an aggressive variant has recently been identified in which the lesions show marked progression, with total exudative retinal detachment and neovascular glaucoma, sometimes necessitating enucleation of the eye [9].

Occasionally, ancillary studies such as fluorescein angiography and ultrasonography assist in the diagnosis of retinal astrocytic hamartoma. With fluorescein angiography, the tumor is relatively hypofluorescent in the arterial phase. A network of fine blood vessels is apparent in the venous phase. Typically, these vessels leak in the recirculation phase and stain the mass in the late angiograms. Ultrasonography is most important for the larger retinal astrocytic hamartoma. With A- and B-scan ultrasonography, the mass appears as a sessile or dome-shaped retinal mass with acoustic solidity and orbital shadowing if there is calcification in the lesion [1].

Management

With exception of the rare aggressive variant mentioned previously, retinal astrocytic hamartomas are generally asymptomatic and nonprogressive and do not require treatment. Ocular examination should be performed yearly and the patient followed for other manifestations of TSC. If there should be associated subretinal fluid that extends into the foveal area, then laser photocoagulation or photodynamic therapy can be employed in order to bring about resolution of the subretinal fluid [1–3]. The astrocytic hamartoma of the retina has an extremely low tendency to undergo malignant change and has no recognized tendency to metastasize. The visual prognosis is also excellent, except in the rare instances in which exudation, subretinal fluid, or vitreous hemorrhage occur.

Neurofibromatosis (von

Recklinghausen’s Syndrome)

Definition

ment that can lead to a wide variety of clinical symptoms and signs [10–17]. von Recklinghausen [11] published a classic monograph on this disease in 1882, and the condition is now known as von Recklinghausen’s syndrome. More recently, NF has been subcategorized into type 1 (NF-1) and type 2 (NF-2) [12]. Since there is some overlap in the two types, they are discussed together in this chapter.

Demographics

The frequency of a new mutation for NF is estimated to be about 1 in 2,500–3,000 births. There appears to be no appreciable predilection for gender [13].

Genetics

NF is transmitted by an autosomal dominant mode of inheritance with about 80% penetrance. NF-1isalsoknownasperipheralneurofibromatosis or von Recklinghausen’s syndrome. It is recognized to occur from an abnormality of chromosome 17. NF-2 is called central or bilateral acoustic neurofibromatosis. It is characterized by CNS tumors and early onset of posterior subcapsular cataract and is recognized to be related to an abnormality in chromosome 22 [12, 13].

Ophthalmologic Features

NF has the most diverse systemic and ocular findings among the ONCS [1–3, 12, 13]. Ocular changes include abnormalities in the uveal tract (80%), eyelid (25%), optic nerve (12%), retina (9%), and conjunctiva (4%) [11]. These are described in detail elsewhere [1].

Fundus Manifestations

Neurofibromatosis (NF) is an oculoneurocutaneous syndrome characterized by multisystem involve-

Uveal tract involvement is present in about 80% of patients with NF [13]. Multiple iris hamartomas, known as Lisch nodules, are the most

Fig. 17.3 Neurofibromatosis type 1. Multiple choroidal nevi. There are several subtle lesions, with the two most prominent ones near the superotemporal vascular arcade and inferotemporal to the fovea

Fig. 17.4 Neurofibromatosis type 1. Choroidal melanoma located near equator superonasally

common uveal abnormality in NF-1 [13]. They first appear in childhood around age 5 years or later as discrete, multiple, lightly pigmented elevations of the anterior border layer. Relatively flat pigmented choroidal lesions, presumably melanocytic hamartomas identical to choroidal nevi, are often seen in NF-1 (Fig. 17.3). Other choroidal tumors that rarely associated with NF are choroidal melanoma (Fig. 17.4) and schwannoma. Most cases of choroidal schwannoma,

Fig. 17.5 Neurofibromatosis type 1. Retinal vasoproliferative tumor. The tumor is located superotemporally, but there is massive exudation inferiorly

however, are isolated and not associated with NF-1 or NF-2 [1, 15]. The retinal findings of NF are less common and include retinal astrocytic hamartoma, retinal vasoproliferative tumor (Fig. 17.5), myelinated retinal nerve fibers, multifocal congenital hypertrophy of the retinal pigment epithelium (“bear tracks”), and a lesion similar to combined hamartoma of the retina and retinal pigment epithelium [12]. The latter typicallyoccursinpatientswithneurofibromatosis type 2 but can be seen with NF-1. The astrocytic hamartoma is relatively rare in NF but is very common in TSC.

Management

The management of the fundus lesions of NF varies with the location and the extent of the disease. Treatment can be very complex. In general, the fundus tumors including retinal astrocytic hamartoma, myelinated nerve fibers, and combined hamartoma of the retina and RPE require no treatment. Choroidal neurilemoma, choroidal melanoma, and vasoproliferative tumor are managed with any of several methods depending on many factors [1].

