Diabetic Retinopathy

Diabetes mellitus results when blood sugar levels stay too high due to an abnormal decrease in insulin production, or when the insulin produced is ineffective.

Ten percent of diabetics are Type I (juvenile onset, insulin dependent), which begins before age 35 and is caused by a destruction of the beta cells that produce insulin.  This can be caused by genetic factors, viral infection of the pancreas, or an immune system gone awry. These patients have to take insulin.

Type II diabetes (adult onset) generally begins after age 35. Insulin levels may be normal but the body does not use the insulin to maintain proper blood sugar levels.  The pancreas eventually decreases insulin production, making the situation worse.  Genetics and obesity are major factors.  Treatment involves diet control, exercise, and oral medications.

Diabetic retinopathy is a disease of the retinal blood vessels.  It is thought that hyperglycemia (increased levels of sugar in the blood) alters retinal blood vessel metabolism.  Blood platelets become abnormally sticky and retinal blood vessels narrow.  Diabetic retinopathy is a leading cause of blindness. 

According to the National Institute of Health, the U.S. has 16 million diabetics, and half of them have some stage of diabetic retinopathy.  About 8% of those with diabetic retinopathy have retinopathy at a vision loss stage.  Advanced diabetic retinopathy is the leading cause of blindness among working age Americans, with 25,000 patients developing blindness each year from the disease.

There are three important risk factors for the development of vision threatening diabetic retinopathy:

Type of diabetes — Type I diabetics are more likely to develop diabetic retinopathy than Type II diabetics.

Duration of diabetes —  The longer you have diabetes,   the more likely you are to develop serious diabetic retinopathy.

Blood sugar control —  Diabetics with poor control of their blood sugar levels are more likely to develop significant diabetic retinopathy.

Almost all Type I diabetics with diabetes for more than 15 years have diabetic retinopathy.  Type II diabetics who are on insulin and have had diabetes for more than 20 years have a 50% chance of developing proliferative diabetic retinopathy.

Once a diagnosis of diabetic retinopathy has been made, the ophthalmologist may use the results and guidelines of various studies to guide the treatment of the disease with laser photocoagulation of the retina.

Diabetic retinopathy arises from a deterioration of the retinal capillary bed.  

The capillaries bleed (dot and blot hemorrhages) and leak fluid in the form of exudates (yellow blotches in photo) into the retinal tissue.  

Veins dilate as areas of the capillary bed exhibit non-perfusion (blood ceases to flow in the capillary bed).

Adjacent areas of the nerve fiber layer may die (cotton-wool spots).  Eventually the oxygen starved retina produces new blood vessels (neovascularization) to bring more blood to the area.  These new blood vessels are malformed and eventually may bleed into the retina, the sub-retina, and into the vitreous, causing a vitreous hemorrhage, and possibly a traction retinal detachment and blindness.

Above left: A neovascular frond at the optic nerve head in the early venous phase of a fluorescein angiogram.  Above right: the same frond latter in the angiogram demonstrating leaking of serous fluid from the vessels.

Diabetic retinopathy is classified into background diabetic retinopathy (BDR) and proliferative diabetic retinopathy (PDR).  PDR is characterized by neovascularization.  The photos above are of PDR.

Diabetic retinopathy can be treated with focal laser to seal off bleeding blood vessels.  PDR can be treated with pan-retinal photocoagulation (PRP).  PRP involves "carpet bombing" the peripheral retina with around 1000 laser spots. 

Pictured above: laser scars in the peripheral retina. The theory is that PRP decreases the retina's need for oxygen, causing areas of neovascularization to recede.

Macular Degeneration

Macular degeneration results from a deterioration of the retinal tissue in the macula.  Vision loss can be mild to severe with the possibility of a total loss of central vision (approx. 5 to 15 degrees of central vision).  Age related macular degeneration (ARMD, or AMD) does not result in total blindness as it does not affect the peripheral vision.  The patient may, however, lose the ability to  read, to recognize faces, and to perform common tasks such as cooking and driving a car.  To get an idea of the visual effect, close one eye and hold your fist about 6 inches away from your open eye, directly in line with the visual axis.

