Author: Ameen Marashi, MD
Documenting the visual loss is essential, which includes the location, duration, and presence of floaters along with detailed ocular history, such as associated ophthalmic diseases such as glaucoma, cataract, amblyopia, trauma, etc..
Precise previous ocular treatments documented such as topical medications, surgical interventions (pars plana vitrectomy, cataract, refractive, etc.) laser, injections (intravitreal, sub-tenon, etc.) and medication such as Anti-VEGF, steroids or other.
Knowledge of the previous history of diagnoses and treatment of diabetic retinopathy and diabetic macular edema (DME) can affect management decisions.
Medical history of diabetes mellitus, which includes:
· Type of diabetes, which is usually type one(insulin-dependent), has a worse prognosis than type two (insulin-independent) .
· Duration as diabetes type one requires fundus examination after five years of diagnosis, while type two requires fundus examination promptly after diagnosis, and the longer duration of diabetes, the more likely to have diabetic retinopathy .
· Pregnant patients evaluated soon after conception or in the 1st trimester and follow up depends on the severity of the diabetic retinopathy every one to three months in severe non-proliferative diabetic retinopathy and worse. However, gestational diabetes may not increase the risk of diabetic retinopathy nor needs eye examination during pregnancy .
· Medications (insulin or antihyperglycemic agents) and compliance.
· Level of HbA1c and glycemic control status as individuals with 10% HbA1c have a fivefold increased progression of diabetic retinopathy in comparison to those with 7% .
· Documenting systemic hypertension, along with hypercholesterolemia, which associated with increased severity of hard exudates and high levels of triglycerides associated with increased risk of PDR, other systemic disorders such as cardiovascular diseases, previous strokes, sleep apnea, thrombotic, etc.. are documented.
A list of ocular examination should set
1) Best-corrected visual acuity (BCVA), this is an essential step which can be performed by a trained optometrist or certified ophthalmologist to document the visual impairment.
BCVA affects treatment decisions and follow-up assessments, evaluating the efficacy of the treatment.
2) A slit-lamp examination with a thorough exam of clarity and regularity of the cornea; any conjunctival abnormality such injection of conjunctival vessels documented, and any other inflammations of the conjunctiva or eyelids documented and managed before any treatment decision.
Meticulous iris exam to rule out neovascularization is essential where the crystalline lens examined to rule out cataract wherein pseudophakic eyes an intraocular lens (IOL) examined to document the position and clarity of the posterior capsule.
3) Intra Ocular Pressure (IOP) documentation is essential as high IOP is associated with neovascular glaucoma, iris, or/and angle neovascularization or patient with glaucoma history.
Note when high IOP spotted a corrected IOP documented after central corneal thickness measurement.
4) Gonioscopy before dilated eye exam is essential to document anterior chamber angle status (open or closed) and to rule out neovascularization on the angle, blood in Schlemm’s canal, fibrovascular tissue, and synechia especially in cases
of high IOP, proliferative diabetic retinopathy and ischemic retinal changes .
Gonioscopy can be scheduled after the dilated fundus exam (if not done in the initial ocular examination) when ischemic changes are confirmed.
5) Assessment of pupillary reaction to rule out optic disc dysfunction
6) Bilateral dilated fundus exam is an essential  as undilated fundus exam can classify diabetic retinopathy for 50% of cases only ; a detailed examination of the optic disc, macula, posterior pole, a mid-peripheral and peripheral retinal exam done with specialized indirect wide-field lenses using slit-lamp biomicroscopy or indirect ophthalmoscopy to document:
· The presence and location of clinically significant diabetic macular edema which presented as thickening of the macula at or within central 500 µm or presence of hard exudates associated with a retinal thickening at or within 500 µm or retinal thickening more than one disc area located within of one disc diameter from central the fovea  however, using OCT depict DME more accurately and determine the location of macular thickening (central or non-central) and hard exudates, along with vitreomacular abnormalities.
· Severity and features of non-proliferative diabetic retinopathy (NPDR):
Microaneurysms, which is the first sign of diabetic retinopathy and the presence of microaneurysms alone, is a mild NPDR feature.
Hard exudates, cotton wool spots, and intraretinal bleedings are signs of moderate NPDR
Venous beading in two quadrants, intraretinal microvascular abnormalities (IRMA) in one quadrant, or severe intraretinal bleedings in four quadrants are signs for severe NPDR
Very severe NPDR is when there are two or more signs of severe NPDR.
· Severity and features of proliferative diabetic retinopathy (PDR):
Neovascularization of disc (NVD) less than 1/3 disc area, or else were (NVE) are features of early PDR.
High-risk PDR features one of the following criteria:
NVD 1/3 disc area or more without preretinal or vitreous hemorrhage.
NVD with preretinal or vitreous hemorrhage.
NVE ½ disc area with preretinal or vitreous hemorrhage.
High-risk PDR features three of the following criteria:
Location of neovascularization within one diameter of the optic disc
NVD is less than 1/3 disc area or NVE less than ½ disc area.
Advanced PDR features one of the following:
Progressive fibrovascular proliferation
Anterior hyaloid fibrovascular proliferation
· Complications of PDR such as Vitreous hemorrhage or/and tractional retinal detachment.
· Detection of peripheral diabetic retinopathy lesions increases the risk of PDR progression ; however, in cases of vitreous hemorrhage not associated with neovascularization, a thorough peripheral retinal exam carried out to rule out a retinal tear.
It is essential to educate the patient about the importance of effective treatment depending on ocular findings and the need for regular follow up along with glycemic and hypertension control in addition to communication with a primary care physician.
Capturing fundus images has a great value to document the retinal findings and location such as microaneurysms, cotton wool spots, hard exudates, intraretinal, preretinal blood, venous beading, and neovascularization.
Capturing fundus images has a great value to document the retinal findings and location such as microaneurysms, cotton wool spots, hard exudates, which may increase in number and size after or during treatment with AntiVEGF , intraretinal, preretinal blood, venous beading, and neovascularization.
Fundus images are useful to follow up on the progression of diabetic retinopathy; for example, if one or two-step progression of diabetic retinopathy confirmed within four years follow up, then the progress of high-risk PDR may occur within subsequent six years .
