Diabetic Retinopathy

A Realistic Look at Treatment Options
Alan Kadish, NMD, ABAAM, CCT

As all practitioners know from their patients’ increasing weight and chem panel results, the incidence of diabetes, along with its complications, is one of the major health issues facing and potentially breaking the health care system worldwide. For the purpose of this article, we will focus on one aspect of the disease – diabetic retinopathy, a major contributor to disability.

I will review the clinical implications and options for treatment, and provide a checklist to help you focus on the most salient aspects of the disorder. All of your pre-diabetic and current diabetic patients are inevitably going to need your ongoing evaluation and care. As a naturopathic physician, you’re in a unique position to preempt this cascade of degeneration, with our emphasis on preventive medicine.

Let’s start by understanding the depth of the problem and appreciating the cost, both in medical and social terms. It is estimated by the World Health Organization that 285 million people are visually impaired worldwide, including 39 million blind and 246 million having low vision.1 The incidence of blindness increases by 1–2 million each year.2 Diabetes is the leading cause of new cases of blindness among adults aged 20–74 years, according to the National Institute of Health.3

In the United States, as of 2011, there were approximately 25.8 million children and adults diagnosed as diabetic. This represents 8.3% of the population.4 To amplify your recognition of this ongoing issue, consider that the National Diabetes fact sheet indicates that 79 million folks are pre-diabetic, as defined by both fasting glucose and HbA1c levels.

An estimated 7.6 million people, age 40 years and older, have been diagnosed with diabetic retinopathy (DR). This is an 89-percent increase since 2000.3,4,5 The cost of medications, as estimated on a per-outpatient basis in 2007, is $629 per year – an amount that refers only to the DR, not to the constellation of other diabetic needs.6 Some quick math, disregarding inflation, and we get roughly 4.8 billion dollars per year and climbing, without consideration of the lost productivity and other associated social ramifications.

Take a moment and consider your professional life. Could you practice medicine without your sight, or live your current lifestyle?

Pathophysiology of DR

retinopathy1

Figure 1. Normal vision

retinopathy

Figure 2. Diabetic Retinopathy

Diabetic retinopathy occurs as a result of the ravages of elevated blood glucose.7 This includes increased levels of advanced glycosylated endproducts (AGEs) and reactive oxygen species (ROS) and the subsequent oxidative damage,8 excessive inflammatory mediators,9,10 and innate immune pathway activation,10,11,12 resulting in diabetes-induced leakage and degeneration of capillary integrity. This, in turn, causes abnormal circulation within the retina.4 Micro-aneurysms9 develop within the retinal tissue, due to improperly formed new vessel walls. These abnormally formed blood vessels can then become occluded, producing subsequent areas of anoxic tissue due to compromised circulation. The result is incomplete capillary perfusion and further tissue dysfunction.13

This cascade effect causes the retina to secrete increasing vascularization signals, including vascular endothelial growth factor (VEGF),14 which creates more aberrant neovasculature. The degenerative effects become magnified (Figures 1,2).

This vicious cycle will continue as the disorder inevitably progresses. While abnormal vessels proliferate in the retinal tissue, they can also extend into the surface of the vitreous gel. The primary problem with the neovasculature is the faulty construction of thin, fragile vessel walls. This malformation will leak blood and other exudates into the vitreous gel, resulting in vision loss, multiple medical procedures, and long-term, potential blindness.

After a period of time the disease will progress, including the abnormal vessel growths and exudates, resulting in scar formation. This contributes to progressive retinal degeneration, along with potential retinal detachment and glaucoma as a sequel.

The disease severity of DR is divided into two clinical stages: the early, nonproliferative stage (NPDR), and the progressed, proliferative or neovascular stage (PDR).

Confounding Factors

Most of us were taught that both blood pressure and blood lipid levels can be players in DR. That may or may not be the case, with newer findings conflicting with these earlier considerations.13,15 However, a complete evaluation of the patient’s risk factors remains one of the keys to addressing DR; newer studies suggest that the mechanisms are far more integrated with systemic considerations.

