by Emily Y. Chew, M.D., Deputy Director, Division of Epidemiology and Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA

Dr. Emily Chew

Retinal angioma in the eye may be one of the earliest manifestations of VHL disease. As many as 60% of patients in some studies of large kindreds may have eye involvement. The clinical appearance of these angiomas is very typical and diagnostic of VHL. The initial appearance of a retinal angioma is a subtle red or grayish dot no larger than a few hundred microns. As the proliferation of the vascular tumors (mostly of capillaries) progresses, secondary alterations occur to produce a distinctive clinical appearance. The blood vessels leading to and away from the tumor become characteristically dilated with marked enlargement. This tumor can lead to leakage of fluid and fatty deposits both around the tumor and in the central important area of the retina, the macula, which is responsible for the fine vision needed for reading, driving, etc. If the angiomas enlarge to an extent that the retina can be detached, hemorrhaging and scarring can occur. These can all lead to decrease in visual acuity of the affected individual. Rarely can these tumors regress spontaneously.

Preclassical Angioma

Figure 1: A small, preclassical angioma is located slightly below the center of the photograph. This small lesion can
easily be overlooked during an eye examination.

Often patients do not have symptoms as these lesions tend to progress slowly. The tumors can be detected in children to adults in the eighth decade of life on a routine exam. Symptoms such as decreased vision or a turned-in eye (crossed-eye) may result in the detection of VHL in children. Decreased visual acuity can also cause adults to seek medical help and subsequent detection of the disease.

The treatment of the retinal angiomas will depend on the location and size of the lesions. Small lesions are easy to treat successfully while large lesions are notoriously difficult to treat. Laser photocoagulation can eradicate small retinal angiomas in most locations. However, for those tumors too large or located in the very periphery of the retina, cryotherapy (freezing treatment) may be indicated.

If the tumor is located on the optic nerve, the nerve that connects the eye to the brain, treatment is fraught with difficulties. Marked adverse side-effects are associated with treatment of such tumors with laser photocoagulation. Fortunately, these tumors may remain asymptomatic for long periods of time. For patients with the more severe changes such as retinal detachment, hemorrhage and scarring, the procedure called vitrectomy can be performed. This involves the introduction of microinstruments under the guidance of a microscope to remove the areas of scarring and to flatten out the retina. Other treatments that have had some limited success include radiotherapy. However, experience with this modality is somewhat limited. Other therapies have also included photodynamic therapy which has been reported to have beneficial results in few cases.

Angioma

Figure 2: This angioma shows a large feeder vessel leading to the angioma with a large vein as a draining vessel.

More recently, 10 cases of severe optic nerve tumors or multiple tumors of the retina were treated with 2 different types of anti-Vascular Endothelial Growth Factor (VEGF) drugs (Macugen and Lucentis) with very limited success at the National Eye Institute/NIH. We are now testing the use of oral Sutent (sunitinib malate) in cases of severe optic nerve tumors or multiple tumors of the retina that are causing vision loss. This drug is FDA approved for the treatment of metastatic renal cell carcinoma. Because of its ability to attack the tumor through different mechanisms of action, it might be important in the therapy of these retinal angiomas that are not amenable to other treatment. This is an open label study in which all patients will receive the therapy for at least 9 months. The study is now open for recruitment.

eye diagram

Figure 3: Illustration of the human eye, showing the optic nerve. The periphery is the part of the retina farthest away
from the optic nerve.

The importance of maintaining good visual function in patients affected with VHL depends on regular dilated (the opening of the pupil of the eye with drops) eye examination. For patients who are at risk of developing VHL, an annual dilated eye exam will provide important information and help maintain good vision. It is very important that all patients affected or who are at risk be examined annually through DILATED pupils. Good vision can be achieved and maintained in many affected individuals, especially if the lesions are detected and treated early in the course of the disease.

For those individuals who are interested in the NEI/NIH trial of Sutent for optic nerve tumors associated with VHL, please contact Katherine Shimel, RN at Katherine.Shimel@nih.gov or by telephone: (301 402 2863).

Photo-Dynamic Therapy

Dr. Arun Singh

Dr. Singh

-- Arun D. Singh, M.D., Director, Department of Ophthalmic Oncology, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio, gave a presentation on treatment of VHL eye lesions in Sandusky, Ohio, October 2007. Joyce Graff asked some follow-up questions about photodynamic therapy.

Joyce: Let me ask you one more question about the tumors on the optic nerve, since those seem to be the most problematic. You said that we should wait and not treat them until there is some visual disturbance?

Singh: Absolutely. I have no hesitation in saying that, because the tumors on the optic disc tend to be inactive for many, many years. So number one, if they are causing no problems whatsoever with the vision, you are better off leaving them alone. Because many times they may just stay that way for a long time. That’s number two. And number three is the fact that if you were to treat them, chances are you would end up losing some vision because of the treatment related complications.

Joyce: So if the tumor begins to grow and begins to disturb the vision, then what is your preferred way of dealing with them?

Singh: Well, the preferred treatment for optic disc hemangioma presently is photodynamic therapy (PDT), where in a dye is injected that specifically locates itself in the tumor, and with the a special wave length laser one can preferentially destroy the area where the dye pools, which is the hemangioma. So the aim is to achieve selective ablation or destruction of the hemangioma while attempting to spare the surrounding blood vessels, retina, and the optic disc.

Joyce: So this dye goes and hooks onto the tumor cells in the hemangioma, and not the healthy cells, and then this special laser light goes in and essentially kills off those tumor cells?

Singh: Yes. The laser light is picked up by the dye, so wherever the dye is, that’s where the energy will be taken up. The normal blood vessels don’t have the dye, so they will not be affected by the laser. And this laser is not heat-dependent. It triggers a chemical reaction in the dye and that chemical reaction kills the cells. The tumor will shrink with time. The end point or objective here is not necessarily the total ablation of the tumor, but enough scarring or fibrosis within the tumor that it stops leaking and stops causing the exudation around it.

Joyce: So it makes it less active, and less likely to secrete the fluid that causes the visual problems.

Singh: Exactly. So the end point is resolution of the fluid and the symptoms and improvement of vision, and not necessarily complete ablation of the tumor.

Joyce: So if this tumor is made up of capillaries, though, and you kill off these capillaries, isn’t that going to cause some bleeding?

Singh: There can be small hemorrhages around the tumor from the laser uptake. That is an indication that you did the laser alright, and there has been laser energy uptake. Those hemorrhages typically will go away in a few weeks and should not cause any permanent problems.

Joyce: OK. It does take a few weeks, though, for that blood to clear out of the eyeball.

Singh: Yes. These hemorrhages are typically in the retina, not in the vitreous cavity. These are small hemorrhages and they will go away. The response to laser treatment is not immediate, though. It may take anything up to six weeks or so before you see the tumor shrinking away, and many months for the lipid exudation to go away. And it may take a few weeks for the fluid to go away. So the response is not immediate. But if one has to repeat the treatment you almost always end up waiting as much as three months because you want to give that much time for the response to begin to show.

Joyce: But the point here really is that we are not damaging the healthy retinal tissue by using PDT, right?

Singh: That is the aim, but there is some damage to the optic nerve, one would imagine, because the tumor is right on the optic nerve. So there will be some spill-over collateral damage, although PDT would still be the best method that we have out there right now.

Joyce: Right. There is no perfect method for this.

Singh: No. There is no perfect method.

For the link to Dr. Singh’s presentation with his original slides, please see the online version of this article at http://vhl.org.

As printed in the VHL Family Forum 16:3, September 2008. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org.