case study of diabetic macular edema

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  • / Diabetic Macular Edema: Diagnosis and Management

Diabetic Macular Edema: Diagnosis and Management

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Diabetic retinopathy (DR) is the leading cause of new cases of blindness among adults aged 18 to 64 years in the United States. 1 Dia­betic macular edema (DME), a severe complication of DR that occurs specifi­cally as a result of inadequately treated diabetes mellitus (DM), has overtaken proliferative diabetic retinopathy as the most common cause of vision impairment in individuals with DM. 2 In recent epidemiologic studies, approximately 30% of patients worldwide with DM were found to have vision-threatening DR; and in the United States, 3.8% of patients were found to have DME. 3

DME, which is characterized by hard exudates and edema within the macula secondary to damage to retinal microvasculature, is detected by clinical examination or with OCT. Before the advent of pharmacotherapy for DME, the first-line treatment was tradition­ally focal laser photocoagulation of the macula. More recently, large-scale clinical evidence from the DRCR.net has established intravitreal anti-VEGF injections as the first-line therapy, followed by the use of intravitreal corticosteroids if treatment response is unsatisfactory. 4

Etiology and Pathogenesis

DR. DR develops from the loss of both endothelial tight junctions and peri­cytes in retinal capillaries, eventually leading to leakage of protein, lipids, inflammatory molecules, and other plasma components into the interstitial space. Further production of proin­flammatory cytokines and VEGF by retinal pigment epithelium, glial cells, and macrophages leads to breakdown of the blood-retina barrier, causing further leakage of fluid into the retina.

DME. DME arises from the accu­mulation of fluid, protein, and lipids throughout the layers of the retina in the form of intraretinal cystic spaces, best seen by OCT. 5 It is now believed that the etiology of DME, though com­plex, is largely twofold.

First, retinal microvascular obstruc­tion and capillary dropout throughout the retina in patients with poorly controlled DM lead to retinal ischemia. The subsequent hypoxia-induced upregulation of VEGF then causes neovascularization both in the retinal periphery and in existing macular ves­sels, increasing vascular permeability.

Second, in many patients with long-standing DM, production of free radicals and accumulation of advanced glycosylation end products cause upregulation of proinflammatory cytokines such as interleukin (IL)-1b and IL-6. This process leads to further vision-threatening consequences of DME as inflammation develops and vascular pericytes are lost. Compro­mised junctional proteins in macular microcapillaries cause them to become more liable to leakage, contributing to the extravascular fluid and hard lipid exudates that are a hallmark of DME. 6

Diagnosis and Screening

Because of the insidious nature of both DR and DME, all diabetic patients should have an ophthalmic evaluation to screen for eye disease, consisting of a comprehensive eye examination, with ancillary testing and imaging as appropriate. According to the Academy’s Preferred Practice Patterns guidelines for DR, patients with type 1 DM should be screened for DR starting five years after diagnosis of DM, while patients with type 2 DM should be screened for DR upon diagnosis and then annually or more often, depending on the severity of their systemic disease. 7

Imaging. OCT has become a main­stay in screening and diagnosis. This modality allows clinicians to detect thickening, structural changes, and edema that are difficult to capture in a clinical funduscopic exam.

Nonmydriatic or mydriatic digital retinal photography is often used in comprehensive ophthalmology settings for noninvasive screening. It has the potential to be employed in combi­nation with advanced artificial intel­ligence algorithms that automate the diagnostic process. 8,9

Classification. After DME has been detected, the ophthalmologist should perform a detailed clinical examination to determine its severity. DME is typ­ically classified in the following three categories:

  • Mild: Retinal thickening and hard exudates are present in the posterior pole but fall more than 1,000 μm out­side the central macular subfield.
  • Moderate: Retinal thickening or hard exudates are present within the central subfield of the macula but do not involve the center.
  • Severe: Retinal thickening or hard exudates involve the center of the macula. 10

Table 1: Important Recent Studies in DME Treatment

Treatment and prevention.

Treatment of DME begins with management of the systemic disease. Stringent regulation and treatment of hyperglycemia, hypertension, and hyperlipidemia can delay the onset and progression of various microvasculopa­thies, including DR and DME.

Treatment options for DME vary depending on the severity of disease and the patient’s baseline visual acuity (VA). However, on the basis of recent studies by the DRCR.net, discussed below, ophthalmologists have generally adopted anti-VEGF intravitreal therapy as the first-line treatment. (See  Table 1 for an overview of important treatment studies.)

Laser. Laser photocoagulation became the primary therapy for DME in the mid-1980s, when the Early Treatment Diabetic Retinopathy Study demonstrated its ability to decrease the risk of vision loss. However, the introduction of anti-VEGF drugs in the 2000s changed the treatment paradigms because these drugs can reverse vision loss, an outcome that is uncommon with laser therapy. 11 The DRCR.net Protocol I study showed a significant improvement in participants treated with ranibizumab and laser therapy (whether on a fixed or flexible schedule) compared with those treated with sham injections and laser therapy.

Anti-VEGF agents. The RISE and RIDE studies, performed in 2010, looked at three groups of patients with a baseline VA of 20/30 or worse: The treatment groups received either 0.3-mg or 0.5-mg doses of ranibizumab, and a control group received sham injections. Both treatment groups experienced greater improvement in BCVA than did the control group. 12

Similarly, in the VISTA and VIVID studies of patients with central DME, 2 mg of intravitreal aflibercept, admin­istered either every four or eight weeks (the latter after five monthly doses), produced visual gains that were far su­perior to the results with laser therapy. 13

The DRCR.net Protocol T study compared the efficacy of the three anti-VEGF drugs currently in widespread clinical use for DME: ranibizumab, aflibercept, and bevacizumab (used off label). Participants were randomly assigned to one of the three treatment groups. The study concluded that aflibercept is the most effective drug in eyes with a baseline VA of 20/50 or worse. There was no significant dif­ference in efficacy among the drugs in eyes with better baseline VA.

In the DRCR.net Protocol V study, the investigators compared aflibercept, laser photocoagulation, and observation in the initial management of patients with center-involving DME and a base­line BCVA of 20/25 or better. No signif­icant difference was found, suggesting that in eyes with mild VA loss, the three approaches are equally effective. 14

Corticosteroids. In approximately 40% of patients with chronic DME, anti-VEGF therapy is unsuccessful or inadequate. Intravitreal corticosteroid therapy is indicated for these patients, as it is presumed that inflammation may be contributing to the pathogen­esis of DME. Treatment can be administered via intravitreal injection or sustained-release intravitreal implants. Physicians considering intravitreal steroids should keep in mind the risks, including premature cataract forma­tion, increased IOP, and worsening vision loss.

As a second-line pharmacologic agent for DME, intravitreal corticoste­roid implants have been associated with variable outcomes. For example, in the DRCR.net Protocol U study, patients with persistent DME who received intravitreal dexamethasone implants in combination with ranibizumab had decreased retinal thickening on OCT, although BCVA did not improve.

In the MEAD study of a dexameth­asone implant, patients who completed the trial had a 0.9 letter gain in BCVA compared with those who dropped out. Among the participants, 37.5% had no change in BCVA, while 23.2% gained more than 10 letters, and 16.0% lost more than 10 letters. 15

Putting it together. These data suggest a stepwise approach to treat­ment (see Table 2 ), with anti-VEGF treatment initiated in patients with moderate to severe DME (VA of 20/30 or worse). Approximately three months or more after starting anti-VEGF treat­ment, the patient should be reevaluated clinically and with OCT, and further treatment options should be considered if VA and/or central macular thickness have not improved or stabilized suffi­ciently. If the response to anti-VEGF therapy is suboptimal at this point, some retina specialists choose to initi­ate intravitreal corticosteroid therapy and focal or grid laser photocoagu­lation, while many others prefer to continue with six months of anti-VEGF injections before considering intravitreal corticosteroid therapy.

__________________________

1 CDC. National Diabetes Statistics Report, 2020. www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf . Accessed Dec. 27, 2020.

2 Yau JW et al. Diabetes Care. 2012;35(3):556-564.

3 Varma R et al. JAMA Ophthalmol. 2014;132(11):1334-1340.

4 Maturi RK et al. JAMA Ophthalmol. 2018;136(1):29-38.

5 Joussen AM et al. Am J Pathol. 2001;158(1):147-152.

6 Wong TY et al. Nat Rev Dis Primers. 2016;2:16012. doi:10.1038/nrdp.2016.12.

7 American Academy of Ophthalmology, Retina/Vitreous Panel. Diabetic Retinopathy Preferred Practice Pattern Guidelines. 2019. aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp . Accessed Feb. 22, 2021.

8 Mitchell P, Wong TY; Diabetic Macular Edema Treatment Guideline Working Group. Am J Oph­thalmol. 2014;157(3):505-513.

9 Fenner BJ et al.  Ophthalmol Ther.  2018;7(2):333-346.

10 Cheung CY et al. Asia-Pac J Ophthalmol. Published online April 24, 2019. doi:10.22608/APO.201976.

11 Cantrill HL.  Int Ophthalmol Clin. 1984;24(4):13-29.

12 Bressler NM et al. Ophthalmology . 2014;121(12):2461-2472.

13 Korobelnik JF et al. Ophthalmology . 2014;121(11):2247-2254.

14 Baker CW et al.  JAMA . 2019;321(19):1880-1894.

15 Boyer DS et al; Ozurdex MEAD Study Group. Ophthalmology . 2014;121(10):1904-1919.

Ms. Elyasi is a medical student at the Bruce and Ruth Rappaport Faculty of Medicine at the Technion Israel Institute of Technology, Bat Galim, Haifa, Israel. Dr. Hemmati is a cornea specialist and chief medical officer of Optigo Biotherapeu­tics, Vancouver, B.C., Canada. Relevant financial disclosures: Ms. Elyasi: None. Dr. Hemmati: Cell Care Therapeutics: C,O; Optigo Biotherapeutics: E,O.

For full disclosures and the disclosure key,  see below.

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  • Original article
  • Open access
  • Published: 28 February 2024

Recommendations for diabetic macular edema management by retina specialists and large language model-based artificial intelligence platforms

  • Ayushi Choudhary 1   na1 ,
  • Nikhil Gopalakrishnan 1   na1 ,
  • Aishwarya Joshi 1 ,
  • Divya Balakrishnan 2 ,
  • Jay Chhablani 3 ,
  • Naresh Kumar Yadav 1 ,
  • Nikitha Gurram Reddy 4 ,
  • Padmaja Kumari Rani 4 ,
  • Priyanka Gandhi 1 ,
  • Rohit Shetty 5 ,
  • Rupak Roy 6 ,
  • Snehal Bavaskar 1 ,
  • Vishma Prabhu 1 &
  • Ramesh Venkatesh   ORCID: orcid.org/0000-0002-4479-9390 1  

International Journal of Retina and Vitreous volume  10 , Article number:  22 ( 2024 ) Cite this article

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Metrics details

To study the role of artificial intelligence (AI) in developing diabetic macular edema (DME) management recommendations by creating and comparing responses to clinicians in hypothetical AI-generated case scenarios. The study also examined whether its joint recommendations followed national DME management guidelines.

The AI hypothetically generated 50 ocular case scenarios from 25 patients using keywords like age, gender, type, duration and control of diabetes, visual acuity, lens status, retinopathy stage, coexisting ocular and systemic co-morbidities, and DME-related retinal imaging findings. For DME and ocular co-morbidity management, we calculated inter-rater agreements (kappa analysis) separately for clinician responses, AI-platforms, and the “majority clinician response” (the maximum number of identical clinician responses) and “majority AI-platform” (the maximum number of identical AI responses). Treatment recommendations for various situations were compared to the Indian national guidelines.

For DME management, clinicians (ĸ=0.6), AI platforms (ĸ=0.58), and the ‘majority clinician response’ and ‘majority AI response’ (ĸ=0.69) had moderate to substantial inter-rate agreement. The study showed fair to substantial agreement for ocular co-morbidity management between clinicians (ĸ=0.8), AI platforms (ĸ=0.36), and the ‘majority clinician response’ and ‘majority AI response’ (ĸ=0.49). Many of the current study’s recommendations and national clinical guidelines agreed and disagreed. When treating center-involving DME with very good visual acuity, lattice degeneration, renal disease, anaemia, and a recent history of cardiovascular disease, there were clear disagreements.

For the first time, this study recommends DME management using large language model-based generative AI. The study’s findings could guide in revising the global DME management guidelines.

Introduction

Diabetic retinopathy (DR) is one of the many serious eye complications associated with diabetes mellitus [ 1 , 2 ]. Diabetic macular edema (DME) is one of two reasons for sight-threatening DR, the other being proliferative DR. In India, the prevalence of DME is less than 10% (range: 2.4 − 8.9%) [ 3 , 4 , 5 , 6 ]. The absolute number of people with DME in India is significant due to the rising number of diabetics. Various treatment modalities exist for the management of DME, and the selection of treatment depends primarily on the availability of retinal specialists and treatment facilities, as well as the patient’s economic status and underlying ocular and systemic conditions [ 7 ]. Because the prevalence of diabetes mellitus, and thus DR and DME, varies across the globe, several countries and regions have developed their own independent guidelines for the screening and management of DR and DME [ 8 , 9 , 10 , 11 , 12 ]. Similarly, the All-India Ophthalmology Society (AIOS) and the Vitreo-Retinal Society of India (VRSI) [national guidelines] have collaborated to develop a consensus statement on the practice points of DME management in India, with the objective of describing the preferred practice patterns for DME management in different clinical situations [ 13 ].

Several discussions have centered on the potential advantages and disadvantages of incorporating artificial intelligence (AI) into medicine, including ophthalmology. To date, several papers have been published using deep machine learning-based algorithms to identify and guide DME treatment using color fundus photographs and optical coherence tomography (OCT) images [ 14 , 15 , 16 , 17 ]. Concerns have been raised about data acquisition, data bias, identifying ground truth, comparing different algorithms, machine learning challenges, its application to different groups of people, and human barriers to AI adoption in health care [ 18 ]. A large language model (LLM) or natural language processing is a form of generative AI algorithm that understands, summarizes, generates, and predicts new text-based content using deep learning techniques and massively large data sets [ 19 ]. Many such open source LLM-based generative AI algorithms are currently freely and easily available, including OpenAI’s ChatGPT3.5v and ChatGPT4.0v, BARD from Google, Bing AI from Microsoft, and others [ 20 ]. Most researchers and clinicians believe that AIs based on LLM, when integrated into the electronic health record, could aid in the development of the best DME treatment strategy [ 21 ]. To the best of our knowledge, we could not find any literature that explored the role of LLM-based AI in DME management.

Thus, the primary objective of this study was to investigate the role of AI in formulating treatment recommendations for DME management by generating and comparing its responses to those of clinicians in different AI-generated clinical case situations. The authors also intended to compare the recommendations obtained collectively by clinicians and different AI platforms to the national guidelines for DME management for the case situations described in this study.

This was a prospectively conducted questionnaire-based study. The first stage of the study began by asking ChatGPT 3.5v (OpenAI, San Francisco, CA, USA) to generate 25 hypothetical clinical cases involving diabetes mellitus and providing information about the DR and DME status for each eye separately. This was accomplished by instructing the ChatGPT to use the pointers listed below while creating the clinical case. The following pointers were included: (1) patient demographics - age and gender; (2) diabetes type, duration, and control; (3) recent onset visual symptoms; (4) visual acuity (VA) of both eyes in Snellen’s format; (5) lens status - whether clear lens, cataractous lens, pseudophakia, or aphakia; (6) clinical fundus findings description - include cases of both non-proliferative and proliferative disease; (7) presence of systemic co-morbidities such as renal disease, hypertension, anemia, cardiovascular disease, and a deranged lipid profile; (8) co-existing pregnancy for female cases; (9) OCT findings on macular edema location i.e., center-involving DME (CIDME) or non-center-involving DME (NCIDME) and central macular thickness of both eyes, and (10) fundus fluorescein angiography findings on focal or diffuse leakage or macular ischemia, particularly in NCIDME cases.

The AI generated 25 hypothetical clinical patients and 50 clinical ocular case situations. They were then presented in a text format without any clinical images to a group of three experts (NR, NKY, SB) from various institutions to validate the clinical details and imaging findings in the case scenarios in order to make them appear as close to an actual clinical situation as possible. The experts’ recommendations were taken into account. The final version of the questionnaire identified 13 patients with identical ocular findings in both eyes. Thus, a total of 50 hypothetical case scenarios having 37 different ocular situations in 25 virtual patients was available for evaluation and analysis (Supplement 1 ). The final version of the clinical scenarios was then presented to a second group of five (VP, JC, RKR, PRK, DB) retina specialists/clinicians with at least five years of clinical experience in the field of retina, DR screening, and DME management. These retina specialists worked in a variety of settings, including government hospitals, independent private practices, tertiary eye care hospitals serving both free and paying patients, and tertiary eye care corporate hospitals serving only paying patients. Clinicians were asked to provide the single best treatment option for each eye in the case scenario, while keeping in mind that the patient was visiting the clinician for the first time for treatment and that the focus was on DME and ocular co-morbidity management. Any additional treatment for co-existing ocular co-morbidities like cataract, glaucoma, proliferative DR, etc., had to be mentioned separately as well. The maximum number of identical clinician responses in each category was used to determine the ‘majority DME management response’ and ‘majority ocular co-morbidity management response’ for the clinicians. Following that, the same set of clinical case scenarios was presented to three important AI platforms, which included ChatGPT 3.5v, ChatGPT 4.0v, and Bing AI. The text was fed into various AI platforms in such a way that the ophthalmologist appeared to be asking the AI for the best recommended treatment option based on the most recent available guidelines, with separate answers for each eye. After each case scenario, the AI received no feedback, and the case descriptions were entered sequentially without starting a new chat session. The formal responses for each case scenario were documented separately for DME management and co-existing ocular co-morbidity management based on the results generated by various AI platforms. For each specific case scenario, the ‘majority DME management response’ and ‘majority ocular co-morbidity management response’ were determined by identifying the most identical responses among the three distinct AI platforms in each category separately.

Based on clinician and AI platform responses, a consensus was reached on the most common response for each individual case scenario in order to determine the optimal treatment to be followed by a retina specialist in specific clinical situations. For each specific case scenario, the ‘majority’ DME management and ocular co-morbidity management responses were determined by identifying the response with the highest frequency among clinicians and AI platforms. A total of eight responses were considered, with five coming from clinicians and three from AI platforms ( Fig.  1 ) .

figure 1

Flow chart depicting the methodology process

The AIOS-DR Task Force and the VRSI collectively published a consensus paper on the management of DME. The paper suggested treatment guidelines for DME management in a variety of clinical situations involving ocular and systemic co-morbidities. We looked at the treatment practices recommended by our group of clinicians and different AI platforms for similar clinical situations described in that paper. For that, the clinical situations from our current case list were divided into 4 categories: (a) DME management in cases with NCIDME; (b) DME management in cases with treatment-naïve and previously treated CIDME; (c) DME management in cases with co-existing ocular co-morbidities and (d) DME management in cases with co-existing systemic co-morbidities. The purpose of this exercise was to see if recommendations suggested collectively by the clinicians and different AI platforms were consistent with the National guidelines for DME management.

Given the nature of the study, this research was exempted from further approvals by the institutional review board.

Statistical analysis

The inter-rater reliability agreements among various clinicians, different AI platforms, and the ‘majority response’ for AI and clinician, separately for DME management and co-existing ocular co-morbidity management, were determined using Fleiss Kappa and Cohen’s Kappa (ĸ values) analysis. The calculations were performed on DATAtab: Online Statistics Calculator, developed by DATAtab E.U. in Graz, Austria. The calculator can be accessed at the following URL: https://datatab.net . The Kappa result is interpreted as follows: ĸ values ≤ 0 as indicating no agreement and 0.01–0.20 as none to slight, 0.21–0.40 as fair, 0.41– 0.60 as moderate, 0.61–0.80 as substantial, and 0.81–1.00 as almost perfect agreement [ 22 ].

Inter-reliability agreement amongst and between clinicians and different AI platforms for management of DME

The Fleiss kappa test revealed that there was moderate agreement between the five clinicians, with ĸ = 0.60 (95% CI: 0.55–0.65). According to the Fleiss Kappa, there was a moderate agreement between ChatGPT 3.5, ChatGPT 4.0, and Bing AI, with ĸ = 0.58 (95% CI: 0.47–0.69). Cohen’s Kappa revealed a substantial agreement between ‘majority clinician response’ and ‘majority AI response’ for DME management, with ĸ = 0.69 (95% CI: 0.5–0.88). The Cohen’s kappa for the inter-rate reliability agreements between the individual AI platforms and the ‘majority clinician response’ was also calculated. ChatGPT 3.5v, ChatGPT 4.0v, and Bing AI had ĸ values of 0.5 (95% CI: 0.31–0.7), 0.61 (95% CI: 0.41–0.81), and 0.53 (95% CI: 0.34–0.72), respectively.

Inter-reliability agreement amongst and between clinicians and different AI platforms for management of co-existing ocular co-morbidities

There was substantial agreement among the five clinicians for the management of co-existing ocular morbidities, with ĸ=0.80 (95% CI: 0.72–0.88). The Fleiss kappa revealed a fair agreement between ChatGPT 3.5, ChatGPT 4.0, and Bing AI, with ĸ= 0.36 (95% CI: 0.23–0.48). Cohen’s kappa analysis revealed a moderate agreement (ĸ=0.49) between the ‘majority clinician response’ and the ‘majority AI response’. Using Cohen’s kappa analysis, the inter-rater reliability agreements between the individual AI platforms and the ‘majority clinician response’ were calculated. ChatGPT 3.5v, ChatGPT 4.0v, and Bing AI had ĸ values of 0.6, 0.28, and 0.32, respectively ( Tables  1 and 2 ) .

Further analysis of case scenarios was performed to determine whether the recommendations for DME management generated jointly by the clinician and AI were consistent with the National guidelines:

Management of NCIDME:

In our study, we discovered eight (16%) eyes with NCIDME. These eyes all had 20/30 or better VA. In our study, the most common response for this specific situation was observation ( n  = 7, 88%) for DME management.