Fundus images can assess treatment efficacy in terms of improvement of diabetic retinopathy post-treatment along with hard exudates resolution.
Wide-field fundus images may provide early detection of diabetic retinopathy, especially if standard fundus images don’t show any diabetic retinopathy changes .
Optical Coherence Tomography (OCT)
OCT is the most important and accurate tool to diagnose diabetic macular edema, which precisely shows the location of macular thickening whether it is central or non-central and thus affects treatment decision. However, it worth noting that the relation between central macular thickness (CMT) and vision is modest .
OCT is handy to document patterns of DME, which can be as diffuse thickening or presented with cystic spaces that have an oval or round shape with clear or non-clear content along with or without hard exudates which appear as hyperreflective foci which may precede the formation hard exudates. The presence of subretinal fluids,  which has a favorable visual prognosis , diffuse thickening may hold a better prognosis when comparing it with another edema .
OCT may show thinning of inner retinal layers, indicate ischemic changes; however, this should not replace FFA or OCTa in the diagnosis of ischemic maculopathy and changes in FAZ .
OCT is the gold standard for documenting the presence of vitreomacular interface abnormalities (VMA), which is presented as vitreomacular traction (VMT) or/and the epiretinal membrane (ERM).
OCT shows the disturbance of inner retinal tissues induced by the tangential or anterior-posterior traction and depicts the macular thickening caused by tractional elements.
However, in cases of VMA not causing significant tangential traction with cystic spaces and increased macular thickening, fluorescein angiography is an essential tool to diagnose microaneurysm leakage to choose the optimal therapy for the case.
There are certain prognostic factors that OCT highlights, such as the disorganization of inner retinal layers (DRIL), which every 299 µm of DRIL for four months is associated with one line decrease of vision for one year . Another independent prognostic factor is the disruption of the ellipsoid zone or/and external limiting membrane, in which patients with intact ellipsoid zone may have a favorable prognosis .
OCT is very sensitive too to follow up treatment efficacy by measuring macular thickness changes before and after treatment, which plays a significant role in management decisions and follow up plans .
OCT can study subretinal scar formation and RPE atrophy, especially post laser treatments and other RPE changes such as drusen, RPE detachments, and atrophy.
Is a noninvasive method to document ischemic macular changes, which precisely demonstrates the level of capillary drop out and size of macular ischemia .
OCT angiography can show early foveal avascular zone (FAZ) changes, which may present earlier than other retinal findings  and maybe recommend to advice patients with NPDR cases for shorter follow up.
OCT angiography can clearly demonstrate microvascular changes in different levels  but does not show a leak and does not always correspond to microaneurysms leakage in fluorescein angiography.
Cystic spaces appear as oblong shaped, which may affect the measurements of FAZ and reproducibility of OCT angiography in deep capillary plexus . However, deep capillary plexus loss, along with outer plexiform layer disruption and enlarged FAZ, may indicate poor response to Anti-VEGF  .
Cotton wool spots may appear as capillary perfusion abnormalities in the superficial capillary plexus.
Wide-field swept-source OCT angiography and mosaic image processing can produce wide-field OCT angiography images that are very useful to detect peripheral retinal ischemic changes and neovascularization,  especially those which are subtle for fundus examination.
Superficial capillary plexus density changes are independently correlated to renal function, making OCTa a non-invasive method for quantitive evaluation of vascular changes in the retina and chronic kidney failure 
In the early stages of NPDR, the retinal capillary closure can be found in the perifoveal area. In moderate to severe NPDR, the retinal capillary closure can be found in the mid periphery. The superficial capillary plexus is affected initially then the deep capillary plexus become involved later .
Fundus Fluorescein Angiography (FFA)
FFA is a tool to study the perfusion of the macula and peripheral retina, which can be very helpful in diagnosis and treatment plans.
FFA features of macular ischemia are enlarged or irregular borders of FAZ, which can be accompanied by thinning, normal, or increased CMT .
Macular ischemia can explain reduced vision despite attempted treatment and is a prognostic factor before treatment initiation such as intravitreal injections to treat DME or vitrectomy to remove ERM, especially in cases of advanced PDR.
Microaneurysms appear as hyperfluorescent dots that may or may not leak in late phases, this is very useful when planning to apply focal laser, however, in contrast, intraretinal hemorrhages and hard exudates which appear as hypofluorescence. Thus, FFA can help to distinguish between intraretinal hemorrhages and microaneurysms. In contrast, preretinal hemorrhage may appear as a blocked fluorescence.
FFA can confirm the vascular component of diabetic macular edema in cases presented with VMA.
However, leaking microaneurysms is not an indicator of DME, and it may be associated with normal, thickened, or thinned macular tissues .
FFA is an excellent way to diagnose posterior pole and mid-peripheral ischemic changes, which appears as areas of retinal non-perfusion and capillary dropouts, areas of preretinal hemorrhage appear hypo fluorescence due to blockage of fluorescein dye.
FFA helps to detect neovascularization subtle to fundus examination and to distinguish it from IRMA as neovascularization will leak in early phases while IRMA appears as hyperfluorescence in early phases and won’t leak until late phases. Laser scars appear hyperfluorescent with central hypofluorescent in FFA.
Thus FFA may detect laser scars that are subtle to fundus examination and may show areas of non-perfusion that are not well covered with laser in cases of PDR recurrence or treatment failure.
FFA is useful to follow-up PDR treatment efficacy; FFA used to plan laser application in patients with compromised visual fields such as glaucoma patients; in such cases, wide-field FFA excels more than regular 45 degrees FFA.
Wide-field FFA identifies peripheral diabetic retinopathy lesions such as nonperfusion and vascular leakages, which are a prognostic factor for diabetic retinopathy progression to PDR .
The size of the ischemic area is inversely related to the central macular thickness in cases presented with diabetic macular edema .
Note that the physician should obtain signed consent explaining the rare complications of FFA, including death 1/200000, and FFA facility should have an emergency plan in situ .
B-scan echography is essential in cases of non-clear media due to vitreous hemorrhage to rule out tractional retinal detachment or fibrovascular tractions or in the case of media opacity to rule out retinal detachment or vitreous hemorrhage.
