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Technology advances ability to diagnose, manage diabetic macular edema
How have new technologies affected the way in which you diagnose diabetic macular edema?
Brett J. King, OD, FAAO: The advent of Optical Coherence Tomography (OCT, Carl Zeiss Meditec, Dublin, Calif.) has greatly enhanced our ability to visualize and quantify diabetic macular edema. For doctors who are not accustomed to viewing macular edema, this technology is a great confidence builder because it shows the thickened tissue, and the practitioner can compare this to the clinical exam.
In my practice, OCT has been very helpful in quantifying the amount of thickening and thereby helps me assess whether it is stable, progressing or improving. In the past, judging efficacy was sometimes difficult in patients with diffuse thickening because it was a subjective determination by the examiner. OCT has been able to actually quantify these changes for us and therefore helps in deciding if we should continue with our treatment plan or change strategies.
Anthony A. Cavallerano, OD, FAAO: The gold standard for diagnosing DME is 35-mm stereoscopic fundus photography. However, the recent advances in digital retinal imaging technology have improved our ability to determine the presence of retinal thickening. Devices such as the Heidelberg Retinal Tomograph II (Heidelberg Engineering, Vista, Calif.), the OCT and the Retinal Thickness Analyzer (RTA, Talia Technologies, Tampa, Fla.) are some of the newer technologies that enhance our ability to diagnose and ultimately treat DME.
These devices have the capability of verifying diagnostic findings and determining suitability and eligibility for treatment of DME. While these devices improve our ability to diagnose DME, we still must rely on fundus fluorescein angiography to identify sites of focal or diffuse leakage characteristic of DME so that these areas can be treated with focal laser or modified grid focal argon green laser application.
The HRT II is a confocal laser scanning system that acquires a series of images at different focal planes and forms a three-dimensional rendering of the retina or optic nerve. The HRT II retina module (Macular Edema Module) obtains confocal tomographic images in the x, y and z planes, produces an intensity profile and determines the amount of light scatter. The results provide the examiner with a dimensionless number, indicating an index of retinal edema based on the amount of light scatter.
The OCT uses near infrared frequency light to obtain an image and measures retinal optical reflectivity to generate a map indicating retinal thickness.
The RTA uses a green helium neon (HeNe) laser as a slit beam similar to a slit lamp biomicroscopy to obtain topographic measurements of retinal thickness.
The RTA has nonmydriatic and mydriatic scanning modes, while the OCT and HRT obtain a retinal map without dilation. Media opacities can interfere with the imaging process with all three devices, however, thus limiting sensitivity and specificity in patients with cataract. All advanced imaging systems can be of enormous value in a busy primary care practice. The HRT II and RTA are more suited to primary care practices, while the OCT is of more interest to a specialty practice, such as a retinologist.
Which current clinical trials do you think show promise in
improving the way you manage diabetic macular edema?
Dr. King: If we are just looking at studies for DME, then I would have to say that Eli Lilly’s (Eli Lilly & Co., Indianapolis) Protein Kinase C (PKC) inhibitor and intravitreal steroids show promise. However, if you take a broader look, then all the anti-angiogenesis agents currently being investigated for age-related macular degeneration may also have a role to play in the treatment of diabetic retinopathy. Macugen (Eyetech Pharmaceuticals, New York) and Lucentis (Genentech, San Francisco) have already looked into this area for expansion of their therapeutic indications.
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Lilly’s PKC beta inhibitor is an oral investigational medication that works on the vasculature. In diabetes, there is thought to be an increased activation of vascular cell PKC beta leading to, among other things, an increase in vascular leakage. The increased vascular leakage contributes to the development of conditions such as diabetic macular edema.
PKC beta has been shown to be important in diabetic microvascular complications, including diabetic retinopathy, and Ruboxistaurin by Lilly is a PKC beta inhibitor. The PKC enzyme has an adenosine triphosphate (ATP) binding site that is important for its activity as a kinase. Ruboxistaurin binds at the ATP site, blocking ATP and preventing activation of the enzyme. This oral medication, therefore, has the potential of halting or preventing the development of diabetic macular edema.
The other area of interest would be with intravitreal steroids. Corticosteroids have been shown to stabilize the vascular endothelium and, therefore, decrease permeability and affect tissue edema.
