Diabetic Eye Center

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Diabetic Eye Center – A Review of Diabetic Retinopathy
by Chris A. Knobbe, M.D.

Introduction to Diabetic Retinopathy:  Diabetes, a disease associated with blood sugar control issues, poses great potential threat to the eyes of those afflicted with the disease.   Diabetic retinopathy is the leading cause of blindness in working age Americans.  Unfortunately, many diabetics don’t realize that they may have progressive eye disease, until it’s too late.  And many believe that, if their vision is fine, their eyes must be fine.  But nothing could be further from the truth.Diabetic Eye Disease

Diabetic retinopathy may progress to the point that reversal with preservation of vision is impossible, period.  Hence, the need for annual dilated eye exams by qualified eye practitioners.  Patients with non-insulin dependent diabetes (NIDDM) should be evaluated immediately after their initial diagnosis, and every year thereafter, at a minimum.  Patients with juvenile-onset, insulin-dependent diabetes mellitus (IDDM), should be evaluated five years after their initial diagnosis and every year thereafter, at a minimum.

I’ve laid out the AAO (American Academy of Ophthalmology) recommendations for diabetic eye evaluations, in the second paragraph of this review, so that those that read only for the first minute will, hopefully, read this.  As the treating physician, I don’t want to see patients with severe, end-stage, diabetic eye disease resulting in blindness, which would have been completely preventable.

 

What is Diabetic Retinopathy?

 Diabetic retinopathy is a group of eye disorders that broadly fall into two general categories:  non-proliferative diabetic retinopathy and proliferative diabetic retinopathy.  These are diseases of blood vessels and this is exactly what I try to make my patients with diabetic retinopathy understand, that is, diabetic eye disease is a vascular disease.  So, anything at all that is an insult to the vascular system (smoking, high blood pressure, cholesterol profile issues, sedentary lifestyle, overweight and/or obesity, etc.) further adds to their risk.

Non proliferative diabetic retinopathy

Non proliferative diabetic retinopathy - with hemorrhages, exudates, and microaneurysms

Non-proliferative diabetic retinopathy (NPDR) consists of  microaneurysms, retinal hemorrhages, hard exudates, macular edema, and macular ischemia.  Let me explain each of these below:

 

    • Microaneurysms are tiny bulges, or pockets, in blood vessels of the retina, which may leak fluid.  These are caused by vessel walls becoming weak and abnormal.
  • Retinal hemorrhages are tiny dots or blots of blood that have developed in the retina, caused by vessels breaking down.
  • Hard exudates are deposits of cholesterol or other fats that have leaked into the retina from abnormal blood vessels.
  • Cotton wool spots are micro-infarctions.  That is, small areas of loss of blood flow due to capillaries or tiny arterioles closing down.
  • Macular edema is swelling or thickening of the macula (central retina) caused by abnormal blood vessels that have become compromised and leaky.  This condition is explored in detail below.
  • Macular ischemia is a condition of poor blood flow to the macula, as a result of small blood vessels (capillaries) actually closing down.

What is Diabetic Macular Edema (DME) – and How is it Treated?

OCT Image Normal Macula

OCT Image of Normal Macula

Diabetic macular edema (DME) is the most common cause of vision loss in diabetics.  As mentioned above, DME is a condition of swelling of the macula caused by abnormally leaking blood vessels.  As fluid accumulates in the macula, it distorts the micro-architecture of the macula and, ultimately, the photoreceptors (cones) are permanently damaged or destroyed, resulting in permanent and irreversible vision loss.

OCT Diabetic Macular Edema

OCT Image of Diabetic Macular Edema ("Swelling")

 

The natural course of DME is progressive vision loss.  The Early Treatment Diabetic Retinopathy Study (ETDRS) found that 53% of the 135 eyes with clinically significant macular edema (CSME, often referred to now as DME) lost two or more lines of visual acuity over a two-year period[i].  Those with DME left untreated experienced a “doubling of the visual angle,” which essentially means the visual acuity was cut in half, for example, from 20/25 to 20/50, or from 20/50 to 20/100, or 20/200 to 20/400 and so on.