Glucose fasting, HbA1c, serum cholesterol, and triglycerides, along with serum creatinine ordered, a referral to a primary care physician or endocrinologist, is a must to adjust systemic factors and to rule out systemic hypertension and risks of stroke or cardiovascular disease.
Metabolic control for pregnant patients done in cooperation with primary care physicians and obstetricians.
Flow chart summarizes OCT findings in diabetic macular edema
Flow chart summarizes FFA findings in diabetic retinopathy
Managing patients with diabetic retinopathy and diabetic macular edema
Medical Treatment options
VEGF Blockade agents
VEGF Blockade agents are the most popular and proved both safety and efficacy.
The commercially available VEGF blockade agents are Anti-VEGF, such as Bevacizumab, which used off label & Ranibizumab and VEGF trap agents such as Aflibercept and Conbercept (Available in China).
1) A solution such as Triamcinolone acetonide 2 mg/0.05ml with similar effect to 4mg/ 0.1ml but with a safer profile.
2) Biodegradable inserts such as Dexamethasone 0.7 mg intravitreal implant with efficacy for up to 4 months .
3) Non-biodegradable fluocinolone acetonide intravitreal implant for the treatment of DME which may offer efficacy up to 36 months but with increased risk of inducing elevated IOP and cataract
Although studies have demonstrated the effectiveness of intravitreal steroids for macular edema, there is a risk of cataract development and an increase of intraocular pressure .
Treatment of steroids is considered as second-line therapy in cases that DME did not respond to AntiVEGF treatment. However, steroids can be used as a first-line treatment in high-risk patients to myocardial infarction or stroke, and patients are not willing to visit monthly, but keep in mind IOP monitoring is a must .
The laser used to be the treatment of choice for DME, but It has been replaced with intravitreal VEGF blockade agents and become a second-line therapy .
The indication for laser usage to DME treatment may be limited to some cases such as
1. In non-central clinically significant macular edema as defined by ETDRS .
2. Whenever a patient refuses intravitreal injections.
3. Laser for DME utilized whenever intravitreal injections contraindicated in cases such as high-risk patients to stroke, myocardial infarction, or glaucoma for intravitreal steroids.
4. In cases of exhibited DME after 24 weeks of intravitreal injections, the laser can add as a combined treatment  , which may reduce the number of needed injections .
5. In cases of central DME improvement after the initial four injections but only residual non-central CSME, laser treatment can offer temporary relieve from intravitreal injections.
However Pan Retinal laser Photocoagulation (PRP) remains the standard of care and the most cost-effective treatment for PDR especially in cases with no DME however, intravitreal VEGF blockade agents may offer rapid PDR and DME improvement, but with short durability and may add cost burden, so it is best utilized in cases of PDR with DME .
Other treatment options
Subthreshold microsecond laser may offer a safe method for laser delivery to treat macular edema without causing retinal scars when comparing it with traditional grid laser .
Suprachoroidal injection of triamcinolone acetonide is an effective method to treat cystoid macular edema when it is resistant to VEGF blockade agents; suprachoroidal injection induces fewer compilations when comparing it to intravitreal steroids injections  .
Posterior sub-tenon injection of triamcinolone acetonide small studies showed that this procedure could be effective and safe in the treatment of macular edema .
The injection should be carried out in sterile conditions where the injection site is prepared by disinfecting the skin using povidone-iodine 10%.
After installing topical anesthesia, and the conjunctiva disinfected using povidone-iodine 4%.
The injection is carried out after placing sterile drape and lid speculum isolating eyelashes in the superior temporal quadrant.
Injection site measured with calipers 4.00 mm for phakic and 3.5 mm from limbus for pseudophakic or aphakic, a 30 gauge half-inch needle is used to inject triamcinolone or VEGF blockade agents. In contrast, the dexamethasone implant comes with a 23 gauge injector that needs to be inserted obliquely after conjunctival displacement then inserted vertically and then injected after that a cotton tip applicator is placed over the injection site to prevent reflux of fluid.
Laser photocoagulation technique
For Pan Retinal Photocoagulation (PRP): 500 μm spot size should be achieved on the retina, so if you are using a Mainster Wide-Field or Volk Quad contact lens, put 300 μm spot size on your slit lamp laser attachment.
The duration should be 0.1 s then power adjusted until a burn inducing a whitish color reaction on the retina applying 1600-3000 (4000-6000 burns in multi-spot machines using 20 ms) burns spaced one burn apart in one or more sessions.
In cases of mild PDR 1200-1800 burns while in moderate and severe PDR, 2000-2500 burns are needed.
Laser burn shouldn't extend more than 3000 μm from the center of the macula and 500 μm from the optic disc.
Laser application should avoid intraretinal hemorrhage, areas of tractional retinal detachment, and chorioretinal scars, even in cases of retreatment for active PDR in the settings of existing PRP scars laser burns applied between the previous scars and areas of non-perfusions.
For Focal laser: Laser burn underneath leaking microaneurysms as identified by fluorescein angiogram with mild gray to white burn using 50-100 μm and 0.1 s. laser applied up to 3000 μm reaching temporal arcades avoiding application on the foveal avascular zone and 500 μm of the disc.
For Grid laser: Laser burns with light gray intensity with at least two burns apart using 50-100 μm spot size and 0.1 s duration. Laser applied in a grid fashion to the leaking areas defined by fluorescein angiogram avoiding application on the foveal avascular zone and 500 μm of the disc reaching 3000 μm up to temporal arcades
For Microsecond subthreshold laser: Low-intensity high-density protocol with spot size 100-200 μm with duration 0.2s.
Power adjusted (on the non-edematous nasal retina) using the titration method with a 5 % duty cycle, the power used is 50 % off from power used to achieve tissue reaction using a microsecond laser with 5% duty cycle.
Laser applied in painting fashion on the edematous area defined by OCT.
Pars plana vitrectomy technique
Pre-operative care includes intravitreal VEGF blockade agents one week before vitrectomy can reduce intraoperative and postoperative bleeding  while performing PRP (if possible) may improve post-surgical outcomes while performing B-SCAN can determine the location of vitreous detachment, proliferative tractions, and detachment.