Management of CIDME:

This study identified 22 (44%) eyes with CIDME. Half of the eyes ( n  = 11, 50%) had untreated CIDME, while the others had already been treated. Four (36%) of the eleven eyes had vision better than 20/30, four (36%) had visual acuities between 20/30 and 20/40, and three (28%) had vision worse than 20/50. Treatment with intravitreal injections was advised in three (75%) of the four eyes with VA ≥ 20/30. Intravitreal injections remained the most preferred treatment option for DME management in eyes with visual acuities ranging from 20/30 to 20/40 (3 out of 4 cases, 75%). In eyes with reduced VA, i.e., 20/50, intravitreal pharmacotherapeutic agents were the only treatment option. Only one (12%) of the eight eyes with good VA, i.e., vision acuity ≥ 20/40, had no visual symptoms. Patients reported visual symptoms in the remaining 7 (88%) cases. Treatment was considered in all eight eyes with good VA, regardless of visual complaints, according to the joint recommendations in our study.

The remaining 11 (50%) eyes with CIDME had previously been treated for DME. Six (55%) eyes had very good VA ranging from 20/20 to 20/30, three (27%) eyes had good VA ranging from 20/30 to 20/40, and two eyes (18%) had reduced VA, i.e., worse than 20/50. Two-thirds (4 eyes, 67%) of the eyes with very good VA, i.e., better than 20/30, were treated with intravitreal injections of steroids or anti vascular endothelial growth factors (VEGF) agents. Only intravitreal pharmacotherapeutic agents were used to treat eyes with VA ≤ 20/40.

Management of CIDME with co-existing ocular co-morbidities:

Six (27%) of the 22 CIDME eyes also had proliferative DR. In such cases, DME was treated with intravitreal antiVEGF injections in three (50%) eyes, intravitreal steroids in one (17%) eye, and macular laser therapy in two (33%) eyes. Macular laser was preferred in two cases where the patient was pregnant at the time. The current study included six (27%) eyes with pseudophakia and CIDME. Treatment for DME was primarily considered with intravitreal steroid agents in four (67%) eyes and intravitreal antiVEGF agents in two (33%) eyes. The remaining 16 (73%) eyes were all phakic. Significant cataract was found in ten (63%) of the sixteen eyes. The rest of the lenses were clear. Treatment with an intravitreal antiVEGF agent was the only preferred treatment of choice in eyes with significant cataract for the management of DME. Cataract surgery was not considered in any of the ten eyes at the same time as intravitreal injection. None of the eyes with CIDME in the current case list had co-existing glaucoma. In the current case list, there was only one eye (5%) with CIDME that had previously undergone pars plana vitrectomy surgery. There were 2 (9%) eyes in the current study who had CIDME and co-existing peripheral lattice degeneration. Prophylactic barrage laser was not advised in both these cases prior to treatment with intravitreal injections.

Management of CIDME with co-existing systemic abnormalities:

There were 15 (68%) eyes with CIDME in the current list of case scenarios that had poor diabetes control, i.e., HbA1c > 6.5%. In none of the clinical situations was DME management withheld in order to achieve metabolic control of diabetes. There were eleven (50%) eyes that had CIDME as well as renal disease and anemia. In such eyes, the most preferred treatment for CIDME was intravitreal antiVEGF agents in 8 eyes (73%) and intravitreal steroids in 3 (27%) eyes. In no case was DME treatment postponed to allow for renal status control. There were 18 (82%) eyes of CIDME with co-existing hypertension on the current list of cases. According to the clinicians’ and AI’s joint recommendations, treatment for CIDME with hypertension in the form of macular laser or intravitreal injections was considered immediately. There were five (23%) eyes with CIDME and a pregnancy. In these eyes, DME was treated with either a macular laser in four (80%) of them or intravitreal steroids in one (20%). In eyes with CIDME and concurrent pregnancy, an intravitreal antiVEGF agent was not considered the best treatment option. Thirteen (43%) of the current cases had DME and a history of cardiovascular disease. Eleven (50%) of these eyes had CIDME, and three (27%) of them had a history of cardiovascular disease within the previous three months. In patients with cardiovascular disease, regardless of its recent history, intravitreal antiVEGF injections were the preferred treatment option.

In summary, this one-of-a-kind study involved noting treatment suggestions for DME and ocular co-morbidity management separately to a set of ocular case scenarios generated by the AI, comparing the responses provided by clinicians and different AI platforms to different clinical situations, and finally match the collective responses provided by the different AI platforms and clinicians to different clinical situations with the previously published recommendations by the AIOS-DR Task Force and the VRSI.

The prevalence of DME, as well as the availability of trained medical personnel, retinal imaging tools, and management options, varies by geographic region [ 4 , 23 , 24 ]. Furthermore, treatment practices differ significantly within a defined region based on a variety of factors such as the type of patient (urban versus rural), the patient’s economic status and countries resource settings, and the availability of treatment options such as intravitreal injections or lasers. As a result, different parts of the world establish their own treatment guidelines for DME management [ 8 , 9 , 10 , 11 , 12 , 13 ]. The International Council of Ophthalmology Guidelines for Diabetic Eye Care 2017 summarised and provided a comprehensive guide for DR screening, referral and follow-up schedules, and appropriate management of vision-threatening DR, including DME and proliferative DR, for countries with high, low, or intermediate resource levels [ 25 ]. We found varying levels of agreement among clinicians in this study for the management of DME as well as the management of ocular co-morbidities. The clinicians who participated in this study provided responses from different regions of the country, treating different groups of patients with varying social and economic backgrounds, which explains the varying levels of agreement among the clinicians.

The current role of AI in DME management is primarily limited to identifying and classifying DME using color fundus photographs and/or optical coherence tomography images, as well as predicting the response to antiVEGF therapy using machine learning or deep learning models [ 14 , 15 , 26 ]. Several chatbots developed using LLM-based generative AI applications have shown promising results in generalizing to previously unseen tasks, such as medical question-answering requiring scientific expert knowledge [ 27 , 28 , 29 ]. LLM understands the medical context, recalls and interprets relevant medical information, and produces a response in a text-based format in order to formulate an answer. Despite mixed results in ophthalmology, LLM appears to have potential for use in eye health care applications. LLM-based generative AI with ChatGPT3.5v and ChatGPT 4.0v has been used in retina for a variety of indications, including ICD for various case encounters [ 30 , 31 ]. The use of LLM-based generative AI for DME management recommendations in the presence of other ocular co-morbidities has yet to be investigated. Furthermore, different chatbot applications react differently to the same situations [ 32 ]. Even in this study, the different AI platforms demonstrated varying levels of agreement for the same clinical case scenario. There was moderate agreement among the different AI platforms for the management of DME and fair agreement for the management of co-existing ocular morbidities. To address this issue, the ‘majority AI response’ was chosen as the preferred method for managing the DME using AI. To improve both the precision and speed of responses, the AI platform must have real-time access to the internet and receive the most up-to-date information. In this study, we discovered that ChatGPT 4.0v performed better and had closer agreements with clinician responses than the other two AI platforms for DME management, while ChatGPT3.5v performed better for co-existing ocular comorbidities management.

A complete ophthalmic examination, as well as a thorough ocular and systemic history, are required for DME management. Most globally accepted treatment guidelines for DME management available in the literature, including protocols developed by the Diabetic Retinopathy Clinical Research Network (DRCR.net), use limited criteria for guiding DME treatment, such as metabolic control status, VA, treatment-naive status, and the involvement of a 1-mm central subfield region on OCT by retinal thickening [ 8 , 9 , 10 , 11 , 12 , 13 , 33 , 34 ]. The AIOS-DR Task Force and the VRSI recently published consensus guidelines in 2021 that looked at some additional criteria such as the presence of co-existing ocular and systemic co-morbidities in addition to the above-mentioned criteria when planning DME management [ 13 ]. As a result, we compared the recommendations made by the clinicians and AI in this study for various clinical case scenarios to the consensus recommendations made by the AIOS-DR Task Force and the VRSI.

According to the current study recommendations, most eyes with NCIDME and good VA (i.e., 20/30) were only observed or rarely treated with topical non-steroidal anti-inflammatory drugs. According to the recommendations of the AIOS-DR Task Force and the VRSI, eyes with good VA should be observed and followed up on at monthly intervals to look for conversion to CIDME or deterioration in VA [ 13 ]. According to protocol R of the DRCR.net, topical non-steroidal anti-inflammatory drugs have no noticeable effect in eyes with NCIDME and good VA [ 35 ].

Intravitreal antiVEGF injections are the first line of treatment for naive CIDME [ 36 , 37 ]. VA is the most important criterion for deciding to initiate treatment, selecting the right intravitreal pharmacotherapeutic antiVEGF agent for its management, and for prognosis purposes, according to most well-established DME treatment guidelines [ 8 , 9 , 10 , 11 , 12 , 13 , 33 , 34 ]. According to DRCR.net protocol V, eyes with treatment-naive CIDME and very good VA, i.e., ≥ 20/30, can be observed and followed up on a monthly basis instead of being treated with intravitreal antiVEGF injections [ 38 ]. In practice, however, treatment of naive CIDME eyes with very good VA is typically initiated with intravitreal antiVEGF injections only if the patient complains of visual symptoms. Intravitreal antiVEGF agents are typically used to treat naive CIDME eyes with VA below 20/30. The presenting VA also influences the choice of antiVEGF agents; for example, in eyes with acuity ≤ 20/50, intravitreal aflibercept injection is the preferred treatment option [ 39 ]. Regardless of presenting VA or patient visual symptoms, intravitreal antiVEGF injection was the only preferred treatment option in the current study recommendations for naive CIDME eyes. In the current study, intravitreal injections, either with antiVEGF agents or steroids, remained the mainstay of DME management for previously treated CIDME eyes. Intravitreal steroids are typically reserved for eyes that have persistent DME or do not respond to monthly antiVEGF injections [ 40 , 41 ].

Proliferative DR and DME are both distinct patterns of retinal microvascular features indicative of small-vessel disease. Treatment-naive proliferative DR should be treated with pan-retinal photocoagulation, according to the AIOS-DR Task Force and the VRSI guidelines [ 13 ]. The presence or absence of vision-threatening traction determines the management regime of CIDME treatment in proliferative DR eyes. Traction that threatens or involves the fovea is an indication for vitrectomy surgery. Intravitreal injections, however, remain the mainstay of DME treatment in the presence of extramacular traction [ 42 ]. Intravitreal steroids are usually preferred in proliferative DR and DME eyes with extensive extramacular proliferations because intravitreal antiVEGF injections can worsen traction due to the crunch phenomenon [ 43 ]. The current study suggests that eyes with DME and proliferative DR without advanced fibrovascular proliferation be treated with intravitreal antiVEGF injections, whereas intravitreal steroid injections are preferred in DME eyes with proliferative DR and extensive fibrovascular proliferation.

The current study included a high proportion of cases with clear lenses, cataractous lenses, and pseudophakia, all of which co-existed with CIDME. In the absence of a visually disabling cataract, the AIOS-DR Task Force and the VRSI recommend that DME be stabilized first with intravitreal injections. However, in the presence of clinically significant cataracts with a poor view of the fundus, and preexisting DME, surgery along with intravitreal antiVEGF or steroid injections can be planned. In some cases, treatment can be scheduled two weeks after surgery and the subsequent protocol be followed [ 13 ]. The current study considered treating DME with intravitreal antiVEGF injections prior to cataract surgery. Vision in the study’s case scenarios ranged from 20/25 to 20/80, indicating moderate vision loss and visually insignificant cataract. This could be the reason why these eyes were treated for DME prior to cataract surgery rather than concurrently with cataract surgery. In the current study, intravitreal steroids were the preferred choice for DME management in pseudophakic eyes in two-thirds of the cases. According to national guidelines, the first step is to determine whether the macular edema in pseudophakic eyes is caused by DME or by Irvine-Gass syndrome. In the presence of DME without the presence of Irvine-Gass syndrome, treatment with antiVEGF injections can be initiated for CIDME, whereas topical or sub tenon’s steroids are recommended as first-line therapy for pseudophakic edema. Topical nonsteroidal anti-inflammatory drugs should be used first, followed by antiVEGF, in the presence of both DME and Irvine-Gass syndrome. It is reasonable to switch to steroids in eyes that have not responded to previous antiVEGF injections (after 3–6 injections) [ 13 ]. Many international experts around the world believe that intravitreal steroids injection with dexamethasone implant is a viable alternative first-line treatment option, particularly in pseudophakic eyes [ 44 ].

National guidelines recommend treating DME in eyes with established glaucoma, ocular hypertension, or steroid responders with either macular laser or antiVEGF injections. In these patients, steroids should be avoided [ 13 ]. There were no cases of CIDME and co-existing glaucoma in the current study’s case scenarios. As a result, comparisons with the National guidelines were not possible in this study. According to experts affiliated with the National guidelines, careful examination of the retinal periphery for identifying lesions that may predispose to retinal detachment, as well as prophylactic barrage laser treatment of those lesions, is recommended. In addition, the time between laser prophylaxis and antiVEGF injections should ideally be three weeks [ 13 ]. However, the current study’s joint experts (AI and clinicians) did not recommend prophylactic laser barrage to lattice degenerations prior to beginning DME treatment with intravitreal injections.

DME treatment in a vitrectomised eye is difficult. There is limited data on the preferred agent for treatment in these eyes. Furthermore, as the environment of the vitreous cavity changes, the pharmacokinetic parameters of antiVEGF may be affected. A recent study comparing the efficacy of ranibizumab injections for the treatment of DME in eyes with and without previous vitrectomy over a two-year period found similar results [ 45 ]. In a similar study, Koyanagi et al. found no significant differences in the mean changes in VA and central macular thickness between the two groups after 6 months [ 46 ]. However, some studies show that intravitreal antiVEGF injections have a lower efficacy in vitrectomised eyes [ 47 ]. Intravitreal dexamethasone implant has also been shown to be effective in both vitrectomised and non-vitrectomised eyes [ 48 , 49 ]. Thus, current evidence suggests that both antiVEGF and steroids have a role in the treatment of DME in vitrectomised eyes.

Poor glycemic control is a risk factor for the progression of DR and DME. Strict glycemic control is beneficial at any stage of diabetes. Poor or fluctuating glycemic control can affect adherence to monthly intravitreal injections. However, in order to achieve good glycemic control, DME management should not be delayed. In the current study, DME management was not postponed in cases of poor diabetes control.

Little is known about the treatment of DME during pregnancy [ 50 ]. According to experts, watchful waiting may be used in cases of mild to moderate DME because the outcomes are similar in patients who receive prompt versus delayed DME treatment [ 51 ]. Because of potential adverse effects on developing embryos or foetuses, intravitreal antiVEGF injections are not recommended during pregnancy. Women should therefore wait at least three months after their last intravitreal injection before conceiving. Ranibizumab is usually preferred over other antiVEGF agents because of its shorter half-life and faster plasma clearance [ 52 ]. When the disease permits it, focal laser or intravitreal steroids are the preferred treatment options for DME in pregnancy [ 50 , 51 ].

The current study’s clinicians and AI jointly proposed the use of intravitreal antiVEGF or steroid injection in eyes with CIDME and deranged renal status. Diabetic nephropathy is often associated with other systemic co-morbidities that affect DME. Secondary hypertension, anemia, patients on or after dialysis, and renal transplantation, for example, may all have an impact on the presence of DME and its management [ 53 , 54 , 55 ]. VEGF inhibitors may have nephrotoxic effects, according to emerging evidence [ 56 ]. However, a recent study published by Ku et al. found no correlation between the use of intravitreal antiVEGF injections and a decrease in estimated glomerular filtration rate [ 57 ]. Several DME treatment guidelines recommend identifying the cause of hypertension and controlling it before beginning treatment with intravitreal antiVEGF injections [ 8 , 9 , 12 , 13 ]. AntiVEGF injections are effective in eyes with DME and well-controlled hypertension [ 58 ]. According to studies, patients with DME or proliferative DR are more likely to have incident or fatal cardiovascular disease than those who do not have DME or PDR [ 59 ]. If a patient has had a stroke or myocardial infarction within the previous 3 months, the AIOS-DR Task Force and the VRSI recommend that antiVEGF treatment be avoided; instead, PRP or steroid treatments should be considered in these patients [ 13 ]. However, a recent systematic review and meta-analysis published by Ngo Ntjam et al. examined the incidence of major cardiovascular adverse events in patients receiving intravitreal administration of anti-vascular endothelial growth factor drugs. They confirmed that intravitreal antiVEGF injections did not cause serious cardiovascular events [ 60 ]. Even in this study, intravitreal antiVEGF injections were the preferred treatment option in DME patients with a history of cardiovascular disease. Table  3 summarizes study’s joint recommendations for managing DME and provides comparisons with the national recommendations for DME management.

There are a few weaknesses with this study. Regarding the clinical case scenarios generated by the AI, the number of case scenarios provided could have been greater, taking into account all possible permutations and combinations involving the DME status, as well as the ocular and systemic co-morbidity status. The clinical case scenarios could have been presented to a larger group of clinicians on a national and international scale, as well as to multiple AI applications. The term ‘majority’ clinician and AI responses used in this study may mislead readers and be misinterpreted as the best response from the entire fraternity of retina specialists and different AI platforms. In the current study, the AI and clinician responses were only compared to the National guidelines proposed by a group of experts affiliated with the AIOS-DR Task Force and the VRSI. The current study’s recommendations could have been compared to international DME management guidelines, making the study’s findings more globally acceptable. Nonetheless, the study has the advantage of adding a completely new dimension to the formulation of DME treatment guidelines by incorporating the role of LLM-based generative AI. The study also emphasizes the importance of considering the patient’s eye and body as a whole when planning DME management. It is possible to make these recommendations globally acceptable by addressing the aforementioned flaws in future DME and AI-related studies. Furthermore, in the future, these globally acceptable DME management recommendations could be integrated with the hospital’s electronic medical record system, alerting ophthalmologists to the best possible treatment option after considering the various factors that may influence DME developments and management. The AI has the capability to analyse and assess its recommendations based on the specific approaches used by different clinicians for managing DME by setting up prompts on the electronic medical record. In the future, AI will incorporate self-learning algorithms tailored to each clinician’s practices, allowing the algorithm to learn from a clinician’s recommendations for a particular patient. This adaptive learning process will help enhance the algorithm’s performance.

In conclusion, this study highlights the significance of AI in aiding experts in revising the existing treatment guidelines for managing DME. An optimal approach for the future would involve merging these treatment guidelines with the hospital’s electronic medical record software, enabling clinicians to promptly select the most effective treatment option for managing DME.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

diabetic macular edema

diabetic retinopathy

artificial intelligence

large language model

All-India Ophthalmological Society

Vitreo-Retina Society of India

optical coherence tomography

visual acuity

center-involving diabetic macular edema

non-center involving diabetic macular edema

vascular endothelial growth factor

Diabetic Retinopathy Clinical Research Network

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Acknowledgements

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Author information

Dr. Ayushi Choudhary and Dr. Nikhil Gopalakrishnan, both claim first authorship for their equal contributions in the study.

Authors and Affiliations

Dept. of Retina and Vitreous, Narayana Nethralaya, #121/C, 1st R Block, Chord Road, Rajaji Nagar, 560010, Bengaluru, Karnataka, India

Ayushi Choudhary, Nikhil Gopalakrishnan, Aishwarya Joshi, Naresh Kumar Yadav, Priyanka Gandhi, Snehal Bavaskar, Vishma Prabhu & Ramesh Venkatesh

Dept of Retina and Vitreous, Little Flower Hospital and Research Centre, 683572, Angamaly, Kerala, India

Divya Balakrishnan

Medical Retina and Vitreoretinal Surgery, University of Pittsburgh School of Medicine, 203 Lothrop Street, Suite 800, 15213, Pittsburg, PA, USA

Jay Chhablani

Anant Bajaj Retina Institute, L V Prasad Eye Institute, Kallam Anji Reddy Campus, 500034, Hyderabad, Telangana, India

Nikitha Gurram Reddy & Padmaja Kumari Rani

Dept. of Cornea and Refractive Services, Narayana Nethralaya, #121/C, 1st R Block, Chord Road, Rajaji Nagar, 560010, Bengaluru, Karnataka, India

Rohit Shetty

Dept. of Vitreo-Retina, Aditya Birla Sankara Nethralaya, 700099, Kolkata, India

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Contributions

RV, RS– conceptualising the study, data acquisition, analysing the data, statistics and results, interpreting the findings, writing & reviewing the manuscript. NG, SB, NKY– validating the questionnaire generated by the AI platform. VP, RPK, JC, DB, RKR– Clinicians responding to the final clinical case scenarios. NG, AJ, AC, PG– collecting the AI responses and collating and analysing the clinician responses. RS– critically reviewing the manuscript.

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Correspondence to Ramesh Venkatesh .

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Choudhary, A., Gopalakrishnan, N., Joshi, A. et al. Recommendations for diabetic macular edema management by retina specialists and large language model-based artificial intelligence platforms. Int J Retin Vitr 10 , 22 (2024). https://doi.org/10.1186/s40942-024-00544-6

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case study of diabetic macular edema

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Functional and anatomical changes in diabetic macular edema after hemodialysis initiation: One-year follow-up multicenter study

  • Yoshihiro Takamura 1 , 2 ,
  • Takehiro Matsumura 2 ,
  • Kishiko Ohkoshi 1 , 3 ,
  • Tatsuhiko Takei 1 , 3 ,
  • Kunihiro Ishikawa 1 , 4 ,
  • Masahiko Shimura 1 , 5 ,
  • Tetsuo Ueda 1 , 6 ,
  • Masahiko Sugimoto 1 , 7 ,
  • Takao Hirano 1 , 8 ,
  • Kei Takayama 1 , 9 ,
  • Makoto Gozawa 2 ,
  • Yutaka Yamada 2 ,
  • Masakazu Morioka 2 ,
  • Masayuki Iwano 10 &
  • Masaru Inatani 2  

Scientific Reports volume  10 , Article number:  7788 ( 2020 ) Cite this article

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Diabetic nephropathy and retinopathy (DR) including diabetic macular edema (DME) are representative microvascular complications of diabetes. We conducted a retrospective multicenter study analyzing records from patients with DR (132 eyes in 70 patients) and end-stage renal diseases (ESRD) who underwent hemodialysis for the first time. We demonstrated that the central retinal thickness (CRT) values were significantly decreased (p < 0.0001), and the best-corrected visual acuity (BCVA) values were improved (p < 0.05) at 1, 3, 6, 9, and 12 months after hemodialysis initiation, in spite of a lack of specific ocular treatments for DME in 93.2% of eyes. We found a significant positive correlation in the rates of CRT changes between right and left eyes. The CRT reductions were greater in eyes with DME type subretinal detachment than in those with spongelike swelling and cystoid macular edema. The visual outcome gain was associated with the CRT reduction at 12 months in the eyes with good initial BCVA ( ≧ 20/50). Hemodialysis induction contributed to functional and anatomical improvements after 1 year, independently of initial laboratory values before the hemodialysis.