Studies have shown that the rate of DR progression correlates with HbA1c levels. A second rule of thumb is that patients with longer times since diagnosis of diabetes are most likely to progress or have signs of PDR.7,17

The UK Prospective Diabetes Study (UKPDS)16 investigated the influence of blood pressure control. Hypertensive patients with type 2 diabetes (n = 1148) were divided into 2 groups; one had blood pressures of < 180/105 mm Hg, while the other had blood pressures of < 150/85 mm Hg. Two different medications, an ACE-inhibitor or a beta-blocker, were used. Nine years later, patients in the lower-blood pressure group showed a 34% reduction in their progression of DR and had a 47% reduced risk of deterioration in visual acuity by 3 lines, in association with a modest blood pressure reduction of 10/5 mm Hg. As an added finding, there was a reduction in deaths related to both diabetes and stroke.

While this study demonstrated profound benefits from controlling blood pressure, alone, other studies have not shown similar outcomes. It’s critical to appreciate that even the best of treatments, save for 2 – lifestyle modifications and stem cell therapy – are palliative at best, tend not to restore sight, and have considerable risk-to-benefit ratios.

Allopathic Approaches

Primary conventional treatments for diabetic retinopathy include the use of photocoagulation and vitrectomy. Photocoagulation involves the use of a laser therapy to treat proliferative diabetic retinopathy. The laser cauterizes the abnormal blood vessels, decreasing the leakage of blood and other exudates into the vitreous humor. Laser ablation can be applied directly to specific lesions or, if the abnormal vessels become diffuse, applied in a grid pattern over a broad area.

Panretinal photocoagulation is a laser-based treatment that uses scattered laser burns across the entire retina, excluding the macula. The intent is to shrink the aberrant vessels and reduce the chances of additional hemorrhages into the vitreous. Unfortunately, panretinal photocoagulation therapy has potential undesirable side effects, including compromised night vision and the loss of peripheral vision.

A more invasive means of treatment is a vitreoctomy. This surgical procedure is used when large blood vessels have leaked into the vitreous and created an opaque or translucent gel. The vitreous is surgically removed from the eye and replaced with a salt solution to maintain the integrity of the eye’s contours and proper interocular pressures. Vitrectomy involves an extended recovery period which limits the patient’s ability to change position and engage in any activities. If this is not enough to give you pause, consider that the procedure can also cause retinal detachment. More common complications include elevated intraocular pressure, additional bleeding in the eye, and cataract formation, the most frequent complication of vitrectomy surgery.18

These palliative treatments are, at best, temporary solutions to the vision loss caused by diabetic retinopathy. This is because these procedures only treat abnormal blood vessel formations as they occur. They do not offer a lasting solution nor address the underlying etiology of the abnormal blood vessel formation. Since the progressive nature of the damage is only temporarily considered, both photocoagulation and vitrectomies generally need to be performed repeatedly to maintain any long-term vision.

The real need for those suffering from diabetic retinopathy is the prevention of the abnormal blood vessel formation, immune dysfunction, blood glucose swings, and the inflammatory cascades.9 Interestingly, there have been a substantial amount of published positive results utilizing stem cells to address the local environment in the eye. This approach is discussed below.

Naturopathic Interventions

Obviously, the main thrust of interventions, by necessity, have both a common sense and sound scientific basis. Overall appropriate and generalized lifestyle interventions, consistent with naturopathic beliefs and practices, appear to be the most effective approaches for long-term influence and maintenance of these patients.

Anti-inflammatories

There is inadequate space in this article to discuss the many possible interventions that can be implemented to modulate the inflammation so prominent within the retinal tissues of DR patients.19 Modifying the cascade of eicosanoid metabolites in the cyclooxygenase and leukotriene families via selective lipid intake can result in better integrity of the vessels. Examples include increased intake of omega-3 fats and decreased intake of arachidonic acid-rich foods. There are a host of botanical, fat modulators, and medications that can impact this aspect of DR.

Smoking and Diet

It’s tempting to say little here, save for the obvious. I would direct your attention to the R in the TRACK model (Figure 3), ie, to reach and maintain a healthy weight. Also apply the necessary cofactors to ensure integrity of vessel construction. Anti-oxidants and products that impact connective tissue are necessary areas of consideration, examples being cost-effective vitamin C, a host of flavonoids, and carotenoids such as zeaxanthin and lutein. Clearly, simple interventions that can be easily increased through both diet (fresh fruits and vegetables) and supplementation, should constitute baseline therapy.

Exercise

Weight and stress management, in addition to their impact on blood pressure and glycemic regulation, make regular exercise an obvious course of action.