According to the Eye Foundation of Kansas City, AMD is the most common cause of legal blindness in people over the age of 50.  Remember that legal blindness is usually defined as vision less than 20/200 in the better eye, or a total visual field angle of less than 20 degrees.  

Those between the ages of 64 and 74 have a one-in-four chance of developing AMD.  Above the age of 74, the risk increases to one-in-three.  Risk factors include race (Caucasian), family history of the disease, and smoking (doubles the incidence).

AMD is classified as either wet AMD or dry AMD.  Dry AMD is associated with the formation of drusen bodies in the macula.

It is theorized that drusen is an accumulation of waste byproducts from a retinal metabolism that is functioning abnormally.  Dry AMD accounts for 90 percent of the diagnosed cases of AMD and usually involves a slow deterioration of macular function and visual acuity.  There is no conventional treatment for dry AMD, other than taking a vitamin supplement with ingredients believed to slow the progress of the disease.  Dry AMD may develop into wet AMD.

Wet AMD is associated with new blood vessels (neovascularization) that originate in the choroid and break through Bruch's membrane and the RPE layer.  The arrow in the second OCT image below indicates the RPE layer that has been broken through by the choroidal new blood vessels.  A normal OCT image is given for comparison.

The new blood vessels are thought to be a response to oxygen starvation of the diseased retina, but they are malformed and they leak blood and serous fluid from the blood into the sub-retinal spaces. This is what creates the hump in the OCT image above. These networks of new blood vessels are called subretinal neovascular membranes (SRNVM) or choroidal neovascular membranes (CNV).  Below are early and late fluorescein angiogram frames of a CNV.  The network of choroidal new blood vessels can be seen in the early frame, and the serous leakage from the membrane is apparent in the late photo.

The end result is scarring and a loss of retinal function in the area affected. Ninety percent of the cases of severe vision loss from AMD results from wet AMD.  Below are a fundus photo and an OCT image of a macular scar secondary to AMD.

Treatment of wet AMD has progressed through several phases, beginning in the 1970s with focal laser burns to cauterize the new blood vessels.  Laser treatment was used for many years, but is rarely used today.  It is still an option for treating leakage that is away from the fovea.   Photodynamic Therapy (PDT) was approved by the FDA in 2001 for treatment of choroidal neovascularization secondary to AMD.  This involves injection of a special dye (Visudyne) into the blood stream.  The dye is "activated" by a low intensity laser aimed at the affected area in the macula to shrink the new blood vessels.  Although PDT treatment is still available, the treatments of choice are now intra-vitreal drug therapies.

Some new intra-vitreal drug therapies, called anti-VEGF therapies, have been approved by the FDA. These include Macugen and Lucentis.  These drugs inhibit the "vascular endothelial growth factor" (VEGF) that plays an important part in the degenerative process in the retina.  The drug Avastin, which also has anti-VEGF properties, has been used "off-label" in a similar manner although it has not been through FDA trials.  Avastin is primarily used to treat colon cancer.  Lucentis is a part of the Avastin molecular structure.

Early clinical use of Lucentis and Avastin have been encouraging.  Many treated eyes have shown a reduction in subretinal and intraretinal fluid as documented by OCT scans. A substantial number of eyes have shown improved vision concurrent with the fluid reduction. 

2007 update:  Lucentis has become the treatment of choice for wet AMD.  Avastin is being used for treatment of diabetic macular edema and macular edema secondary to vascular occlusions.  Lucentis has been in clinical trials for the treatment of diabetic macular edema and macular edema secondary to vascular occlusions.

