In 1904 Eugen von Hippel, M.D., described retinal angiomatosis retinae, the retinal angiomas we now recognize as occurring in von Hippel-Lindau disease. About 30 years later Arvid Lindau, M.D., described angiomas of the spine and cerebellum. We now recognize von Hippel-Lindau disease (VHL) as a genetic condition which involves the growth of angiomas in vascular-rich areas of the body, including the retina, the light-sensitive tissue of the eye which is important for our vision. In addition to the eye, the lesions frequently affect the central nervous system, the pancreas and the kidney, as well as numerous other organs in humans.

Von Hippel-Lindau disease is transmitted genetically in an autosomal dominant fashion. Consequently, a child of a person with von Hippel-Lindau disease has a 50% chance of having the condition. The expressivity of the disease is often delayed, and a person who has the disease may not be diagnosed for many years. While an angioma from VHL can grow in the brain, spinal cord, adrenal glands, kidney, pancreas, and other organs, an angioma in the eye is the only VHL hemangioma that can be directly observed.

eye.gif (10616 bytes)

Fig. 1. Illustration of the human eye

Review of Retinal Anatomy

The human eye can be considered as a forward extension of the brain. Embryologically, the eye develops from the same tissue as the brain. The human eye functions by focusing images on a light sensitive tissue within the eyeball. This tissue, the retina, is highly vascularized, receiving nutrients from blood vessels within the retina itself and from circulation in the underlying choroid. (Figure 1) The retina is able to take the light signal that is focused on its surface and convert the signal to a neural message which is conducted to a cortical area of our brain that is responsible for sight.

The sclera, which is the "white" of the eye, provides the eye with a degree of rigidity. The eye is usually divided into two main sections, the anterior segment and the posterior segment. The anterior segment includes the cornea, the iris (the colored portion of the eye), and the lens of the eye. The internal structures of the anterior segment of the eye are bathed with a fluid called aqueous.

Behind the lens of the eye is the posterior segment of the eye. The posterior segment is filled with a highly viscous substance called vitreous. The vitreous pushes against the retina of the eye. The light sensitive retina of the eye contains blood vessels which deliver oxygenated blood to the eye (arteries) and blood vessels which drain deoxygenated blood from the eye (veins). Capillaries are small vessels where arteries and veins meet. In a healthy eye, fluids are well contained in the vessels of the retina. In some disease conditions, fluids, lipids, and other molecules leak from the vessels in the retina. These leaking areas can be identified by a special procedure called fluorescein angiography, where a fluorescein dye is injected into a vein in a person’s arm, and the flow of the dye can be traced in the retina of the eye. In a healthy eye, the fluorescein does not leak out of the vessels. In disease cases, such as retinal angiomas, dye can leak into the retina.

When angiomas are examined using fluorescein angiography, the classical lesion will show leakage of dye from the tumor. The feeder vessels are easily visualized, and shunting of blood through the tumor is likely to be present. Blood flow is generally rapid through the tumor, and there is poor perfusion or blood flow through capillaries surrounding the lesions. Fluorescein dye which has leaked from the tumor will collect in the retinal tissue, causing hyperfluorescent areas of fluorescein pooling -- an area which "lights up" on the photograph.

Retinal Disease in VHL

A retinal angioma observed during a routine eye exam may be the first clinical sign that a person has VHL, and may be a reason for conducting additional specialized testing. Other patients may experience other VHL issues long before retinal angiomas occur. Even if no eye lesions occur early, it is important to continue screening throughout the patient's life.

vessels.gif (11271 bytes)

Figure 2: An illustration of a retinal angioma, showing interwoven capillaries arising between the arterial and venous system of the retina.

In the earlier stages (see below) of development, the angiomas are usually asymptomatic, causing no change in visual acuity. The lesions are painless in the early stages. Angiomas in the eye may be solitary or multiple, and the angiomas occur in both eyes approximately 50% of the time. These retinal capillary angiomas develop in approximately 57% of persons who have systemic lesions of VHL (lesions in other organs of the body).