Focal Laser Photocoagulation for Diabetic Macular Edema

Focal Macular Laser Photocoagulation for Diabetic Macular Edema (DME)

 

At the time of the ETDRS study, focal laser photocoagulation (“laser treatment”) was shown to reduce the risk of moderate vision loss by approximately 50% at three years from the initiation of treatment.  Most patients required either two or three separate laser treatments during the first two years after making the diagnosis of DME.

 

However, the down side of laser treatment is that it doesn’t always resolve the DME.  The ETDRS study showed that 40% of eyes with DME still had retinal swelling at one year after the onset of treatment, and 25% of treated eyes still had macular swelling three years after beginning treatment.  Finally, 12% of treated eyes still had moderate vision loss despite being treated appropriately with laser.  The bottom line?  Laser treatment isn’t completely effective.  But, then again, nothing is “completely effective”.  The only thing that completely prevents diabetic retinopathy is not having diabetes.  I’ll explore that in more detail later.

So, you might ask, “What other ways are there to help control diabetic retinopathy?”   The Diabetes Control and Complications Trials (DCCT) showed that intensive blood sugar control helps prevent diabetic retinopathy.[ii]  Similiarly, the United Kingdom Prospective Diabetes study (UKPDS) showed that blood pressure control is also beneficial, in this regard.[iii]  In fact, the DCCT study showed that intensive blood sugar control reduced the risk of onset of diabetic macular edema (DME) by 23%, as compared to conventional management.

Read on and I’ll introduce you to the most recent management of DME:  Anti-VEGF injections, combined with laser photocoagulation and, in some, cases, steroid injections.

Anti-VEGF (Avastin, Macugen, Lucentis) Treatment

As mentioned earlier in this review, diabetic macular edema results from abnormal leakage of molecules, such as fats (lipoproteins, for those who want the technicalities), from retinal capillaries right into the retina.  And this is followed by an (oncotic) influx of water into that space.  Hence, we have swelling!  This increase in retinal capillary permeability, resulting in this “leakage”, may be regulated in part by a glycoprotein called vascular endothelial growth factor (VEGF).  The normal retina contains very little VEGF.  But, hypoxia (think poor blood flow – and, therefore, not enough oxygen) causes increased production of VEGF.[iv]  So, if you’re still with me… do you see where the anti-VEGF drugs come in?  Good!

There are several different anti-VEGF drugs, including Macugen (pegaptanib), Lucentis (ranibizumab), and Avastin (bevacizumab).  Of these, the first two are FDA-approved for intravitreal use, that is, injection into the eye.   Avastin, which is only FDA-approved for treatment of patients with colon cancer, is being used “off label” by physicians for the treatment of multiple conditions of the eye (wet AMD, DME, proliferative diabetic retinopathy, neovascular glaucoma, branch retinal vein occlusions, and central retinal vein occlusion).  Off-label use of a medicine, as reviewed elsewhere in this site, is common and acceptable practice among physicians.  A drug may only be FDA-approved for use in one condition, but physicians may choose to use that drug in any condition in which they deem it to be medically appropriate, reasonable, and safe.  In this regard, Avastin has gained the most widespread use among retina specialists and ophthalmologists, in general, for DME, wet macular degeneration, and all of the other conditions listed above.

Intravitreal Injection of Avastin

Intravitreal Injection of Avastin

Avastin binds to and inhibits all VEGF-A isoforms, that is, all of the most common forms of VEGF that our bodies produce.  When this drug is injected into the eye, which, in our office, can be done painlessly, it is given at a dose of 1.25mg in 0.05 ml of solution.  This dose is about 1/500th the dose that is given to colon cancer patients and, numerous studies have shown benefit to patients’ eyes in the above-mentioned conditions, with no corresponding safety concerns from the drug itself.[v],[vi],[vii],[viii],[ix],[x]  The only risks are those associated with giving the drug, i.e., hemorrhage, infection, cataract, and retinal detachment, all of which are very rare complications.

