Michael D. Tibbetts, MD

Vitelliform Macular Dystrophy

Vitelliform macular dystrophy is an inherited disease associated with deposition of lipofuscin in the central macula.¹ The condition is described as Best disease when present early in life and as adult-onset vitelliform dystrophy (AOVD) when present in middle age or later.² Lipofuscin deposition can lead to progressive central vision loss when atrophy and scarring occur. The clinical phenotype can be highly variable. Men and women are equally affected but the incidence of Best disease and AOVD are not known. Best disease is caused by an autosomal dominant mutation in the bestrophin (VMD2) gene³ and AOVD is associated with mutations of VMD2, retinal degeneration slow (RDS), interphotoreceptor matrix 1 and 2 (IMPG1 and IMPG2), as well as a polymorphism in the HtrA Serine Peptidase 1 gene (HTRA1).^4,5 However, the causative gene cannot be found in most AOVD patients.

Vitelliform dystrophies are characterized by central yolk-like (vitelliform), yellow macular lesions (Figures 14-1 and 14-2). In patients with Best disease, the macular lesion progresses to cause scarring and atrophy, which contribute to vision loss. Most patients will maintain sufficient central visual acuity to read and drive but vision can decrease to the 20/200 range. AOVD typically results in metamorphopsia and mildly blurred vision with vision loss only occurring with atrophy and scarring. In both diseases, choroidal neovascular membranes (CNVM) may develop from macular scarring.^6,7 Best disease is diagnosed based on clinical examination, fluorescein angiography (FA), optical coherence tomography (OCT), and electro-oculogram (EOG). Patients with Best disease will have a light-to-dark Arden ratio of less than 1.5 on EOG. In contrast, patients with AOVD will have a near normal EOG with Arden ratio greater than 1.7.

In Best disease, the macular lesions evolve from a previtelliform stage to vitelliform stage to the “scrambled egg” stage with pseudohypopyon (Figure 14-1) to the atrophic stage. The macular OCT in Best disease demonstrates a dome-shaped, hyper-reflective, and homogenous lesion located below the hyper-reflective photoreceptor layer.8 In AOVD, the lesions are localized to the photoreceptor-retinal pigment epithelium complex. OCT also demonstrates a dome-shaped hyper-reflective lesion and there may be overlying loss of the photoreceptor layer (Figure 14-2).

There is no validated therapy for preventing the development of a vitelliform lesion or reducing the size of the subfoveal vitelliform deposit. The use of anti-vascular endothelial growth factor (VEGF) therapy for vitelliform macular dystrophy is limited to the treatment of choroidal neovascularization.² Anti-VEGF agents have been used to successfully treat CNVM secondary to Best disease in children as young as 6 years old.⁹ In a case series of 11 eyes with CNVM secondary to AOVD treated with intravitreal bevacizumab, there was a reduction in foveal thickness but a guarded visual outcome.10 Further studies are needed to determine the optimal choice of therapy and duration of treatment for CNVM secondary to vitelliform dystrophy.

Anti-VEGF treatment of vitelliform dystrophy macular lesions with associated vision loss but without evidence of CNVM has been reported with variable functional and anatomic responses. In 1 small case series of 6 patients, there was an improvement in visual acuity after 3 consecutive monthly injections of ranibizumab, but no improvement on OCT thickness analysis.¹¹ The lack of structural correlation to the functional findings is not consistent with the response to anti-VEGF therapy in multiple diseases studied in randomized clinical trials. In another case, 3 consecutive monthly injections of 0.5 mg intravitreal ranibizumab were given to treat a 72-year-old female patient with central vision loss secondary to AOVD.¹² There was no improvement in visual acuity or in the size of the vitelliform detachment as measured by spectral-domain (SD)-OCT. Currently, the treatment of Best disease or AOVD in the absence of CNVM is not justified by the medical literature.

Ocular Tumors

Malignant neoplasms can arise from primary sites in the eye or metastatic invasion from distant primary tumors. The most common primary intraocular malignancy in children is retinoblastoma and the most common primary intraocular malignancy in adults is uveal melanoma. However, metastatic cancer to the eye is the most common intraocular malignant neoplasm. A review of all intraocular tumors is beyond the scope of this chapter. We will briefly review those neoplasms for which anti-VEGF therapy has been studied and may have a role in the treatment paradigm including choroidal osteoma, capillary hemangioma of the retina, choroidal hemangioma, and choroidal metastasis.

Choroidal Osteoma

Choroidal osteoma is an uncommon, benign, acquired bony tumor of the choroid.^13,14 They typically appear in the second and third decades of life with more than 90% occurring in women. The typical choroidal osteoma is yellowish to orange, juxtapapillary or circumpapillary, and has well-defined margins (Figure 14-3[A]). Patients may present with painless, progressive loss of vision or the sudden onset of visual distortion. Visual acuity can be impaired if there is degeneration of the overlying photoreceptors and sensory retina or from the formation of a CNVM. The diagnosis of a choroidal osteoma is made based on fundus examination in combination with ancillary testing (Figure 14-3). B-scan ultrasonography demonstrates shadowing due to the composition of dense bone (Figure 14-3[C]) and computed tomography scan shows thickening of the posterior ocular wall that is isodense with normal skeletal bone.¹³ Some patients may have hyperpara-thyroidism with alterations of serum calcium and phosphorus levels, but most patients have no systemic abnormalities.