Retinal angiomas arise in the capillary bed of the retina, in the vascular tissue between the arterioles and venules in the circulatory system. (Figure 2) The initial appearance of the lesion may be as a small micro-aneurysm, which then may assume the appearance of a red nodule and eventually a larger, orange-red tumor. Arterio-venous shunting in the tumor leads to dilatation and tortuosity [twisting] of the artery supplying blood to the tumor and the vein draining the tumor. When the angiomas are untreated, the tumor will leak plasma and other blood constituents into the retinal tissue, which leads to retinal hard exudates, edema, serous retinal detachment, bleeding, and, in some cases, eventually blindness.

Natural History of VHL Eye Disease

Different researchers have identified various stages of retinal angiomas in VHL. It is important to remember as we describe these stages that progression is not inevitable. The ophthalmologist will be working with you to halt or slow the progress of the disease.

The lesions can be single or multiple and there is considerable variation in presentations and progression through the various stages. While the different categories vary depending on the categorization method used, five clinical stages can definitely be identified as follows:

fig3angi.gif (43923 bytes)

Figure 3: A small, preclassical angioma is located slightly below the center of the photograph. This small lesion can easily be overlooked during an eye examination.

Stage 1: Preclassical. (Figure 3) In the preclassical stage small capillary clusters can be seen in the retina. In this preclassical stage the lesions appear as simple red spots or micro-aneurysms, similar to those associated with diabetic retinopathy or hypertension, among other diseases. These lesions are easy to overlook, especially if the retinal examination is conducted without pupillary dilation. These lesions are most likely to be asymptomatic (i.e., no change in sight or vision is noted).

Stage 2: Classical. (Figure 4) Although the presentation is variable, the classical retinal hemangioma is a knot of vessels with a large artery as a feeder vessel leading to the hemangioma and a large vein as a draining vessel. In the early stages of the classical lesion, the hemangioma may appear as a nodule with normal-sized vessels on either side of the nodule. The nodule can be either light or dark reddish or pale grey in color. As the lesion develops, the feeder vessels can become 2 to 3 times the size of a normal retinal artery or vein. These vessels usually assume a tortuous configuration. Eventually the lesion becomes elevated, usually growing toward the vitreous of the eye, and subsequently leading to the next stage of the disease. Depending on location in the retina, these lesions may be symptomatic, although most peripheral retinal lesions at this stage remain asymptomatic.

angiomas.gif (115502 bytes)

Figure 4: This angioma shows a large feeder vessel leading to the angioma with a large vein as a draining vessel. Figure 4B: A fluorescein photograph showing the large feeder vessel and drainage vessel of a VHL angioma. The angioma appears bright white in this photograph since it has filled with fluorescein.

Stage 3: Exudative. In the exudative stage of the hemangio-ma, leakage of fluid across the walls of the lesion results in retinal edema, retinal exudates, and leaked proteins and plasma from the blood. The accumulation of fluid which has leaked from the fenestrated walls of the angioma cause retinal swelling and edema, which leads to the next stage of the disease. Depending on location, lesions which have reached the exudative stage may also be asymptomatic. Lesions which affect the macula, the area of the retina responsible for fine visual tasks and sharpest acuity, are likely to cause symptoms. These symptoms may include blurring of vision, loss of visual acuity, or distortion of vision. In some cases, straight lines may appear warped or distorted.

Stage 4: Retinal detachment. In the retinal detachment stage of the disease, the retinal exudates and edema result in a lifting of the light sensitive retinal layer from the underlying tissue. Localized retinal detachments are likely to occur in all but the smallest angiomas. This retinal detachment has a tendency to spread, particularly as the lesions permit additional exudations. Symptoms similar to those described for stage 3 above are usually present at this stage. A retinal detachment may cause a curtain-like effect across the field of vision, or sudden, marked loss of all or some vision.

Stage 5: End stage. In the end stage of the disease, the retinal detachment has progressed. A long-standing retinal detachment can result in changes in the retinal tumor itself. Glial or scar tissue is likely to form. A painful glaucoma is likely to develop, vision is permanently and completely lost, and the eye becomes phthisical or shrunken.