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Introduction

Diabetes mellitus (DM) is a chronic disease characterized by persistent hyperglycemia requiring continuous care and management. Diabetic retinopathy (DR) and nephropathy (DN) are representative microvascular complications of DM 1 . DR and DN are life-threatening because these complications can lead to blindness and end-stage renal diseases (ESRD), respectively 1 .

In patients with DR, the visual function can be severely damaged by complications of diabetic macular edema (DME) 2 . DME results from the hyperpermeability of retinal vessels, and intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents has become a gold standard in DME treatment 3 , 4 , 5 . However, many patients with DME show a low response to anti-VEGF treatment, and repeated injections are required to maintain its therapeutic effects 6 , 7 , 8 .

Dialysis is an effective treatment modality for ESRD. In Japan, the number of patients undergoing dialysis increases yearly, and the prevalence was 2,597 patients per million population in 2016 9 . DN was the most common kidney disease (38.8%) requiring dialysis in 2016, followed by chronic glomerulonephritis (28.8%) and nephrosclerosis (9.9%). ESRD and DME are sometimes present in the same patient, and assessing the effect of hemodialysis on DME is clinically important.

Whether dialysis influences the status of DME remains controversial 10 , 11 , 12 , 13 , 14 . Tokuyama et al . found that angiography fluorescein leakage remained constant after dialysis 10 . On the other hand, Perkovich et al . reported that hemodialysis was involved in the resolution of hard exudates and DME 11 . In contrast to these subjective estimations, an objective and quantitative method using optical coherence tomography (OCT) may be more accurate at estimating subtle changes in the retinal thickness. A study found significant reductions in macular thickness by OCT immediately after dialysis, but another one found no changes 30 minutes after hemodialysis 12 , 13 . However, in these studies, the enrolled patients were already on dialysis, and thus, the effect of the hemodialysis initiation is unclear. To clarify this issue, Hwang et al . showed that central retinal thickness (CRT) decreased significantly at 1 month after the first hemodialysis 14 . These studies were small scaled and had short observation terms, and no studies have assessed the DME effects of hemodialysis initiation for longer periods. Therefore, we conducted a large-scale, retrospective, multicenter study and assessed the temporal profiles of CRT and best-corrected visual acuities (BCVAs) for 1 year in patients with DM and ESRD after hemodialysis initiation.

Anatomical change of DME after initiation of hemodialysis

In all, we enrolled 132 eyes from 70 patients in this study. In eight patients, we only included one eye in the analysis, because the other eight eyes did not meet the inclusion criteria: five eyes from five patients had severe corneal opacities with neovascular glaucoma and three had a tractional retinal detachment. Table  1 lists characteristics of the patients at baseline. The mean age was 58.91 ± 10.37 years. Among 132 eyes, 36, 49, and 47 were mild non-proliferative DRs, severe non-proliferative DRs, and proliferative DRs, respectively. We found 118 eyes (89.4%) with DME before the first hemodialysis.

Figure  1A shows the temporal CRT profiles before and after starting hemodialysis in all eyes (a) and in one side of eyes showing thick CRTs at baseline (b). In all eyes, the mean CRTs decreased significantly to 273.4 ± 95.3 μm at 1 month, to 273.7 ± 101.9 μm at 3 months, to 261.8 ± 69.7 μm at 6 months, to 261.3 ± 89.1 μm at 9 months, and to 266.8 ± 78.5 μm at 12 months compared to the mean baseline at 334.0 ± 142.6 μm (p < 0.0001 for each time point). The data of the eyes with thick CRTs also showed a significant decrease from 373.2 ± 149.5 μm to 285.5 ± 102.5 μm at 1 month, to 279.7 ± 81.7 μm at 3 months, to 275.9 ± 69.2 μm at 6 months, to 266.1 ± 84.9 μm at 9 months, and to 268.5 ± 68.7 μm at 12 months (p < 0.0001 for each time point). We investigated the association between the CRT change rates in right and left eyes (Fig.  1B ) and found significant positive correlations at 1 month (p < 0.0001, R 2  = 0.323), 3 months (p < 0.0001, R 2  = 0.323), 6 months (p = 0.002, R 2  = 0.202), and 12 months (p = 0.0008, R 2  = 0.269). The numbers of eyes with intravitreal anti-VEGF injection and sub-Tenon’s triamcinolone acetonide (STTA) injection were seven eyes (5.3%) (5 eyes: aflibercept, 2 eyes: ranibizumab) and two eyes (1.5%), respectively, during 12 months after hemodialysis initiation. The other 123 eyes (93.2%) had no injections of anti-VEGF agents or steroids during the observational periods.

figure 1

OCT findings after hemodialysis initiation. ( A ) Changes in CRT after hemodialysis initiation in all eyes (a) and in the eyes with thick CRTs at baseline (b). Data represent means ± standard deviations (SD). *p < 0.05 (versus baseline). ( B ) Linear correlation in the rate of CRT changes between the right eye and the left eye. We found significant association at 1 ( A ; P < 0.0001, R 2  = 0.323), and 6 ( C ; P = 0.002, R 2  = 0.202). Proximity of the point to the broken line implies a similar CRT rate change between right and left eyes.

In 24.2% of eyes with DME (32/132 eyes), there was a history of intravitreal injections of anti-VEGF drugs and STTA for 1 year prior to the first hemodialysis. In these 32 eyes, the CRT significantly decreased from 349.5 ± 128.4 μm at baseline to 287.5 ± 83.4 μm at 1 month after initiation of hemodialysis (p < 0.0001). No additional injections were performed in 78.1% (25/32 eyes) after first hemodialysis. The average numbers of injections were 2.96 ± 1.92 and 0.25 ± 0.56 for 1 year before and after initiation of hemodialysis, respectively.

Subretinal detachment was sensitive type of DME to induction of hemodialysis

Next, we investigated the type of DME that was sensitive to the induction of hemodialysis. We classified 118 eyes with DME into 3 types including those with spongelike swelling, cystoid macular edema (CME), and subretinal detachment (SRD). At baseline, the incidences for eyes with spongelike swelling, CME, and SRD were 52.5% (62/118), 49.2% (58/118), and 20.3% (24/118), respectively (the number was higher than 118 because some DME types were present on the same eye). We compared the CRT change rates after hemodialysis initiation between the eyes with and without spongelike swelling, CME, or SRD (Fig.  2A ). We found no significant differences in the eyes with the spongelike swelling and CME, but the rate of CRT change in the eyes presenting SRD was significantly lower than that in eyes without SRD at 3 months (p = 0.0304), 6 months (p = 0.0135), and 12 months (p = 0.0305) after hemodialysis initiation. Figure  2B shows the OCT findings of a representative eye with SRD. Before hemodialysis initiation, we observed severe macular swelling on the OCT map and cross-sectional images. One month after dialysis initiation, the CRT decreased from 603 μm to 293 μm, and the BCVA improved from 20/100 to 20/40. Cross-sectional OCT images showed that the subretinal fluid space disappeared in 25.0% (6/24), 16.7% (4/24), and 58.3% (14/24) of the eyes with SRD at 1 month, 3 months, and 6 months, and we did not detect any subretinal fluid at either 9 or 12 months.

figure 2

OCT findings after hemodialysis initiation according to different types of DME. ( A ) CRT change rates between the presence (black bar) and absence (white bar) of spongelike swelling (a), CME (b), and SRD (c). We found significant differences (*p < 0.05) in SRD type at 3, 6, and 12 months after hemodialysis initiation. ( B ) Representative case showing OCT changes after hemodialysis initiation. A 46-year-old man with ESRD and DME initiated hemodialysis. Previous OCTs showed severe SRD (a). At 1 month after the hemodialysis initiation, DME had improved (b), and the BCVA improved from 20/100 to 20/40. Cross-sectional image corresponds to the green line.

BCVA changes after hemodialysis initiation

Figure  3A shows the BCVA changes after hemodialysis initiation in all eyes (a) and the eyes with thick CRTs at baseline (b). In all eyes, the mean BCVAs improved significantly from 0.353 ± 0.365 to 0.318 ± 0.426 at 1 month (p = 0.0011), to 0.297 ± 0.386 at 3 months (p = 0.0012), to 0.276 ± 0.382 at 6 months (p = 0.0023), to 0.239 ± 0.326 at 9 months (p = 0.0028), and to 0.258 ± 0.361 at 12 months (p = 0.0030). In the eyes with thick CRTs, the mean BCVA also improved from 0.335 ± 0.383 to 0.276 ± 0.405 at 1 month (p = 0.0026), to 0.245 ± 0.369 at 3 months (p = 0.0018), to 0.234 ± 0.386 at 6 months (p = 0.0135), to 0.173 ± 0.279 at 9 months (p = 0.0003), and to 0.234 ± 0.329 at 12 months (p = 0.0265).

figure 3

BCVA change after hemodialysis initiation and relation to CRT. ( A ) BCVA changes after hemodialysis initiation in all eyes (a) and in the eyes with thick CRTs at baseline (b). Visual acuity is expressed as the logMAR. Data represent means ± standard deviations (SD). *p < 0.05 (versus baseline). ( B ) Temporal profiles of BCVA and CRT in the patients with good BCVA ( ≧ 20/50) and poor BCVA (<20/50) at baseline. Changes of BCVA (a) and CRT (b) after hemodialysis initiation in the patients with good BCVAs (white circle) and poor BCVAs (black circle). *p < 0.05 (versus baseline). We found a significant correlation between changes of BCVA and CRT at 12 months after hemodialysis initiation in the patients with good BCVAs (c: p = 0.028, R 2  = 0.084), but not in the patients with poor BCVAs (d). The broken line indicates the baseline CRT and BCVA values.

Based on the initial BCVAs, we separated eyes into two groups, eyes with good BCVA (20/50 and higher) and eyes with poor BCVA (lower than 20/50), and then analyzed the BCVA changes (Fig.  3Ba ). In the eyes with good BCVA, the BCVA improved significantly from 0.160 ± 0.198 to 0.111 ± 0.188 at 1 month (p < 0.0001), to 0.103 ± 0.167 at 3 months (p < 0.0001), to 0.115 ± 0.187 at 6 months (p = 0.027), to 0.0994 ± 0.167 at 9 months (p = 0.0017), and to 0.093 ± 0.173 at 12 months (p = 0.0038). On the other hand, the eyes with poor initial BCVA showed no significant BCVA improvements through the observational periods. We also analyzed the CRT changes after hemodialysis initiation (Fig.  3Bb ). In the eyes with good BCVA, we found significant CRT decreases at 1, 3, 6, and 12 months (p < 0.0001 for each time point). In the eyes with poor BCVA, we found significant CRT decreases at 1 (p < 0.0001), 3 (p = 0.0001), 6 (p = 0.0006), and 12 months (p = 0.0027). We found a significant correlation between the BCVA change and the CRT at 12 months in the eyes with good initial BCVA (p = 0.028, R 2  = 0.084) (Fig.  3Bc ) but found no such association in the eyes with poor initial BCVA (Fig.  3Bd ).

We found no significant correlation between renal function markers including serum creatinine (Cr), blood urea nitrogen (BUN), and estimated glomerular filtration rate (eGFR), or systemic factors such as hemoglobin A1c (HbA1c), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), body weight, height, systolic BP, diastolic BP before the hemodialysis initiation and BCVA or CRT change at any time point.

The data of this retrospective multicenter study showed that DME and BCVA improved significantly after the induction of hemodialysis in the eyes with DR of patients with ESRD. The significant CRT reductions were induced rapidly at 1 month after hemodialysis initiation. This finding is consistent with the results of a small-scale study by Hwang et al . 14 showing the CRT change 1 month after hemodialysis initiation. In our study, we showed that the CRT reduction effects were maintained at least for 1 year. We analyzed data from patients who had started hemodialysis for the first time and thus were able to estimate the exact effect on the DME and visual acuity. Also, the accumulation of data from multiple centers enabled us to analyze a large number of cases. To avoid potential biases, we analyzed the data of one eye from each patient, as well as data from both eyes from each patient, and obtained similar results. The enrollment of both eyes led us to find a significant correlation between the CRT changes in the right and left eyes. This indicates that the CRT of the right and left eyes changed in parallel after the hemodialysis initiation. It is possible that the normalization of systemic conditions by the dialysis affected both eyes. Our findings also suggest that renal function systemic factors are associated with the pathogenesis of DME. We observed significantly positive correlations at 1, 3, 6, and 12 months that the hemodialysis effects on the eyes were long-lasting.

Intravitreal anti-VEGF injections have become a standard DME treatment 3 , 4 , 5 , 15 , 16 . Since most eyes in our study (94.7%) had no intravitreal anti-VEGF injections during the year after hemodialysis initiation, we unlikely believe that anti-VEGF therapy contributed to the CRT reductions we observed. The small number of anti-VEGF injections in our patients may be due to the rapid CRT decreases after induction of the hemodialysis, making additional treatments unnecessary. Also, given the poor systemic conditions of patients in this study, the clinicians may have moderated the use of medications to avoid adverse effects of the drugs on the whole body 16 . Eyes with the history of anti-VEGF therapy for DME also showed the significant reduction of CRT and decrease in the number of injections after the initiation of hemodialysis. Based on this result, it is possible that the induction of the hemodialysis may be effective to treat the refractory DME cases to anti-VEGF therapy.

Our data demonstrates that eyes with DME and SRD showed a greater CRT reduction than those without SRD. This suggests that the DME classification, based on OCT images, may have important clinical implications for predicting anatomical improvement of DME in response to hemodialysis induction. SRD is common in DME with a reported incidence of 13% to 45% 17 , 18 that reached 20.3% in our case series. Cross-sectional OCT images of all DME cases with SRD in our study showed that the area of subretinal fluid had disappeared at 6 months after hemodialysis initiation. The mechanism by which hemodialysis initiation may have promoted the absorption of the subretinal fluid is unclear, but we believe that the mutual flow of the excess fluid between the retina and the choroidal tissue or the retinal pigment epithelium may have improved after hemodialysis. Other studies have shown significant decreases of choroidal thickness after hemodialysis 14 , 19 , 20 , 21 . Ishibazawa et al . showed that the reduction of choroidal thickness was greater in patients with diabetes than in patients without it after hemodialysis, implying that systemic fluid accumulation has a greater effect on the diabetic choroid, probably due to damage to the choroidal vasculature, in patients with ESRD 19 . The significant increase in vessel diameter after hemodialysis reflects the ease by which it changes the retinal circulation 22 . The dynamic changes in retinal and choroidal circulations may be associated with the DME improvement. Based on our data, the CRT reduction rates in the eyes with spongelike swelling and CME were approximately 20%, while that of the eyes with SRD was 40%. These data suggest that the SRD type is particularly responsive, although our results showed edema improvements also for the eyes with spongelike swelling and CME after hemodialysis.

We demonstrated that the BCVAs also improved significantly at 1 month and thereafter after hemodialysis initiation. Introducing hemodialysis may contribute to functional and anatomical improvements in patients with ESRD. Moreover, our subgroup analysis showed significant BCVA improvements in the patients with better initial BCVAs ( ≧ 20/50), but not in the patients with poor initial BCVAs (less than 20/50). In the group with good initial BCVA, we found a significant association between the change of BCVA and the CRT at 12 months, and thus, the recovery from edema may have resulted in the improved visual outcomes. On the other hand, the group with poor initial BCVA had no significant visual recovery despite a good anatomical response, and we did not find a significant correlation between the CRT change and the BCVA at 12 months. Therefore, the absorption of excess fluid in retinal tissues did not lead to vision recovery in the eyes with poor initial BCVA. Different causes of functional impairment have been proposed including ischemia, glial reactivity, apoptosis, and photoreceptor integrity 23 , 24 , 25 . In the eyes with these impairments, visual disturbances may be irreversible, even after edema resolution by hemodialysis. Based on our data, the visual acuity at baseline may be clinical predictor of the visual outcome after hemodialysis initiation.

In this study, we found no significant association between the BCVA or CRT changes and systemic values at baseline including those for serum Cr, BUN, eGFR, lipids, BP, or HbA1c. The renal and systemic statuses, which were extremely poor in the patients scheduled to undergo hemodialysis, improved dramatically and rapidly after the first dialysis. Even with some variation in the laboratory values, we expect that improvements in the systemic condition after hemodialysis may effectively improve the visual acuity of patients.

This study had some limitations. Due to its multicenter nature, the conditions determining the hemodialysis initiation timing varied according to each facility. However, we confirmed the significance in the improvements of CRT and BCVA by analyses in each facility (data not shown), strengthening the reliability of our findings. Also, we did not collect blood samples after hemodialysis at the same times; thus, we could not investigate the laboratory value changes after hemodialysis and their associations to the CRT and BCVA changes. Further prospective studies are required to clarify this issue.

In conclusion, our multicenter study demonstrated that hemodialysis initiation results in improvements in DME (especially in those of the SRD type) and in BCVA in patients with ESRD. The CRT changes in right and left eyes were parallel, implying an association between DME pathogenesis and the systemic conditions modified by hemodialysis. Better visual acuity at baseline may be important for obtaining the best visual outcomes after dialysis. Determining the appropriate hemodialysis initiation timing is difficult, but our data suggests that the therapeutic effect on the DME may provide a basis for recommending that patients with ESRD and DME undergo hemodialysis.

We collected data from eight clinical centers throughout Japan. The current study was performed in accordance with the Declaration of Helsinki and with approval from the University of Fukui Institutional Review Board and the ethics committees of the other participating hospitals. All patients provided signed informed consent forms. We registered the study with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) of Japan (ID UMIN 000038081; date of access and registration, September 23, 2019). We retrospectively reviewed the medical records of patients with DR, who started hemodialysis due to ESRD for the first time. The primary objective of this study is to identify any CRT and BCVA changes after dialysis initiation. The secondary objective was to find associations between the types of DME (including spongelike swelling, CME, and SRD) and the hemodialysis induction DME changes. The third objective was to assess any correlations between BCVA changes and the laboratory values before the hemodialysis initiation including serum levels of BUN, blood sugar, HbA1c, Cr, eGFR, total protein, TG, LDL, and HDL.

We enrolled patients with ESRD due to type 2 DM who had started hemodialysis for the first time and who had had it for at least 12 months in each medical center. We invited patients with DR, 20 years and older, who were regularly treated in the hemodialysis unit 3 times a week to participate in this study. We defined the grade of DR in accordance with the criteria of the International Clinical Disease Severity Scale for DR 26 . We excluded patients 1) with retinal diseases other than DR; 2) with severe cataract, corneal diseases, or vitreous hemorrhage resulting in poor-quality OCT image; 3) with intravitreal injection of anti-VEGF drugs and STTA within 3 months before the dialysis start; and 4) treated by peritoneal dialysis.

All patients underwent a complete ophthalmic examination, including BCVA, fundus examination, and OCT (SPECTRALIS, Heidelberg Engineering, Vista, CA, USA) before and at 1, 3, 6, 9, and 12 months after the initiation of the hemodialysis. CRTs were automatically measured as the average retinal thicknesses within a 500 μm radius using the macular thickness protocol. We calculated the CRT rate changes by dividing the CRT before initiation of dialysis by the last measurement. We converted the BCVAs to the logarithm of the minimum angle of resolution (logMAR) scale. We analyzed the temporal profiles of CRT and BCVA in both eyes and one side of eyes in which CRT was greater than other eyes at baseline and defined as “eyes with thick CRT”. We measured eGFR, Cr, BUN, HbA1c, serum albumin, and lipids (HDL, LDL, and TG) in blood samples before the hemodialysis. We reviewed body weight, height, and systolic and diastolic BPs using the patients’ medical records. We classified DME based on OCT scans into three types including spongelike swelling, CME, and SRD 27 . We included eyes with images showing both CME and SRD into both CME and SRD groups.

We performed statistical analyses using JMP (SAS institute, Tokyo, Japan). We compared CRTs and BCVAs among the different time points using the Wilcoxon signed-rank test and considered differences with p-values <0.05 as statistically significant. We expressed data as means ± standard deviations (SD). We used ordinary least square regression analyses to assess correlations between BCVA or CRT and laboratory values before the initiation of dialysis and between the rates of CRT changes of right and left eyes, and CRT changes and BCVA changes at 12 months.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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I am deeply grateful to Prof. Taiji Sakamoto in Kagoshima University Graduate School of Medical and Dental Sciences for his support and encouragement. Publication of this article was supported in part by grants-in aid for scientific research (J160000936) from the Japan Society for the Promotion of Science, Tokyo, Japan.

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Yoshihiro Takamura, Kishiko Ohkoshi, Tatsuhiko Takei, Kunihiro Ishikawa, Masahiko Shimura, Tetsuo Ueda, Masahiko Sugimoto, Takao Hirano & Kei Takayama

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Y.T. contributed with conception or design of the work, data collection, data analysis, drafting the article, and critical revision of the article. T.M., K.O., T.T., K.I., M. Shimura, M. Sugimoto, T.U., T.H., Y.Y., M.M. and K.T. participated in data collection. M.G. participated in data analysis. M. Iwano designed the work. M. Inatani contributed with conception and design of the work.

