraretinal spaces, indicating cystoid or schitic fluid, were seen in ora serrata pearl, ora tooth, TCD, cystic retinal tuft, meridional fold, retinal hole, and typical degenerative senile retinoschisis. The vitreoretinal interface, which often consisted of lamellae-like structures of the condensed cortical vitreous near or adherent to the neural retina, appeared clearly in most peripheral findings, confirming its association with many low-risk and vision-threatening pathologies, such as lattice degeneration, meridional folds, retinal breaks, and rhegmatogenous retinal detachments. CONCLUSIONS: Ultra-widefield steering-based SD OCT imaging of the retinal periphery is feasible with current commercially available devices and provides detailed anatomic information of the peripheral retina, including benign and pathologic entities, not previously imaged. This imaging technique may deepen our structural understanding of these entities and their potentially associated macular and systemic pathologies, and may influence decision-making in clinical practice, particularly in areas with teleretinal capabilities but poor access to retinal specialists.

DIDANOSINE RETINAL TOXICITY.

PURPOSE: To report nine new cases of retinal degeneration secondary to didanosine toxicity and to summarize the previously reported cases in the literature. METHODS: This was a multicenter, retrospective, observational case study from seven institutions. Medical records of patients who demonstrated well-demarcated severe midperipheral chorioretinal degeneration and who were previously treated with didanosine therapy were collected and the following information was reviewed: age, gender, medical history, detailed medication history including current and previous antiretroviral use, ocular and retinal examination findings, and multimodal imaging findings with optical coherence tomography, fundus photography, wide-field fundus autofluorescence, and wide-field fluorescein angiography. When available, findings with electrophysiology testing and automated perimetry were also collected and reviewed. A literature review was also performed to collect all reported cases of chorioretinal degeneration secondary to didanosine toxicity. RESULTS: Nine patients were identified who had findings consistent with peripheral retinal toxicity secondary to didanosine use. Eight of the 9 patients were men, and the median age was 54 years at the time of presentation (mean: 55 years, range, 42-71 years). Snellen distance acuity ranged from 20/20 to 20/32. At least three of the cases in the series demonstrated progression of the peripheral retinal pigment epithelium and photoreceptor atrophy despite didanosine cessation. A review of the literature revealed 10 additional cases of didanosine toxicity. Seven of the 10 cases were in men (70%), and the average age was 26 years with a wide range (2-54 years). Chorioretinal findings were very similar to this cohort. CONCLUSION: Herein, we report the largest series of nine cases of peripheral chorioretinal degeneration secondary to didanosine toxicity in adults. When combined with the cases in the literature, 19 cases of didanosine toxicity, 4 of which occurred in children, were collected and analyzed. Three of the new cases presented showed clear progression of degeneration despite didanosine cessation. Newer nucleoside reverse transcriptase inhibitors may potentiate mitochondrial DNA damage and lead to continued chorioretinal degeneration.

Spectral domain optical coherence tomography findings in patients with acute syphilitic posterior placoid chorioretinopathy.

PURPOSE: To describe the appearance of acute syphilitic posterior placoid chorioretinitis, a rare ocular manifestation of syphilis, on spectral domain optical coherence tomography (SD OCT) both before and after treatment. METHODS: Ophthalmic examination and imaging studies of 30 eyes of 19 confirmed cases were analyzed both at the time of presentation and at each follow-up visit. Patients with SD OCT and fluorescein angiography at the time of presentation, and at least three documented follow-up visits after initiation of therapy, were included in the study. Standard treatment of neurosyphilis was given to each patient, including 4 million units of penicillin G administered intravenously every 4 hours for 14 days. RESULTS: Fundus examination and imaging studies were consistent with previous reports and confirmed the diagnosis of acute syphilitic posterior placoid chorioretinitis. In 13 eyes (43.3%), baseline SD OCT scans were performed within 1 to 2 days of presentation and revealed a small amount of subretinal fluid, disruption of the inner segment/outer segment junction, and hyperreflective thickening of the retinal pigment epithelium (RPE). All 30 eyes were again scanned between Days 7 and 9 after presentation and revealed loss of the inner segment/outer segment and OS/RPE bands, and irregular hyperreflectivity of the RPE with prominent nodular elevations but without subretinal fluid. Early disruption of the external limiting membrane and punctate choroidal hyperreflectivity were seen in 1 of the 30 eyes (3.3%) and 14 of the 30 eyes (46.6%), respectively. Vision improved and the outer retinal abnormalities normalized in 28 of the 30 eyes (93.3%) after the treatment of neurosyphilis. The external limiting membrane, inner segment/outer segment band, and/or linear outer segment/RPE junction remained substantially abnormal despite treatment in 2 eyes left with 20/200 vision. CONCLUSION: Patients with acute syphilitic posterior placoid chorioretinitis show characteristic outer retinal abnormalities on SD OCT imaging, including disruption of the inner segment/outer segment band, nodular thickening of the RPE with loss of the linear outer segment/RPE junction, and, in some cases, loss of the external limiting membrane, accumulation of subretinal fluid, and punctate hyperreflectivity in the choroid. Vision improved and these abnormalities reversed after treatment of neurosyphilis in most of the patients. Persistently, poor vision despite treatment was associated with long-term loss or disruption of outer retinal anatomy on SD OCT.

