PHAKOMATOSES: TUBEROUS SCLEROSIS

The classic triad of tuberous sclerosis includes seizures, mental retardation, and facial angiofibromas (adenoma sebaceum).

Symptoms

Vision loss can occur secondary to cortical tubers, astrocytic hamartomas of the retina, optic nerve

gliomas, and optic atrophy (secondary to hydrocephalus).

Clinical Features

Ophthalmic findings in tuberous sclerosis include astrocytic hamartomas of the retina, leaf-shaped retinal pigment epithelium defects, sectoral iris hypopigmentation, optic nerve glioma, angiofibromas of the eyelids, and retinal detachment. Astrocytic hamartomas are typically elevated, nodular, calcific, mulberry-like lesions.

Systemic findings in tuberous sclerosis include ash-leaf spots, café-au-lait spots, shagreen patches, subungual fibromas, cortical tubers of basal ganglia, lateral ventricles and third ventricle, obstructive hydrocephalus, subependymal nodules, subependymal giant cell astrocytoma, and tumors or cysts of the bone, lung, heart, liver, and kidney.

Diagnosis of tuberous sclerosis requires that the patient have one of the following: cortical tuber, subependymal glial nodules, subependymal-intraventricular giant cell astrocytoma, retinal hamartoma, facial angiofibromas (70% by 4 years of age), periungual/subungual fibromas, forehead/scalp fibrous plaques, and multiple renal angiomyolipomas.

Presumptive diagnosis of tuberous sclerosis can be made if the patient has two of the following: infantile spasms, seizures (90%), areas of increased attenuation in cerebral cortex, calcified lesion in cortex/subcortex, ash-leaf spots, peripapillary retinal hamartoma, gingival fibromas, dental enamel pits, and multiple renal tumors, multiple renal cysts, cardiac rhabdomyoma, pulmonary lymphangiomyomatosis, radiographic honeycomb lungs, and an immediate relative with tuberous sclerosis.

Ancillary Testing

Astrocytic hamartomas may be autofluorescent depending on the extent of calcification. In the arterial phase of the fluorescein angiogram, the astrocytic hamartoma is hypofluorescent and tortuous vessels are seen around the tumor. In the venous phase, the fine vessels on the tumor surface begin to leak and lead to homogeneous staining of the mass. Ultrasonography is of use in the larger calcified astrocytic hamartomas. The lesion is acoustically solid, well demarcated, and lacks choroidal excavation. The tumors have high internal reflectivity with attenuation of orbital echoes posterior to the tumor.

Pathology/Pathogenesis

Tuberous sclerosis is inherited as an autosomal dominant trait with an incidence of one in 15000 live births. The genes for tuberous sclerosis have been located on chromosomes 9q and 11q. There is no race or sex predilection. The retinal astrocytic hamartoma arises from the nerve fiber layer. It contains elongated fibrous astrocytes that are well differentiated. Mitotic figures are rare. Sometimes calcified bodies are present within the tumor.

Treatment/Prognosis

Patients with tuberous sclerosis have a normal life expectancy. The seizures typically present in infancy as infantile spasms and progress to grand mal seizures later in life. Patients may need a shunt procedure for obstructive hydrocephalus. The retinal astrocytic hamartomas usually remain stable over time and have no effect on visual function.

Systemic Evaluation

Patients should have a multidisciplinary evaluation including dermatology, ophthalmology, neurology, cardiology, urology, and pulmonology. These examinations can be coordinated through the patient’s primary care provider.

This photograph demonstrates the facial angiofibromas (adenoma sebaceum) seen with tuberous sclerosis.

Fundus photograph of the same patient’s right eye reveals prominent optic disc edema. He was diagnosed with papilledema and sent for an immediate neuroimaging study.

Fundus photograph of the same patient reveals a calcific astrocytic hamartoma in the superior macula of the left eye. The tumor has mulberry-like deposits and fine vascularization. Note the associated disc edema.

The computed tomography scan revealed a prominent subependymal astrocytoma with dilated ventricles consistent with obstructive hydrocephalus.

Von Hippel-Lindau disease is a disorder characterized by vascular tumors of the retina and central nervous system. In addition, patients are predisposed to developing additional tumors including renal cell carcinoma, pheochromocytoma, and renal, pancreatic, and epididymal cysts. Most patients present in the third to fourth decade of life, but manifestations of von Hippel-Lindau disease can be observed at birth.

Symptoms

Vision loss can occur from the retinal hemangioma or cerebellar/cerebral hemangioblastoma.