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Takamura, Y., Matsumura, T., Ohkoshi, K. et al. Functional and anatomical changes in diabetic macular edema after hemodialysis initiation: One-year follow-up multicenter study. Sci Rep 10 , 7788 (2020). https://doi.org/10.1038/s41598-020-64798-4

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case study of diabetic macular edema

case study of diabetic macular edema

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Diabetic Macular Edema

Sponsored in part by Boehringer Ingelheim International GmbH

  • 1.1 Pathophysiology
  • 1.2 Natural History
  • 1.3 Prevalence
  • 1.4 Risk Factors
  • 1.5 Prevention
  • 2.1 History
  • 2.2 Physical Examination
  • 2.4.1 Vision and DME
  • 2.5.1.1 OCT Biomarkers for DME
  • 2.5.2 2. Fluorescein Angiography
  • 2.6 Laboratory Testing
  • 2.7 Differential Diagnosis
  • 3.1 Medical therapy
  • 3.2.1 DRCR Retina Network anti-VEGF treatment algorithm
  • 3.2.2 Clinical considerations in the anti-VEGF treatment of DME
  • 3.2.3 Steroids
  • 3.3.1 Anti-VEGF
  • 3.3.2 Steroids
  • 3.4 Laser Photocoagulation
  • 3.5 Combined Therapy
  • 3.6 Surgery
  • 3.7.1 Intravitreal injections
  • 3.7.2 Laser Photocoagulation
  • 3.8 Prognosis
  • 3.9 Future Directions
  • 4 Further reading
  • 5 References

Disease Definition

Diabetic macular edema (DME) is the accumulation of excess fluid in the extracellular space within the retina in the macular area, typically in the inner nuclear, outer plexiform, Henle’s fiber layer, and subretinal space. [1] [2]

Pathophysiology

case study of diabetic macular edema

Chronic hyperglycemia-related accumulation of advanced glycated end products (AGEs) disrupts the blood retinal barrier (BRB) characterized by endothelial cell junction breakdown and pericyte loss. The inner BRB is composed of endothelial cells in the retinal capillaries, while the outer BRB is composed of retinal pigment epithelium (RPE) cells. Altered BRB leads to interstitial fluid accumulation within and underneath the retina through leakage of molecules dependent on intact cell to cell junctions ( Figure 1 ). [3] Evidence also shows that DME has an inflammatory component to the disease, with several chemokines and cytokines involved in its development. These factors include vascular endothelial growth factor (VEGF), interleukins (ILs), matrix metalloproteinases (MMPs), and tumor necrosis factor (TNF). Upregulation of multiple pathways leads to increased inflammation, oxidative stress, and vascular dysfunction. [4] There are also significant changes in the neurovascular unit, altering the homeostasis between astrocytes, ganglion cells, Müller cells, retinal vascular endothelial cells, and amacrine cells. [5] Retinal vascular permeability changes also involve the kallikrein-kinin system, which induces vasorelaxation via bradykinin and nitric oxide. [6] [7] [8]

Natural History

DME can develop at any stage of diabetic retinopathy (DR), from mild nonproliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR), but is more frequent as the severity of DR increases. DME threatening or at the fovea is more likely to result in blurred vision and metamorphopsia. When the DME involves or threatens the fovea, the risk of moderate visual loss (MVL, defined as a three-line or more decrease of visual acuity, equivalent to a doubling of the visual angle) over 3 years in the Early Treatment of Diabetic Retinopathy Study (ETDRS) was 24% without treatment. [9] The disease course is variable, with some eyes having chronic persistent DME spanning several years, while other eyes have rapid spontaneous resolution, although the risk of recurrence is always present.

The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) found that DME incidence over 25 years among people with type 1 DM (T1DM) was 29%. [10] The Diabetes Control and Complications Trial (DCCT) reported that 27% of people with T1DM had DME within 9 years of onset of diabetes. [11] For people with type 2 DM (T2DM), the WESDR found that 25.4% of those who used insulin and 13.9% of those who did not use insulin had DME. [10] Yau et al. estimated the global prevalence of DME at 6.8% among people with DM. Estimates in the United States are between 2.7% to 3.8%, with non-Hispanic whites less likely to have DME versus non-Hispanic blacks. [12] [13] [14]

case study of diabetic macular edema

Risk Factors

Risk factors for DME and DR are similar. These risks include a longer duration of diabetes mellitus (DM), poor control of DM with elevated hemoglobin A1c (HbA1c), hypertension, and hyperlipidemia. Other secondary risk factors include impaired renal function and the use of thiazolidinediones. [15] [16] [17]

Primary prevention of DME involves intensive control of DM, blood glucose, hypertension, blood lipids, and other systemic risk factors. The Diabetic Retinopathy Clinical Research (DRCR) Protocol W investigated whether aflibercept injections in eyes with baseline moderate to severe NPDR could prevent the eventual development of center-involved DME (ci-DME) with vision loss. [18] Vision loss was defined as a 10 letter or more decrease in visual acuity (VA) at 1 visit, or a 5 to 9 letter decrease at 2 consecutive visits, with the decrease in vision attributed to the ci-DME. The 2-year cumulative probability of developing ci-DME with vision loss was 14.8% in the sham group versus 4.1% in the aflibercept group. However, there was no significant difference in mean change of visual acuity (VA) between both groups. From baseline to the 2-year checkup, eyes treated with sham had a mean (SD) change of -2.0 (6.1) letters, while aflibercept treated eyes had a -0.9 (5.8) letter change (adjusted mean difference 0.5 letters, [97.5% CI: -1.0 to 1.9 letters, p=0.47]. At present, the use of anti-VEGF injections for the prevention of ci-DME is still not the standard of care.

DME is suspected in patients with any level of DR who present with blurred vision or metamorphopsias. A detailed history including the approximate date of onset of diabetes, the use of insulin versus oral antihyperglycemic agents, and the quality of metabolic control (e.g., HbA1c level) should be elicited. Any associated medical problems such as hypertension, hypercholesterolemia, renal disease, and thyroid disease should be identified, along with a thorough review of medications. It should be noted that mild to extensive DME may be present without symptoms evident to the patient.

case study of diabetic macular edema

Physical Examination

Patients undergo a detailed biomicroscopic examination using the slit lamp biomicroscope and indirect ophthalmoscope. Historically, DME classifications were based on the ETDRS definitions of clinically significant macular edema (CSME). The specific criteria for diagnosing CSME were:

  • Retinal thickening at or within 500 μm of the center of the fovea
  • Hard exudates at or within 500 μm of the center of the fovea if adjacent to an area of retinal thickening
  • Retinal thickening of at least 1 disc area any portion of which is within 1500 μm (approximately 1 disc diameter) from the center of the fovea

Thus, CSME as defined by the ETDRS in the 1980s is a clinical diagnosis made by slit-lamp examination using a contact lens. While clinical examinations remain essential for the full evaluation of DME, Optical Coherence Tomography (OCT) is now routinely used to complement physical examination in the diagnosis of DME. The management of DME is currently based on the central subfoveal thickness (CST) on the macular OCT.

Macular thickening with or without hard exudates may be seen with stereo biomicroscopy. However, some eyes may present without apparent signs of retinal thickening on clinical examination despite significant DME as observed using OCT. Thickening can occur in various patterns: focal, multifocal, and diffuse areas of retina thickening. Despite these terms being frequently used, there are no well-established standard definitions, and different authors use them inconsistently. [19] In the ETDRS, focal leakage results from microaneurysms that may be treated with fluorescein angiography (FA) guided focal laser, while diffuse capillary leakage is from a more widespread breakdown of the BRB, which may be treated with grid laser. [20] Hard exudates in various patterns may also be seen, including circinate rings and focal aggregations of exudates ( Figures 2-3 ). Hard exudates consist of lipoprotein residues of serous leakage from damaged vessels, serving as biomarkers for DME.

case study of diabetic macular edema

DME may present with decreased visual acuity (VA), metamorphopsia, changes in color perception, and difficulty reading, although it may also present asymptomatically.

Vision and DME

Studies show a poor to modest correlation between visual acuity and central subfoveal thickness (CST) on OCT, within the range of 0.3-0.5. [21] [22] Over two years, only around 12-14% of the change in VA can be attributed to the change in OCT thickness for eyes with DME. In a study by the DRCR Network, the slope of the best fit line shows an approximately 4.4 letter improvement (95% CI: 3.5, 5.3) for every 100-micron decrease in CST at baseline. [22] Interestingly, on follow-up after treatment with macular laser photocoagulation, there were some eyes with paradoxical improvement in VA with increased CST (7-17% at different time points) and paradoxical worsening of VA with decreased CST (18-26% at different time points). These findings highlight how OCT measurements cannot be used as a perfect surrogate for visual acuity; however, in clinical and research settings, the technology remains an important tool. The DRCR has recommended a 10% change in CST to indicate a real change that can be considered in clinical decision-making.

Diagnostic Procedures

1. optical coherence tomography (oct).

case study of diabetic macular edema

OCT within recent years has quickly become an important ancillary procedure in the diagnosis and treatment of DME. Three basic structural changes can be seen: retinal swelling, cystoid macular edema, and subretinal fluid ( Figure 4 ). Macular scans can quickly and accurately identify even subtle areas of thickening, along with quantitative metrics for different areas. Changes in the anatomic distribution of DME can be monitored over time, especially the fluid’s relationship to the fovea. This information has proven crucial regarding clinical and research implications for the evaluation and management of DME. More recently, the International Council of Ophthalmology (ICO) guidelines for diabetic eye care in 2018 have adopted the clinical entity of center-involved DME (ci-DME) versus non-center involved DME (non-ciDME) for the evaluation of macular fluid ( Figure 5 ). The classification is:

  • Center-involved DME: Retinal thickening in the macula that involves the central subfield zone (1 mm in diameter)
  • Non-center involved DME: Retinal thickening in the macula that does not involve the central subfield zone (1 mm in diameter)

Aside from the location of the swelling, the DRCR retina network has given recommendations on CST treatment thresholds based on sex-matched standards. [23] The thresholds were different per OCT machine since thickness measurements cannot be compared between different devices, with each device having its own normative database and algorithms. In DRCR Protocol T, in conjunction with visual acuity, treatment eligibility thresholds per machine were:

  • Heidelberg Spectralis - 320 μm for men or 305 μm for women
  • Zeiss Cirrus OCT - 305 μm for men or 290 μm for women
  • Zeiss Stratus OCT - 250 μm for both men and women

Moreover, OCT is a more sensitive method for objective evaluation of vitreomacular interface abnormalities (VMIA), which include vitreomacular adhesion (VMA), vitreomacular traction (VMT), and epiretinal membrane (ERM). Identifying VMIA is crucial when diagnosing the etiology of macular edema, whether it is primarily from DME, from secondary causes of VMIA, or combined mechanism macular edema.

case study of diabetic macular edema

OCT Biomarkers for DME

DME's different OCT features have been associated with disparate prognostic outcomes and treatment responses.

  • Disorganization of the retinal inner layers (DRIL) is thought to represent damaged cells within the inner retinal layers, indicating a disruption in the normal visual pathway from the photoreceptors to the ganglion cells. [24] DRIL is identified on OCT when there is disruption of the demarcating interface lines between the ganglion cell-inner plexiform complex (GCL-IPL), inner nuclear layer (INL), outer plexiform layer (OPL), and outer nuclear layer (ONL). Eyes with DRIL have a worse baseline and final VA despite anti-Vascular Endothelial Growth Factor (VEGF) injections and have almost eight times greater risk for poor visual recovery. In contrast, the resolution of DRIL has resulted in better visual outcomes ( Figure 6 ). [25] [26] [27] DRIL was better correlated to VA when compared to glycemic status and CST. [24]
  • External limiting membrane (ELM) and ellipsoid zone (EZ) disruption strongly correlate with baseline and final BCVA. At the same time, restoration of the EZ was a requirement for good visual recovery in some studies ( Figure 7 ). [28] [29] [30] [31] [32] The ELM connects a row of zonular adherents to the photoreceptor cell bodies, while the EZ represents the isthmus between the outer and inner segments of photoreceptors. [33]

case study of diabetic macular edema

2. Fluorescein Angiography

case study of diabetic macular edema

Fluorescein angiography (FA) is performed to identify leaking microaneurysms or capillaries to guide laser treatment, and areas of retinal ischemia. Leakage on the angiogram is not synonymous with retinal edema. Focal DME is characterized by focal leakage from microaneurysms or capillaries. In contrast, diffuse DME is diagnosed when poorly demarcated areas of capillary leakage are present ( Figure 9 ). Recently, there has been a decreasing trend in the use of FA in the management of DME, likely due to the procedure being more invasive and time-consuming compared to OCT. [45] Contraindications to the use of FA include pregnancy and allergy associated with the contrast dye.

Laboratory Testing

Primary: HbA1c (Glycated Hemoglobin), Blood pressure, Lipid Profile.  Secondary: Hemoglobin (anemia exacerbates diabetic retinopathy and may be associated with diabetic nephropathy), Fasting Blood Sugar (FBS), Post Prandial Blood Sugar (PPBS), Urea, Creatinine, Urine microalbumin levels, Thyroid panel.

Differential Diagnosis

case study of diabetic macular edema

Other causes of macular edema include retinal vein occlusion, ruptured macroaneurysm, Irvine-Gass syndrome, radiation retinopathy, hypertensive retinopathy, subfoveal choroidal neovascularization, retinal vein occlusion, and VMIA. OCT and FA ancillary diagnostics can help differentiate between these differential diagnoses ( Figures 10-11 ).

case study of diabetic macular edema

Medical therapy

  • Strict control of diabetes, blood glucose, hypertension, and hypercholesterolemia [46]
  • Diet Modification
  • Weight Loss

Pharmacotherapy

At present, anti-VEGF agents are the first-line treatment for DME requiring treatment. Since 2005, intravitreal bevacizumab has been used off-label for ocular conditions. FDA approved ranibizumab for DME in 2012, Aflibercept in 2014 and Brolucizumab and Faricimab in 2022.  

DRCR Retina Network anti-VEGF treatment algorithm

Six monthly injections are given unless VA is 20/20 or better, and CST is <320μm for men or <305μm for women on the Heidelberg Spectralis, in which case treatment may be withheld starting the 4 th month. At the 6 th monthly visit, if stability is achieved in vision or CST from the previous 2 or more visits, or DME has resolved, further treatment may be withheld. Stability is defined as:

  • No BCVA increase of ≥5 letters (approximately 1 line on a Snellen chart)
  • No decrease in OCT CST ≥10%
  • BCVA decreases ≥5 letters (approximately 1 line on a Snellen chart) in the setting of persistent DME
  • OCT CST increases ≥10%

If there is worsening on follow-up, anti-VEGF injections are resumed. In general, eyes showing stability may be followed-up in 3-4 months, and sooner as needed. Withholding injections does not require 20/20 vision or a dry macula, only evidence of stability over the previous 2 or more visits. DRCR Protocol I published the first anti-VEGF PRN treatment algorithm for DME. Long-term data show that even without using a monthly treatment protocol, eyes with persistent DME often maintain good BCVA over the long term in clinical trial settings. [47] Outside of trial settings, the five-year extension study of Protocol I showed that CST remained stable among eyes given anti-VEGF; however, mean BCVA worsened between the 5 th and 2nd-year time points. [48] On average, patients are given 6-8 injections in the first year, 2-4 injections in the second year, and 0-1 injections beginning the third year. [49]

Clinical considerations in the anti-VEGF treatment of DME

Observation is recommended for eyes with ci-DME and visual acuity of 20/25 or better. This recommendation is based on the findings of DRCR Protocol V, where patients were randomized to receive either aflibercept injections, macular laser, or observation. At the 2-year endpoint, the mean BCVA was 20/20, and the rates of ≥ 5 letter vision loss (16-19%) were similar among all three groups. Given the risks of ocular infection and the costs associated with intravitreal injections, observation is a viable treatment option in these patients if they can reliably follow up and receive appropriate therapy when there is clinical deterioration. In contrast, among eyes with ci-DME presenting with 20/50 vision or worse, Protocol T results showed that aflibercept was superior to both ranibizumab and bevacizumab, with area under the curve analysis showing better visual outcomes over 1 year. [50] However, the superiority of aflibercept over ranibizumab was not maintained at the 2-year checkup. [23] Bevacizumab thinned the retina the least; however, all 3 medications had similar visual outcomes among eyes with baseline vision of 20/40 or better.

Not all treatment results in complete resolution of DME, with 40% of eyes still showing persistent DME (defined as never having a CST < 250μm through 6 months on time-domain OCT) in Protocol I over 2 years. [47] Eyes given bevacizumab were more likely to have persistent DME than eyes given aflibercept. The percentage of eyes with complete resolution increases with each ranibizumab or aflibercept injection. [51] At the 3-year follow-up, eyes with chronic persistent DME still had a significant 7 letter mean improvement compared to baseline, lower than the 13 letter mean improvement in eyes with complete DME resolution. [52] Importantly, only 3.4% of eyes with chronic persistent DME lost ≥ 2 lines of vision over 2 years regardless of the type of anti-VEGF they received. [53] To summarize, in clinical trial settings, a substantial proportion of eyes with persistent DME still have ≥ 2 lines of improvement in vision over the long term, with very few eyes developing considerable vision loss.

For eyes that do not respond optimally, switching to another anti-VEGF drug is a treatment option. The switch is typically from bevacizumab to either ranibizumab or aflibercept, or ranibizumab to aflibercept. The rationale for switching is that aflibercept has 100 times more affinity to VEGF-A than bevacizumab or ranibizumab, while concurrently binding placental growth factor (PIGF) and VEGF-B. [54] Aflibercept also has a longer half-life and can negate more cytokines that promote DME development. Most studies looking at switching are retrospective and show a significant reduction in CST; however, visual outcomes vary. [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] Some eyes may be delayed responders to anti-VEGF. These eyes need more than the initial 3-6 monthly injections to show significant improvement but eventually catch up with immediate responders. [69] [70] It may be viable to continue treatment with the same medication if there is at least a trend of continued improvement, as bevacizumab and ranibizumab are more cost-effective options. Caution is warranted for switching, as any clinical improvement may be due to continued treatment among delayed responders instead of the shift in medications.

DRCR protocol AC was a randomized controlled trial evaluating the relative efficacy of administering aflibercept monotherapy compared with bevacizumab first with a switch to aflibercept (step therapy) in eyes with suboptimal response despite treatment. A total of 312 eyes with moderate vision loss from ci-DME were enrolled. Over a 2-year period, the mean improvement in VA was 14.0 letters in the bevacizumab-first group and 15.0 letters in the aflibercept-monotherapy group (adjusted difference, 0.8 letters; 95% confidence interval, −0.9 to 2.5; P=0.37). At 2 years, the mean changes in VA and retinal CST were similar in the two groups. [71]

Intravitreal steroids improve vision and decrease retinal thickness, as there is an inflammatory component to DME. Steroids have powerful anti-edematous and anti-inflammatory effects as they decrease several pro-inflammatory mediators (IL-6, IL-8, TNF-α, MCP-1, ICAM-1, VEGF, etc). [72] However, long-term results have not shown maintenance of initial clinical improvement. In DRCR Protocol I, although the group given intravitreal triamcinolone had a similar response with ranibizumab in the first 6 months, vision declined due to cataracts. Even with cataract surgery, the final vision did not recover to the levels comparable to the group given ranibizumab. [47] In Protocol U eyes with persistent DME despite at least 6 ranibizumab injections were randomized to continue ranibizumab monotherapy, or shift to ranibizumab plus dexamethasone (Ozurdex). [73] At 6 months average visual gain was similar in both groups, although the improvement in CST was greater in the combination group. Phakic eyes given intravitreal steroids often develop cataracts needing surgery, and are at risk for intraocular pressure (IOP) elevations leading to glaucoma.

Pharmacotherapy Landmark Studies

  • Bevacizumab: Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds VEGF. Bevacizumab is given off-label for the treatment of DME, and remains the most cost-effective treatment option among anti-VEGF medications. [74] In the BOLT study, intravitreal Bevacizumab (1.25 mg) at 6-week intervals was reported to be more effective than modified ETDRS focal/grid laser in terms of improvement in visual acuity at 12 months. [75] In DRCR Protocol T, a comparison between bevacizumab, ranibizumab, and aflibercept, 1-year results showed that bevacizumab thinned the retina the least. [23] However, all 3 medications had similar visual outcomes among eyes with baseline vision of 20/40 or better. [53] Intravitreal bevacizumab doses of 1.25 to 2.5mg have shown improvement in best-corrected visual acuity and reduced macular thickness on OCT at 24 months in The Pan-American Collaborative Retina Study Group. [76]
  • DRCR Protocol I was the first definitive phase III study demonstrating the effectiveness of ranibizumab for DME treatment. [47] Four treatment arms were compared: ranibizumab with immediate grid/focal laser, ranibizumab with macular laser given only for at least 6 months of persistent DME, intravitreal triamcinolone with immediate macular laser, and macular laser with sham injections. Results showed that ranibizumab in an as-needed treatment protocol was superior to laser therapy. Eyes treated with ranibizumab gained an average of 8-9 letters, versus an average of only 3 letters gained with laser therapy at the 1-year endpoint. Protocol I revolutionized the treatment protocol for DME when it was published in 2011. Before this study, macular laser was considered the 1 st line therapy for DME, a treatment protocol originating from the original ETDRS papers first published in 1985.
  • RISE and RIDE - The two-year results for ranibizumab in DME showed that 98% of patients maintained vision (lost less than 15 letters) with 0.3mg monthly injections, 34-45% of patients gained at least 15 letters, and mean visual acuity gain was 10.9 to 12.5 letters. [78] Only 45-49% of patients needed macular laser compared with 91-94% in the control group. No additional benefit was seen with 0.5mg monthly versus 0.3mg ranibizumab monthly. [79]
  • Aflibercept: Aflibercept is a soluble decoy receptor that binds VEGF-A, VEGF-B, and placental growth factor with high affinity. [79] It is termed a decoy receptor or a “VEGF-trap” as VEGF mistakenly binds with aflibercept instead of the body’s native receptors, reducing VEGF’s activity. It is FDA approved for the treatment of DME. In the Da Vinci study, DME patients were assigned randomly to 1 of 5 treatment regimens: Aflibercept 0.5mg every 4 weeks (0.5q4); 2mg every 4 weeks (2q4); 2mg every 8 weeks after 3 initial monthly doses (2q8); or 2mg dosing as needed after 3 initial monthly doses (2prn), or macular laser photocoagulation. [80] Mean improvements in BCVA in the aflibercept groups at week 52 were 11.0, 13.1, 9.7, and 12.0 letters for 0.5q4, 2q4, 2q8, and 2prn regimens, respectively, versus -1.3 letters for the laser group. The proportion of eyes with gains in BCVA of 15 or more ETDRS letters at week 52 in the aflibercept groups were 40.9%, 45.5%, 23.8%, and 42.2% versus 11.4% for laser. Mean reductions in CST in the aflibercept groups at week 52 were -165.4μm, -227.4μm, -187.8μm, and -180.3μm versus -58.4μm for laser. [79] The PHOTON trial evaluated the use of high-dose 8mg aflibercept every 12 (8q12) or 16 (8q16) weeks, compared with conventional dosing of 2mg every 8 weeks. [81] Results showed that the 8mg extended interval dosage was non-inferior to conventional treatment when comparing gains in BCVA and retinal thinning at 48 weeks. There was an increase of 9.2, 8.8, and 7.9 letters, and a mean CST reduction of -165μm, -172μm, and -148μm, for the 2q8, 8q12, and 8q16 groups at 48 weeks, respectively. Patients in the high-dose group with a 50μm increase in CST or a 10-letter loss from week 12 onwards had their dosing schedule shortened to either 12 or 8 weeks, but 93% of patients remained on dosing intervals of 12 weeks or more. There was no increase in hypertension in the high-dose group.
  • Faricimab: Faricimab is a novel combined mechanism inhibitor that binds both Angiopoietin-2 (Ang-2) and VEGF-A with high specificity and affinity. The 1-year results from the phase II BOULEVARD study show that in patients given the 6.0mg dose, there was a statistically significant gain of 3.6 letters over ranibizumab. [82] Moreover, faricimab showed improvement in DR severity, reduced CST, and had a longer time to retreatment than ranibizumab. There were no unexpected safety concerns noted. The phase III YOSEMITE and RHINE non-inferiority trials compared faricimab with aflibercept in patients with DME. [83] The non-inferiority primary endpoint of BCVA was achieved with faricimab given every 8 weeks. More than 50% of patients achieved dosing of every 16 weeks, and more than 70% achieved dosing of every 12 weeks or longer. These results demonstrate the potential of faricimab to decrease the treatment burden on patients by extending the intraocular durability of anti-VEGF. FDA approved the use of faricimab for DME as 4 monthly loading doses followed by injections every 1-4 months, or a loading dose of 6 monthly injections followed up with injections every 2 months.
  • Brolucizumab: Brolucizumab is a single-chain antibody fragment with a high affinity for VEGF. Brolucizumab’s low molecular weight of 26kDa allows more of the drug to be delivered intraocularly per injection, with the potential for increased durability and effective tissue penetration in the eye. The phase III KESTREL and KITE 52 week results showed that brolucizumab was non-inferior to aflibercept in the mean improvement of BCVA, more patients had CST <280μm without persistent macular fluid, and >50% of brolucizumab 6mg patients were maintained on q12 weekly dosage after loading. [84] However, reports of retinal vascular occlusion (RVO) and retinal vasculitis (RV) with intraocular inflammation (IOI) have been reported. [85] [86] Risk factors for developing these adverse reactions include a prior history of IOI or RVO in the 12 months before brolucizumab initiation, female sex, and same-day bilateral injections. [87] [88] FDA approved use of Brolucimab 6 mg for the treatment of DME in June 2022 for an injection every 8-12 weeks after a loading dose of 5 injections 6 weeks apart.
  • Triamcinolone (1 mg or 4 mg) preservative-free intravitreal injection was less effective and had more side-effects for most patients with DME than focal/grid photocoagulation at 2-years follow-up (Protocol B). [89]
  • Dexamethasone (Ozurdex) 0.7 mg biodegradable implant improved vision by at least 15 letters in 22% of patients at 3 years in the phase III MEAD study. [90] The FDA approved the 0.7 mg implant for DME, and at this dose, 41.5% of patients needed anti-glaucoma medications, with 0.6% needing glaucoma surgery. Around 60% of eyes in the 0.7 mg implant group had cataract surgery. The implant is effective for approximately 3-6 months intraocularly.
  • Fluocinolone acetonide (Iluvien) 0.19 mg non-biodegradable implant is a sustained release device effective for up to 3 years intraocularly. It is FDA approved to treat DME in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in IOP. [91] [92] At the 0.2 μg/day dosage BCVA improvement of at least 15 letters was found in 28.7% of patients, with 38.4% needing anti-glaucoma medications and 4.8% needing glaucoma surgery. The latter figure was reduced to 0% among eyes that did not have a history of IOP elevation with a prior steroid challenge. The implant can have complications like the dexamethasone implant, including cataracts and implant migration.

