We will be talking today about how a VHL lesion can cause damage to the eye. How do we diagnose the presence of a tumor? What can the patient do to help us diagnose the lesion early so that we can treat it most successfully?

We have a lot of treatments for the retinal tumors which accompany VHL, but our treatment results are much better if we can diagnose the presence of a tumor when the tumors are small. I’ll give you some examples of some diagnostic techniques, like fluorescein angiography. We’ll touch upon laser therapy and cryotherapy which are the two most widely used means of ablating these tumors at the present time. And I will briefly touch on photodynamic therapy (PDT).

The retinal lesions caused by VHL are capillary hemangiomas (CH). They can start out as little teeny nubbins in the retina that are very hard to see, but eventually they grow to a size where they are fairly obvious. There are a few characteristics that accompany these lesions. Generally speaking there is a dilated arteriole (small artery) which is draped bringing blood to the tumor, and a dilated vein that is taking blood away from the tumor. If the tumor has been present for some time, the tumor will leak serous fluid, protein and fat into the subretinal space, the space beneath the retina. These collections of protein and fat can sometimes signify the presence of a very tiny tumor.

In the normal retina you see the macula in the center, the most sensitive part of the retina. Half of the light-receptors in the entire retina are collected in this one little area. Even though VHL tumors may be way out in the periphery of the eye, they can cause reduction of vision. The products from the tumor gravitate toward the macula, and fat and other proteins can accumulate in this region.

The normal retinal vessels branch gracefully like trees; around the tumor there will be abnormal retinal vessels, swollen and tangled. And sometimes these dilated vessels will signal to the ophthalmologist that there is a tumor lurking out in the periphery. Near the center of the retina is the optic nerve (see Figure 1).

The discovery of new lesions is very important. The smaller the lesion is when we discover it, the more favorably it will respond to treatment. What can the patient do to help us discover these lesions early?

Anyone with a family history of VHL should have an ophthalmic examination at least one a year. This examination should consist of dilating the pupil, and examining the retina with an indirect ophthalmoscope. This is the instrument that the ophthalmologist will put on his or her head and shine a light through a prism or lens held in the hand.

For those without a family history of VHL — in other words, for everyone in the general population — anybody that has a reduction in central vision should have an examination to determine why there is a central blur in the visual field?

In VHL, the most common cause of reduced central vision is the accumulation of proteins and fats in the region of the macula. These proteins and fats actually travel from the periphery to the center of the retina, accumulating within the macula. So when a lesion is seen, especially if it is associated with dilated retinal vessels, one must suspect VHL. To confirm the presence of a tumor, and/or to diagnose new lesions, we will frequently use a test that is called a fluorescein angiogram. This is a test where sodium fluorescein dye, which is a very inert dye, is injected into the patient’s vein in the arm. The dye reaches the retina within 19-20 seconds. This test is usually done in the company of a fundus camera, positioned to take video of the back, or fundus, of the eye. The camera then begins to record the dye running in the vessels and going toward the tumor, approximately 20-25 seconds after completion of the injection.

After 3-5 minutes we see dye begin to leak out of the tumor and enter the vitreous cavity (the large space in the center of the eye, normally filled with a clear gel). In the later stages of the disease, you may see a whole quadrant of the vitreous cavity lighting up. These lesions, then, can be seen either with the fundus camera or with the indirect ophthalmoscope which covers a much larger zone, and with the proper filter in place on the ophthalmoscope the ophthalmologist is able to see even the tiniest lesions out on the periphery of the retina. They look like stars in a midnight sky.

Once diagnosed, then, we want to eradicate the tumor. The most common modality is the laser or photo-coagulation with the so-called "hot laser". If the tumor is so large that we cannot use laser, then we will rely on cryotherapy. The difference between the two is that laser therapy is thoroughly innocuous. It does not involve any invasive cutting. The laser energy is directed through the patient’s dilated pupil, and you can do multiple sessions of treatment without having the patient admitted to the hospital or actually having to go through a cutting procedure.

