Mohammad Rafieetary, OD, FAAO

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Diabetic retinopathy treatment practical review

The question of “When should ODs sends their patient to a retina specialist?” is often asked. There are a number of recommendation schemes for examination and follow-up as well as management, including referral guidelines for ODs as well as general ophthalmologists and primary-care providers.

The American Optometric Association’s Clinical Practice Guideline Eye Care of the Patient with Diabetes Mellitus (2019)

American Academy of Ophthalmology Preferred Practice Patterns

International Council of Ophthalmology Diabetic Eye Care

American Diabetic Association’s Standards of Medical Care

 which is updated annually and encompasses all aspects of diabetes care

Beyond algorithmic care, a number of peripheral factors dictate the patient’s pathway of care. These factors include the provider’s comfort level, experience, and expertise with the disease. Other factors are access to subspecialty facilities, patient insurance coverage and limitations, patient wiliness and compliance to follow-up with the referral, patient consent to receive treatment, and patient adherence to follow-up care.

Diabetic retinopathy treatment is not always as clear-cut as charts and algorithm recommendations and protocols.

Keep in mind that many malpractice cases are poor outcomes not from receiving an improper treatment regimen but due to delayed and misdiagnosis. Therefore, to determine the time for referral and course of management, ODs should first properly detect and stage the disease.

Complications of diabetic retinopathy that require ocular intervention are in a few categories. Since the 1980-90s mainly by publications of Early Treatment Diabetic Retinopathy (ETDRS),1 Diabetic Retinopathy Study (DRS),2 and Diabetic Vitrectomy Study (DRVS)3 became evident that photocoagulation was an effective treatment in focal form (focal or grid) for diabetic macular edema (Figures 1A and 2) or, based on the ETDRS terminology, clinically significant macular edema a categorization that is no longer applicable. It is effective in the panretinal form for irradiating retinal neovascularization (Figure 3) in the proliferative stage of diabetic retinopathy. Vitrectomy in presence of vitreous hemorrhage with or without tractional retinal detachment can help as well.

In past decade and half, the utilization of anti-vascular endothelial growth factor (VEGF) agents in the form of intravitreal injection, which is highly effective against the same complications, have been added to the armament of diabetic eye care (Figures 1B, 2, 3, 4). Anti-VEGF has been utilized as either a monotherapy or combination with laser and/or vitrectomy when needed in both trials and clinically (Figure 4).

A crucial factor determining the visual outcome of these treatment strategies, is the timely diagnosis of vision-threatening macular edema, presence of retinal and iris neovascularization particularly before escalation of the disease, and evolving vitreous hemorrhage, tractional retinal detachment, and neovascular glaucoma. Therefore, providers should vigilantly look for macular edema by careful examination and use of optical coherence tomography (OCT), which is highly effective in diagnosing macular disease. Retinal neovascularization can be found with careful dilated fundus examination, widefield and ultra-widefield photography, fluorescein angiography, and OCT angiography when available.

A recent paradigm shift in treating diabetic retinopathy is the use of anti-VEGF in moderately severe and severe nonproliferative diabetic retinopathy to regress the disease to the earlier stages. In the RISE and RID clinical trials while evaluating the efficacy of ranibizumab (Lucentis, Genentech) for diabetic macular edema, it was noted that patients in the treated arm had a 2- to 3-step improvement in their level of nonproliferative diabetic retinopathy as determined by the ETDRS diabetic retinopathy classification and less likely to develop proliferative DR.4 This improvement was statistically significant as compared to the sham group.

In other words, patients with the ETDRS diabetic retinopathy severity scale of 47 and 53 (moderately severe and severe nonproliferative diabetic retinopathy) improved to level 35 (mild nonproliferative diabetic retinopathy).5,6 It is worth nothing the patients with levels 43 and 47 begin to demonstrate vision loss, and levels 47 have 66 percent and 53 an 80 percent chance of conversion to proliferative diabetic retinopathy in 5 years.5,7

These and other clinical trials such as PANORAMA, which evaluated the effect of intravitreal aflibercept (Eylea, Regeneron) for treatment of severe nonproliferative diabetic retinopathy, lead to the U.S. Food and Drug Administration approval of the two agents (ranibizumab and aflibercept) for treatment of diabetic retinopathy even in the absence of macular edema (Figures 5 and 6).8

In summary, it is imperative to refer patients with diabetic macular edema and presence or suspicion of retinal and/or iris neovascularization. It is highly recommended to refer patient with advancing disease from mild to moderate retinopathy.