Laser Photocoagulation

case study of diabetic macular edema

Before developing anti-VEGF for DME, the standard treatment for CSME was macular laser photocoagulation since the ETDRS was published in 1985. In “focal” CSME, a focal laser pattern is used to treat leaking microaneurysms identified on the FA that contribute to the retinal edema ( Figure 12 ). In “diffuse” CSME, intraretinal leakage is noted on the FA from dilated retinal capillary beds or intraretinal microvascular abnormalities (IRMA) without isolated, discrete foci of leakage. Macular grid is done for diffuse macular edema ( Figure 13 ). Laser photocoagulation has been shown to decrease the risk of moderate visual loss (loss of 15 or more ETDRS letters) from 24% to 12% by 3 years. [9] After laser treatment, the follow-up examination is at three months. If residual CSME is noted, OCT and FA may be performed to evaluate the benefit and location of repeat laser treatment. With the FDA approval of anti-VEGF for DME, focal/grid laser is only indicated in patients with non-ciDME. Especially in resource-limited countries with decreased access to anti-VEGF agents, macular laser remains a viable treatment option for patients with DME.

case study of diabetic macular edema

Combined Therapy

  • Intravitreal ranibizumab with laser: Intravitreal ranibizumab with prompt (within 1 week) or deferred (after 24 weeks) laser is more effective compared to focal/grid laser alone for the treatment of ci-DME (Protocol I). [47] Ranibizumab is injected intravitreally at baseline with prompt laser, followed by monthly ranibizumab injections for 4 months followed by the continuation of injections at 16 weeks if the OCT central subfield thickness is ≥250 um with visual acuity worse than 20/20.
  • Steroid with laser: Intravitreal triamcinolone (IVT, 4 mg) with focal/grid laser within a week is more effective than laser alone at 4 months (Protocol B). However, long-term benefit with this combined therapy was not seen, with mean BCVA better in the laser monotherapy group than the combined therapy group from the 16-month timepoint until the 2-year endpoint. Complications of steroid therapy included cataracts, ocular hypertension, and glaucoma. The difference in BCVA could not be attributed fully to the development of cataracts. In DRCR Protocol I, visual acuity improvement in eyes given IVT with prompt laser were comparable to eyes given ranibizumab at 6 months, but vision declined afterward until the 2-year timepoint. [47] [93] Subgroup analysis in pseudophakic eyes given IVT showed visual improvement was significantly better than in phakic eyes, with results comparable to pseudophakic eyes given ranibizumab at the 1 and 2-year time points.
  • Intravitreal ranibizumab with peripheral targeted retinal photocoagulation (TRP): The DAVE study was a phase I/II clinical trial that evaluated if ranibizumab with TRP could reduce the number of required anti-VEGF injections compared to ranibizumab monotherapy. [94] Peripheral TRP was defined as retinal photocoagulation administered outside the macula to areas of retinal capillary nonperfusion identified on widefield FA. The nonperfused hypoxic retina is thought to upregulate hypoxia-inducible factors and cytokines, including VEGF and erythropoietin, with small studies suggesting that TRP can decrease the anti-VEGF treatment burden. [95] [96] [97] [98] [99] At the 3-year endpoint, there was no evidence that combined ranibizumab plus TRP reduced treatment burden or improved vision outcomes compared to ranibizumab alone.

No well-constructed studies show a definitive benefit of pars plana vitrectomy (PPV) for managing DME. The theoretical basis for PPV as a treatment option comes from reports that it increases vitreous oxygenation in ischemia, leading to decreased VEGF production, and from the observation that DME is less common among eyes with PVD. [100] [101] [102] [103] [104] [105] Vitreous viscosity also significantly decreases, which may bring about a greater diffusion of pro-inflammatory cytokines away from the macula. [106] Other authors suggest PPV plus internal limiting membrane (ILM) peeling should be attempted, as its removal brings better resolution of the tractional forces at the vitreoretinal interface known to worsen DME. This procedure also prevents proliferating astrocytes from using the ILM as a scaffold which may lead to ERM. [107] In a systematic review looking at PPV for DME, CST was significantly decreased by 102 μm, and a non-significant VA increase of 2 letters was observed. [108] However, the anatomic benefit was not maintained by the 12-month timepoint. A similar meta-analysis looking at PPV plus ILM peeling versus PPV alone showed no significant difference in postoperative vision and macular thickness. [109] DRCR Protocol D, a prospective study of eyes with DME and VMT, found that at 6 months postop, 43% of eyes had a reduction in central subfield thickness to <250 μm. [110] However, the median VA did not change at 6 months. In 38% of eyes the median visual acuity improved by ≥10 letters, and in 22% the median VA decreased by ≥10 letters. Posthoc analysis of DRCR Protocol I showed that previously vitrectomized eyes given anti-VEGF for ci-DME had no improved clinical outcomes compared to non-vitrectomized eyes. [111]

Treatment Complications

Complications, listed below, may arise from the various treatment modalities. The per-injection risk of developing complications is also listed below, when available.

Intravitreal injections

  • Endophthalmitis (0.019-0.05%) [112] [113] [114]
  • Intraocular inflammation (0.09-0.4%) [115]
  • Retinal tears/detachment (0.01-0.08%) [116] [117] [118]
  • Increase in intraocular pressure (For intravitreal steroids, IOP ≥21 mmHg in 45% at 1 month, 20% at 3 months, and 13% of eyes 6 months post-injection.) [119]
  • Cataract (Common after intravitreal steroid injections. By year three, 83% of patients given IVT had cataract surgery.) [120]
  • Subconjunctival hemorrhage (10%) [121]
  • Vitreous hemorrhage
  • Subretinal fibrosis
  • Extension of the laser scar into the fovea
  • Choroidal neovascular membrane
  • Paracentral scotoma
  • Decreased visual acuity
  • Retinal tears and retinal detachment
  • Elevated intraocular pressure
  • Endophthalmitis

Clinical factors associated with better visual outcomes with anti-VEGF treatment include lower hemoglobin A1c, younger age, less severe DR, absence of ERM, quick and consistent CST decreases with anti-VEGF therapy, and absence of prior panretinal photocoagulation (PRP). [122] [123] In terms of anatomic outcomes, eyes with hard exudates within the 6mm foveal center had a larger CST decrease at the end of 1 year. The presence of exudates may be a marker of BRB abnormalities typical of DME responsive to anti-VEGF. Eyes that lack exudates may have other underlying mechanisms of retinal thickening, including cystoid degeneration, traction, or ischemia. In contrast, eyes with high baseline CST ≥ 570μm had a significantly higher chance of developing persistent DME despite monthly ranibizumab therapy. [124] In terms of response to macular laser therapy, the ETDRS reported that worse clinical outcomes were associated with higher blood lipid levels, presence of hard exudates, and diffuse edema. [125]

Matsunaga et al. looked at eyes with DME treated with at least 1 dose of anti-VEGF, and then afterward were lost to follow-up (LTFU) for at least 6 months before returning to the clinic. [126] Their vision worsened significantly at the initial return visit to ~20/69 from ~20/52, however at the 3, 6, and 12-month follow-up, and final checkup, their vision recovered and had no significant difference with their baseline vision. OCT CST also showed similar trends. Gao et al. found that 25% of patients with NPDR and DME had no follow-up for at least 1 year after receiving 1 anti-VEGF injection. [127] Factors associated with LTFU included being Hispanic (OR 1.66), American Indian, Pacific Islander, multiple races (OR 2.6), and unknown race (OR 1.59) compared to whites. Lower adjusted gross income and decreasing baseline vision were also factors significantly associated with LTFU.

Future Directions

Numerous pharmacotherapy trials for DME treatment are underway. The development of a long-acting anti-VEGF that could remain effective in the vitreous for multiple months or years would significantly decrease the treatment burden for patients needing monthly injections. Novel pharmacotherapies based on different mechanisms of action include anti-VEGF designed ankyrin repeat proteins (DARPins), growth factor inhibitors, anti-inflammatory medications, hormone modulators, acetylcholine receptor blockers, IGF-1 receptor blockers, and neuroprotective/antiapoptotic agents. [128] Port delivery systems FDA approved for wet AMD are in development to treat DR and DME. [129] These experimental therapies have the potential to significantly decrease the burden of treatment while restoring vision to DME patients in the coming years ahead.

Teleophthalmology and Artificial intelligence (AI) are being developed as screening tools for diabetic retinopathy and DME. These modalities can detect the retinal complications of diabetes remotely, and if this technology is placed in the offices of internists and endocrinologists, it may allow for early detection and timely intervention. [130] [131]

Further reading

  • Bhagat N, Grigorian RA, Tutela A, Zarbin MA. Diabetic macular edema: pathogenesis and treatment. 2009 Jan-Feb;54(1):1-32
  • Diabetic Retinopathy Clinical Research Network Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology June 2010; 117(6):1064-1077.
  • Early Treatment Diabetic Retinopathy Study: Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 103:1796-1806, 1985.
  • Michaelides M, Kaines A et al A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12 month data. Ophthalmology June 2010; 117(6):1059-1060.
  • Schachat AP. A new approach to the management of diabetic macular edema. Ophthalmology 2010 June;117(6):1059-1060.
  • ↑ Otani T, Kishi S, Maruyama Y. Patterns of diabetic macular edema with optical coherence tomography. American journal of ophthalmology. 1999;127(6):688-693.
  • ↑ Yanoff M, Fine BS, Brucker AJ, et al. Pathology of human cystoid macular edema. Survey of ophthalmology. 1984;28:505-511.
  • ↑ Xu H-Z, Le Y-Z. Significance of outer blood–retina barrier breakdown in diabetes and ischemia. Investigative Ophthalmology & Visual Science. 2011;52(5):2160-2164.
  • ↑ Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. diabetes. 2005;54(6):1615-1625.
  • ↑ Del Zoppo G. The neurovascular unit in the setting of stroke. Journal of internal medicine. 2010;267(2):156-171.
  • ↑ Gao B-B, Clermont A, Rook S, et al. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nature medicine. 2007;13(2):181-188.
  • ↑ Jeppesen P, Aalkjær C, Bek T. Bradykinin relaxation in small porcine retinal arterioles. Investigative ophthalmology & visual science. 2002;43(6):1891-1896.
  • ↑ Parpura V, Basarsky TA, Liu F, et al. Glutamate-mediated astrocyte–neuron signalling. Nature. 1994;369(6483):744-747.
  • ↑ 9.0 9.1 Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Arch ophthalmol. 1985;103:1796-1806.
  • ↑ 10.0 10.1 Klein R, Klein BE, Moss SE, et al. The Wisconsin epidemiologic study of diabetic retinopathy XV: the long-term incidence of macular edema. Ophthalmology. 1995;102(1):7-16.
  • ↑ White NH, Sun W, Cleary PA, et al. Effect of prior intensive therapy in type 1 diabetes on 10-year progression of retinopathy in the DCCT/EDIC: comparison of adults and adolescents. Diabetes. 2010;59(5):1244-1253.
  • ↑ Varma R, Bressler NM, Doan QV, et al. Prevalence of and risk factors for diabetic macular edema in the United States. JAMA ophthalmology. 2014;132(11):1334-1340.
  • ↑ Wong TY, Klein R, Islam FA, et al. Diabetic retinopathy in a multi-ethnic cohort in the United States. American journal of ophthalmology. 2006;141(3):446-455. e441.
  • ↑ Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes care. 2012;35(3):556-564.
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  • ↑ Hsieh Y-T, Tsai M-J, Tu S-T, et al. Association of abnormal renal profiles and proliferative diabetic retinopathy and diabetic macular edema in an Asian population with type 2 diabetes. JAMA ophthalmology. 2018;136(1):68-74.
  • ↑ Fong DS, Contreras R. Glitazone use associated with diabetic macular edema. American journal of ophthalmology. 2009;147(4):583-586. e581.
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  • ↑ Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 2. Ophthalmology. 1987;94(7):761-774.
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  • ↑ Glassman AR, Wells III JA, Josic K, et al. Five-year outcomes after initial aflibercept, bevacizumab, or ranibizumab treatment for diabetic macular edema (Protocol T Extension Study). Ophthalmology. 2020;127(9):1201-1210.
  • ↑ Elman MJ, Ayala A, Bressler NM, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015;122(2):375-381.
  • ↑ Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. The New England journal of medicine. 2015;372(13):1193-1203.
  • ↑ Bressler NM, Beaulieu WT, Glassman AR, et al. Persistent macular thickening following intravitreous aflibercept, bevacizumab, or ranibizumab for central-involved diabetic macular edema with vision impairment: a secondary analysis of a randomized clinical trial. JAMA ophthalmology. 2018;136(3):257-269.
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  • ↑ Lim LS, Ng WY, Mathur R, et al. Conversion to aflibercept for diabetic macular edema unresponsive to ranibizumab or bevacizumab. Clinical Ophthalmology (Auckland, NZ). 2015;9:1715.
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  • ↑ Ashraf M, Souka AA, ElKayal H. Short-term effects of early switching to ranibizumab or aflibercept in diabetic macular edema cases with non-response to bevacizumab. Ophthalmic Surgery, Lasers and Imaging Retina. 2017;48(3):230-236.
  • ↑ Bahrami B, Hong T, Zhu M, et al. Switching therapy from bevacizumab to aflibercept for the management of persistent diabetic macular edema. Graefe's Archive for Clinical and Experimental Ophthalmology. 2017;255(6):1133-1140.
  • ↑ Klein KA, Cleary TS, Reichel E. Effect of intravitreal aflibercept on recalcitrant diabetic macular edema. International journal of retina and vitreous. 2017;3(1):1-7.
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  • ↑ Fechter C, Frazier H, Marcus WB, et al. Ranibizumab 0.3 mg for persistent diabetic macular edema after recent, frequent, and chronic bevacizumab: the ROTATE trial. Ophthalmic Surgery, Lasers and Imaging Retina. 2016;47(11):1-18.
  • ↑ Ferris FL, Maguire MG, Glassman AR, et al. Evaluating effects of switching anti–vascular endothelial growth factor drugs for age-related macular degeneration and diabetic macular edema. JAMA ophthalmology. 2017;135(2):145-149.
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  • ↑ Ross EL, Hutton DW, Stein JD, et al. Cost-effectiveness of aflibercept, bevacizumab, and ranibizumab for diabetic macular edema treatment: analysis from the diabetic retinopathy clinical research network comparative effectiveness trial. JAMA ophthalmology. 2016;134(8):888-896.
  • ↑ Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study): 12-month data: report 2. Ophthalmology. 2010;117(6):1078-1086. e1072.
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  • ↑ Krispel C, Rodrigues M, Xin X, et al. Ranibizumab in diabetic macular edema. World journal of diabetes. 2013;4(6):310.
  • ↑ Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789-801.
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  • ↑ Do DV, Nguyen QD, Boyer D, et al. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology. 2012;119(8):1658-1665.
  • ↑ David M. Brown, on behalf of the PHOTON study investigators. Intravitreal Aflibercept Injection 8mg for DME: 48-Week Results From the Phase 2/3 PHOTON Trial. Presented at the American Academy of Ophthalmology 2022, September 30-October 3, 2022. Website: https://investor.regeneron.com/static-files/da20405e-b843-402e-855b-d824a15dec60. Accessed: November 29, 2022.
  • ↑ Sahni J, Patel SS, Dugel PU, et al. Simultaneous inhibition of angiopoietin-2 and vascular endothelial growth factor-A with faricimab in diabetic macular edema: BOULEVARD phase 2 randomized trial. Ophthalmology. 2019;126(8):1155-1170.
  • ↑ Wykoff CC, Abreu F, Adamis AP, et al. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials. The Lancet. 2022.
  • ↑ Brown DM, Emanuelli A, Bandello F, et al. KESTREL and KITE: 52-week results from two Phase III pivotal trials of brolucizumab for diabetic macular edema. American Journal of Ophthalmology. 2022.
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  • ↑ Takamura Y, Tomomatsu T, Matsumura T, et al. The effect of photocoagulation in ischemic areas to prevent recurrence of diabetic macular edema after intravitreal bevacizumab injection. Investigative ophthalmology & visual science. 2014;55(8):4741-4746.
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  • ↑ Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. New England Journal of Medicine. 2006;355(14):1419-1431.
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  • ↑ Bressler SB, Odia I, Maguire MG, et al. Factors associated with visual acuity and central subfield thickness changes when treating diabetic macular edema with anti–vascular endothelial growth factor therapy: an exploratory analysis of the protocol T randomized clinical trial. JAMA ophthalmology. 2019;137(4):382-389.
  • ↑ Bressler SB, Qin H, Beck RW, et al. Factors associated with changes in visual acuity and central subfield thickness at 1 year after treatment for diabetic macular edema with ranibizumab. Archives of Ophthalmology. 2012;130(9):1153-1161.
  • ↑ Halim MS, Afridi R, Hasanreisoglu M, et al. Differences in the characteristics of subjects achieving complete, partial, or no resolution of macular edema in the READ-3 study. Graefe's Archive for Clinical and Experimental Ophthalmology. 2021:1-8.
  • ↑ Chew EY, Klein ML, Ferris FL, et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy: Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Archives of ophthalmology. 1996;114(9):1079-1084.
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Association of systemic and ocular risk factors with neurosensory retinal detachment in diabetic macular edema: a case–control study

  • Aditi Gupta 1 ,
  • Rajiv Raman 1 ,
  • Vaitheeswaran Kulothungan 2 &
  • Tarun Sharma 1  

BMC Ophthalmology volume  14 , Article number:  47 ( 2014 ) Cite this article

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Diabetic macular edema (DME) with neurosensory retinal detachment (NSD) remains an important cause of visual loss in patients with diabetes. The aim of the study was to elucidate the association of systemic and ocular risk factors with NSD in DME.

In a retrospective case–control study, we reviewed clinical records of all the subjects with DME seen between January 2010 and December 2010. Cases and controls were selected based on optical coherence tomography and stereoscopic biomicroscopy review. NSD was defined as subfoveal fluid accumulation under detached retina with or without overlying foveal thickening. The association between the presence of NSD, blood pressure, lipid status and various other biochemical parameters was evaluated.

Group I (cases) included 37 eyes of 33 patients having DME with NSD and Group II (controls) included 30 eyes of 21 patients having DME without NSD. Patients ranged in age (mean ± SD) from 50 to 62 years (56.6 +/-6.78) for cases and from 51 to 65 years (58.4+/-7.84) for controls. The duration of diabetes ranged from 4 to 15 year (mean 9.45+/-6.08) among cases and 4 to 14 years (9.7+/-5.12) among controls. Significant risk factors for NSD were high values of systolic and diastolic blood pressure (p = 0.039 and 0.043 respectively).

High systolic and diastolic blood pressures are independent and significant risk factors for NSD in DME.

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Diabetic macular edema (DME) remains a major cause of visual loss in patients with diabetes [ 1 ]. Optical coherence tomography (OCT) has specifically been used for characterizing the morphological features of DME, and five OCT patterns of DME have been described: diffuse retinal thickening (DRT), cystoid macular edema (CME), neurosensory retinal detachment (NSD) without posterior hyaloidal traction, posterior hyaloidal traction (PHT) without tractional retinal detachment (TRD) and PHT with TRD [ 2 – 5 ]. NSD under the fovea has been reported in 3–31% of patients with DME [ 2 , 4 – 10 ].

The prognosis of DME is decided by many factors, such as the presence of NSD, inner segment/outer segment (IS/OS) conjunction and integrity of the external limiting membrane (ELM) line [ 11 – 13 ]. IS/OS integrity and intact ELM are important indicators in the evaluation of foveal photoreceptor layer integrity, and correlate strongly with best-corrected visual acuity (BCVA) after medical or surgical treatment of DME [ 11 , 12 ].