The pars plana vitrectomy technique is based on three ports trans-conjunctival insertion of (23-25 gauge) trocars where the infusion line is inserted in the inferior temporal quadrant where other ports are a cutter and light pipe.
Core vitrectomy performed, and afterward, posterior hyaloid separation done by lifting the posterior hyaloid to Ora after cutting vitreous over the posterior pole.
Endodiathermy performed to the bleeding source after blood removal, then endolaser performed, and in cases of macular epiretinal membrane, a dye used to remove it along with ILM peeling.
In cases of tractional retinal detachment, it is essential to define the status of preoperative posterior hyaloid in cases of complete posterior hyaloid separation, which incised to allow adequate retinal view where the cut-rate maintained in high levels where the vacuum increased in core vitrectomy.
In cases of incomplete posterior hyaloid separation, a core vitrectomy performed to permit the view; if the hyaloid adhesion to the retina is widely separated, then gentle suction is applied to complete the posterior hyaloid separation after doing vitreo-rhexis in the mid-peripheral retina.
In the case of firm adhesion, then scissors are used to do delineation or segmentation with an en-bloc technique to the fibrovascular tissue, which is removed by gentle grasping to avoid bleeding and hole formations.
Dissecting fibrovascular tissue is best to be done using bimanual end grasping, or ILM micro forceps in one hand and micro retinal curved scissors in the other side or back-flush flute needle in one hand with Atkinson blunt needle in another hand for smaller fibrovascular adhesions while light source can be supplied by chandelier light.
In cases of subtotal posterior hyaloid adhesion, core vitrectomy performed then suction performed to areas where posterior hyaloid is less attached (usually in areas of subhyaloid hemorrhage) if this not possible, then posterior cortical hyaloid incision can be performed near to the optic disc using vitrector or blade to reach the subhyaloidal space then hyaloid lifted, and the fibrovascular tissue is separated.
In case of bleeding, the bleeding source should cauterize, the retina flattened using perfluorocarbon (if needed) to perform sufficient laser treatment.
In cases combined with rhegmatogenous retinal detachment core vitrectomy performed, then tissue dissection started on the attached part of the retina, starting from center to the periphery.
Perfluorocarbon can be used in cases of the non-atrophic retina to flatten the posterior pole; the retinotomy created if needed in the periphery using diathermy to shallow the detachment then all tractions around retinal tears or holes should be relieved before applying tamponed which in this case silicon oil should be used.
Pan laser endo photocoagulation always performed in all cases of diabetic vitrectomy to regress the neovascularization and to attach the retina by creating adhesions around retinal breaks, holes, and retinotomy; laser added in the periphery reaching the Ora Serrata even in cases of pre exciting laser treatment.
After the fluid-Air exchange, a tamponed used, usually, gas tamponed, such as 18% SF6 or 14% C3F8 used, but when in severe cases, reoperation, air travel, or positioning problems silicon oil used as tamponed and can be removed within 3-6 months.
Postoperative complications may range from epithelial defects and raised intraocular pressure to recurrent hemorrhage and rhegmatogenous retinal detachment as results of retinal tears mostly due to fibrovascular membrane dissection.
Pars plana vitrectomy indicated in situations
· Non-clearing vitreous hemorrhage for 2 or 3 months despite treatment attempts.
· Recalcitrant florid preretinal hemorrhage, especially if it covers the macula.
· Tractional retinal detachment, especially if it is threatening or involves the macula.
· In cases are presented with combined tractional and rhegmatogenous retinal detachment.
· In cases are presented with macular hole due to epiretinal membrane causing central fusion tangential traction.
· Vitreomacular abnormalities causing moderate visual loss
· Recalcitrant Rubeosis Iridis.
· Anterior hyaloid fibrovascular proliferation
· In cases are presented with progressive fibrovascular proliferation despite treatment attempts.
· Ghost cell glaucoma due to recalcitrant vitreous hemorrhage.
Management of diabetic maculopathy
Recommendations for ischemic diabetic maculopathy without central macular thickening treatment and follow up
-No effective treatment for ischemic diabetic maculopathy however it is recommended to treat proliferative diabetic retinopathy with PRP promptly
-Poor visual prognosis, follow up with dilated fundus exam every 2-4 months
-Glycemic and blood pressure control where HbA1c kept under 7%
Recommendations for vitreomacular interface abnormality
-Pars Plana Vitrectomy indicated in cases of vitreomacular traction (VMT) or epiretinal membrane (ERM) and its removal and Internal limiting membrane peeling (ILM) in cases of moderate visual loss .
- In cases of VMT less than 1500 microns with no or minimal ERM formation, a pneumatic vitreolysis with 0.3 ml C3F8 or 0.5 ml SF6 and drinking bird head position (face down position with bobbing the head up every 10 min) for ten days can release the VMT and improve vision, but this procedure itself may induce retinal detachment so thorough detailed peripheral retinal exam should be carried out to rule out any full-thickness retinal defect or lattice degenerations which should be managed two weeks with laser retinopexy before gas injection ; however, if pneumatic vitreolysis fails to release the VMT then pars plana Vitrectomy indicated.
-In cases of VMT with good visual acuity, then only follow up warranted as a spontaneous release of VMT may occur within several months.
Recommendations for vitreomacular interface abnormality in the setting microvascular alterations
-When there is VMA such as ERM but not disrupting the inner retinal tissues and associated with CMT with cystic changes especially in the level of the outer nuclear layer, in these cases FFA is done to confirm the presence of leaking microaneurysms, which means the main driver of the macular edema is a vascular element more than the tractional element so management should be carried out following the steps:
- In central DME and BCVA less than 20/25 VEGF blockade agents may have reduced effect. Still, they can successfully reduce edema after several injections  with an increased risk of inducing more tangential traction. However, in chronic (Anti-VEGF poor responders), DME intravitreal steroids may achieve a reduction of CMT but with increased risk of IOP elevation and cataract formation in phakic patients.
- In non-central DME focal laser photocoagulation to leaking microaneurysms recommended using FFA as a guide; however, subthreshold microsecond laser may stabilize the edema without causing scars nor increasing the tangential traction.
- In case of edema didn’t subside or even got worse despite the treatment attempts, especially in cases with moderate visual loss. Pars Plana Vitrectomy indicated with epiretinal membrane removal and internal limiting membrane peeling.