Patients with diabetic retinopathy should always be educated about the possibility of vision loss and even blindness. Patient education also needs to include the symptoms for which patients need to seek immediate care and be made aware that lack of visual and ocular symptoms and even at time 

improvement in the patient’s vision is 

 indicative of stability or improvement of this progressive disease

emphasis on management of coexisting conditions and comorbidities that can be result in progression of diabetic disease is an essential component of patient education and awareness

Diabetic retinopathy is one of the most common causes of blindness in the U.S. and the world. With better detection, timely referral and adherence to treatment of this chronic disease many can be saved from having to live with diabetic related impaired vision.

1. Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. 

2. Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy. 

3. Two-year course of visual acuity in severe proliferative diabetic retinopathy with conventional management. Diabetic Retinopathy Vitrectomy Study (DRVS) report #1. 

4. Brown DM, Nguyen QD, Boyer DS, Marcus DD, Boyer DS, Patel S, Feiner L, Schlottmann PG, Chen Rundle A, Zhang J, Rubio RG, Adamis AP, Ehrlich JS, Hopkins JJ, RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III Trials (Rise and Ride). 

5. Early Treatment Diabetic Retinopathy Study Research Group. Fundus photographic risk factors for progression of diabetic retinopathy: ETDRS Report Number 12. 

6. Ip MS, Domalpally A, Hopkins JJ, Wong P, Ehrlich JS. Long-term effect of ranibizumab on diabetic retinopathy severity and progression. 

7. Mazhar K, Varma R, Choudhury F, McKean-Cowdin R, Azen S. Severity of diabetic retinopathy and health-related quality of life: The Los Angeles Latino Eye Study. 

8. Wykoff CC. Intravitreal Aflibercept for Moderately Severe to Severe Non-Proliferative Diabetic Retinopathy (NPDR): 2-Year Outcomes of the Phase 3 PANORAMA Study. Data presented at: Angiogenesis, Exudation and Degeneration Annual Meeting; February 8, 2020; Miami, FL.

Articles

When should ODs sends their patient to a retina specialist?

What causes vision loss in diabetic patients

Vision loss caused by diabetic retinopathy comes in different packages. Some form of vision loss can be reversable, for instance, when associated with diabetic macular edema (DME), vitreous hemorrhage, and tractional retinal detachment. However, vision loss associated with neovascular glaucoma and tractional retinal detachment involving the macula may not be recovered.

Loss of vision associated with macular and/or retinal ischemia may not only be irreversible, it is also the precursor for the above-mentioned complication.

Retinal ischemia results in upregulation of vascular endothelial growth factor (VEGF),1 a mediator of increased vascular permeability resulting in retinal edema and angiogenesis resulting in retinal neovascularization.

Retinal ischemia is referred to by a different lexicon and depends on the context in which it is discovered. For example, an angiographic term such as capillary dropout and/or capillary and vascular nonperfusion is used to describe this finding. Clinically, ischemic retinal changes may be difficult to detect.

The clues suggesting presence of an ischemic or hypoxic retina include cotton-wool spots. These fluffy white retinal lesions located in the retinal nerve fiber layer (RNLF) are representative of accumulation of axoplasm, caused by localized or diffuse ischemia. Although these don’t cause generalized ischemia, once they disappear, they result in localized RNFL loss (Figure 1).

Other clinical clues suggesting retinal hypoxia include presence of venous beading and loops, occluded (ghost) arteries and arterioles, retinal and/or iris neovascularization, preretinal hemorrhages, vitreous hemorrhage, fibrovascular proliferation, and tractional retinal detachment (Figures 2 and 3).

Another more subtle sign is the lack or resolution of previously noted common diabetic retinopathy findings such as microaneurysms, intraretinal hemorrhage (dot/blot), and cotton-wool spots (Figure 4).

In the same fashion that a dried tree branch cannot bear any fruits, absence of capillary beds will result in resolution and/or absence of typical retinopathy. With increased capillary loss, the typical retinal features may disappear leading to a “featureless retina.”

On optical coherence tomography (OCT), disorganization and atrophic loss of inner-retinal layers, such as RNFL, ganglion cell, inner plexiform, and inner nuclear layers as these retinal structures are mainly supplied by the superficial and deep retinal vascular plexus (Figure 6).

The most effective technique for detecting retinal ischemia is studying the actual vessels. This is accomplished by retinal angiography via use of contrast dye, fluorescein sodium (FA) (Figures 5 and 6) and/or the newer technique known as optical coherence tomography angiography (OCTA; Figure 7).

There is no specific treatment for loss of retinal vasculature. The best approach is prevention by improved glycemic control as well as improvement of other comorbidities, such as systemic hypertension and hyperlipidemia. There are some suggestions that use of intravitreal anti-VEGF can reverse capillary nonperfusion in its early stages;2 however, advanced cases are irreversible.

In examination of patients with diabetes, ODs need to be in search of tell-tale signs of retinal ischemia and its complications and pursue appropriate management to reduce vision loss and prevent diabetic blindness.