The presence of NSD is found to adversely affect the prognosis of DME. NSD can significantly limit effective laser treatment of the macula [ 14 ]. The presence of NSD in DME associated with subretinal exudation has been reported to be associated with poor visual prognosis after vitrectomy [ 2 ]. Likewise, in macular edema secondary to branch retinal vein occlusion, the presence of subfoveal NSD was shown to retard the absorption of macular edema and recovery of vision after grid laser photocoagulation [ 14 ]. The high percentage of NSD in CRVO [ 9 ] may have played a role in the poor response of macular edema to grid laser photocoagulation in the multicenter trial on CRVO by the Central Retinal Vein Occlusion Study Group [ 15 ]. Hence, the need to better understand the pathogenesis of NSD has been stressed [ 15 ]. Although previous studies have extensively reported the systemic and ocular risk factors for the presence of DME [ 16 – 20 ], the risk factors associated with NSD in DME have been rarely studied in detail [ 21 ]. A recent study indicated the presence of high glycosylated hemoglobin (HbA1c) as a risk factor for NSD, suggesting the role of systemic factors in the causation of NSD in DME [ 21 ]. The aim of this study was to elucidate the association of various systemic and ocular risk factors with NSD in Indian subjects with DME.

This study was a retrospective chart review of patients with diagnosed DME seen between Jan 2010 to Dec 2010. Cases and controls were selected based on SD-OCT review. Group I (cases) included 37 eyes of 33 patients who were diagnosed as DME with NSD on OCT and Group II (controls) included 30 eyes of 21 patients who had DME without NSD. The macular edema was diagnosed by biomicroscopy according to the criteria reported by ETDRS. NSD type DME was defined as subfoveal fluid accumulation with distinct outer border of detached retina with or without overlying foveal thickening (Figure  1 ). All cases had NSD associated with DRT or CME (Figure  1 ). All controls had DRT or CME without any NSD (Figure  2 ). Patients with posterior hyaloidal traction (PHT) without TRD and PHT with TRD as documented on OCT, and media opacities such as corneal opacity, dense cataract, vitreous or preretinal hemorrhage, uveitis were excluded from the study. This study was approved by the Institutional Review Board, Vision Research Foundation and adhered to the Declaration of Helsinki. The medical records of all the patients including cases and controls were reviewed, with documentation of patients’ age, gender, duration and type of diabetes mellitus, history of any associated systemic disease like hypertension, hyperlipidemia, nephropathy, ischemic heart disease status post coronary artery bypass surgery, details of systemic medications, history of ocular surgeries including intravitreal injections and laser treatment in the past. The details of patients’ ocular examination findings including BCVA on Snellen chart (later converted to logMAR for statistical analyses), lens status, stage of diabetic retinopathy, OCT findings, and systemic biochemical parameters were also noted. A prototype SD-OCT system (Topcon 3D1000, Tokyo, Japan) was used with an axial resolution of 6u and acquisition rate of approximately 18,000 scans per second. All OCT images were acquired through a dilated pupil. During the OCT examination, macula was scanned on six radial sections including the horizontal, vertical and oblique planes through the centre of the fovea. The retinal thickness was measured as distance of vitreoretinal interface and inner edge of retinal pigment epithelium (RPE) at the maximum point of edema. Central subfield retinal thickness was also noted on OCT.

figure 1

Spectral domain OCT shows diffuse retinal thickening (A) and hyporeflective cystic spaces in the inner retina suggestive of cystoid macular edema (B) with associated subfoveal neurosensory detachment.

figure 2

Spectral domain OCT shows diffuse retinal thickening (A) and hyporeflective cystic spaces in the inner retina suggestive of cystoid macular edema (B) without any neurosensory detachment.

The blood pressure was recorded, in the sitting position, in the right arm to the nearest 2 mm Hg using the mercury sphygmomanometer (Diamond Deluxe BP apparatus, Pune, India). Two readings were taken with a five minutes interval and their mean indication was taken as the blood pressure. In most of the subjects, the blood pressure measurement was taken on the day of complete ophthalmic examination which included OCT. In the remaining subjects, blood pressure was measured on the day of OCT review which was 1 or 2 days later. The biochemical parameters noted were fasting and post-prandial blood sugar levels, hemoglobin, glycosylated hemoglobin, blood pressure and renal function tests (serum urea and serum creatinine). All biochemical parameters were done at same laboratory using standard techniques. The grading of diabetic retinopathy was done based on modified klein classification as mild, moderate and severe nonproliferative diabetic retinopathy and proliferative diabetic retinopathy [ 22 ]. The modification was proposed as a standardized alternative to the more detailed Early Treatment Diabetic Retinopathy Study (ETDRS) system. It involves grading seven stereoscopic standard fields as a whole, and assigning a level of severity for the eye according to the greatest degree of retinopathy using a modified Airlie House Classification scheme [ 22 ].

Statistical analysis

A computerized database was created for all the records. Statistical analyses were performed using SPSS Windows version 14.0 (SPSS Science, Chicago, IL, USA). All the data were expressed as mean ± S.D or as percentage. The normality of distribution was checked for all factors by Kolmogorov–Smirnov analysis. The data in the study followed normal distribution, hence we used the parametric tests to determine significance. Chi-square test was used to compare proportions among neurosensory detachment status with the independent categorical variables and the Student’s t -test was used to compare proportions among neurosensory detachment status with the independent measured (continuous) variables in Univariate analyses. P value less than 0.05 was considered significant. Multivariate analyses could not be done because of small sample size in both the groups.

A total of 37 eyes of 33 patients who had NSD with DME (Group 1, cases) and 30 eyes of 21 patients who had DME without NSD (Group 2, controls) were included in our study. All patients included were of type 2 diabetes mellitus. The patients ranged in age from 50 to 62 years among the cases (mean 56.6 +/-6.7) and 51 to 65 among the controls (mean 58.4+/7.84). The duration of diabetes ranged from 4 to 15 years (mean 9.45+/-6.08) among cases and 4 to 14 years (9.7+/-5.12) among controls. Group 1 included 28 males (84.8%) and 5 females (15.2%) and Group 2 included 14 males (67.7%) and 7 females (33.3%).

Table  1 depicts the comparison of systemic factors associated with cases and controls. There were no significant differences in the two groups in terms of the mean age (p = 0.375), duration of diabetes (p = 0.876), fasting blood sugar and post prandial blood sugar levels (p = 0.959 and 0.436 respectively), glycosylated hemoglobin (p = 0.859), hemoglobin (p = 0.118) and presence of hypertension (p = 0.634). However, the mean systolic and diastolic blood pressures were significantly higher (p = 0.039 and 0.043 respectively) in the NSD group than the control group.

Table  2 compares the ocular factors among eyes with NSD and control eyes. The mean log MAR BCVA was 0.822 +/-0.421 in NSD group and 0.61+/-0.47 in the control group (p 0.056). The mean central macular thickness as determined by OCT was higher in cases than in the controls (485.7 +/-189.81 versus 332.2+/-134.14 microns, p = 0.0004). Cystoid macular edema was more commonly seen than diffuse edema in NSD group, although the difference was not significant (p = 0.085). 35.1% of eyes with NSD had associated proliferative diabetic retinopathy compared to 23.3% in the control group (p = 0.820). There were no significant differences in the two groups in terms of pseudophakic status (p = 0.370). As expected, ocular surgery including anti- VEGF injections were performed more frequently in Group 1 (p = 0.008).

DME remains the leading cause of visual loss among patients with diabetes mellitus. Among the various patterns of DME, NSD under the fovea has been reported in 3–31% of patients. The pathogenesis of NSD is linked not only to the limitations of the draining vascular system, but also to impairment in the function of the RPE. Kang et al. reported that in diabetic eyes, the incidence of CME and NSD increasd with the existence of retinal vascular hyperpermeability and the pathology of these two phenomena might share a common pathogenesis in this regard [ 4 ].

Various systemic factors have been associated with increased incidence of DME like severity of diabetic retinopathy, poor glycemic control and duration of diabetes. Hypertension, proteinuria, dyslipidemia, uncontrolled renal parameters, and PRP for PDR (causing acute choroidal ischemia), have also been associated with increased risk of DME. Although all these factors are known to correlate with increased incidence of DME, very few studies have correlated the presence of uncontrolled systemic disease and biochemical parameters with increased incidence of NSD in DME. Poor control of systemic factors could be related to increased leakage from the capillaries with loss of vascular integrity as well to an impaired function of RPE. One study demonstrated the presence of high HbA1c levels in the patients with diabetic CME and NSD, compared to those with diabetic CME and no associated NSD [ 21 ]. In our study, we did not find a significant association between HbA1c and presence of NSD. Instead, only high mean systolic and diastolic blood pressures were found to be independent and significant risk factors for NSD in DME.

Increased blood pressure has been implicated, through the effects of increased blood flow, to cause damage to the retinal capillary endothelial cells in eyes of diabetic patients [ 23 ]. Elevated blood pressure also alters the retinal arteriolar hemodynamics, causing a reduction in the compliance (i.e., an increase of vascular rigidity) of the arteriolar circulation with increasing risk of DME [ 20 ]. Hypertension is a well recognized cause of NSD preferentially affecting the macular region, although NSD is more commonly accompanied with malignant hypertension [ 24 , 25 ]. The occurrence of NSD in DME can be secondary to excessive leakage in retina or to a poorly functioning RPE. Raised blood pressure can lead to increased retinal leakage as well as ischemic damage to RPE. Another possibility is that diabetes may have caused subclinical choroidal vascular damage in diabetic subjects, rendering the circulatory system more susceptible to further ischemic insult by raised blood pressure.

Choroidal vascular damage causes ischemic damage to the RPE and leads to breakdown of the blood-retinal barrier with transudation of fluid into subretinal space. Hayreh observed that the presence of NSD was correlated to the degree of choroidal circulation disruption. Fluid overload has also been implicated as a cause of NSD [ 26 ].

Anemia is another known risk factor for DME. Low hemoglobin levels can occur in diabetic patients secondary to renal disease or can occur independently. However, the renal disease as measured by serum urea and creatinine was not found to be associated with NSD in this study. Futhermore, anemia was not found as an independent risk factor for formation of NSD. Low hemoglobin has been described as an independent baseline risk factor in the EDTRS for the development of DME and severe visual loss [ 27 ]. Other studies have corroborated this finding [ 18 ] and have also found improvement in the DME status following correction of anemia [ 28 – 30 ]. Correction of anemia (and also supplementation of erythropoietin) was noted to decrease the effects of retinopathy with structural improvement, possibly through improved oxygenation of the macula [ 28 ]. Singh et al. noted spontaneous closure of microaneurysms in diabetic retinopathy with treatment of co-existing anemia [ 30 ]. Friedman et al. reported that increased hematocrit may improve visual acuity due to resolution of macular edema in diabetic retinopathy [ 29 ]. Over the past few years, growing evidence supports the hypothesis that hypoxia contributes to progression of tissue injury in diabetic individuals [ 31 ]. In our study, although the patients with NSD had lower hemoglobin, none of them had significantly low hemoglobin levels which could be clinically called as anemia. This could be the reason why we were unable to find any significant effect of anemia on NSD.

In conclusion, we found high systolic and diastolic blood pressures to be independent and significant risk factors for NSD in DME. The present study suggests that the treating ophthalmologists should get a complete systemic workup done for the presence of co-morbidities especially high blood pressure in subjects with NSD in DME. Achieving adequate metabolic control of associated conditions should be aimed in such subjects. Prospective studies are warranted to see whether decreasing the blood pressure of the patient will help in the resolution of NSD in DME.

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We acknowledge the support of RD Tata Trust, Mumbai, for this project.

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Shri Bhagwan Mahavir Department of Vitreoretinal Services, Sankara Nethralaya, 18, College Road, Chennai 600 006, Tamil Nadu, India

Aditi Gupta, Rajiv Raman & Tarun Sharma

Department of Preventive Medicine and Biostatistics, Sankara Nethralaya, 18, College Road, Chennai, 600 006, Tamil Nadu, India

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AG carried out the data collection, data analysis, and drafted the manuscript. RR conceived the study, and participated in its design and coordination and helped to draft the manuscript. VK helped in data collection, data analysis and performed the statistical analysis. TS helped to conceive the study, supervised the entire study and helped to draft the manuscript. All authors read and approved the final manuscript.

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Gupta, A., Raman, R., Kulothungan, V. et al. Association of systemic and ocular risk factors with neurosensory retinal detachment in diabetic macular edema: a case–control study. BMC Ophthalmol 14 , 47 (2014). https://doi.org/10.1186/1471-2415-14-47

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  • Diabetic macular edema
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  • Blood Pressure

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Assessment of Parafoveal Diabetic Macular Ischemia on Optical Coherence Tomography Angiography Images to Predict Diabetic Retinal Disease Progression and Visual Acuity Deterioration

  • 1 Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
  • 2 Hong Kong Eye Hospital, Hong Kong Special Administrative Region, China
  • 3 NIHR Biomedical Research Centre, Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom
  • 4 2010 Eye & Cataract Centre, Hong Kong Special Administrative Region, China
  • Invited Commentary Optical Coherence Tomography Angiography, Artificial Intelligence, and the Missing Capillaries Amir H. Kashani, MD, PhD; T. Y. Alvin Liu, MD; Craig Jones, PhD JAMA Ophthalmology

Question   Can an automated binary diabetic macular ischemia (DMI) algorithm using optical coherence tomography angiography (OCTA) images predict diabetic retinal disease progression and visual acuity (VA) deterioration?

Findings   In this cohort study of 321 eyes from 178 patients, the presence of DMI on OCTA images demonstrated prognostic value for diabetic retinopathy progression, diabetic macular edema development, and VA deterioration.

Meaning   These findings provide evidence that an OCTA-based DMI evaluation may improve the evaluation of risk of diabetic retinopathy progression, diabetic macular edema development, and VA deterioration beyond traditional risk factors and may provide insights for incorporating both OCTA and artificial intelligence to early detect DMI and further enhance diabetic retinopathy management.

Importance   The presence of diabetic macular ischemia (DMI) on optical coherence tomography angiography (OCTA) images predicts diabetic retinal disease progression and visual acuity (VA) deterioration, suggesting an OCTA-based DMI evaluation can further enhance diabetic retinopathy (DR) management.

Objective   To investigate whether an automated binary DMI algorithm using OCTA images provides prognostic value on DR progression, diabetic macular edema (DME) development, and VA deterioration in a cohort of patients with diabetes.

Design, Setting, and Participants   In this cohort study, DMI assessment of superficial capillary plexus and deep capillary plexus OCTA images was performed by a previously developed deep learning algorithm. The presence of DMI was defined as images exhibiting disruption of fovea avascular zone with or without additional areas of capillary loss, while absence of DMI was defined as images presented with intact fovea avascular zone outline and normal distribution of vasculature. Patients with diabetes were recruited starting in July 2015 and were followed up for at least 4 years. Cox proportional hazards models were used to evaluate the association of the presence of DMI with DR progression, DME development, and VA deterioration. Analysis took place between June and December 2022.

Main Outcomes and Measures   DR progression, DME development, and VA deterioration.

Results   A total of 321 eyes from 178 patients were included for analysis (85 [47.75%] female; mean [SD] age, 63.39 [11.04] years). Over a median (IQR) follow-up of 50.41 (48.16-56.48) months, 105 eyes (32.71%) had DR progression, 33 eyes (10.28%) developed DME, and 68 eyes (21.18%) had VA deterioration. Presence of superficial capillary plexus–DMI (hazard ratio [HR], 2.69; 95% CI, 1.64-4.43; P  < .001) and deep capillary plexus–DMI (HR, 3.21; 95% CI, 1.94-5.30; P  < .001) at baseline were significantly associated with DR progression, whereas presence of deep capillary plexus–DMI was also associated with DME development (HR, 4.60; 95% CI, 1.15-8.20; P  = .003) and VA deterioration (HR, 2.12; 95% CI, 1.01-5.22; P  = .04) after adjusting for age, duration of diabetes, fasting glucose, glycated hemoglobin, mean arterial blood pressure, DR severity, ganglion cell–inner plexiform layer thickness, axial length, and smoking at baseline.

Conclusions and Relevance   In this study, the presence of DMI on OCTA images demonstrates prognostic value for DR progression, DME development, and VA deterioration.

  • Invited Commentary Optical Coherence Tomography Angiography, Artificial Intelligence, and the Missing Capillaries JAMA Ophthalmology

Read More About

Yang D , Tang Z , Ran A, et al. Assessment of Parafoveal Diabetic Macular Ischemia on Optical Coherence Tomography Angiography Images to Predict Diabetic Retinal Disease Progression and Visual Acuity Deterioration. JAMA Ophthalmol. 2023;141(7):641–649. doi:10.1001/jamaophthalmol.2023.1821

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ITF2357 regulates NF-κB signaling pathway to protect barrier integrity in retinal pigment epithelial cells

Affiliations.

  • 1 Ocular Immunology and Angiogenesis Lab, Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin Eye Institute, Milwaukee, Wisconsin, USA.
  • 2 Singapore Eye Research Institute, Singapore, Singapore.
  • 3 Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 4 Epithelial Polarity in Disease & Tissue Regeneration Laboratory, Institute of Molecular and Cellular Biology, A*STAR Agency, Singapore, Singapore.
  • 5 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 6 Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 7 Centre for Vision Research, Duke NUS Medical School, Singapore, Singapore.
  • 8 GROW Research Laboratory, Narayana Nethralaya, Bangalore, India.
  • 9 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
  • PMID: 38430220
  • DOI: 10.1096/fj.202301592R

The robust integrity of the retinal pigment epithelium (RPE), which contributes to the outer brain retina barrier (oBRB), is compromised in several retinal degenerative and vascular disorders, including diabetic macular edema (DME). This study evaluates the role of a new generation of histone deacetylase inhibitor (HDACi), ITF2357, in regulating outer blood-retinal barrier function and investigates the underlying mechanism of action in inhibiting TNFα-induced damage to RPE integrity. Using the immortalized RPE cell line (ARPE-19), ITF2357 was found to be non-toxic between 50 nM and 5 μM concentrations. When applied as a pre-treatment in conjunction with an inflammatory cytokine, TNFα, the HDACi was safe and effective in preventing epithelial permeability by fortifying tight junction (ZO-1, -2, -3, occludin, claudin-1, -2, -3, -5, -19) and adherens junction (E-cadherin, Nectin-1) protein expression post-TNFα stress. Mechanistically, ITF2357 depicted a late action at 24 h via attenuating IKK, IκBα, and p65 phosphorylation and ameliorated the expression of IL-1β, IL-6, and MCP-1. Also, ITF2357 delayed IκBα synthesis and turnover. The use of Bay 11-7082 and MG132 further uncovered a possible role for ITF2357 in non-canonical NF-κB activation. Overall, this study revealed the protection effects of ITF2357 by regulating the turnover of tight and adherens junction proteins and modulating NF-κB signaling pathway in the presence of an inflammatory stressor, making it a potential therapeutic application for retinal vascular diseases such as DME with compromised outer blood-retinal barrier.

Keywords: HDAC inhibitor; ITF2357; NF-κB; diabetic macular edema; inflammation; outer blood-retinal barrier; retinal pigment epithelium.

© 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

  • Blood-Retinal Barrier / metabolism
  • Diabetic Retinopathy* / metabolism
  • Epithelial Cells / metabolism
  • Hydroxamic Acids*
  • Macular Edema* / metabolism
  • NF-KappaB Inhibitor alpha / metabolism
  • NF-kappa B / metabolism
  • Retinal Pigment Epithelium / metabolism
  • Retinal Pigments / metabolism
  • Retinal Pigments / pharmacology
  • Retinal Pigments / therapeutic use
  • Signal Transduction
  • Tight Junctions / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • givinostat hydrochloride
  • NF-KappaB Inhibitor alpha
  • Tumor Necrosis Factor-alpha
  • Retinal Pigments
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Association of systemic and ocular risk factors with neurosensory retinal detachment in diabetic macular edema: a case–control study

Aditi gupta.

1 Shri Bhagwan Mahavir Department of Vitreoretinal Services, Sankara Nethralaya, 18, College Road, Chennai 600 006, Tamil Nadu, India

Rajiv Raman

Vaitheeswaran kulothungan.

2 Department of Preventive Medicine and Biostatistics, Sankara Nethralaya, 18, College Road, Chennai, 600 006 Tamil Nadu, India

Tarun Sharma

Diabetic macular edema (DME) with neurosensory retinal detachment (NSD) remains an important cause of visual loss in patients with diabetes. The aim of the study was to elucidate the association of systemic and ocular risk factors with NSD in DME.

In a retrospective case–control study, we reviewed clinical records of all the subjects with DME seen between January 2010 and December 2010. Cases and controls were selected based on optical coherence tomography and stereoscopic biomicroscopy review. NSD was defined as subfoveal fluid accumulation under detached retina with or without overlying foveal thickening. The association between the presence of NSD, blood pressure, lipid status and various other biochemical parameters was evaluated.

Group I (cases) included 37 eyes of 33 patients having DME with NSD and Group II (controls) included 30 eyes of 21 patients having DME without NSD. Patients ranged in age (mean ± SD) from 50 to 62 years (56.6 +/-6.78) for cases and from 51 to 65 years (58.4+/-7.84) for controls. The duration of diabetes ranged from 4 to 15 year (mean 9.45+/-6.08) among cases and 4 to 14 years (9.7+/-5.12) among controls. Significant risk factors for NSD were high values of systolic and diastolic blood pressure (p = 0.039 and 0.043 respectively).

High systolic and diastolic blood pressures are independent and significant risk factors for NSD in DME.

Diabetic macular edema (DME) remains a major cause of visual loss in patients with diabetes [ 1 ]. Optical coherence tomography (OCT) has specifically been used for characterizing the morphological features of DME, and five OCT patterns of DME have been described: diffuse retinal thickening (DRT), cystoid macular edema (CME), neurosensory retinal detachment (NSD) without posterior hyaloidal traction, posterior hyaloidal traction (PHT) without tractional retinal detachment (TRD) and PHT with TRD [ 2 - 5 ]. NSD under the fovea has been reported in 3–31% of patients with DME [ 2 , 4 - 10 ].

The prognosis of DME is decided by many factors, such as the presence of NSD, inner segment/outer segment (IS/OS) conjunction and integrity of the external limiting membrane (ELM) line [ 11 - 13 ]. IS/OS integrity and intact ELM are important indicators in the evaluation of foveal photoreceptor layer integrity, and correlate strongly with best-corrected visual acuity (BCVA) after medical or surgical treatment of DME [ 11 , 12 ].