Recommendations for non-central diabetic macular edema treatment
-The precise location of edema should be identified with OCT ToMography using raster, and radial scans and not ToPography as topographic maps may falsely show that edema located non-centrally and hence the management highly defers.
- Non-central DME should meet the criteria of clinically significant macular edema in non-central non-clinically significant edemas; no treatment is warranted and only follow-up.
- The laser is currently mainstay treatment for non-central CSME , and when attempting to do focal laser, a precise location of leaking microaneurysms identified with FFA to reduce unnecessary laser applications to minimize the number of scars however grid laser applied in guidance of both OCT and FFA (area of leaking microaneurysms) .
- The subthreshold microsecond laser may achieve stability of non-central macular edema without causing scars or scotomas induced by continuous wave (traditional laser) and needs only OCT as a guide for applying low-intensity high-density subthreshold laser applications .
- Non-central DME treated with laser, are followed within eight weeks with OCT, and if edema didn’t improve, then the laser is repeated. If edema got worse and progressed to central with a reduced BCVA to 20/32 and lower, then the case should be treated as central diabetic macular edema.
- A key point in the management of non-central DME is glycemic control, by keeping HbA1c under 7%.
Recommendations for central diabetic macular edema treatment
Naïve or de novo central DME in cases of fresh DME never been treated before or DME not treated for at least four months.
In cases of central DME and BCVA is 20/25 or better
- Close follow up recommended no need for intravitreal injection of VEGF blockade agents  .
-Follow up done by doing OCT every eight weeks and monitoring changes in BCVA, along with glycemic control, by keeping HbA1C under 7%.
-Intravitreal injection of VEGF blockade agent recommended when vision drops to 20/32 and lower.
In cases of central DME and BCVA is between 20/32 to 20/40
- Intravitreal injection of Bevacizumab 1.25 mg (0.05ml) every four weeks for four consecutive injections, however other agents such as Ranibizumab 0.3 mg and Aflibercept 2.0 mg can be used as well. Still, Bevacizumab may have a similar effect in the current case .
- In cases of CMT, more than 400 μm, Bevacizumab may be less effective than Ranibizumab or Aflibercept as found in a small group in post hoc analysis of Protocol T .
-OCT repeated four weeks after the fourth injection to assess treatment efficacy.
In cases of central DME and BCVA is 20/50 and worse
- Intravitreal injection of Aflibercept 2.0 mg (0.05ml) every four weeks for four consecutive injections, however other agents such as Ranibizumab and Bevacizumab can be used as well, but Aflibercept is more effective in cases of worse BCVA at baseline, especially at the first year  however in two years follow up, Aflibercept and Ranibizumab may have the same efficacy .
- Due to the high price tag of Aflibercept and Ranibizumab, Bevacizumab is a cost-effective  treatment in such cases. It is a good practice to start with Bevacizumab in the initial four injections in patients that can’t afford Aflibercept and reassess the edema using OCT and BCVA.
-OCT repeated four weeks after the fourth injection to assess treatment efficacy.
“DME improvement assessed with OCT and BCVA and not with clinical examination only. To judge the efficacy of previous treatment, OCT should be repeated four weeks after the fourth injection, and there should be a reduction of CMT at least more than 10% from previous OCT scans; BCVA is very important in the assessment of treatment efficacy and follow-up. In cases of DME failing to improve (non-responder to Anti-VEGF), OCT shows CMT persistence (less than 10% reduction of CMT from the previous OCT scan) and with no improvement of BCVA..”
"In contrast, treatment withheld whenever the CMT reaches 250 microns and less or/and 20/25 or better"
In cases of central DME improvement after the initial four injections
-Additional two intravitreal injections with the same VEGF blockade agent used in the initial treatment, when there is a residual CMT.
-Assessment of CMT and BCVA within four weeks after the second injection  using OCT.
In cases of central DME presented for 24 weeks from initial treatment
- FFA ordered to identify leaking microaneurysms and treated with focal/grid laser or subthreshold microsecond laser, especially if residual macular thickness around 400 μm .
- In conjunction with laser treatment, a monthly injection of VEGF blockage agents continued until resolving edema or improved vision to 20/20.
-The laser may reduce the need for needed intravitreal injections of VEGF blockade agents .
In cases of central DME improvement after the initial four injections but only residual non-central CSME
- In the case of residual non-central edema, FFA ordered to identify leaking microaneurysms to perform focal/grid laser with continuous-wave mode .
- In the case of subthreshold microsecond laser used, there is no need for FFA; subthreshold microsecond laser may stabilize the edema without causing retinal scars .
- OCT repeated to assess treatment efficacy after eight weeks of treatment and retreat with laser only if there is still non-central edema.
- In the case of non-central edema progressed to central with BCVA 20/32 and worse, then two consecutive monthly injections of VEGF blockade agents repeated.
In cases of central DME didn’t improve after the initial four injections
-If the Bevacizumab or Ranibizumab used as initial treatment, it is rational to switch to Aflibercept for additional two intravitreal injections four weeks apart, although this may reduce CMT but may not improve vision due to permanent macular functional damage induced by DME  .
- If the Aflibercept used as an initial treatment or after switching to two additional intravitreal injections of Aflibercept after four injections of Bevacizumab or Ranibizumab failed to improve central DME, then switch to intravitreal steroids.
When choosing between intravitreal triamcinolone 2mg/ml (0.05ml) or dexamethasone 0.7 mg intravitreal implant , the latter has a safer profile, with efficacy up to 90 – 120 days where OCT repeated to assess the need for an additional intravitreal steroid.
- Intravitreal steroids increase the risk of IOP elevation and cataract progression ; it is better to inject pseudophakic patients with no history of glaucoma.
-Treatment with intravitreal steroids repeated only if there were no increased IOP from the first injection; thus, IOP monitoring during patient visits is mandatory.
- Although intravitreal dexamethasone implant appears to have a safer profile than intravitreal triamcinolone, it is expansive, therefore injecting triamcinolone in the suprachoroidal space may offer a cheap alternative with a safer profile with efficacy up to 8 weeks .