The color photo and the late phase fluorescein angiogram below are of an eye with what at first glance appears to be a pigment epithelial detachment (compare to the image of a PED later in this module).  The arrows mark the location and the direction of the OCT scans below.  The first OCT scan was acquired on the same day that the photos were taken.  The OCT scan shows that it is not a PED, but rather intra-retinal fluid with a probable occult (hidden on the angiogram) choroidal neovascular membrane.  This eye was treated with three Lucentis injections over a 6 month period.

The OCT image directly above is a scan of the same eye 6 months after the first Lucentis treatment.  Notice the dramatic reduction of fluid.  Also notice that scar tissue remains (the red-orange intra-retinal area).  Visual acuity started at 20/50, reduced to 20/100 at the 3 month interval, and then recovered to 20/50 at the time of the above OCT scan.

All treatments thus far are considered to be successful if the deterioration is arrested, or a least slowed down, and the vision is stabilized.  Retinal tissue does not regenerate, so once damage is done, vision does not improve.  Sometimes visual acuity does improve if subretinal fluid is "drained" by the treatment from underneath an area of otherwise healthy retina.  Performance on visual acuity tests can improve for some of these patients as they "learn" to use the visual information from areas of healthy retina adjacent to a macular scar.  However, vision from the para-foveal and para-macular retina can never approach the 20/20 acuity of a healthy fovea because the density of cone distribution drops off rapidly as you move away from the fovea.

Macular Holes and Cysts

As discussed earlier, traction from the vitreous pulling on the retina can cause a hole or a tear in the peripheral retina that could lead to a retinal detachment.  A similar process can occur with vitreous traction in the macular area, causing a macular hole or macular cyst.  Because of the location (fovea), a macular hole can cause visual distortion and a significant decrease in central visual acuity.

The OCT has become the method of choice for imaging macular cysts and holes. You can see why from the excellent detail shown in the following images.  The first image is of a macular cyst.  Notice the fine line in the vitreous space indicating vitreous traction on the fovea.

The following is an OCT image of a full thickness macular hole.  Again notice the fine line in the vitreous indicating vitreous traction on the fovea.  The vitreous has lifted off a piece of the retina, this is called an operculum.  Also notice that the hole goes all the way down to the highly reflective RPE layer (indicated by the red-orange line).

Macular holes are treatable with a surgical procedure called a vitrectomy.  The adherence of the vitreous to the retina is removed with instruments inserted through small holes in the eye.  An air bubble is inserted into the eye and the patient must remain in a face down position for two to three weeks so that the bubble can exert pressure on the macula to close the hole.  There is potential for a 2 to 3 line improvement in visual acuity, but results vary.  Results are better if surgery is performed soon after the hole is formed.

Retinal Detachment

The most common type of retinal detachment occurs because of fluid pushing the sensory retina away from the underlying pigment iepithelial layer (RPE).  A rhegmatogenous RD occurs when the fluid enters through a retinal hole or tear.  This is the one associated with floaters and flashes.  Symptoms may include a "curtain" coming down (or up, left, or right) over the visual field.

The following B-scan image shows vitreous traction and a resultant retinal tear (arrow).

This B-scan image (below) shows a retinal detachment (line).

The image above shows the leading edge of a retinal detachment (arrow) just above the posterior pole.  Notice that the vessels coming from the optic nerve are in focus, but the area of the retinal detachment appears to be out of focus.  This is because the RD is elevated and anterior to the plane of focus of the camera.  Also notice that the RD casts a shadow (tip of the arrow).  This is another clue that this area is elevated (anterior).

In the image below, the camera has been focused more anteriorly.  Now the vessels coming from the optic nerve are out of focus, but the vessels on the area of the retina that is detached (arrows) have now come into focus.

A retinal detachment is an ocular emergency that requires surgery within a day or so to limit the extent of the detachment, particularly to keep the detachment away from the macula if possible.  Any part, or all of the retina can potentially detach.  The only areas that are firmly attached are at the ora serrata in the far periphery and at the optic nerve head.

