Fig. 10.2  Fundus photograph showing fusiform dilatation of the superotemporal vessels and scattered intraretinal hemorrhages. There is associated submacular fluid and exudation in varying stages of resorption

organization into a disciform mass in the macula may ensue, resulting in significant visual decline [4].

The optic disc may appear hyperemic [10]. The vitreous remains clear until advanced stages, during which areas of vitreous condensation may contract and cause retinal detachment and vitreous hemorrhage. Intraretinal macrocysts may develop, likely as a result of longstanding retinal detachment [18, 28, 30].

In the early stage of Coats’ disease, ocular abnormalities outside the fundus are rare. Isolated associated ­findings include congenital retinoschisis [31], uveal coloboma [13], choroidal angioma [25], morning glory disc [32] and microphthalmos [20]. There is one report of bilateral Coats’ disease associated with infantile cataracts, congenital glaucoma, and later ketotic hypoglycemia [33]. A fundus appearance resembling Coats’ disease is seen in up to 4% of patients with retinitis pigmentosa [34].

Fig. 10.3  Montage color fundus photograph depicting a large coalescence of submacular lipid exudation

10.4  Pathology and Pathophysiology

The source of Coats’ disease remains unclear. Reese observed periodic acid-Schiff staining of basement membrane under the endothelium of retinal veins and theorized that deposition of polysaccharide led to atresia­

and occlusion of vessel lumina, “thereby occasioning­

vascular ectasia and the formation of collateral channels” [5]. Wise speculated that local retinal hypoxia

Fig. 10.4  Montage of the left eye of a 10-year-old girl with Coats’ disease before and after treatment. (a) There are peripheral vascular changes (most notably inferotemporally) with associated intraretinal hemorrhage and intraretinal lipid. Visual acuity at this time had declined to 20/40, most likely as a result

of macular exudation. (b) Eight months following peripheral scatter laser photocoagulation to the areas of vascular change inferotemporally, the macular exudate has begun to resolve. Visual acuity at this time had improved to 20/25

awakened “a dormant vasoproliferative factor,” stimulating growth of new vessels from veins and capillaries [35]. Imre postulated an endocrine source, on the basis of increased urinary excretion of 17-ketosteroids and 11-oxysteroids [36].

Histologic and ultrastructural studies support Coats’ original speculation “that some of the vascular changes are primary” [1] and lead to the classic histopathologic findings of vessel thickening and hyalinization, interspersed with thinning and loss of endothelial elements [22, 37, 38]. It is believed that breakdown of the ­blood–retinal barrier, at the level of the endothelium, causes plasma leakage into vessel walls, which become necrotic and disorganized and form dilatations and telangiectasias. Further leakage into adjacent retinal tissue produces the recognizable intraretinal and subretinal cholesterol exudates, hemorrhage, cysts, edema, lymphocytic infiltration, and deposition of lipid and fibrin [39, 40]. These changes lead to degeneration of the neural retina and to infiltration by phagocytic, lipid-laden “ghost” cells, which appear to be transformed retinal pigment epithelial cells [41]. Clinically, these microscopic changes manifest as irregular, raised patches of yellow– white or yellow–green material, often with superficial hemorrhage. Partial serous retinal detachment may ensue and worsen with increasing vasculopathy and exudation. The exudation may be so abundant as to drain into the orbit and stimulate an inflammatory reaction [42].

10.5  Genetics

A genetic cause for Coats’ disease has been proposed on the basis of several observations: (1) the association of retinal telangiectasias with muscular dystrophy and deafness in one family [43]; (2) occurrence of exudative retinopathy in a few members of families with retinitis pigmentosa [44–46]; (3) the case of a mother purported to have unilateral retinal telangiectasias and a son with Norrie disease [47]. Cytogenetic studies of isolated cases have demonstrated pericentric inversion of chromosome 3 in one child [48] and a partial deletion of chromosome 13 in another [49]. However, the overwhelmingly sporadic occurrence of Coats’ disease precludes any substantive genetic linkage studies.