- In cases of recurrent DME after a successful response to intravitreal steroids, and the need to repeat intravitreal injections without inducing IOP elevation, then intravitreal fluocinolone acetonide 0.19 mg implant may offer the stability of DME up to 36 months . However, it may require to add several intravitreal Anti-VEGF injections during follow-up.
In cases of recalcitrant central DME despite attempted treatment
-In cases that DME partially responded to intravitreal steroids after non-responding to several Anti-VEGF injections, then injecting both intravitreal steroids and intravitreal VEGF blockade agents in the same setting may help to reduce CMT.
- In the case of all previous treatment strategies, failing to show DME improvement with moderate visual loss, a pars plana vitrectomy with ILM peeling may be helpful,  especially in patients with poor BCVA, which PPV yielded with better visual gain. In contrast, the increased central macular thickness with poor glycemic control and disruption of the ellipsoid zone yielded poor visual outcomes .
DME in special cases
-Cataract patients planning for cataract removal surgery suffering from DME may get worse  after cataract removal, so it is preferable to treat DME before cataract removal with close follow-up, up to 4months after surgery to monitor for any DME relapsing.
However, in cases that cataract is dense and not adequate for treatment follow up, intravitreal steroids combined with cataract surgery indicated, then followed up with OCT monthly for four months post-cataract-removal surgery.
-In cases of DME in pregnant women, the management is slightly different: in mild cases, observation will be sufficient, or laser performed in cases of more prominent edema, intravitreal steroid indicated in diffuse, severe cases, but discussion with the patient is necessary to disclose the risk and benefits of steroids. Intravitreal anti-VEGF has no proven risks to the pregnant woman or the fetus, but it should remain the last option.
Flow chart summarizes the approach and management of diabetic macular edema
Management of diabetic retinopathy
Non-proliferative diabetic retinopathy without DME
Cases of NPDR with DME are managed the same as cases of DME, as mentioned earlier.
Management of mild and moderate NPDR without DME
In early stages, NPDR requires only monitoring along with good glycemic and blood pressure control, which may be sufficient to reduce visual loss as the United Kingdom Prospective Diabetes Study  showed a reduced risk of diabetic retinopathy development by 34% in intensive glycemic control.
Mild to moderate NPDR requires patient follow up, which may range from annually to every six months in mild and moderate cases as the risk of PDR development is 16% within four years .
At this stage, it recommended treating the diabetic macular edema if presented as instructed above.
Management of severe and very severe NPDR without DME
In severe NPDR close follow up needed every three-two months, PRP  indicated in selected cases such as
1) The other eye had a bad outcome due to PDR without PRP.
2) The other eye is treated with PRP only after advanced PDR.
3) Whenever it is hard to follow up, especially in patients with poor glycemic control, cataract, and pregnant women.
4) Whenever there is a large area of peripheral capillary non-perfusion on FFA  .
- In cases of very severe NPDR close follow up needed every two months and consider early PRP (1200-1800 burns) in two sessions two weeks apart in patients who have diabetes type two and very severe NPDR, which may reduce risk of High-risk PDR progression up to 50% within one year .
-In patients with severe NPDR and high-risk characteristics for progression to PDR, intravitreal VEGF blockade agents every 16 weeks after five monthly injections, may reduce the risk of PDR and DME development and improve NPDR severity .
Proliferative Diabetic Retinopathy
Early PDR without DME
When early PDR not combined with diabetic macular edema, then PRP for (1200-1800 burns) carried out in two sessions one week apart, especially in elderly patients and in young patients with type one diabetes associated with intraretinal signs of severe or very severe NPDR .
When using pattern multi-spot laser systems using a PRP with 20 ms duration, then 2400-3500 burns should be applied.
Early PDR with DME
When early PDR combined with diabetic macular edema, then treatment initiated with VEGF blockade agents and after three injections of VEGF blockade, assessment of PDR carried out if the neovascularization regressed, treatment with intravitreal VEGF blockade agents continued to address the macular edema.
PRP (1200-1800 burns) deferred in this case and applied to those with poor compliance, especially in patients with poor glycemic control or treatment failure .
High-risk PDR without DME
When high-risk PDR not combined with diabetic macular edema, then PRP  for 2000-2500 (up to 3000 in very severe high-risk PDR) burns carried out in two sessions one week apart. However, combining both intravitreal VEGF blockade agents and PRP (1200-1800 burns) may reduce the need for aggressive PRP and its complications with better visual acuity and faster regression of neovascularization .
When using pattern multi-spot laser systems using a PRP with 20 ms duration, then 4000-5000 burns should be applied even 5500-6000 in severe High-Risk PDR.
Intravitreal VEGF blockade agents initiated with three injections every four weeks; if the neovascularization resolved within 12 weeks, then treatment stopped.
Retreatment initiated again between the 16 and 20 weeks in a case of neovascularization recurrences and treatment withheld again whenever the neovascularization regressed or stable after two consecutive injections .
“PDR patients treated with intravitreal VEGF blockade agents alone and lost follow up showed an increased risk of neovascular glaucoma development , and inferior outcomes in terms of PDR worsening to those treated with PRP.” 
High-risk PDR with DME
When high-risk PDR combined with diabetic macular edema, then treatment initiated with PRP (1200-1800 burns) for two sessions two weeks apart combined with VEGF blockade agents and after three injections of VEGF blockade, assessment of PDR should be carried out if the neovascularization has regressed, then the treatment with intravitreal VEGF blockade agents continued to address the macular edema .
The worse PDR features presented in the baseline, the worse it will progress despite attempted treatment .
“Pattern multi-spot laser application has a higher risk of PDR progression in contrast to single spot laser “ 
When it comes to choosing the VEGF blockade agent, Aflibercept may show better visual acuity and diabetic retinopathy outcome than Ranibizumab and Bevacizumab in cases of thick DME and bad BCVA at baseline. However, three agents may have the same effectiveness in DME with good baseline BCVA .
When combining both PRP and intravitreal VEGF blockade agents, treatment initiated with intravitreal VEGF blockade agents, then the first session of PRP applied one week after the first injection. The second laser session applied within two weeks, after one week from the second laser session (i.e., four weeks from the first injection), the second intravitreal injection of the VEGF blockade agent administered. After four weeks, the third VEGF blockade agent carried out.