The presence of NSD is found to adversely affect the prognosis of DME. NSD can significantly limit effective laser treatment of the macula [ 14 ]. The presence of NSD in DME associated with subretinal exudation has been reported to be associated with poor visual prognosis after vitrectomy [ 2 ]. Likewise, in macular edema secondary to branch retinal vein occlusion, the presence of subfoveal NSD was shown to retard the absorption of macular edema and recovery of vision after grid laser photocoagulation [ 14 ]. The high percentage of NSD in CRVO [ 9 ] may have played a role in the poor response of macular edema to grid laser photocoagulation in the multicenter trial on CRVO by the Central Retinal Vein Occlusion Study Group [ 15 ]. Hence, the need to better understand the pathogenesis of NSD has been stressed [ 15 ]. Although previous studies have extensively reported the systemic and ocular risk factors for the presence of DME [ 16 - 20 ], the risk factors associated with NSD in DME have been rarely studied in detail [ 21 ]. A recent study indicated the presence of high glycosylated hemoglobin (HbA1c) as a risk factor for NSD, suggesting the role of systemic factors in the causation of NSD in DME [ 21 ]. The aim of this study was to elucidate the association of various systemic and ocular risk factors with NSD in Indian subjects with DME.

This study was a retrospective chart review of patients with diagnosed DME seen between Jan 2010 to Dec 2010. Cases and controls were selected based on SD-OCT review. Group I (cases) included 37 eyes of 33 patients who were diagnosed as DME with NSD on OCT and Group II (controls) included 30 eyes of 21 patients who had DME without NSD. The macular edema was diagnosed by biomicroscopy according to the criteria reported by ETDRS. NSD type DME was defined as subfoveal fluid accumulation with distinct outer border of detached retina with or without overlying foveal thickening (Figure  1 ). All cases had NSD associated with DRT or CME (Figure  1 ). All controls had DRT or CME without any NSD (Figure  2 ). Patients with posterior hyaloidal traction (PHT) without TRD and PHT with TRD as documented on OCT, and media opacities such as corneal opacity, dense cataract, vitreous or preretinal hemorrhage, uveitis were excluded from the study. This study was approved by the Institutional Review Board, Vision Research Foundation and adhered to the Declaration of Helsinki. The medical records of all the patients including cases and controls were reviewed, with documentation of patients’ age, gender, duration and type of diabetes mellitus, history of any associated systemic disease like hypertension, hyperlipidemia, nephropathy, ischemic heart disease status post coronary artery bypass surgery, details of systemic medications, history of ocular surgeries including intravitreal injections and laser treatment in the past. The details of patients’ ocular examination findings including BCVA on Snellen chart (later converted to logMAR for statistical analyses), lens status, stage of diabetic retinopathy, OCT findings, and systemic biochemical parameters were also noted. A prototype SD-OCT system (Topcon 3D1000, Tokyo, Japan) was used with an axial resolution of 6u and acquisition rate of approximately 18,000 scans per second. All OCT images were acquired through a dilated pupil. During the OCT examination, macula was scanned on six radial sections including the horizontal, vertical and oblique planes through the centre of the fovea. The retinal thickness was measured as distance of vitreoretinal interface and inner edge of retinal pigment epithelium (RPE) at the maximum point of edema. Central subfield retinal thickness was also noted on OCT.

An external file that holds a picture, illustration, etc.
Object name is 1471-2415-14-47-1.jpg

Spectral domain OCT shows diffuse retinal thickening (A) and hyporeflective cystic spaces in the inner retina suggestive of cystoid macular edema (B) with associated subfoveal neurosensory detachment.

An external file that holds a picture, illustration, etc.
Object name is 1471-2415-14-47-2.jpg

Spectral domain OCT shows diffuse retinal thickening (A) and hyporeflective cystic spaces in the inner retina suggestive of cystoid macular edema (B) without any neurosensory detachment.

The blood pressure was recorded, in the sitting position, in the right arm to the nearest 2 mm Hg using the mercury sphygmomanometer (Diamond Deluxe BP apparatus, Pune, India). Two readings were taken with a five minutes interval and their mean indication was taken as the blood pressure. In most of the subjects, the blood pressure measurement was taken on the day of complete ophthalmic examination which included OCT. In the remaining subjects, blood pressure was measured on the day of OCT review which was 1 or 2 days later. The biochemical parameters noted were fasting and post-prandial blood sugar levels, hemoglobin, glycosylated hemoglobin, blood pressure and renal function tests (serum urea and serum creatinine). All biochemical parameters were done at same laboratory using standard techniques. The grading of diabetic retinopathy was done based on modified klein classification as mild, moderate and severe nonproliferative diabetic retinopathy and proliferative diabetic retinopathy [ 22 ]. The modification was proposed as a standardized alternative to the more detailed Early Treatment Diabetic Retinopathy Study (ETDRS) system. It involves grading seven stereoscopic standard fields as a whole, and assigning a level of severity for the eye according to the greatest degree of retinopathy using a modified Airlie House Classification scheme [ 22 ].

Statistical analysis

A computerized database was created for all the records. Statistical analyses were performed using SPSS Windows version 14.0 (SPSS Science, Chicago, IL, USA). All the data were expressed as mean ± S.D or as percentage. The normality of distribution was checked for all factors by Kolmogorov–Smirnov analysis. The data in the study followed normal distribution, hence we used the parametric tests to determine significance. Chi-square test was used to compare proportions among neurosensory detachment status with the independent categorical variables and the Student’s t -test was used to compare proportions among neurosensory detachment status with the independent measured (continuous) variables in Univariate analyses. P value less than 0.05 was considered significant. Multivariate analyses could not be done because of small sample size in both the groups.

A total of 37 eyes of 33 patients who had NSD with DME (Group 1, cases) and 30 eyes of 21 patients who had DME without NSD (Group 2, controls) were included in our study. All patients included were of type 2 diabetes mellitus. The patients ranged in age from 50 to 62 years among the cases (mean 56.6 +/-6.7) and 51 to 65 among the controls (mean 58.4+/7.84). The duration of diabetes ranged from 4 to 15 years (mean 9.45+/-6.08) among cases and 4 to 14 years (9.7+/-5.12) among controls. Group 1 included 28 males (84.8%) and 5 females (15.2%) and Group 2 included 14 males (67.7%) and 7 females (33.3%).

Table  1 depicts the comparison of systemic factors associated with cases and controls. There were no significant differences in the two groups in terms of the mean age (p = 0.375), duration of diabetes (p = 0.876), fasting blood sugar and post prandial blood sugar levels (p = 0.959 and 0.436 respectively), glycosylated hemoglobin (p = 0.859), hemoglobin (p = 0.118) and presence of hypertension (p = 0.634). However, the mean systolic and diastolic blood pressures were significantly higher (p = 0.039 and 0.043 respectively) in the NSD group than the control group.

Comparison of systemic features amongst cases and controls

S/P CABG: Status post coronary artery bypass graft, HbA1c: Glycosylated hemoglobin, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, FBS: fdasting blood sugar, PPBS: Post prandial blood sugar.

P value <0.05 considered significant (boldface).

Table  2 compares the ocular factors among eyes with NSD and control eyes. The mean log MAR BCVA was 0.822 +/-0.421 in NSD group and 0.61+/-0.47 in the control group (p 0.056). The mean central macular thickness as determined by OCT was higher in cases than in the controls (485.7 +/-189.81 versus 332.2+/-134.14 microns, p = 0.0004). Cystoid macular edema was more commonly seen than diffuse edema in NSD group, although the difference was not significant (p = 0.085). 35.1% of eyes with NSD had associated proliferative diabetic retinopathy compared to 23.3% in the control group (p = 0.820). There were no significant differences in the two groups in terms of pseudophakic status (p = 0.370). As expected, ocular surgery including anti- VEGF injections were performed more frequently in Group 1 (p = 0.008).

Comparison of ocular findings amongst cases and controls

Bcva: Best corrected visual acuity, CMT: Central macular thickness, CME: Cystoid macular edema, DR: Diabetic retinopathy, NPDR: Non proliferative DR, VEGF: Vascular endothelial growth factor, S/P PRP: status post pan retinal therapy.

DME remains the leading cause of visual loss among patients with diabetes mellitus. Among the various patterns of DME, NSD under the fovea has been reported in 3–31% of patients. The pathogenesis of NSD is linked not only to the limitations of the draining vascular system, but also to impairment in the function of the RPE. Kang et al. reported that in diabetic eyes, the incidence of CME and NSD increasd with the existence of retinal vascular hyperpermeability and the pathology of these two phenomena might share a common pathogenesis in this regard [ 4 ].

Various systemic factors have been associated with increased incidence of DME like severity of diabetic retinopathy, poor glycemic control and duration of diabetes. Hypertension, proteinuria, dyslipidemia, uncontrolled renal parameters, and PRP for PDR (causing acute choroidal ischemia), have also been associated with increased risk of DME. Although all these factors are known to correlate with increased incidence of DME, very few studies have correlated the presence of uncontrolled systemic disease and biochemical parameters with increased incidence of NSD in DME. Poor control of systemic factors could be related to increased leakage from the capillaries with loss of vascular integrity as well to an impaired function of RPE. One study demonstrated the presence of high HbA1c levels in the patients with diabetic CME and NSD, compared to those with diabetic CME and no associated NSD [ 21 ]. In our study, we did not find a significant association between HbA1c and presence of NSD. Instead, only high mean systolic and diastolic blood pressures were found to be independent and significant risk factors for NSD in DME.

Increased blood pressure has been implicated, through the effects of increased blood flow, to cause damage to the retinal capillary endothelial cells in eyes of diabetic patients [ 23 ]. Elevated blood pressure also alters the retinal arteriolar hemodynamics, causing a reduction in the compliance (i.e., an increase of vascular rigidity) of the arteriolar circulation with increasing risk of DME [ 20 ]. Hypertension is a well recognized cause of NSD preferentially affecting the macular region, although NSD is more commonly accompanied with malignant hypertension [ 24 , 25 ]. The occurrence of NSD in DME can be secondary to excessive leakage in retina or to a poorly functioning RPE. Raised blood pressure can lead to increased retinal leakage as well as ischemic damage to RPE. Another possibility is that diabetes may have caused subclinical choroidal vascular damage in diabetic subjects, rendering the circulatory system more susceptible to further ischemic insult by raised blood pressure.

Choroidal vascular damage causes ischemic damage to the RPE and leads to breakdown of the blood-retinal barrier with transudation of fluid into subretinal space. Hayreh observed that the presence of NSD was correlated to the degree of choroidal circulation disruption. Fluid overload has also been implicated as a cause of NSD [ 26 ].

Anemia is another known risk factor for DME. Low hemoglobin levels can occur in diabetic patients secondary to renal disease or can occur independently. However, the renal disease as measured by serum urea and creatinine was not found to be associated with NSD in this study. Futhermore, anemia was not found as an independent risk factor for formation of NSD. Low hemoglobin has been described as an independent baseline risk factor in the EDTRS for the development of DME and severe visual loss [ 27 ]. Other studies have corroborated this finding [ 18 ] and have also found improvement in the DME status following correction of anemia [ 28 - 30 ]. Correction of anemia (and also supplementation of erythropoietin) was noted to decrease the effects of retinopathy with structural improvement, possibly through improved oxygenation of the macula [ 28 ]. Singh et al. noted spontaneous closure of microaneurysms in diabetic retinopathy with treatment of co-existing anemia [ 30 ]. Friedman et al. reported that increased hematocrit may improve visual acuity due to resolution of macular edema in diabetic retinopathy [ 29 ]. Over the past few years, growing evidence supports the hypothesis that hypoxia contributes to progression of tissue injury in diabetic individuals [ 31 ]. In our study, although the patients with NSD had lower hemoglobin, none of them had significantly low hemoglobin levels which could be clinically called as anemia. This could be the reason why we were unable to find any significant effect of anemia on NSD.

In conclusion, we found high systolic and diastolic blood pressures to be independent and significant risk factors for NSD in DME. The present study suggests that the treating ophthalmologists should get a complete systemic workup done for the presence of co-morbidities especially high blood pressure in subjects with NSD in DME. Achieving adequate metabolic control of associated conditions should be aimed in such subjects. Prospective studies are warranted to see whether decreasing the blood pressure of the patient will help in the resolution of NSD in DME.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

AG carried out the data collection, data analysis, and drafted the manuscript. RR conceived the study, and participated in its design and coordination and helped to draft the manuscript. VK helped in data collection, data analysis and performed the statistical analysis. TS helped to conceive the study, supervised the entire study and helped to draft the manuscript. All authors read and approved the final manuscript.

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2415/14/47/prepub

Acknowledgements

We acknowledge the support of RD Tata Trust, Mumbai, for this project.

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Medical Xpress

Scientists develop experimental medication that shows promise in treating diabetic macular edema

D iabetes can lead to eye problems, and a common one is diabetic macular edema (DME), causing vision loss. A study published in Nature Medicine suggests a new experimental drug could someday help make treatment of DME more successful and longer-lasting.

The drug—part of a new class of therapeutics called "senolytics"—was developed by scientists at San-Francisco-based UNITY Biotechnology and the Maisonneuve-Rosemont Hospital Research Center, affiliated with Université de Montréal.

Called UBX1325, or foselutoclax, the drug was tested on diabetic patients who didn't respond well to regular treatment.

DME occurs when tiny blood vessels that supply the retina start to leak, cause swelling and vision problems. Current treatments, effective for about half of diabetic patients, often require frequent eye injections and may come with side effects.

The new drug eliminates the troublesome cells, helping the eye to heal.

"We developed UBX1325 to selectively eliminate damaged, senescent cells that propagate disease in the diabetic retina," said the study's lead author, UdeM ophthalmology professor Przemyslaw (Mike) Sapieha, the chief scientist at UNITY.

"By removing senescent cells from the vascular unit, we believe we stimulate healing of the retina," said Sapieha, who holds a Canada Research Chair in Retinal Cell Biology and UdeM's Chaire du FROUM (Fonds de recherche en ophtalmologie).

Just one shot

In the study, patients received just one shot of UBX1325, and the positive effects on their vision lasted at least six months.

"This project was initiated over six years ago, and seeing the translation of this work from bench to bedside has been very exciting," said UdeM assistant professor of optometry Sergio Crespo-Garcia, the study's first author.

"We look forward to exploring the role of cellular senescence in retinal disease beyond diabetic retinopathy."

With 93 million people globally affected by some degree of diabetic retinopathy, according to the American Academy of Ophthalmology, the prevalence of this condition is expected to rise significantly as diabetes continues to spread worldwide.

For over a decade now, the UdeM scientists have worked hard with UNITY to identify molecular pathways that can be targeted to selectively eliminate senescent cells while sparing healthy ones.

UNITY Biotechnology is currently advancing UBX1325 in the Phase 2II ASPIRE trial, a randomized, double-masked, active-controlled study. Data from this trial is expected in the fourth quarter of 2024.

More information: Sergio Crespo-Garcia et al, Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results, Nature Medicine (2024). DOI: 10.1038/s41591-024-02802-4

Provided by University of Montreal

Credit: Unsplash/CC0 Public Domain

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Anterior segment migration of intravitreal dexamethasone implant in a patient with scleral fixation intraocular lens implant: a case report

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Hani B ALBalawi, Naif M Alali, Abdullah H Altemani, Moustafa S Magliyah, Khaled S ASharari, Maram S ALRubayyi, Faris Hashem, Saad H Alenezi, Anterior segment migration of intravitreal dexamethasone implant in a patient with scleral fixation intraocular lens implant: a case report, Journal of Surgical Case Reports , Volume 2024, Issue 3, March 2024, rjae121, https://doi.org/10.1093/jscr/rjae121

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Corticosteroids are crucial for treating inflammatory ocular conditions. The development of dexamethasone revolutionized targeted ocular therapy. Ozurdex, a dexamethasone implant, effectively treats various eye conditions but carries risks such as implant migration. This is a case of anterior segment migration of intravitreal dexamethasone implant, Ozurdex, in a patient with scleral fixation intraocular lens implant in whom conservative management with supine positioning and pharmacologic pupil dilation can help retain the implant back in the vitreous. Patients at high risk of Ozurdex migration should avoid its use. Educate patients on the risk of implant migration and signs of migration to present immediately to an ophthalmology emergency department to avoid corneal damage. It is essential to identify high-risk patients before considering Ozurdex migration. In some cases, conservative management can be initiated while preparing for surgical removal.

Corticosteroids have anti-inflammatory and anti-angiogenic properties that make them an ideal therapeutic option for a variety of posterior segment diseases [ 1 , 2 ], as many highly prevalent ocular diseases are initiated by inflammation and angiogenesis factors [ 3 ]. In the 1950s, the use of corticosteroids in treating ocular diseases started when ophthalmologists used corticosteroids to treat uveitis [ 4–6 ]. The ocular inflammation had been treated previously by elevating body temperature to induce endogenous corticosteroid production [ 7 ]. Dexamethasone was first made in 1957 and was approved for medical use in 1961 [ 8 , 9 ]. Ozurdex is a biodegradable, sustained-release intravitreal implant containing 0.7-mg of preservative-free Dexamethasone of preservative-free Dexamethasone [ 10 ]. In 2009, it was approved by the US Food and Drug Administration to treat macular edema following branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO), and also, for treating non-infectious uveitis affecting the posterior segment of the eye. However, it is contraindicated in ocular or periocular infections, advanced glaucoma, non-intact posterior lens capsules, and hypersensitivity [ 11 ]. Reported side effects include intravitreal injection-related side effects like endophthalmitis [ 12 ] and steroid-related side effects like posterior subcapsular cataracts, increased intraocular pressure, and others [ 13 ]. Patients whose posterior capsule of the lens is absent or defective, have zonular damage, or have a history of vitrectomy are associated with migration of dexamethasone intravitreal implants into the anterior chamber [ 14 ]. This report describes a case in a hospital, of a pseudophakic patient with scleral fixation IOL presented 2 weeks after the Ozurdex procedure with anterior chamber migration of implant in which conservative measurement resolved the migration and avoidance of the surgical intervention for implant removal.

Case report

A 66-year-old male with a history of ‘phacoemulsification’ with posterior chamber ‘intraocular lenses (IOL) implantation5 years back’ in the right eye. Three years later, the patient returned with dislocated IOL in the anterior chamber due to trauma. The patient underwent IOL removal with anterior vitrectomy and scleral fixated IOL. Seven months postoperatively, the patient complained of blurry vision in the right eye. The patient was referred to the retina service, which showed the visual acuity in the right eye was 20/80, the left eye 20/30, and intraocular pressure (IOP) was 16 OU; slit lamp biomicroscopic examination showed the lid and conjunctiva were within normal limits bilaterally. The corneal exanimation shows normal and clear cornea in both eyes; the anterior chamber was deep and quiet bilaterally. The pupil was normal in size with no relative afferent pupillary defect. The scleral fixed IOL is in place OD, and PC-IOL is in place OS. A fundoscopic examination of both eyes indicates a flat retina, normal optic disc, and no vasculitis or retinitis in either eye. In the right eye, a macular edema with central involvement was detected. The patient was diagnosed with pseudophakic cystoid macular edema ( Fig. 1 ) with a central macular thickness of 856 μm. The patient underwent an intravitreal dexamethasone implant (Ozurdex) in the right eye. Two weeks later, the patient presented to the emergency department complaining of painless decreased vision of the right eye with a whitish discoloration object seen behind the cornea. A slit-lamp examination of the right eye indicated mild conjunctival injection and moderate corneal edema. The Ozurdex implant was in the inferior aspect of the anterior chamber, and the IOL was in place with normal IOP. Slit-lamp photos were taken to show the Ozurdex implant in the anterior chamber ( Fig. 2 A and B). B-scan ultrasonography indicated no implant in the posterior chamber. The patient was admitted for bed rest in the supine position, cycloplegic, and scheduled for Ozurdex implant removal with anterior chamber washout the next day.

Optical Coherence Tomography (OCT) of the right eye showed central involvement macular edema with intra-retinal and sub-retinal fluid accumulation.

Optical Coherence Tomography (OCT) of the right eye showed central involvement macular edema with intra-retinal and sub-retinal fluid accumulation.

Anterior segment photo showed the Ozurdex implant migration to the anterior chamber with secondary corneal edema (A), with Descemet folds (B).

Anterior segment photo showed the Ozurdex implant migration to the anterior chamber with secondary corneal edema (A), with Descemet folds (B).

Just before the planned implant removal surgery, the examination indicated no Ozurdex implant in the anterior chamber; the surgery was postponed for re-evaluation. B - scan ultrasonography revealed the Ozurdex implant was back in the vitreous and showed a highly reflective small tube inferior and posterior to the equator and freely mobile ( Fig. 3 ). The patient was discharged with hypertonic saline and topical prednisolone for corneal edema. On follow-up 2 weeks later, the fundus examination showed that the implant was still in place at the vitreous.

Ultrasound b-scan exam of the right eye showed a reflective small tube inferior and posterior to the equator on the 1st day of admission with only bed rest in the supine position and using cycloplegic drops.

Ultrasound b - scan exam of the right eye showed a reflective small tube inferior and posterior to the equator on the 1st day of admission with only bed rest in the supine position and using cycloplegic drops.

The largest series of patients with Ozurdex implants with anterior chamber migration was reported by Khurana et al. They reviewed the risk factors, management, and complications of 15 patients who had prior pars plana vitrectomy, and 93% had no lens capsule. They reported that the average interval from Ozurdex implant injection to the detection of implant migration into the anterior chamber was 13 days. They also reported on two patients with a scleral-fixated posterior chamber IOL. Their first case was treated with surgical removal with no resolution of cornea edema, and the other case was treated with supine bed rest and corneal transplant [ 14 ]. Management options in literature for Ozurdex implant with anterior chamber migration include observation, supine positioning, YAG fragmentation, and surgical removal involving either forceps, aspiration of implant fragments, or repositioning into the posterior chamber [ 15 ].

Our patient had an increased risk for migration because he had undergone an anterior vitrectomy, and there was no capsule and a scleral fixated IOL, so it is better to avoid the use of Ozurdex in high-risk migration patients. However, conservative management with supine positioning and pharmacological pupil dilation can help in returning the migrated Ozurdex implant. Early surgical intervention can help avoid corneal decompensation. We advise that the patient be educated on the risk of implant migration and the signs of migration to present immediately to an ophthalmology emergency department to avoid corneal decompensation. Knowing the high risk of Ozurdex migration patients is critical in choosing candidates. Starting conservative management while preparing patients for surgical removal can help in some cases.

All authors have contributed significantly to the design and conduct of the study. All authors were involved in writing the manuscript at the draft and all revision stages and have read and approved the final manuscript.