Treatment may involve a scleral buckling procedure, pneumatic retinopexy, vitrectomy, or a combination of procedures.  Cyrotherapy (cold probe), diathermy, or laser may be used in the procedure to "tack down" the retina.  Scleral buckling is a surgical procedure that encircles the eye with a band that pushes the retina back in place.  The pneumatic retinopexy procedure involves injecting air or a gas into the eye to push the retina back into place.  A vitrectomy involves removing vitreous material that may be pulling on the retinal tissue.

The retina can also be detached by traction from a vitreous membrane, or by serum or blood from a secondary cause.  Diabetic retinopathy is a common cause of secondary retinal detachment.

The nerve fiber layer can detach from the other retinal layers.  This is called retinoschesis.  The retinal can also detach at the RPE layer.  This is called an RPE detachment or a pigment epithelial detachment (PED).  A PED is limited in area, is located in or adjacent to the macula, and is usually associated with macular degeneration.

Below is an OCT image of a PED.  The arrow points to the orange-red RPE layer, which has been pushed up by the fluid.

Below is a late stage fluorescein angiogram of a PED demonstrating the leakage of serous fluid underneath the RPE in a localized area.

Retinal Artery and Vein Occlusions

Retinal veins and arteries are susceptible to occlusion, as are all the blood vessels in the body.  An occlusion in the brain causes a stroke.  An occlusion in the eye causes decreased retinal function in the area affected.  Occlusion in the eye occur at vessel crossings and bifurcations (branching).  Veins and arteries that cross in the retina may come into contact with each other, reducing the lumen (inside diameter) at the point of contact and creating a narrowing where an embolism can lodge.

An occlusion of a vessel inside the optic nerve head is called a central retinal artery occlusion (CRAO) or a central retinal vein occlusion (CRVO).  The severity of a CRAO may be reduced if the intraocular pressure can be dramatically lowered surgically within a few minutes of the occurrence.  Otherwise, central occlusions are not conventionally treatable.  A retina with a CRVO is sometimes treated with laser, but the procedure is meant to reduce the chance of developing neovascular glaucoma and it does not improve the visual function of the retina.

Below are pictured a color photo and a fluorescein angiogram of a hemi-central vein occlusion.  The occlusion has occurred in the optic nerve head, but only affects the inferior branch.

The optic nerve enters the eye about 3mm nasally to the fovea in each eye.  If you draw a horizontal line through the middle of the optic nerve, the macula will be slightly below that line.  These anatomical features help to identify the left eye from the right eye in a photograph of the retina, as discussed in Module 25.

Glaucomatous Optic Nerve Appearance

Glaucoma develops when an abnormally high intraocular pressure over a sustain period of time causes the retinal nerve fiber layer to atrophy.  When retinal nerve fibers atrophy, they shrink in size.  The hump of nerve fiber tissue at the rim of the optic nerve becomes less thick, and the size of the optic nerve cup, relative to the area of the optic nerve head, becomes greater.  This is measured by the cup-to-disk (C/D) ratio.  

The ratio is based upon the number 10.  Ten represents the area of the optic nerve head.  A C/D ration of 5/10, or .5, means that the area of the optic cup makes up half of the total area of the optic nerve head.  A C/D of .3 is considered to be normal.  Glaucomatous atrophy of the optic nerve causes a gradual increase in the C/D ratio.  Advanced stages of glaucoma may demonstrate a C/D ration of .8, .9, or even total cupping where the optic disk has no rim of nerve tissue left.  Below left is pictured a .5 cup, and below right a .9 cup.  The lines indicate the edges of the cups.

There are, however, individuals who have a C/D of .5 or larger who do not have glaucoma.  The C/D ration is only one piece of information that the ophthalmologist must consider when evaluating glaucoma.  Disk pallor (whiteness), asymmetry of the C/D ration between eyes, and the shape of the cup are also evaluated.

Other factors the ophthalmologist considers when evaluating glaucoma:

1. Family history, race, and medical history:  A positive family history of glaucoma, being afro-american, having diabetes, having high blood pressure, and smoking are all risk factors for glaucoma.