1. Ozaki H, Yu AY, Della N, Ozaki K, Luna JD, Yamada H, Hackett SF, Okamoto N, Zack DJ, Semenza GL, Campochiaro PA. Hypoxia inducible factor-1alpha increased in ischemic retina: temporal and spatial correlation with VEGF expression. 

2. Shruti C, Sheth J, Anantharaman G, Gopalakrishnan M. Ranibizumab-induced retinal reperfusion and regression of neovascularization in diabetic retinopathy: An angiographic illustration. 

Vision loss caused by diabetic retinopathy comes in different packages.

What causes vision loss in diabetic patients 

Pictoral Review

Beyond duration of the disease and status of the blood sugar control, other factors tat negatively influence the prognostic outcomes of patients with diabetic retinopathy.

Related: Diabetic retinopathy clinical pearl pictoral

• Patient’s poor compliance with follow-up care

Related: OCT in DR follow-up highlights importance of retina-vitreous attachment

Related: New guidelines out for diabetes patient care

The case summarized here is that of a 47-year-old African-American female. At the time of her initial presentation, she had been diagnosed with poorly controlled type 2 diabetes and hypertension for approximately 15 years. She was on dialysis as well and was sporadically treated for anemia.

The patient was initially diagnosed with proliferative diabetic retinopathy and underwent a series of treatments including intravitreal anti-vascular endothelial growth factor (VEGF) injections (IVI) and panretinal photocoagulation (PRP).

The retinopathy was subsiding, as shown in Figure 1, and the patient was asked to follow up in 2 months; she failed to appear.

Related: When to refer patients with diabetic retinopathy

Nearly 6 months later, she presents with a complaint seeing sudden onset floaters in the right eye. As evident in Figure 2, the patient’s symptoms were caused by a vitreous hemorrhage in the right eye, and a worsening of the retinopathy was noted in both eyes. Clinically, the observation of multiple deep vascular plexus retinal hemorrhages (also referred to as blot hemorrhages, as well as a number of white-centered hemorrhages (also called 

 was made, as seen in Figure 3. Although these types of hemorrhages can be associated with diabetic retinopathy, they often are associated with other blood disorders, including anemia and leukemia.

Clinicians also need to keep in mind the anemia, which is a complication of chronic kidney disease.

Related: Proliferative retinopathy leads to risk of sight loss

The patient was treated with anti-VEGF IVI in both eyes. The findings and concern with her blood count were communicated to her primary-care physician (PCP).

At the patient’s one-month follow-up visit, significant resolution of retinal hemorrhages was noted (Figure 4). The patient also indicated receiving additional iron therapy from her PCP.

ODs must pay close attention and manage all factors responsible for disease progression to improve the patient’s final outcome.

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ODs must pay close attention and manage all factors responsible for disease progression to improve the patient’s final outcome. The patient in this case report shows the importance of such management.

Role of comorbidities in management of diabetic retinopathy

Pictoral Review 

Retinal (macular) edema is caused by the breakdown of the blood-retinal barrier, resulting in leakage of serum, lipids and protein.

On clinical examination, edema may be difficult to see, but vascular changes such as microaneurysms and hard lipids known as exudates are often better visible (Figure 1A).

Related: Patient perception of good vision a trap leading to loss

On optical coherence tomography (OCT), edema results in variable increases in the retinal or macular thickness, and fluid is often represented as hypo-reflective pockets (Figure 1B).

Following successful treatment with anti-vascular endothelial growth factor (VEGF) injections and/or laser photocoagulation, an increase in hard exudates may initially be noted as serum dries out while hard lipid residue forms (Figures 2A and 2B).

Related: Know the many facets of diabetic retinopathy

Once the leakage stops, it may take several months for the hard exudates—seen as intraretinal hyper-reflective deposits on the OCT—to slowly absorb (Figure 3).

Occasionally, the solidifying serum can be seen in mid-phase from liquid to hard deposits. This can be referred to as “soft exudate,” not to be confused with the use of the same term to describe cotton-wool spots. Clinically, “soft exudate” has a creamy color (Figure 4A); on OCT it has a semi hyper-reflective presentation (Figure 4B). After treatment, this material turns to hard exudate and dissipates over time (Figures 5 and 6).

Related: Retina presentation looks familiar

Neglecting continued care of the disease can result in significant worsening of these findings and patients prognosis (Figure 7).

The patient depicted here failed to return for continued treatment for several months, resulting in increased severity of exudative retinopathy.

Related: Time in range as an alternative to HbA1c

Trace the path of diabetic retinopathy disease via images.

Author | Mohammad Rafieetary, OD, FAAO

Articles

Diabetic retinopathy treatment practical review

What causes vision loss in diabetic patients

Role of comorbidities in management of diabetic retinopathy

Diabetic retinopathy clinical pearl pictorial