Optical coherence tomography imaging of the peripheral retina.

This review critically assesses the applicability of retinal periphery imaging technology, scrutinizing its practical limitations and potential advancements within ophthalmology. It underscores the significant costs and the need to evaluate the clinical utility of optical coherence tomography (OCT) and OCT angiography devices. It emphasizes how clinicians should consider their practice-specific use-cases while investing in devices with capabilities like ultra-widefield OCT, autofluorescence imaging, and angiography. The paper also highlights the challenges associated with image acquisition, such as artifact management and patient cooperation for extended fixation periods. This review outlines the utility of these modalities in various retinal pathologies, as well as their contribution to telemedicine and personalized care, facilitated by artificial intelligence for improved image processing, quantification, and interpretation. These techniques potentially offer a more comprehensive understanding of peripheral retinal conditions and associated pathologies, thus influencing clinical decision-making, particularly in remote regions with limited specialist access.

OCTA: Essential or Gimmick?

This commentary article delves into the transformative role of optical coherence tomography angiography (OCTA) in diagnosing and managing a wide array of eye conditions, including diabetic retinopathy, age-related macular degeneration, retinal vein occlusions, and white dot syndromes. Developed in 2005, OCTA has emerged as a non-invasive, high-resolution imaging technique that offers advantages over traditional fluorescein angiography (FA), providing quicker and safer monitoring of ocular conditions with similar diagnostic accuracy. In diabetic retinopathy, OCTA has been instrumental in early identification of retinal changes, offering quantifiable metrics including perfused capillary density (PCD) for assessing vascular alterations. For age-related macular degeneration (AMD), OCTA has deepened our understanding of non-exudative neovascular AMD, allowing for more effective monitoring and potential earlier initiation of treatment. In cases of retinal vein occlusions, OCTA can reveal specific microvascular features and allow for depth-resolved measurements of the foveal avascular zone, providing significant prognostic implications. OCTA has also been invaluable in studying rare white dot syndromes, enabling nuanced differentiation between conditions that often present similarly. Emerging research also suggests that OCTA can have potential utility in neurodegenerative diseases like Alzheimer's, where retinal vascular patterns could offer diagnostic insights. While OCTA is revolutionizing ophthalmic care, further clinical trials and standardization are needed for its broader adoption into clinical practice.

Anti-VEGF and steroid combination therapy relative to anti-VEGF mono therapy for the treatment of refractory DME: A systematic review of efficacy and meta-analysis of safety.

The aim of the study was to determine the efficacy and safety of combined anti-VEGF and steroid therapy in treatment refractory DME patients. We conducted a systematic review and meta-analysis of peer-reviewed articles reporting on visual, anatomical and adverse outcomes to compare the efficacy and safety of combined intravitreal anti-VEGF/steroids versus anti-VEGF monotherapy for refractory DME. Seven studies (4 RCTs and 3 observational studies) reporting on 452 eyes were included. Our systematic review showed that combination therapy is significantly more effective for anatomical outcomes in the treatment of resistant DME compared to anti-VEGF monotherapy in six studies. Two studies found that addition of intravitreal steroids promoted faster visual improvement, but not significantly better final visual outcomes compared to anti-VEGF monotherapy. Combination therapy was associated with a higher incidence of IOP-related adverse events (RR = 0.10, 95% CI = [0.02, 0.42], p = 0.002) and cataract-related adverse events (RR = 0.10, 95% CI = [0.01, 0.71], p = 0.02). Our systematic review and meta-analysis of seven studies and 452 eyes revealed that combination therapy of anti-VEGF and steroid intravitreal drugs in the management of treatment refractory DME resulted in superior anatomical outcomes in all but one study. Combination therapy led to superior short-term visual outcomes in two studies, while others reported no difference between treatment groups. Meta-analysis revealed that combination therapy was associated with more adverse events. Future research should provide guidance on the standard definitions for treatment resistance and therapeutic alternatives for DME patients with sub-optimal response to anti-VEGF treatment.