When patients present to Durant Surgical Eye Center with Diabetic Macular Edema (DME), we adhere fairly closely to the Diabetic Retinopathy Clinical Research Network (DRCR Net)[xi] protocols, which consists of the following:

    • Avastin intravitreal (intraocular) injection every month for three months, combined with early focal laser treatment (focal macular laser).
  • After three injections, we follow closely, monitoring with OCT imaging, and fluorescein angiography, if needed, and repeat Avastin injections as necessary.
  • If patients have diffuse diabetic macular edema, which involves much of the macula (> 3 to 4 disc diameters), we may consider Triesence (triamcinolone steroid) injection, once every four months.

DME can usually be effectively treated, however, it must be treated early to be successful at preventing permanent vision loss.  We use the most advanced methods of treatment set forth by research, clinical study, and experience.  When a patient presents with diabetic macular edema, we work-up that patient fully and rapidly proceed to treatment protocols, if the patient desires treatment.

What is Proliferative Diabetic Retinopathy and How is it Treated?

Proliferative Diabetic Retinopathy

Proliferative Diabetic Retinopat

In general, after a prolonged period of non-proliferative diabetic retinopathy, some patients will go on to develop proliferative diabetic retinopathy.  The term “proliferative” indicates that there is neovascularization, which means there is new vessel growth.  This is the most dreaded form of diabetic retinopathy because the neovascular vessels are abnormal vessels – and they may leak fluid, bleed, and ultimately be responsible for vitreous hemorrhage (bleeding into the vitreous compartment of the eye), traction retinal detachments (the retina is “pulled” from its underlying tissues by contracting blood vessels), and neovascular glaucoma (glaucoma caused by the growth of new vessels in the angle of the eye, preventing normal fluid egress from the eye).

Proliferative Diabetic Retinopathy

Proliferative Diabetic Retinopathy

The development of proliferative diabetic retinopathy (PDR) is preceded by progressive ischemic eye disease, that is, reduction of blood flow from vascular disease resulting in poor oxygenation of tissues.  At this point, the ischemic tissues (retinal cells) begin to secrete vascular endothelial growth factor (VEGF) and erythropoietin, both of which act as local hormones that support angiogenesis (new vessel growth).

Inhibiting the growth of the neovascular vessels and causing regression of existing neovascular vessels, are the keys to controlling this type of disease.  The goals must be to catch it early and treat aggressively, before it causes devastating – and irreversible – vision loss.

This can be accomplished in most cases, by being vigilant about examinations, and treating diabetic retinopathy as early as possible.

Pan-Retinal Photocoagulation (PRP Laser)

Pan-Retinal Photocoagulation (PRP Laser)

 

We recommend treating proliferative diabetic retinopathy, in most cases, with a combination of VEGF-inhibitor (e.g., Avastin) injections combined with laser treatment known as pan-retinal-photocoagulation (PRP).  The Avastin injections have been shown to help rapidly cause regression of the new vessels and PRP laser, which destroys peripheral ischemic retina, produces the more permanent result.[xii],[xiii], [xiv] However, as in almost all disease states, the earlier the treatment can be initiated, the better the outcome.

Diabetic Vitreous Hemorrhage

Diabetic Vitreous Hemorrhage

Vitreous hemorrhage, as pointed out earlier, is the result of proliferative diabetic retinopathy.  It occurs when the neovascular vessels grow into the vitreous humor of the eye and subsequently break down and bleed, often filling the vitreous humor partially or completely.  The diabetic patient with this condition often notices a very sudden onset of loss of vision.  The complaints often include “reddish vision” but the vision is typically measured as “hand motion,” which is the ability to see a hand waving right before the face, or “light perception,” which is the ability only to detect light.