Clinical Features

Diagnosis of von Hippel-Lindau disease requires one of the following: cerebellar, spinal, medullary, or cerebral hemangioblastoma; retinal capillary hemangioma; multiple renal cysts; or renal cell carcinoma; pancreatic cysts; cystadenocarcinoma; islet cell tumor; pheochromocytoma; and epididymal cystadenoma (male infertility); plus a relative who has a central nervous system or eye lesion, renal cysts, or adenocarcinoma.

The retinal capillary hemangiomas are often multifocal and bilateral. The classic presentation is a vascularized tumor mass with prominent feeder and draining vessels. Retinal capillary hemangiomas may be associated with exudation of fluid and lipid. Severe cases are characterized by an exudative retinal detachment, which may lead to retinal ischemia, iris neovascularization, and neovascular glaucoma.

Ancillary Testing

Fluorescein angiography will typically demonstrate in the early arterial phase a dilated feeder arteriole. A few seconds later, the tumor will rapidly fill with fluorescein. In the venous phase, the dilated draining vein will appear. In the late phase, the tumor will demonstrate leakage. Ultrasonography demonstrates high internal reflectivity within the acoustically solid mass. Retinal detachment and subretinal fluid can also be seen on ultrasound.

Pathology/Pathogenesis

Von Hippel-Lindau disease is inherited as an autosomal dominant trait with an incidence of one in 36000 live births. The lesions in this disease are primarily of mesodermal origin. The gene for von Hippel-Lindau disease is located on chromosome 3p25. There is no race or sex predilection. The retinal hemangioma is a mass of fenestrated capillaries that locally replaces retinal architecture. The tumors consist of endothelial cells, pericytes, and lipid-laden foam cells. They are classified as endophytic or exophytic depending on their direction of growth.

Treatment/Prognosis

Von Hippel-Lindau disease is a potentially lethal condition. The most common cause of death is the cerebellar hemangioblastoma or renal cell carcinoma. Patients with confirmed von Hippel-Lindau disease have a median survival of 49 years. Visual prognosis is variable. Treatment of the retinal capillary hemangiomas depends on size, location, and clarity of the media. Small tumors (less than 5 mm) can usually be treated with laser photocoagulation or cyrotherapy. Treatment of large tumors (greater than 5 mm) is more difficult and may require cryotherapy or plaque radiotherapy and retinal detachment surgery. Patients may experience a marked increase in exudation immediately following treatment, particularly with larger tumors. Enucleation may be necessary for uncontrolled hemangiomas causing advanced glaucoma.

Systemic Evaluation

Patients should have periodic evaluations, including a physical, an eye exam, a urine analysis, a urine 24-hour collection for VMA, and a renal ultrasound. Every three years they should have a brain magnetic resonance imaging (MRI) and computed tomography (CT) scan and a CT scan of the kidneys. At-risk relatives need a yearly eye examination and physical. They also need a yearly urine analysis, urine 24-hour collection for VMA, and renal ultrasound. Every three years at risk relatives also need a brain MRI or CT scan starting at age 15 years. They also need a CT scan of the kidneys every three years starting at age 20. Genetic testing is available but the benefits must be weighed in each case.

Fundus photograph of a retinal capillary hemangioma in a patient with von Hippel-Lindau disease. Note the dilated feeder vessel and the vascularized tumor mass. There was dependent lipid exudation into the macula.

Exophytic tumors arise from the outer layers of the retina and tend to be found in the peripapillary distribution. This 36-year-old man had a peripapillary lesion associated with fluid and lipid exudation into the fovea.

This 21-year-old woman was diagnosed with von Hippel-Lindau disease after resection of a large cerebellar hemangioblastoma. Her retina examination revealed bilateral, multifocal retinal capillary hemangiomas. This fundus photograph shows a characteristic endophytic lesion with dilated feeder and draining vessels. Inferiorly, there is a less common sessile exophytic hemangioma.

Fluorescein angiogram of the same patient demonstrates rapid filling of the arterial feeder vessel and marked hyperfluorescence of the retinal capillary hemangioma.

The fluorescein angiogram of the same patient revealed hyperfluorescence in the superior nasal peripapillary region with late leakage. The lesion was located in

the outer retinal layers. The differential diagnosis for exophytic tumors includes peripapillary choroidal neovascularization.

Fluorescein angiography of the same patient demonstrates three hyperfluorescent spots superiorly and a larger hyperfluorescent lesion inferiorly corresponding to the tumors.