Management of TS patients by the ophthalmologist includes monitoring of vision and ocular lesions. Difficult-to-control seizures respond to vigabatrin (up to 95% of patients experience significant reduction of seizures). However, patients treated with vigabatrin are at risk for ocular complications, which may be difficult or impossible to monitor in patients with TS.

Aronow ME, Nakagawa JA, Gupta A, Traboulsi EI, Singh AD. Tuberous sclerosis complex: genotype/phenotype correlation of retinal findings. Ophthalmology. 2012;119(9):1917–1923.

Von Hippel–Lindau Disease

Von Hippel–Lindau disease (VHL; retinal angiomatosis, von Hippel–Lindau syndrome) is an autosomal dominant disorder with 95% penetrance that is characterized by the formation of both benign and malignant tumors in multiple organ systems. It is caused by a mutation in the VHL gene, a tumor-suppressor gene located on the short arm of chromosome 3, which produces the protein pVHL. A 2-hit model (germline plus somatic mutation similar to that in retinoblastoma) has been suggested for VHL. The incidence of VHL is approximately 1 per 36,000 births. Its most common abnormalities are vascular tumors (hemangioblastomas) of the retina and CNS, usually the cerebellum. These tumors have only limited proliferative capacity, but exudation across thin vessel walls leads to fluid accumulations that may attain considerable size and compromise vital structures. Cysts and tumors may also develop in the kidneys (renal cell carcinoma), pancreas, liver, epididymis, and adrenal glands (pheochromocytoma). Despite its well-accepted classification as a neurocutaneous syndrome, VHL rarely has significant cutaneous manifestations, although café-au-lait spots and portwine stains (nevus flammeus) are seen occasionally. Cognitive impairment is not a feature of this disease. Associated malignant tumors make VHL potentially fatal.

The retinal lesions originally described by von Hippel are capillary hemangioblastomas that usually become visible ophthalmoscopically between ages 10 and 35 years, with an average age of onset of 25 years. Retinal capillary hemangioblastomas are found in up to 85% of patients with the VHL mutation. Multiple tumors are present in the same eye in about one-third of cases and bilaterally in as many as one-half of cases. Tumors typically occur in the peripheral fundus, but lesions adjacent to the optic disc have been described.

The hallmark of the mature tumor is a pair of markedly dilated vessels (artery and vein) running between the lesion and the optic disc, indicating significant arteriovenous shunting (Fig 28-8). Characteristic paired or twin retinal vessels of normal caliber may be present before the tumor becomes visible.

Figure 28-8 Von Hippel–Lindau disease (retinal angiomatosis), left eye.

Histologically, retinal capillary hemangioblastomas consist of relatively well-formed capillaries; however, fluorescein angiography shows that these vessels are leaky. Transudation of fluid into the subretinal space causes lipid accumulation, retinal detachment, and consequent loss of vision.

Retinal capillary hemangioblastomas can be effectively treated with cryotherapy or laser photocoagulation in two-thirds or more cases, particularly when the lesions are still small. Antiangiogenesis therapy has also shown potential. Early diagnosis increases the likelihood of successful treatment. The ocular lesions of VHL are asymptomatic prior to retinal detachment. Therefore, children at risk for the disease should undergo periodic ophthalmologic evaluation beginning at approximately age 5 years.

Systemically, early tumor diagnosis can significantly reduce morbidity and mortality. The full recommended screening for patients with VHL can be found on the website of the VHL Alliance (ww w.vhl.org). Molecular genetic testing has been suggested for patients with early-onset (<30 years) cerebellar hemangioblastoma, early-onset retinal capillary hemangioblastomas, or familial clear-cell renal carcinoma.

Maher ER, Neumann HP, Richard S. Von Hippel–Lindau disease: a clinical and scientific review. Eur J Hum Genet. 2011;19(6):617–623.

Toy BC, Agrón E, Nigam D, Chew EY, Wong WT. Longitudinal analysis of retinal hemangio-blastomatosis and visual function in ocular von Hippel–Lindau disease. Ophthalmology. 2012;119(12):2622–2630.

Sturge-Weber Syndrome

Sturge-Weber syndrome (SWS), or encephalofacial angiomatosis, consists of a facial cutaneous vascular malformation (port-wine stain) with an ipsilateral leptomeningeal vascular malformation that typically results in the following:

cerebral calcification seizures

focal neurologic deficits (hemianopia, hemiparesis)

a highly variable degree of cognitive impairment (with normal intelligence in some affected persons)

SWS is unique among the 4 major neurocutaneous syndromes in that it is not genetically transmitted. However, lesions are always present at birth. The distribution of cutaneous and cerebral involvement suggests a disturbance very early in embryonic development (4–8 weeks’ gestation). The incidence is approximately 1 in 50,000.

Calcium deposits that are characteristic of SWS form after birth in brain parenchyma; they usually involve the occipital lobe and varying portions of the parietal, temporal, and occasionally frontal lobes. MRI is less sensitive than computed tomography (CT) for identifying calcification but is preferred for safety reasons and may provide better delineation of other abnormalities (Fig 28-9).

Figure 28-9 Axial gadolinium-enhanced T1-weighted MR image shows vascular malformation with underlying cortical atrophy (arrow) in the left occipital lobe of a 4-month-old girl with Sturge-Weber syndrome.

The Sturge-Weber skin lesion, which can be quite disfiguring, consists of numerous dilated, wellformed capillaries in the dermis. The lesion usually involves the forehead and upper eyelid on the same side as the cerebral vascular malformation, with varying extension to the ipsilateral lower eyelid and maxillary and mandibular regions (Fig 28-10). The port-wine stain occasionally does not

conform to the distribution of the trigeminal divisions, and the contralateral face, the scalp, and the trunk and extremities may be affected. Hypertrophy of soft tissue and bone underlying the port-wine stain is common, and thickening of the involved skin may develop. Notably, not all children who have a port-wine stain necessarily have SWS.

Figure 28-10 Facial port-wine stain involving the left eyelids, associated with ipsilateral buphthalmos in an infant girl with Sturge-Weber syndrome and glaucoma.

Ocular involvement

Any portion of the ocular circulation may be anomalous in SWS. When the skin lesion involves the eyelids, increased conjunctival vascularity commonly produces a pinkish discoloration. An abnormal plexus of episcleral vessels is often present.

The retina sometimes shows tortuous vessels and arteriovenous communications. Choroidal hemangioma is the most significant retinal anomaly associated with SWS. The tumor is composed of well-formed choroidal vessels, which give the fundus a uniform deep-red color that has been compared to tomato ketchup (Fig 28-11). Sometimes only the posterior pole is involved; in other cases, the entire fundus is affected. Choroidal hemangiomas are usually asymptomatic in childhood. During adolescence or adulthood, the choroid sometimes becomes markedly thickened. Degeneration or detachment of the overlying retina with severe vision loss may follow. No treatment has been proven to prevent or reverse such deterioration, although scattered application of laser photocoagulation may help.