 

Before the era of the VEGF inhibitors (e.g., Avastin), when patients presented with diabetic-related vitreous hemorrhage, the usual course of action was to observe for three to six months, in hopes that the vitreous hemorrhage would clear enough to begin pan-retinal photocoagulation (PRP Laser).  If the bleeding stopped for a long enough period, the vitreous might clear enough that PRP laser could be completed.  However, in many cases, the vitreous hemorrhage persisted beyond the three to six month interval and then a vitrectomy procedure was usually recommended.

Vitrectomy for Vitreous Hemorrhage

Vitrectomy for Vitreous Hemorrhage

 

In a vitrectomy, a retinal surgeon surgically removes the vitreous humor located in the vitreous compartment of the eye, which of course, simultaneously removes the blood.  Typically, during the same procedure, the PRP laser is completed intraoperatively.

 

Today, we are able to offer these same patients who present with diabetic vitreous hemorrhage Avastin injections.  Avastin, as reviewed before, is a vascular endothelial growth factor (VEGF) inhibitor, which causes rapid regression of the neovascularization and rapid resolution of the vitreous hemorrhage.  Once the vitreous hemorrhage clears, the definitive procedure can be completed:  PRP laser.  The PRP laser literally destroys ischemic (oxygen starved) retina, however, it is aimed exclusively at the peripheral retina.  Once a significant treatment is completed, there is substantially reduced production of vascular endothelial growth factor and, therefore, regression of the neovascularization (new vessels) and reduced chance for the neovascularization to grow again.

It is important to recognize that patients who present with proliferative diabetic retinopathy that is complicated by vitreous hemorrhage, already have advanced diabetic eye disease.  In general, this can be a very threatening condition, with risk of multiple other complicating factors.  If patients are being followed and managed carefully, this development can almost always be prevented with earlier treatment.  Again, prevention is best.

Traction Retinal Detachment

Fibrous scar tissue with localized traction retinal detachment (white arrow), laser burns (black arrow), neovascularization (red arrow), blot hemorrhage (circle)

Traction retinal detachment (TRD) that is secondary to proliferative diabetic retinopathy (medically, called proliferative vitreoretinopathy) may be associated with devastating and irreversible vision loss, and is actually one of the conditions of PDR that can be prevented by PRP laser at the appropriate time.  The traction retinal detachment is the end-result of the combination of the neovascularization and its associated healing response.  That is, the new vessels and vitreous membranes combine to create a pulling force on the retina, literally pulling it off of the underlying retinal pigment epithelium.

There is essentially no role for medical management of TRD, though Avastin or other VEGF-inhibitors may be used prior to surgical management.  Surgical management may include a vitrectomy and attempts at membrane excision, but the procedures can be extremely complex, to say the least.

Neovascular glaucoma is another dreaded condition that is the end-result of severe proliferative diabetic retinopathy (PDR).  In this condition, the neovascularization (new vessels) not only develop in the retina, but in the angle of the eye, which is where the aqueous humor egresses from the eye.  As such, the neovascular vessels begin to block the drainage pathway of the eye, like hair in a bathtub drain.  This can result in severe and possibly irreversible elevation of pressure in the eye, that is, glaucoma.  The glaucoma, in turn, is associated with damage to the optic nerve, and may result in permanent, irreversible vision loss.

Treatment is aimed at medically or surgically controlling the eye pressure.  But the definitive treatment may require Avastin injection to help reverse the neovascularization, followed by PRP laser to permanently control it.  Patients whose pressure cannot be controlled medically may require a surgical glaucoma procedure, such as trabeculectomy or a tube-shunt.

Can Diabetic Retinopathy be Prevented? 

In general, the short answer to this question is, yes, at least for adult-onset diabetes.  Type 2 diabetes is largely the result of a sedentary lifestyle and obesity, the latter of which is a major risk factor for diabetes.

The United Health Foundation’s records show that diabetes and obesity are on a dramatic rise in the United States.  In 2010, diabetes affected 8.3 percent of the population, and that number grew to 8.7 percent of the population in 2011, which is a 4.8% increase in one year and a 42.5% increase since 2001!