2. High intraocular pressure:  An IOP reading over 24 with the applanation tonometer is a danger sign for glaucoma.  However, this factor alone is not diagnostic of glaucoma.  Some patients with relatively low pressure readings can have glaucoma, and vice-versa.  It has been determined that corneal thickness can skew the pressure readings from the applanation tonometer.  For example, an abnormally thick cornea would be more rigid than normal and might yield an erroneously high pressure reading.

3. Changes in the IOP over time.

4. Visual Field defects:  See Module 11.

5. Nerve Fiber Layer Analysis: New technologies such as scanning laser polarimetry (GDX), optical coherence tomography (Zeiss OCT), and scanning laser tomography (Heidelberg HRT) are measuring the thickness of the nerve fiber layer at the optic nerve head and in the macula.  This information is compared to averages in the normal population, and changes can be followed over time.  Below is pictured the nerve fiber analysis printout from the GDX.

Other Abnormalities of the Optic Nerve

Glaucoma causes atrophy of the optic nerve.  Optic nerve atrophy can also be the result of chronic optic neuritis (inflammation) caused by a drug reaction, trauma, or a systemic disease (e.g. syphilis, Lyme disease, MS).  The underlying disease is treated.

Optic neuritis is usually unilateral.  Symptoms include eye soreness, blurry vision, reduced color perception, and visual field defects.  Other names for optic neuritis are papillitis and retrobulbar neuritis.

The globe can be divided into three layers according to function:

1. The protective layer is composed of the cornea and the sclera.

2. The nourishing layer is composed of the iris, the ciliary body, and choroid.  This is also known as the uveal tract.  Anterior uveitis is an inflammation of the iris.  Posterior uveitis is an inflammation of the choroid (also known as choroiditis).

3. The receptor layer is composed of the retina.

The capillaries of the choroid lie just below the RPE and form the choriocapillaris.  

The larger choroidal blood vessels feed this fine network and lie behind it.  The choroidal veins drain into four vortex veins, one beneath each quadrant of the retina.

The choriocapillaris is separated from the retinal RPE by a thin "basement membrane" called Bruch's membrane.  Nutrients flow through this membrane from the choriocapillaris to the RPE and photo receptors.  Waste products from the retinal RPE and photoreceptors flow back the other way.  It is thought that retinal drusen is waste material that is building up and not being processed back to the choriocapillaris.

Some diseases affect both the retina and choroid (chorioretinitis).  These include histoplasmosis, toxoplasmosis, and sarchoidosis.

Abnormal new blood vessels, a choroidal neovascular membrane (CNV), can form in the choroid and break through the RPE to leak serum or blood under or into the retina.  This is secondary to disease processes such as histoplasmosis or macular degeneration.  See the discussion on macular degeneration.

A choroidal detachment occurs when serum or blood enters the space between the choroid and the sclera.  A serous choroidal detachment can occur from trauma, inflammation, or globe hypotony (sudden reduction in intra-ocular pressure).  A hemorrhagic choroidal detachment arises from a ruptured choroidal vessel from trauma or eye surgery.  Choroidal detachments are dome shaped and are most often associated with ocular surgery.  

Below is a B-scan image of a choroidal detachment and a retinal detachment.  The choroidal detachment is the thick dome shaped line.  The retinal detachment is the thinner line intersecting the choroidal detachment.

Choroidal detachments resolve if the underlying cause is treated, or the suprachoroidal fluid can be surgically drained.

Choroidal Testing - Indocyanine-green (ICG) angiography is used to visualize choroidal blood flow.  The procedure is similar to fluorescein angiography, but the near-infrared wavelength "sees" through the RPE layer to visualize the choroidal vessels.

The cornea can be thought of as an extension of the sclera because it is made up of the same tissue as the sclera, and the cornea also performs a protective function.  Dehydration (by the endothelial cell pump) and the arrangement of the corneal cells make the cornea clear.