CNVM secondary to choroidal osteomas can be treated with intravitreal anti-VEGF injection (Figure 14-4). This therapy is sometimes used in combination with focal laser photocoagulation or photodynamic therapy (PDT) depending on the location of the CNVM. In a series of 8 eyes in 8 patients with CNVM secondary to choroidal osteomas treated with monthly ranibizumab or bevacizumab with or without PDT, there was resolution of subretinal fluid on OCT in all but one patient.¹⁵ Fifty percent of patients had a recurrence of exudation requiring further therapy. In this uncontrolled study, there was a modest increase in visual acuity at a mean of 32 months follow-up. Further studies are needed to determine the choice of anti-VEGF agents and optimum number of treatments for CNVM secondary to choroidal osteomas.

The retinal capillary hemangioma is a benign vascular tumor that can arise from the retina or optic disc.16 They may occur unilaterally or bilaterally and may be unifocal or multifocal, sometimes associated with von Hippel-Lindau syndrome.¹⁷ The lesions tend to enlarge progressively and can lead to exudative or tractional retinal detachment. Capillary hemangiomas are uncommon but the exact frequency is not known. Most patients are diagnosed between the ages of 15 and 35.¹⁷ The typical retinal capillary hemangioma appears as a reddish-orange, spherical lesion fed and drained by dilated tortuous retinal vessels (Figure 14-5). Intraretinal and subretinal exudation may surround the lesion and exudates may accumulate in the macula even when the lesion is located in the retinal periphery. Diagnosis can be made by dilated fundus examination in combination with ancillary testing. FA demonstrates rapid filling of the afferent artery, brisk filling of the tumor with intense hyperfluorescence, and rapid filling of the efferent vein.

The use of anti-VEGF therapy for the treatment of retinal capillary hemangiomas has been reported in small case series. In 1 study of 5 patients with retinal capillary hemangiomas associated with von Hippel-Lindau syndrome, patients received an average of 10 injections over an average period of 47 weeks.¹⁸ The study concluded that anti-VEGF therapy had minimal beneficial effects on most lesions.¹⁸ However, there was possible evidence of effect on a small lesion with less exudation, raising the question as to whether anti-VEGF therapy may be effective if given earlier in the disease course. Isolated case reports have demonstrated a reduction of tumor-associated exudation with intravitreal bevacizumab treatment in combination with PDT.19,20 Further studies are needed to define the role of anti-VEGF therapy in the management of capillary hemangiomas of the retina.

Choroidal Hemangiomas

Choroidal hemangiomas are benign vascular tumors of the choroid.²¹ There are 2 distinct forms: a circumscribed form that is isolated and not associated with a systemic syndrome, and a diffuse form that is associated with Sturge-Weber syndrome of encephalofacial hemangiomatosis.²² Choroidal hemangiomas are uncommon and affect both sexes and all ethnic groups. The lesions are not hereditary but are probably congenital in most patients. Choroidal hemangiomas are typically not detected until the second to fourth decades of life. The visual impairment from both types of lesions can range from completely asymptomatic to total vision loss. The diffuse choroidal hemangioma is usually identified ipsilateral to the facial nevus flammeus in patients with Sturge-Weber syndrome.

There are case reports in the literature documenting the use of intravitreal anti-VEGF injections for the treatment of both circumscribed and diffuse choroidal hemangiomas. In 1 study, 9 patients with circumscribed choroidal hemangiomas were treated with intravitreal bevacizumab.²³ Five of the 9 patients were also treated with transpupillary thermotherapy and therefore the response to bevacizumab alone was not well defined. In another report, 3 patients with circumscribed choroidal hemangiomas were treated with bevacizumab with 2 patients treated in combination with PDT.²⁴ Other reports showed a response to PDT after an initial failure to respond to ranibizumab.²⁵ In a report of a diffuse choroidal hemangioma in a patient with Sturge-Weber syndrome, an associated exudative detachment was treated with intravitreal bevacizumab and found to resolve after 4 treatments over a 6-month period.²⁶ As there have been variable results with the studies published thus far, further research is needed to elucidate the role of anti-VEGF therapy alone or in combination with other treatments both for circumscribed choroidal hemangiomas and diffuse choroidal hemangiomas.

Metastatic Cancer

Metastatic cancer to the eye arises from the implantation of tumor cells spreading from another bodily organ or tissue.²⁷ There are estimates that 1% to 2.5% of all people have metastatic carcinoma in at least one eye at the time of death though many of these tumors may never be clinically apparent.²⁸ The most common site of metastatic invasion is the choroid, but metastases can also invade the iris, ciliary body, optic nerve, and retina.^29,30 The most common primary cancer to cause metastatic disease in the eye is breast cancer in women and lung cancer in men. Overall, the presence of metastasis to the eye bodes a poor prognosis for long-term survival.

Metastatic cancer to the eye can be detected by slit lamp and funduscopic examination. Typical metastatic choroidal tumors arising from the breast, lung, or gastrointestinal tract are yellow to white in color and round or oval in shape (Figure 14-6). They may also be associated with an overlying serous retinal detachment. B-scan ultrasonography typically demonstrates lesions with high internal reflectivity as compared to uveal melanomas.

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