The Centers for Disease Control also determined that approximately 36% of the U.S. population was obese in 2011, which was up by 2.2% since 2010 and up 37.5% since 2001.  In fact, look at this trend:  the rate of obesity in 1960: 13%; in 1988: 23%, and in 2011: 31%.

Diet and Exercise both Prevent – and REVERSE – Diabetes!!

 To find out how this works and how best to go about reversing your diabetes, log back into the site next week and look under the “Diabetic Eye Center” link.  That article is coming next!

 

References: 


  [i] Early Treatment Diabetic Retinopathy Study Research Group.  Early photocoagulation for diabetic retinopathy:  ETDRS report number 9.  Ophthalmology 1991: 98: 766-85.
[ii] The Diabetes Control and Complications Trial Research Group.  (1993).  “The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus”.  N Engl J Med.  1993 Sep 30; 329(14); 977-86.
[iii] UK Prospective Diabetes Study Group.  Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes:  UKPDS 38. Br Med J. 1998;317:703-713.
[iv] Hypoxia-ischemia and retinal ganglion cell damage.  Clin Ophthalmol. 2008, 2(4): 879-889.
[v] The CATT Research Group.  Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration.  NEJM, April 28, 2011.
[vi] Shienbaum G, Gupta OP, Fecarotta C, et al.  Management of Neovascular Age-Related Macular Degeneration Using Bevacizumab With the Treat and Extend Regimen:  Clinical Results and Economic Impact.  ARVO; Fort Lauderdale, Fl  2010.
[vii] Michels S, Rosenfeld PJ, Puliafito CA, et al.  Systemic Bevacizumab (Avastin) Therapy for Neovascular Age-Related Macular Degeneration Twelve-Week Results of an Uncontrolled Open-Label Clinical Study.  Ophthalmology.  Jun 2005; 112(6): 1035-47.
[viii] Rosenfeld PJ, Moshfeghi AA, Puliafito CA.  Optical Coherence Tomography Findings After an Intravitreal Injection of Bevacizumab (Avastin) for Neovascular Age-Related Macular Degeneration.  Ophthalmic Surg Lasers Imaging.  Jul-Aug 2005; 36(4): 331-5.
[ix] Yoganathan P, Deramo VA, Lai JC, Tibrewala RK, Fastenberg DM.  Visual Improvement Following Intravitreal Bevacizumab (Avastin) in Exudative Age-Related Macular Degeneration.  Retina. Nov-Dec 2006; 26(9): 994-8.
[x] Emerson MV, Lauer AK, Flaxel CJ, Wilson DJ, Francis PJ, Stout JT.  Intravitreal Bevacizumab (Avastin) Treatment of Neovascular Age-Related Macular Degeneration.  Retina. Apr-May 2007; 27(4):439-44.
[xi] Diabetic Retinopathy Clinical Research Network:  A Phase 2 Evaluation of Anti-VEGF Therapy for Diabetic Macular Edema:  Bevacizumab (Avastin). Director: Roy W. Beck, M.D., Ph.D.,  Jaeb Center for Health Resarch, Tampa, Fl.  Protocol Chair: Ingrid U. Scott, M.D., M.P.H., Pennsylvania State University College of Medicine.
[xii] Avery RL, Pearlman J, Pieramici DJ, et al.  Intravitreal Bevacizumab (Avastin) in the Treatment of Proliferative Diabetic Retinopathy.  Ophthalmology. Vol. 113, Issue 10, Oct. 2006, 1695-1705.
[xiii] Mason JO, Nixon PA, Milton FW.  Intravitreal Injection of Bevacizumab (Avastin) as Adjunctive Treatment of Proliferative Diabetic Retinopathy. American J Ophth., Vol 142, Issue 4, Oct 2006, pp. 685-88.
[xiv] Ohima Y, Sakaguchi H, Gomi F, Tano Y.  Regression of Iris Neovascularization After Intravitreal Injection of Bevacizumab in Patients With Proliferative Diabetic Retinopathy.  American J Ophth. Vol 142, Issue 1, Jul 2006, pp. 155-57.