In cases of progressive fibrovascular proliferation despite treatment attempts or/and recalcitrant florid pre retinal hemorrhage, especially if it covers the macula, PPV indicated.
“Intravitreal VEGF blockade agents avoided in cases of tractional retinal detachment especially in situations that tractions threatening the macula”
Flow chart summarizes the approach and management of diabetic retinopathy
Management of vitreous hemorrhage
Vitreous hemorrhage with permitted fundus view and diabetic macular edema
Treatment initiated with PRP (1200-1800 burns) for two sessions two weeks apart combined with VEGF blockade agents, and after three injections of VEGF blockade, assessment of vitreous hemorrhage and PDR should be carried out, then the treatment with intravitreal VEGF blockade agents continued to address the macular edema .
Vitreous hemorrhage with permitted fundus view without diabetic macular edema
Treatment initiated with PRP for (2000-2500 burns) carried out in two sessions one week apart , a short worsening of vitreous hemorrhage may occur during treatment due to contraction of vitreous scaffold induced by laser which resolves spontaneously without the need of further intervention .
“When vitreous hemorrhage presented without PDR features, it is essential to do though peripheral fundus exam to rule out peripheral retinal tears or holes”
Vitreous hemorrhage with permitted fundus view with tractional retinal detachment
When tractional retinal detachment presented with vitreous hemorrhage, especially those cases where traction threatens the macula, pars plana vitrectomy (PPV) indicated. However, one week preoperative intravitreal VEGF blockade agents  and PRP (if possible) may enhance PPV outcome and reduce intraoperative complications such as bleeding.
Vitreous hemorrhage without clear fundus view
In cases that vitreous hemorrhage does not permit a fundus view for laser application, then B-scan must be done to rule out tractional retinal detachment and proliferation.
In case of absence of tractional retinal detachment, intravitreal VEGF blockade agents indicated to speed up vitreous hemorrhage clearance Once the fundus view permits laser application, PRP indicated to stop the bleeding .
In the case presented with tractional retinal detachment, PPV indicated; however, one week, preoperative intravitreal VEGF blockade agents  may reduce intraoperative and postoperative complications such as bleeding.
Non-clearing vitreous hemorrhage
In cases that vitreous hemorrhage is not clearing out despite the attempted treatment for two to three months in type two diabetes  or one month in type one diabetes, PPV indicated.
One week preoperative intravitreal VEGF blockade agents  and PRP (if possible) may enhance PPV outcome and reduce intraoperative and post-operative complications such as bleeding.
Vitreous cavity bleeding post pars plana vitrectomy:
In pseudophakic patients, a YAG capsulotomy may facilitate heme absorption via trabecular meshwork, but it is recommended to monitor IOP elevation closely.
B-scan to rule out retinal detachment, in cases that retinal detachment presented, PPV revision indicated.
In cases, retinal detachment NOT presented an intravitreal injection of VEGF blockade agents to speed up hemorrhage clearing process and then laser applied between previous laser scars up to Ora Serrata.
In cases that hemorrhage not responding to intravitreal VEGF blockade agents, a vitreous cavity washout and fluid air exchange carried out then followed by retinal laser applications, silicone oil used in cases of recurrent hemorrhages.
In myotic cases where further laser application up to Ora Serrata is not possible, then peripheral retinal cryo-therapy indicated
“All cases of vitreous hemorrhage requires IOP monitoring to rule out ghost cell glaucoma”
Management of tractional retinal detachment
Tractional retinal detachment happens because of contraction of firm adhesion of the neovascular membrane to the cortical vitreous, which has a concave surface, vitrectomy indicated  whenever the traction is threatening the macula, or detachment involves the macula.
Preoperative PRP or preoperative intravitreal VEGF blockade agents 3 to 7 days  enhance PPV outcome and reduce intraoperative and postoperative complications such as bleeding.
In combined cases with rhegmatogenous retinal detachment, the retina is usually convex and extended to the Ora Serrata, its surface contains hydration lines, which are the hallmark of retinal holes, in combined cases vitrectomy indicated with silicone oil tamponade.
Management of quiescent proliferative diabetic retinopathy
In this stage, vitreous contraction is completed and detached from all retinal areas except vitreoretinal adhesions associated with neovascular formation.
In cases presented with no active PDR nor DME and with good BCVA, then only follow up bi-monthly with glycemic control recommended.
Vision reduced in this stage due to ischemic changes and tractional forces in the macula and chronic DME.
In cases featuring active PDR with or without vitreous hemorrhage, retinal laser application recommended despite the risk of induced traction.
Pars plana vitrectomy indicated when there is tractional retinal detachment , especially in cases involving the macula.
Flow chart summarizes the approach and management of vitreous hemorrhage
Recommendations for Diabetic Rubeosis iridis
-In eyes with clear media and beneficial vision but without an increase in IOP nor angle neovascularization or synechia, pan-retinal laser photocoagulation should be applied  as soon as possible for at least 1500 burns in the 1st session. Intravitreal VEGF blockade agents  can speed up neovascular regression, but keep in mind that the Anti-VEGF effect is only for the short term.
-In eyes with non-clear media and beneficial vision but without an increase in IOP nor angle neovascularization or synechia, Intravitreal VEGF blockade agents can speed up neovascular regression. The Anti-VEGF effect is only for the short term. If cataract or vitreous hemorrhage is preventing laser application, they managed, then pan-retinal laser photocoagulation applied for at least 1500 burns in the 1st session .
-In eyes with clear media and beneficial vision but with an increase in IOP, angle neovascularization, or/and synechia, pan-retinal laser photocoagulation should be applied as soon as possible for at least 1500 burns in the 1st session. High IOP managed topically with steroids, cycloplegic, and hypertension eye drops. In the case of high IOP refractory to topical treatment, then glaucoma drainage surgery indicated with VEGF blockade agent .