Treatment of Retinal Angiomas in VHL

Various strategies have been attempted to prevent visual loss or blindness from VHL retinal angiomas. Some of these treatments have resulted in limited success. Early, unsuccessful treatments included X-ray irradiation, which did more harm to healthy tissue than to the tumor itself. Other types of radiation treatment using radioactive seeds resulted in some limited success, but results were variable and unpredictable. Diathermy has proven to be somewhat successful, but a major breakthrough was achieved in the mid-1950s by Professor Meyer-Schwickerath of Germany with photocoagulation of the tumor itself.

The advent of the argon laser improved the ability of ophthalmologists to treat the tumors, and in some cases the feeder vessels, with a significant level of success, especially when the tumors were treated in the earlier stages and when the tumors were comparatively small. Direct treatment of the tumors and the feeder vessels with laser photocoagulation is now the treatment of choice for tumors that are less than 2 millimeters in diameter. Various lasers have been used for this photocoagulation with a high rate of success, including the dye yellow laser. Multiple laser treatment sessions are usually necessary to obliterate a lesion fully. Regrowth of a lesion is not uncommon. In general, early diagnosis and treatment of the tumor result in favorable prognosis for destruction of the tumor and preservation of sight. Cryotherapy, either alone or as an adjunct to laser photocoagu-lation, is also an important part of the armamentarium [set of options] for the treatment of angiomas.

Side effects and complications of laser treatment include hemorrhage, retinal detachment, increased leakage into the retina, retinal holes, loss of visual field, or wrinkling of the retinal surface. In general, the benefits of laser treatment for angiomas outweigh the risks of treatment, since many untreated lesions usually result in painful blindness.

When lesions are too large to be treated with lasers, other methods have been successfully undertaken. Eye wall resection, which involves the surgical removal of the tumor through a cut in the sclera of the eye, is a drastic procedure with significant risk, but has been successful for treating a number of large tumors, some as large as 4.5 millimeters.

Examination Guidelines

During routine eye examination, any patient with a retinal lesion suggestive of VHL, and any person with a family history of VHL who has a suspicious retinal lesion, should be referred for a systemic neurological and abdominal evaluation. Relatives of a person diagnosed with VHL should also be screened for any manifestations of the disease. Ocular lesions are frequently the first diagnosed lesions, but VHL lesions can be present in the cerebellum, medulla, or pons of the brain, or in the spinal cord. Visceral tumors may be present as cysts of the kidneys, pancreas, adrenal glands, or epididymis. Treatment of retinal tumors is with photocoagulation (usually with a laser), cryosurgery, or penetrating diathermy. Other treatments may be attempted if the tumor is too large. Possible complications of the procedures include serous detachment of the retina, macula or optic nerve damage secondary to treatment, or failure of the lesion to respond to treatment.

All persons with diagnosed VHL should have a thorough eye examination at least once a year. It is important to note that early diagnosis and treatment for retinal lesions of VHL can result in significant savings of vision. Family history and retinal examination for other family members of a person with VHL are advisable. Since VHL is a multisystem condition, a person who has a retinal hemangioma should be referred for additional medical evaluation, and people with VHL in other systems should be referred for eye examination. Silent lesions in other organs of the body may be identified, and early treatment may prove life saving. Genetic counseling, family screening, and construction of a family tree are advisable.

Additional Reading

Bedell, A.J. "Angiomatosis Retinae." American J of Ophthal (1931); 14:389-411.

Welch, R.B. "Von Hippel-Lindau Disease: The Recognition and Treatment of Early Angiomatosis Retinae and the Use of Cryosurgery as an Adjunct to Therapy." Tran Am Ophthal Soc (1970); 68:367-423.

Hardwig, P., Robertson, D.M. "Von Hippel-Lindau Disease: A Familial, often lethal, multi-system Phakomatosis." Ophthalmology 1984; 91:263-272.

Acknowledgements: Figures 1 and 2 courtesy of Vincent Giovanucci, O.D. Figures 3 and 4 courtesy of Denis Fleming.

As published in the VHL Family Forum 2:3, September 1994. For permission to reprint, please contact the VHL Family Alliance at editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.