The authors declare that they have no competing interests.

None declared.

All data generated or analysed during this study are included in this published article.

The patient was appropriately informed and gave written consent to participate in the study, and the Institute’s Review Board granted ethical approval (IRB approval reference number: RD/26001/6710-18).

The patient has consented to the use of anonymized clinical data for publication. Written informed consent was taken from the patient to publish the case report.

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Schmitz K , Maier M , Clemens CR , et al.  German retinal vein occlusion group. Zuverlässigkeit und Sicherheit von intravitrealen Ozurdex-Injektionen. Die ZERO-Studie [reliability and safety of intravitreal Ozurdex injections. The ZERO study] . Ophthalmologe 2014 ; 111 : 44 – 52 .

Khurana RN , Appa SN , McCannel CA , et al.  Dexamethasone implant anterior chamber migration: risk factors, complications, and management strategies . Ophthalmology 2014 ; 121 : 67 – 71 . https://doi.org/10.1016/j.ophtha.2013.06.033 .

Zafar A , Aslanides IM , Selimis V , et al.  Uneventful anterior migration of Intravitreal Ozurdex implant in a patient with iris-sutured intraocular lens and Descemet stripping automated endothelial Keratoplasty . Case Rep Ophthalmol 2018 ; 9 : 143 – 8 .

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What to Expect From Eye Injections for AMD

Eye injection techniques may vary among specialists

  • Are They Painful?

Eye Injections vs. Eye Drops

  • How to Prepare
  • Tips to Stay Calm
  • How Often Needed

Receiving eye injections for age-related macular degeneration (AMD) can be a real sight-saver for those with this condition. These intravitreal (in-the-eye) injections allow an ophthalmologist to place the medication directly into the vitreous cavity at the back of the eye, where it is needed.

Besides AMD, injections can treat other conditions affecting the light-sensitive retina , such as diabetic retinopathy and retinal vein occlusions (blockages).

Injections for AMD include the new drugs Syfovre (pegcetacoplan) and Izervay (avacincaptad pegol) to slow the progress of geographic atrophy , powerful anti-VEGFs (vascular endothelial growth factor) to keep abnormal blood vessels from growing, steroids to tamp down inflammation, and antibiotics, antifungal drugs, and antiviral drugs to fight infection.

This article will highlight the various kinds of eye injections for AMD, how injections compare to eye drops, how to prepare for the injections, how to minimize injection-related anxiety, and more.

Abraham Gonzalez Fernandez / Getty Images

How Different Types of Eye Injections for AMD Work

Syfovre, Izervay, anti-VEGF agents, steroids, and medications to keep infections in check are all among the types of intravitreal injections your ophthalmologist may prescribe. For years, anti-VEGF injections have helped to preserve sight in people with wet AMD by controlling the growth of leaky abnormal blood vessels that could otherwise damage the retina in this form of AMD.

Beyond wet AMD, eye injections help treat:

  • Geographic atrophy : In this late-stage AMD condition, the macula (responsible for fine vision at the retina's center) thins, and protein deposits build up in the area. This eventually destroys the tissue. The drugs Syfovre and Izervay work to keep geographic atrophy from progressing by targeting proteins in an immune system process called the complement cascade. Overactivity of the complement cascade can lead to damaged retinal cells, and these drugs help slow the process. Geographic atrophy is the second leading cause of vision loss in people over 55 in developed countries, just behind wet AMD.
  • Diabetic retinopathy : This condition is a diabetes complication that can cause fluid leakage from abnormal new blood vessels in the retina. To prevent this, ophthalmologists may prescribe injections of anti-VEGF and a steroid medication.
  • A retinal vein occlusion : With this condition, a vein carrying blood away from the retina can get blocked. Pressure can build up in the circulation, and there can be leakage of fluid onto the retina. Anti-VEGF agents are commonly prescribed here.
  • Uveitis : In these cases, the tissue within the eye becomes inflamed and swells and may leak onto the retina, which anti-VEGF can help to prevent.
  • Endophthalmitis : This is an infection inside the eye. For severe infections inside the eye, ophthalmologists may prescribe intravitreal injections of antibiotic, antiviral, and antifungal medication.
  • Retinal detachment : If the retina pulls away from the back of the eye, a tiny gas bubble can be injected into the eye to push this back in place and repair the damage.
  • Diabetic macular edema : With this condition, fluid collects in the retina. To prevent vision loss, an ophthalmologist can inject an anti-VEGF agent into the retina, where it can reduce swelling.

Are Eye Injections Painful?

While the idea of an eye injection may be alarming, it usually is not painful. In some cases, you may feel nothing, while in others, you may briefly feel some moderate discomfort.

As part of the process (in most cases), the ophthalmologist will put numbing eye drops in your eye so that you will likely only feel some pressure during the injection.

Cost of Eye Injections

Eye injections typically come with a significant price tag, although not always. The anti-VEGF agents Eylea (aflibercept) and Eylea HD cost around $1,850 - $3,200 per dose. For treating wet AMD, a 0.5 milligram (mg) dose of Lucentis (ranibizumab) costs between $1,950 and $2,023, and a less concentrated 0.3 mg dose for treating diabetic macular edema goes for around $1,170 per dose.

Meanwhile, Avastin (bevacizumab), which was initially approved by the Food and Drug Administration (FDA) for treating colon cancer, must be used off-label for AMD or diabetic macular edema since it is not FDA-approved for these conditions. Still, it is much less expensive at just $50 or $60 a dose.

Newer geographic atrophy agents include Syfovre (pegcetacoplan), priced at $2,190 per dose, and Izervay (avacincaptad pegol), priced at $2,520 per dose.

All FDA-approved treatments offer financial assistance programs that may lower your costs. For instance, Eylea has the EYLEA4U program. Consult with your doctor to determine your eligibility.

Although the idea of an eye injection may not be as appealing as simply putting in eye drops, there are advantages and disadvantages to both. Here's what to consider.

Intravitreal injections can be sight-saving. Study results show that over 90% of people receiving anti-VEGF injections maintained their vision. While real-world statistics put this more in line with about 50%, those who keep up with their injections as directed by their provider can likely expect results more in line with the research.  

However, while this treatment can keep abnormal new blood vessels from forming, once the retina is damaged, it currently cannot be reversed.

In studies, Syfovre showed as much as a 22% reduction in geographic atrophy lesion growth over two years and Izervay showed a 14% reduction over one year. Receiving Syfovre or Izervay can slow the progression of geographic atrophy but does not reverse it.

Meanwhile, for drops, the big advantage is patient appeal. Research shows that people strongly prefer drops, with around 76% claiming they would prefer this to intravitreal injections. The thinking is this could translate into increased compliance with treatment.

While eye injections are usually considered safe, there can be complications. Some potential complications to watch for include:

  • The threat of endophthalmitis infection in the eye
  • A case of pseudo endophthalmitis (inflammation inside the eye without infection) from a reaction to a medication
  • Bleeding in the eye from a vitreous hemorrhage
  • Retinal detachment

Meanwhile, no drops have yet been shown to be effective in humans for treating AMD.

How to Prepare for Eye Injections

It's natural to be wary of an eye injection at first. The best way to prepare is to understand the process clearly.

Before the injection, the ophthalmologist will numb your eye and use a device to keep you from blinking during the injection. They will also clean the eye surface with an iodine solution.

After numbing the eye, the ophthalmologist will determine where the injection should go. Usually, this will be on the lower part of your eye near your ear. They will likely ask you to look up so they can inject the medication here using a tiny needle.

During the injection, you may see the medication combining with fluid in the eye in the form of a web of lines. That's completely normal.

After completing the injection, the ophthalmologist will examine and clean the eye. Don't be surprised if your eye is sore and your vision is somewhat cloudy for the first few days.

If needed, you can take an over-the-counter pain reliever and use a cool cloth for comfort. You may also need to use antibiotic drops for a few days to prevent infection.

Make sure you have someone available to drive you home immediately after the procedure.

Stay Calm During the Eye Injection

If you're still worried that you may be a little rattled, here are some measures to take that may help you remain calm:

  • Ask for music to be played during the procedure.
  • Have support in the room, such as a family member, friend, or even another staff member.
  • Ask to have a pillow placed under your neck for support.
  • Squeeze a stress ball to ease tension.
  • If you're undergoing treatment in both eyes, ask that both procedures be done on the same day.
  • Ask the ophthalmologist to warn you before doing the injection.

How Often to Have Eye Injections

You will need to receive eye injections to control AMD periodically. Initially, most people can expect to get anti-VEGF injections once a month, although some agents last longer than others.

In some cases, you may get these less often over time and may even eventually be able to stop. But for others, the need for such eye injections to keep abnormal blood vessels from forming and preserve vision will continue.

If you are receiving Syfovre injections, you will need these every 25 to 60 days. Izervay is given monthly.

Eye injections can help treat AMD and other conditions such as diabetic retinopathy and retinal vein occlusions. These can deliver the newly approved Syfovre or Izervay for combating geographic atrophy, anti-VEGF medication, and drugs to fight infection and inflammation.

While it's natural to have concerns about eye injections, the use of numbing drops keeps discomfort to a minimum. The injections themselves can slow AMD, as well as geographic atrophy, and help to preserve vision.

The American Society of Retinal Specialists. Intravitreal injections.

Foundation Fighting Blindness. FDA approves Apellis' Syfovre, for the treatment of geographic atrophy secondary to age-related macular degeneration (AMD) .

Cruz-Pimentel M, Wu L. Complement inhibitors for advanced dry age-related macular degeneration (geographic atrophy): Some light at the end of the tunnel? J Clin Med . 2023 Aug 4;12(15):5131. doi: 10.3390/jcm12155131

Virgili G, Parravano M, Evans JR, Gordon I, Lucenteforte E. Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis. Cochrane Database Syst Rev . 2018;10(10):CD007419. doi:10.1002/14651858.CD007419.pub6

Bright Focus Foundation. Injections for wet macular degeneration: What you need to know.

American Academy of Ophthalmology. Expensive drugs.

Review of Optometry. First geographic atrophy drug approved.

American Academy of Ophthalmology. New treatments for macular degeneration.

Bright Focus Foundation. Can macular degeneration be reversed?

Heier JS, Lad EM, Holz FG, Rosenfeld PJ, Guymer RH, Boyer D, et al. OAKS and DERBY study investigators. Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials . Lancet . 2023 Oct 21;402(10411):1434-1448. doi: 10.1016/S0140-6736(23)01520-9

Khanani AM, Patel SS, Staurenghi G, Tadayoni R, Danzig CJ, Eichenbaum DA, et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial . Lancet . 2023 Oct 21;402(10411):1449-1458. doi: 10.1016/S0140-6736(23)01583-0

Jacobs B, Palmer N, Shetty T, et al. Patient preferences in retinal drug delivery. Sci Rep . 2021;11(1):18996. doi:10.1038/s41598-021-98568-7

American Society of Retina Specialists. Intravitreal injections.

American Academy of Ophthalmology. Eyedrop for AMD.

Texas Retina Associates. What to expect from an eye injection.

Gomez J, Koozekanani DD, Feng AZ, et al. Strategies for improving patient comfort during intravitreal injections: results from a survey-based study . Ophthalmol Ther . 2016;5(2):183-190. doi:10.1007/s40123-016-0058-2

National Eye Institute. Injections to treat eye conditions.

Food and Drug Administration. Syfovre .

By Maxine Lipner Maxine Lipner is a long-time health and medical writer with over 30 years of experience covering ophthalmology, oncology, and general health and wellness.

IMAGES

  1. Diabetic macular edema

    case study of diabetic macular edema

  2. Diabetic Macular Edema

    case study of diabetic macular edema

  3. Diabetic macular oedema

    case study of diabetic macular edema

  4. Diabetic Macular Edema

    case study of diabetic macular edema

  5. (Case 1). Eye with diffuse center-involving diabetic macular edema

    case study of diabetic macular edema

  6. (PDF) A Case of Diabetic Macular Edema with Prominent Chorioretinal Folds

    case study of diabetic macular edema

COMMENTS

  1. Guidelines for the Management of Center-Involving Diabetic Macular

    The Early Treatment Diabetic Retinopathy Study (ETDRS) was a landmark clinical trial that demonstrated the efficacy of the focal macular laser in the treatment of diabetic retinopathy and diabetic macular edema (DME). 5 The criteria for treating "clinically significant macular edema" (CSME) were defined in this study, and they were used to ...

  2. Two cases of diabetic macular edema complicated by an atypical macular

    Background Here we report two patients who developed an atypical macular hole (MH) during the treatment course for diabetic macular edema (DME). Case presentations Patient 1 was a 73-year-old male. Optical coherence tomography (OCT) revealed perifoveal retinoschisis (RS) in addition to cystoid macular edema and serous retinal detachment (SRD) in his left eye, and that an MH had developed ...

  3. Diabetic macular edema: Evidence-based management

    The Diabetes Control and Complications Trial showed that tight blood glucose control in patients with type 1 diabetes reduced the cumulative incidence of macular edema at 9-year follow-up by 29% and reduced the application of focal laser treatment for DME by half.[138,139] The United Kingdom Prospective Diabetes Study was an analogous ...

  4. Evaluation and Care of Patients with Diabetic Retinopathy

    A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT Study) 12-month data: report 2. Ophthalmology 2010;117(6): 1078.e2 ...

  5. Diabetic Macular Edema: Diagnosis and Management

    Download PDF. Diabetic retinopathy (DR) is the leading cause of new cases of blindness among adults aged 18 to 64 years in the United States. 1 Dia­betic macular edema (DME), a severe complication of DR that occurs specifi­cally as a result of inadequately treated diabetes mellitus (DM), has overtaken proliferative diabetic retinopathy as the most common cause of vision impairment in ...

  6. Challenges in Diabetic Macular Edema Management: An Expert Consensus

    Diabetic macular edema (DME) is a prevalent condition that impacts central visual acuity (VA), and, therefore, critically influence on patient's quality of life. 4, 5. The prevalence of DME in Europe was estimated in 3.7% and its pooled mean annual incidence in type-2-diabetes patients was 0.4%. 3. The changes in the paradigm of DME treatment ...

  7. PDF Case Studies in Dry Eye Disease, Glaucoma, and Diabetic Macular Edema

    of DED, OAG, and diabetic macular edema (DME) in current clinical practice. -Thomas Samuelson, MD Case 1. Man With Diabetes Who Has Glaucoma, Cataracts, and Newly Diagnosed Dry Eye Disease From the Files of Elizabeth Yeu, MD • 83-year-old white man was referred by a community optometrist for evaluation of coexisting cataract and OAG

  8. A Case of Diabetic Macular Edema with Prominent Chorioretinal ...

    Purpose: To report a case of diabetic macular edema with prominent chorioretinal folds. Case report: This study involved a 55-year-old male with untreated bilateral diabetic retinopathy who had undergone cataract surgery at another clinic. Following that surgery, diabetic macular edema rapidly exacerbated, accentuating marked cystoid macular edema and radial chorioretinal folds in the macula.

  9. Management of diabetic macular oedema: new insights and global ...

    As the Early Treatment Diabetic Retinopathy Study showed almost 3 decades ago, about 40% of eyes with DMO had good vision (visual acuity 20/20) [ 15 ]. From a global standpoint, we could estimate ...

  10. Recommendations for diabetic macular edema management by retina

    To study the role of artificial intelligence (AI) in developing diabetic macular edema (DME) management recommendations by creating and comparing responses to clinicians in hypothetical AI-generated case scenarios. The study also examined whether its joint recommendations followed national DME management guidelines. The AI hypothetically generated 50 ocular case scenarios from 25 patients ...

  11. Functional and anatomical changes in diabetic macular edema ...

    A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology 113 , 1706-12 (2006). Article ...

  12. Two cases of diabetic macular edema with diminished areas of retinal

    Case 1: A 72-year-old man presented with aflibercept-resistant DME in the left eye, with a best-corrected visual acuity (BCVA) of 20/16. ... Diabetic macular edema (DME) is responsible for vision loss in patients with diabetes mellitus. ... In the clinical trials of faricimab for DME in the YOSEMITE and RHINE studies with over 80% treatment ...

  13. PDF Diabetic Macular Oedema Case Study

    The Treatment of Diabetic Macular Oedema with ILUVIEN® Intravitreal Implant Following Prior Anti-VEGF Therapy - Case Study Fahd Quhill Consultant Ophthalmologist, Royal Hallamshire Hospital, Sheffield, UK Abstract Diabetic macular oedema (DMO) is the main cause of vision loss in diabetic retinopathy. The ILUVIEN ® intravitreal implant ...

  14. Diabetic Macular Edema

    Figure 1: Diabetic macular edema. A: Schematic diagram of DME. Microaneurysms or damaged capillaries resulting from the breakdown of the blood-retina barrier leak fluid to the extracellular space, resulting in a swollen retina. Resorption of DME is dependent on the adjacent capillaries and retinal pigment epithelium.

  15. Dyslipidemia and Diabetic Macular Edema

    Clinical Relevance: Diabetic macular edema causes impairment of vision in patients with diabetes, and dyslipidemia has been reported as a risk factor for its development. A systematic review with a meta-analysis was undertaken to examine the evidence of an association between dyslipidemia and DME. Methods: We defined eligibility criteria as ...

  16. Association of systemic and ocular risk factors with neurosensory

    Diabetic macular edema (DME) with neurosensory retinal detachment (NSD) remains an important cause of visual loss in patients with diabetes. The aim of the study was to elucidate the association of systemic and ocular risk factors with NSD in DME. In a retrospective case-control study, we reviewed clinical records of all the subjects with DME seen between January 2010 and December 2010.

  17. Diabetic macular edema: Evidence-based management

    Abstract. Diabetic macular edema (DME) is the most common cause of vision loss in patients with diabetic retinopathy with an increasing prevalence tied to the global epidemic in type 2 diabetes mellitus. Its pathophysiology starts with decreased retinal oxygen tension that manifests as retinal capillary hyperpermeability and increased ...

  18. Severe macular edema induced by pioglitazone in a patient with diabetic

    We report a case of severe diabetic macular edema (DME) that developed after pioglitazone was used by a patient with proliferative diabetic retinopathy. ... Severe macular edema induced by pioglitazone in a patient with diabetic retinopathy: a case study Vasc Health Risk Manag. 2008;4(5):1137-40. doi: 10.2147/vhrm.s3446. Authors Toshiyuki ...

  19. Severe macular edema induced by pioglitazone in a patient with diabetic

    We report a case of severe diabetic macular edema (DME) that developed after pioglitazone was used by a patient with proliferative diabetic retinopathy. ... Severe macular edema induced by pioglitazone in a patient with diabetic retinopathy: a case study. Toshiyuki Oshitari 1 Department of Ophthalmology, Kimitsu Central Hospital, Kisarazu City ...

  20. Assessment of Parafoveal Diabetic Macular Ischemia on Optical Coherence

    Key Points. Question Can an automated binary diabetic macular ischemia (DMI) algorithm using optical coherence tomography angiography (OCTA) images predict diabetic retinal disease progression and visual acuity (VA) deterioration?. Findings In this cohort study of 321 eyes from 178 patients, the presence of DMI on OCTA images demonstrated prognostic value for diabetic retinopathy progression ...

  21. Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and

    2. OCT-Based DME Classification and Evaluation. Nowadays, OCT is widely used for the early detection of DME. Based on OCT findings, several types of DME were classified, i.e., diffuse edema (sponge-like diffuse retinal thickening), cystoid edema (retinal thickening with intraretinal cystoid change), macular edema with serous retinal detachment (macular thickening with subretinal fluid (SRF ...

  22. Diabetes-Related Macular Edema

    The signs and symptoms of diabetes-related macular edema may include: Blurry vision or double vision. Floaters. Difficulty seeing colors. Dark spots (scotomas). Straight lines that you see as bent or curved. Difficulty seeing when there's a glare or bright light.

  23. Clinical features related to optical coherence tomography angiography

    To investigate the frequency and type of artifacts on optical coherence tomography angiography (OCT-A) images and the relationship with clinical features in eyes with diabetic macular edema (DME).Retrospective, cross-sectional comparative study.192 eyes of 140 patients with DME were included.Medical records, optical coherence tomography (OCT) and OCT angiography (OCT-A) images (Spectralis ...

  24. JCM

    Background: Treatment cessation due to a dry retina has not been systematically addressed in diabetic macular edema (DME). In three out of four patients receiving 6 mg of brolucizumab in the KITE study, treatment was terminated after the study ended. Methods: The KITE study was a double-masked, multicenter, active-controlled, randomized trial (NCT 03481660) in DME patients. Per protocol ...

  25. ITF2357 regulates NF-κB signaling pathway to protect barrier ...

    The robust integrity of the retinal pigment epithelium (RPE), which contributes to the outer brain retina barrier (oBRB), is compromised in several retinal degenerative and vascular disorders, including diabetic macular edema (DME). This study evaluates the role of a new generation of histone deacet …

  26. Let's Talk Ophthalmology: an Evolve Medical Education Podcast Evolve

    In this case-based discussion focused on diabetic macular edema, Murtaza Adam, MD, FASRS, and Lejla Vajzovic, MD, FASRS, highlight the use of more durable treatment options and how to incorporate these second-generation therapies into the armamentarium. ... Dr. Williamson presents complex cataract surgery case studies and each KOL weighs in on ...

  27. Association of systemic and ocular risk factors with neurosensory

    Background. Diabetic macular edema (DME) remains a major cause of visual loss in patients with diabetes [].Optical coherence tomography (OCT) has specifically been used for characterizing the morphological features of DME, and five OCT patterns of DME have been described: diffuse retinal thickening (DRT), cystoid macular edema (CME), neurosensory retinal detachment (NSD) without posterior ...

  28. Scientists develop experimental medication that shows promise in ...

    Diabetes can lead to eye problems, and a common one is diabetic macular edema (DME), causing vision loss. A study published in Nature Medicine suggests a new experimental drug could someday help ...

  29. Anterior segment migration of intravitreal ...

    A fundoscopic examination of both eyes indicates a flat retina, normal optic disc, and no vasculitis or retinitis in either eye. In the right eye, a macular edema with central involvement was detected. The patient was diagnosed with pseudophakic cystoid macular edema with a central macular thickness of 856 μm. The patient underwent an ...

  30. Eye Injections for Macular Degeneration (AMD) Treatment

    Diabetic macular edema: With this condition, fluid collects in the retina. To prevent vision loss, an ophthalmologist can inject an anti-VEGF agent into the retina, where it can reduce swelling. ... Study results show that over 90% of people receiving anti-VEGF injections maintained their vision. While real-world statistics put this more in ...