Retinocerebellar

Hemangioblastomatosis

(von Hippel-Lindau Syndrome)

Definition

In 1895, von Hippel reported the clinical findings of so-called retinal angiomatosis [18], and in 1926, Lindau made a study of cerebellar lesions and pointed out their relationship to the retinal tumors previously described by von Hippel [19]. Consequently, the combination of retinal and cerebellar involvement has been called the von Hippel-Lindau (VHL) syndrome. Subsequently, VHL syndrome was recognized to have several other components in addition to the eye and CNS findings, including renal cell carcinoma, pheochromocytoma, endolymphatic sac tumors, and other less common cystic lesions [20–24].

Demographics

The incidence of VHL syndrome is about 1 in 40,000 live births.

There is no clear-cut predilection for race or gender, although most of our patients have been Caucasians [3, 26, 27].

Genetics

The VHL syndrome is recognized to be a hereditary disorder, with an autosomal dominant mode of inheritance and incomplete penetrance. Many cases that are seen by the ophthalmologist, however, occur as spontaneous mutations with no apparent family history of the disease. Probably about 20% of cases have a positive family history. The condition is related to a partial deletion of the short arm of chromosome 3 [3, 24].

Fundus Manifestations

The ocular manifestations of VHL syndrome are not so diversified as they are in the other systemic

Fig. 17.6 von Hippel-Lindau syndrome. Typical retinal hemangioblastoma, showing red tumor with dilated afferent and efferent retinal blood vessels and lipoproteinaceous exudation

hamartomatoses. Hemangioblastomas (“retinal capillary hemangioma”) of the retina and/or optic disk are the only intraocular hamartomas that are known to occur. When associated with the VHL syndrome, the retinal and optic disk tumors are often multiple and bilateral [1, 3, 24]. The diagnosis of the ocular lesions is usually made in the second or third decade of life.

Retinal hemangioblastoma can occur in the peripheral retina or adjacent to the optic disk. Peripheral retinal hemangioblastoma appears as a variably sized distinct red nodule with a typical dilated tortuous afferent artery and an efferent vein that comes from the optic disk to the tumor, often associated with yellow lipoproteinaceous exudation (Fig. 17.6). Juxtapapillary retinal hemangioblastoma appears as a reddish mass overlying or immediately adjacent to the optic disk (Fig. 17.7). Either type can be associated with extensive intraretinal or subretinal exudation and variable degrees of vitreoretinal traction.

Fluorescein angiography is the most helpful ancillary study in confirming the diagnosis of a hemangioblastoma [1]. In the early arterial phase, the dilated retinal feeder arteriole appears prominent. Within 2–3 s, the retinal tumor is fluorescent as the fine capillaries that comprise the tumor fill

Fig. 17.7 von Hippel-Lindau syndrome: hemangioblastoma adjacent to optic disk, with mild surrounding exudation

with fluorescein. In the venous phase, the dilated draining vein fills with dye and the tumor maintains its bright fluorescence. In the late phase, the tumor generally remains fluorescent and leaks dye into the vitreous. The intrinsic rapid fluorescence of the optic disk hemangioma assists in differentiating this tumor from other optic disk lesions.

Management

The management of retinal hemangioblastoma is difficult and controversial. No active treatment may be necessary for small asymptomatic retinal tumors because some of them remain stable for many years and some even regress spontaneously. The patient should be examined periodically and treatment instituted if the tumor grows or if there is accumulation of exudation or subretinal fluid. In such instances, several methods of treatment have been advocated, including argon laser, cryotherapy, photodynamic therapy, and intravitreal injection of angiostatic agents. No single treatment has emerged as the treatment of choice. If a hemangioblastoma has caused an extensive retinal detachment with subretinal exudation, a vitrectomy and/or a scleral buckling procedure may be necessary to reattach the retina. We have used plaque radiotherapy for selected tumors with extensive retinal detachment.

Analysis of the DNA of the patient and all family members can be performed in an attempt

to identify markers indicating VHL disease. The gene for VHL syndrome has been mapped to the short arm of chromosome 3. All patients with VHL syndrome should be followed carefully with yearly testing for systemic tumors. Furthermore, relatives of patients with VHL disease may benefit from a screening protocol depending on the results of DNA testing. The retinal hemangioblastoma is often the initial sign of VHL disease, and the various other systemic tumors found in this disease are best treated at an early stage. Therefore it is important to routinely evaluate these patients systemically.

Encephalofacial Hemangiomatosis

(SW Syndrome)

Definition

In 1879, Sturge described a syndrome composed of a facial hemangioma with ipsilateral buphthalmos and contralateral seizures [26]. Later, Weber studied the clinical manifestations in greater detail, and the fully expressed entity became known as the Sturge-Weber (SW) syndrome [27]. The SW syndrome is now recognized to consist of a facial hemangioma, buphthalmos, seizures, and radiographic evidence of intracranial calcification [28–30]. Most patients, however, have a forme fruste rather than the entire syndrome.

Genetics

In contrast to most of the other ONCS, there is no recognizable hereditary pattern associated with SW syndrome.

Ophthalmologic Features

The ocular findings associated with SW syndrome include eyelid involvement with the nevus flammeus, prominent epibulbar blood vessels, glaucoma, retinal vascular tortuosity, and diffuse choroidal hemangioma.