Stem Cells

As an introduction to this subject, let me include some of the necessary terminology and specifics of ophthalmic stem cell therapy. To appreciate this treatment, consider that easily accessed and concentrated stem cells can be placed directly into the eye.21 Although the thought of this procedure may make some wince, the pain is minimal and the recovery rapid. This direct cellular effect clearly influences the retinal tissue and vascular abnormalities.

Currently, the majority of published  stem cell papers center on the use of bone marrow-sourced cells from the patient (autologous), in both animal and human models.11,12,20,21 The use of autologous cells eliminates the concerns of graft-versus-host reactions or the introduction of exogenous viruses or bacteria, and it has a long history of safe application. Remember that in the United States, since the widespread acceptance for oncology applications in the 1970s, bone marrow-based stem cell therapy has been considered a standard of care.

The mechanisms of action effected with stem cell applications discussed in the literature is that of anti-inflammatory effects from down-regulating proinflammatory cytokines (specifically VEGF), immune modulation, and a change toward reduced vessel leakage due to better vessel wall construction.14,22,23,24,25,26

It should be noted that only Institutional Review Board (IRB)27-approved studies are available in the United States for the application of stem cells to address DR. Stem cell regulations are “clearly” delineated by the FDA, under the Code of Federal Regulations Title 21, Part 1271.28 The only accepted use within the United States is what is known as a minimally manipulated approach. The raft of successful studies have consistently utilized a more comprehensive method of therapy, including the use of expanded cells, which are not considered to meet minimal manipulation restrictions. Thus, when evaluating clinical applications, your patients will need to look exclusively outside of the United States and Canada.

Summary

Diabetic retinopathy is a serious disorder whose incidence is increasing over time. Although its pathophysiology is well understood, allopathic treatments fail to address the underlying etiology or offer lasting solutions. Naturopathic approaches offer significant benefits to patients with DR. However, to be clear, the combination of dietary and lifestyle modification, appropriate medications, and a natural therapeutic intervention of autologous stem cells appears to be the only current method known to reduce the ultimate progression and complications of DR.

Figure 3. National Eye Institute’s TRACK model for patients

Courtesy, National Eye Institute, National Institutes of Health (NEI/NIH)

(http://www.nei.nih.gov/diabetes/flipchart/slide1_English.htm)

Table. Key Take-Home Points & Questions for the Practitioner

Know how long your patient has been diabetic
Have they ever been told that their ophthalmic exams show signs of DR, at any stage?
When was the last eye exam? Note in chart.
Is the patient hypertensive? Might it be time for a home monitor?
Oxidative and inflammatory markers should be checked
Consider checking homocysteine, which is often elevated in DR patients
Evaluate lipid intake, with regard to eicosanoid pathways
All diabetic patients need frequent dilated eye examinations, annually or less frequently, depending on disease status and progression
All type 1 diabetics will develop DR, especially as they age. Be prepared.
Tight diabetic control for both type 1 and type 2 diabetics will, over time, make a substantial difference in progression
Mexican-American and African-American patients with diabetes are at significantly higher risk for DR
Lifestyle interventions are essential and should be implemented
Use of the TRACK system video and screenshots (available through the NEI website) is an elemental starting place
Consider stem cell therapy and learn more about these options

 

Kadish_Headshot_October_2013Alan Kadish, NMD, ABAAM, CCT has practiced for 30 years as an integrated primary care physician, with a focus on ASD, neurological, and autoimmune disorders. He is the president of World Stem Cells, LLC, specializing in autoimmune, neurologic, orthopedic and ophthalmic disorders using advanced cellular technologies. Dr Kadish develops therapeutic protocols based on current published literature, and evaluates and interfaces with patients and providers of both laboratory and therapeutic services, internationally and domestically. He is a primary investigator and has written 3 IRBs for stem cell applications. Dr Kadish presents at conferences and publishes regularly on a number of subjects.

 

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Mancia G., Effects of intensive blood pressure control in the management of patients with type 2 diabetes mellitus in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Circulation. 2010;122:847–849.

[No authors listed]. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160):708–713.

American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care. 2002;25(Suppl 1):s28-s32.  http://care.diabetesjournals.org/content/25/suppl_1/s28.full.pdf+html. Accessed  July 27, 2013.

Benson WE, Brown GC, Tasman W, McNamara JA. Complications of vitrectomy for non-clearing vitreous hemorrhage in diabetic patients. Ophthalmic Surg. 1988;19(12):862–864.

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