Multiple single-center small patient population studies have been performed on triamcinolone and macular edema, but there has been no definitive clinical trial. Therefore, the Diabetic Retinopathy Clinical Research Network (DRCR.net) is developing a multi-center, randomized clinical trial with a purified triamcinolone to be injected through the pars plana in patients with diabetic macular edema.
Additionally, Allergan (Irvine, Calif.) is working on a long-acting dissolving dexamethasone pellet placed into the vitreal cavity to release a steroid for macular edema. The company is conducting two sets of studies: non-diabetic macular edema and DME.
Dr. Cavallerano: While focal or modified focal grid laser treatment remains the mainstay of treatment for DME, a number of alternative or supplementary therapeutic approaches are being investigated for DME. Several clinical studies in progress or pending are looking at alternate treatment modalities and routes of administration, including oral administration and intravitreal injection, as preventive or adjunctive therapy.
It is now thought that angiogenic factors play an early role in the pathogenesis of diabetic retinopathy and diabetic macular edema. Antiangiogenic factors are being investigated along with protein kinase C inhibitors as a means of blocking the cascade of events that lead to DME very early on in the process.
Additionally, because there appears to be an inflammatory component to DME, adjunctive therapies are being used to treat intractable DME. Clinical trials in various stages are underway using intravitreal injection of fluocinolone (Bausch & Lomb, Rochester, N.Y.), triamcinolone (Kenalog, Bristol-Myers Squibb) and dexamethasone to treat DME. Initially, these agents appear to be effective in reducing DME in recalcitrant or recurrent cases.
The mechanism of action in restoring the integrity of the inner blood retinal barrier likely relates to the role of corticosteroids in inhibiting prostaglandin activity, thus reducing the effect of the vascular endothelial growth factor. Antiangiogenic agents such as Macugen (Eyetech Pharmaceuticals) and rhuFab V2 (Genentech, San Francisco), also administered by intravitreal injection, appear to have potential in treating DME, and investigative studies are either underway or in development.
Nonsteroidal anti-inflammatory agents such as celecoxib capsules (Celebrex, Pfizer, New York), antioxidants and vitamin E are also being evaluated as adjunctive therapy for DME. Prophylactic vitrectomy has also been used to reduce thickening in the macula from diabetes because studies have shown that a patient is more likely to have DME when the posterior hyaloid face of the vitreous remains attached to the macula.
The standard for diagnosing and following the progression of diabetic macular edema will be made easier by the use of advanced imaging techniques. The HRT, the OCT and the RTA are now emerging as the clinical benchmark for diagnosing and following DME. Increased use of these technologies in a clinical setting will provide more data and information regarding the efficacy of some of the experimental treatment options currently under investigation.
Finally, conventional digital retinal imaging using mydriatic and nonmydriatic fundus cameras have begun to find a place in primary care offices to help screen, evaluate and triage the diabetic patient. These systems are relatively easy to use, and a nurse, an assistant or a technician can be taught to use the cameras very quickly to obtain diagnostic quality images.
More than 18 million Americans now have diabetes, and almost one-third of them don’t know they have the disease. Since only 60% of patients with diabetes receive timely and appropriate eye care, this strategy of deploying imaging devices outside of the optometrist’s office, for example in an internist’s or endocrinologist’s office, may be very useful in identifying at-risk individuals with diabetes mellitus. The digital retina images can then be transmitted to an optometrist’s office for evaluation and review, and the patient can then be prioritized into an eye care program. This method of identifying at-risk patients can increase compliance for eye exams because while diabetic patients may be under the care of a primary care physician for their diabetes, they may not necessarily have timely eye exams.
For Your Information:
- Brett J. King, OD, FAAO, can be reached at 4321 Washington, Suite 6000, Kansas City, MO 64111; (816) 931-4733; fax: (816) 931-9498; e-mail: bking@hunkeler.com.
- Anthony A. Cavallerano, OD, FAAO, is a member of the Primary Care Optometry News Editorial Board. He can be reached at VA Boston Health Care System, Jamaica Plain Campus 112A, 150 S. Huntington Ave., Boston, MA 02130; (617) 232-9500, ext. 2281; fax: (617) 264-6538; e-mail: anthony.cavallerano@med.va.gov.
- Neither Dr. King nor Dr. Cavallerano has any direct financial interest in the products mentioned in this story, nor are they consultants for any companies mentioned.