- In eyes with non-clear media and beneficial vision but with an increase in IOP, angle neovascularization, or/and synechia. In case cataract or vitreous hemorrhage is preventing laser application, they managed after IOP stabilization, then pan-retinal laser photocoagulation applied for at least 1500 burns in the 1st session . If High IOP causing corneal edema, then topical treatment with steroids, cycloplegic, and hypertension eye drops used. In the case of high IOP refractory to topical therapy, then glaucoma drainage surgery indicated with VEGF blockade agents. Pan retinal laser photocoagulation applied as soon as retinal view permits.
- In painful eyes with non-beneficial vision, a diode laser transscleral cyclo laser photocoagulation to the ciliary body recommended , which may induce phthisis bulbi, other treatment options include retrobulbar alcohol or sometimes enucleation.
Flow chart summarizes the approach and management of Diabetic Rubeosis iridis
Adjusting systemic factors
All patients diagnosed with diabetes are monitored for glycemic, blood pressure, and serum lipids with cooperation with an internist or endocrinologist as it has an important implication on disease progression and treatment efficacy.
Glycemic control plays a vital role in the management of both diabetic macular edema and diabetic retinopathy as glycemic control can reduce the risk of incidence of DME and developing retinopathy by 76% and slowed the progression of retinopathy by 54% in type one  while diabetic retinopathy progression reduced by 21% and reduced the need for PRP by 29% in type two .
HbA1c should be kept under 7% as fast as safe as possible and thus should be done under internist or endocrinologist supervision, ordering HbA1c at baseline and every three months during treatment follow-up is essential to track glycemic control.
Patients with diabetes may benefit from early intensive glycemic control in the course of diabetes before diabetic retinopathy development . However, patients with good glycemic control and didn’t show any signs of diabetic retinopathy at baseline are not protected from developing diabetic retinopathy in the future as tight control slowed progression, not the incidence .
HbA1c levels do not correspond closely to the VEGF blockade agent's results or prognosis. It is important to understand that poor glycemic control does not indicate a delay in the immediate needed ocular treatment. However, the fluctuations of HbA1c levels affect the progression of diabetic retinopathy .
Blood pressure control:
Intensive control of blood pressure slowed the progression of retinopathy and reduced the risk of other microvascular and macrovascular complications of diabetes ( especially type two) by 13% . However, a 10% increase in diastolic blood pressure would increase the risk of DME up to 330% in type one and 220% in type two within four years . It is worth knowing that controlling blood pressure itself is more important than the used drug to lower it as systolic blood pressure should be kept under 130 mmHg.
In pregnant ladies, rapid optimization of glycemic control is not a contraindication, especially cases with high-levels of HbA1c in early pregnancy.
Serum lipid control:
Increase in serum lipids associated with a higher incidence of hard exudates in both types that treated with insulin, while this association not found in type 2 treated with oral hypoglycemic drugs and the relationship between higher levels of HDL and regression of diabetic retinopathy is modest .
Statin uses not associated with a decrease in the incidence of PDR  while using fenofibrate may reduce LDL and triglyceride with good glycemic control and raise HDL to slow the progression of diabetic retinopathy by 6.5% at four years  . Still, fenofibrate failed to show an effect on DME despite its effect on triglycerides . However, lipid-lowering drugs may help to reduce hard exudates formation  .
Body mass index inversely related to the progression of diabetic retinopathy in type 2 who not using insulin, while underweighted older person had more diabetic retinopathy progression in compared with patients with normal body mass index  .
Gastric bypass surgery may decrease the risk of progression of diabetic retinopathy; however, patients with PDR may warrant close follow-up as they may worsen in the early course, but retinopathy improves later .
“Patients with PDR have a higher risk of developing a heart attack or stroke”
Follow up and prognosis
-In the follow-up, check visual acuity changes, inspect iris, and angle (using gonioscopy) for neovascularization before pupil dilatation along with IOP, dilated fundus exam documenting any clinical retinal changes, while OCT or FFA ordered when appropriate.
-Treatment, when withheld BCVA, reaches 20/20 or/and central macular thickness is 250 µm or less for DME while regression of neovascularization and resolved vitreous hemorrhage in PDR.
- In DME, treatment withheld after BCVA reaches 20/20 or/and central macular thickness is 250 µm or less follow up, and retreatment carried out following one of two protocols:
1. PRO RE NATA (PRN): when the patient achieves good visual acuity (20/25 or better) or dry macula (250 µm or less) after several intravitreal injections. The patient followed up for evaluation of worsening in visual acuity and central macular thickness; if any, then monthly injection until the patient regains dry macula or good visual acuity again, then a monthly follow up is recommended .
2. Treat and Extend (T&E): when the patient achieves good visual acuity (20/25 or better) or dry macula (250 µm or less) after one month after the last VEGF blockade intravitreal injection. The patient receives additional intravitreal injection after two weeks and re-evaluates after eight weeks. If there is no sign of edema, proliferation, nor changes in visual acuity, a further injection added. Then patient evaluation and treatment extended for more two weeks, but the extension shouldn't exceed 12 weeks. During the T&E follow up if a worsening is noticed, then a switch to monthly injection for two consecutive injections and follow up is extended again .
- Clinical trials didn't show a significant difference between T&E and PRN in term of visual acuity, although T&E requires more injections, there is less burden for the patient .
- Despite the regression of neovascularization after laser application or/and intravitreal VEGF blockade agents, neovascularization may grow again, and retreatment based on the following criteria :
1. Change in neovascularization since last visit or last laser treatment
2. New neovascularization appearance and its characteristics such as caliper, extent, network formation, and fibrous tissue.
3. Status of the vitreous hemorrhage since the last treatment.
4. Status of posterior vitreous detachment (PVD) as less aggressive treatment needed in cases of PVD
5.The extent of fibrous tissue and tractional retinal detachment.
- If the extent and activity of neovascularization increased in compresence with the last visit, then retreatment with applying additional laser between previous scars or areas were not treated with laser previously (best identified by FFA). Treatment should be stronger if the degree of neovascularization is more since initial treatment or if vitreous or pre retinal hemorrhage occurs repeatedly.
-However, in cases of extensive laser scar or/and in myotic patients where laser application is not possible, then intravitreal VEGF blockade agents indicated.
-Cooperating with an internist to find the systemic vascular risk factor is essential to control any underlying disease such as diabetes mellitus, systemic hypertension, etc.
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These guidelines were reviewed and updated in February 2021