Cryosurgery, on the other hand, is the application of cold energy through the wall of the eye. Cryosurgery is used when we can no longer use laser therapy. Sometimes cryotherapy needs to involve an incision in the lining over the white of the eye in order for us to get the cryo probe back to the lesion, and for us to deliver the cold energy through the wall of the eye to the lesion. That obviously involves creating a sterile field, and making an incision in the membrane. It usually involves admission into the hospital or clinic.

You have heard talk about the involvement of Vascular Endothelial Growth Factor (VEGF) in the process of development of a VHL tumor. We think it is precisely VEGF which also initiates the wet form of age-related macular degeneration where we see the invasion of capillaries beneath the macula, growing toward the central macula or the fovia. Many of the new drug therapies being developed for macular degeneration seem to have applicability for VHL lesions as well. There are several now in clinical trials, so better treatments are on the way.

Let me describe the process of photocoagulation, the most common treatment currently available to people with VHL. The goal is to shrink or ablate the vascular tumor so that once a tumor like this is discovered we want to deliver hot energy or a hot light to this tumor. The pigment within the tumor absorbs the light. It works best in tumors that are a little darker, but it works well in VHL tumors as well. We want to deliver the energy, and have the energy absorbed by the tumor. The ophthalmologist delivers points of light, making big circles. If you hit it too hard with a narrow beam, the tumor can bleed and the blood can go into the vitreous cavity and then that begins to set up a connection between the vitreous gel in the center of the eye and the tumor. Those kinds of connections can lead to problems in the future.

We apply fairly broad laser doses gingerly at first. A small tumor might receive ten doses, then the patient will go home. About four weeks later we may deliver another ten. Gradually the intensity of the light beam is increased a little more until we are pretty sure that there is enough of a fibrous coating over the lesion so that it will not spontaneously bleed. After a while then the lesion will acquire a little fibrous tissue cap, and the tumor begins to shrink beneath this cap. As long as we can see little portions of the tumor from the side we will continue to deliver laser therapy to the tumor. The objective is to be able to shrink the tumor until it is just a little nubbin in the retina. At that point we can really apply energy to it and ablate it.

Occasionally the tumor will shrink. It will almost always develop this little white fibrous tissue cap, making it difficult now to deliver additional energy if the edges of the tumor are not showing. So our next strategy then is to the try to strangulate the tumor, to decrease the blood supply to the tumor by applying at first gentle and then more strong laser therapy along the sides of the artery supplying the tumor. The laser treatment then stimulates fibrous tissue growth around the edges of the artery, and that fibrous tissue then begins to gradually constrict the lumen, the opening down the middle of the artery. And that is a good strategy.

If laser treatment doesn’t work, the other strategy we invoke then is cryosurgery. We bring a cryosurgical probe around the outside of the eye, advance it until it is right beneath the tumor, and then apply freezing energy which penetrates through the white coat, through the vascular coat, and finally through to the retina. You can apply enough energy so that this entire lesion can be turned frosty white and using a freeze-thaw technique you can achieve very good damage to the lesion.

The main goal is the shrinkage or stabilization of the lesion. We want to decrease the leakage so that the amount of fluid beneath the retina decreases, and we want to improve central vision. In this eye (Figure 1) there was reduced vision, down to the level of 20/30, caused by the accumulation of material beneath the macula. We can see that the fluid action and the exudate action extends downward, and the lesion is out to the left. There are abnormal vessels leading up to the lesion, the artery and the vein.

The lesion was exposed to laser therapy. Six months later we began to see a decrease in the amount of exudation and the vision improved to 20/20. Seventeen months after the treatment the vision came back to 20/10 and we can only see a very small fleck of protein beneath the retina. This is a good response.

Occasionally a lesion will develop in a position near the optic nerve which can be very detrimental to vision. When the lesion develops in this position there is not much we can do to improve vision, but there is still a lot we can do to prevent the lesion from going down the cascade where we will lose the eye.

In summary, this condition can be managed. It is managed very well, especially if we get to the lesion early. Periodic examination is extremely important, especially if there is a family history. With the onset of reduced central vision everybody — whether VHL or not — should consult an ophthalmologist to find out why the central vision is degraded, and then we discussed the treatment options, namely laser and cryosurgery.

Questions:

Q: If there is a lesion on the optic nerve, what would you do?

A: If it is not growing and not exuding material that travels beneath the macula, just watch it. We have excellent ways of watching it now, one of which is photography. But if all of a sudden it begins to grow, what can you do then? Well, you would hesitate to use hot laser unless you were pretty sure that the nerve fiber bundle (the bundle of nerves coming from the macula to the optic nerve) was actually beneath the lesion and not draped over the top. If they are draped over the top of the lesion then you would be excluded from using hot laser. Could you do cryosurgery? If this lesion is sitting right on top of the nerve there is no way that you are going to get the cryo probe beneath the nerve and apply the energy, because cold energy is very destructive to nervous tissue. That’s when you would think about using PDT.

Q:What is Photodynamic therapy?

A: PDT differs from laser therapy in that we take advantage of the fact that the lining of newly growing capillaries tend to attract lipid molecules (fats). There is a dye out there now call visio-dye that when injected into a person’s vein combines itself with molecules of low density fat. This combination molecule then circulates throughout the body. Normal blood vessels will not attract low-density fat, but the lining of new blood capillaries or growing capillaries will. So ten minutes after infusion the dye along with the low-density fat will have saturated the lining of the abnormal new blood vessels in the VHL lesion. That target, then, is irradiated with a cold laser, a diode laser that does not cause any formal effect, but at the wave length of 680 nanometers it will excite the dye. The dye then produces single oxygen molecules which are very toxic to the lining of these capillaries. That then coagulates or thromboses the capillaries and turns them off. So that is probably the modality I would favor.

Q: What is your experience with that? Is PDT successful in treating VHL lesions and maintaining vision?

A: So far we have little experience with PDT and VHL. The results from PDT with age-related macular degeneration are approximately 60% stabilization and/or improvement of vision. So compared to what we had before, that’s super. But there are treatments now in clinical trial involving anti-VEGF molecules. We want to discourage the growth of new blood vessels beneath the macula. Presumably these anti-VEGF treatments might be useful also for VHL.

Q: My daughter’s two angiomas were discovered in 1998, and they are just watching then, they haven’t done anything. I feel like I’m just waiting for something to happen.

A: It all depends on the location of the tumors, if they are too close to the nerve, or too close to the macula. That might be a reason for temporizing.

Q: They say they are in the periphery. What strategy would you follow in a case like that?

A: Because I have seen patients develop multiple tumors over the years, I prefer keeping up with them so that I know that I have handled this one. I keep watching, and if another one pops up I handle that one. It’s just another philosophy.

Q: At what age do you recommend beginning eye exams?

A: If there is a family history, I would recommend beginning at age 3-5. It is easy to do a good exam on a child of five. If there seems to be a high penetrance in the family, I would even recommend doing an exam under anesthesia as early as age 1.

Q: In our family there is a lot of involvement and most people have multiple tumors by age 9. We also see a lot of growth in puberty. Under those circumstances would you not recommend that they be checked every six months?

A: Yes. Once a tumor is seen, then I think a schedule of every six months is a very good schedule to follow.

Q: In our family it seems that when you treat a lesion it only gets worse.

A: Sometimes when you treat a lesion you will actually stimulate that lesion to begin to exude fluid into the subretinal space. Not every lesion responds the same way, and therefore you have to tailor your treatment to the particular case, go slowly, and assess the response.

Based on Dr. Fung's talk at the VHL Conference, Palo Alto, California, June 2001.

As printed in the VHL Family Forum 10:1, March 2002. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org.