Black et al. [47] investigated a mother with “a unilateral variant of Coats’ disease” and her son afflicted with Norrie disease. Both carried a missense mutation in the Norrie disease (NDP) gene, which has been implicated

in retinal vasculogenesis [50]. Archived tissue from nine eyes enucleated for Coats’ disease was then analyzed, and a mutation in the NDP gene was found in retinal tissue from one eye. The authors postulated that Coats’ telangiectasias arise from somatic mutation in the NDP gene [47]. The possibility that the mutation represented a naturally-occurring polymorphism was not conclusively eliminated, however. DNA analysis of a child with coexisting Coats’ disease and congenital retinoschisis failed to reveal mutations in either the NDP gene or the retinoschisin (RS) gene [31].

In a study of five families with a specific form of retinitis pigmentosa (designated RP12) five of eight patients with an associated Coats-like exudative vasculopathy demonstrated mutations in the CRB1 (crumbs homolog 1) gene. Mutations in the CRB1 gene are also seen in patients with RP12 and a small percentage of patients with Leber congenital amaurosis [51]. It remains unclear, however, whether the exudative changes seen in such cases are truly an independent event, or merely secondary to vascular endothelial decompensation associated with retinal degeneration.

10.6  Natural History

If untreated, Coats’ disease most often deteriorates ­progressively at a variable rate. According to Gomez Morales [15], of 22 untreated patients followed for an average of 5 years, 14 (64%) developed total retinal detachment, and seven (32%) developed secondary glaucoma. Of the five patients in whom the disease appeared stable, the youngest was 7 years of age. All four patients younger than 4 years progressed rapidly to retinal detachment [15]. Ridley et al. confirmed that rapidity of decline appears to correlate directly with severity of disease and younger age at presentation [52]. In Haik’s series of advanced disease (exudative retinal detachment with subretinal mass), 20 of 25 untreated eyes (80%) developed glaucoma or phthisis within 5 years, and 14 required enucleation [20]. Factors that portend clinical and visual decline include: extensive telangiectasias (involving three or more quadrants), diffuse exudation, presence of retinal macrocysts, and macular involvement [13, 17, 23, 53, 54].

Spontaneous regression of telangiectasias with resorption of subretinal fluid has been reported in rare instances [10, 55]. However, given the natural clinical course of the vast majority of children with Coats’

disease,­ observation of actively leaking retinal telangiectasias is not recommended.

10.7  Differential Diagnosis

and Diagnostic Aids

Accurate diagnosis of Coats’ disease, especially in advanced stages, may be difficult. In a series of 62 histologically confirmed cases, Coats’ disease was the primary clinical diagnosis in only 13 (21%) [28]. It must be distinguished from other conditions, some of them life-threatening, that cause leukocoria, strabismus, or intraocular mass lesions (Fig. 10.5). The differential diagnosis of Coats’ disease is given in Table 10.1.

The most serious of these lesions is retinoblastoma, the most common primary intraocular malignancy in children. In cases of retinoblastoma, the average age at diagnosis (18 months) is younger than in Coats’ ­disease. Retinoblastoma has no gender predilection, bilaterality occurs in roughly one-third of cases, and there is sometimes a family history of the disease [56].

Fig. 10.5  Fundus photograph of the eye of a 2-year-old child referred for evaluation of leukocoria. A bullous, total exudative retinal detachment from advanced Coats’ disease extended into the retrolenticular space and nearly completely filled the pupil

Table 10.1  Differential diagnosis of juvenile Coats’ disease

Retinoblastoma

Von Hippel’s angiomatosis retinae

Retinopathy of prematurity

Familial exudative vitreoretinopathy

Persistent fetal vasculature

Ocular toxocariasis

Incontinentia pigmenti

Pars planitis

Choroidal hemangioma

Ophthalmoscopically, the retinoblastoma lesion is pink-white, highly vascular, and often contains calcifications. Difficulty in differentiating retinoblastoma from Coats’ disease arises most often in cases of exophytic retinoblastoma, in which the tumor grows into the subretinal space and causes a large exudative retinal detachment. In such instances, typical radiographic findings (usually from computed tomography [CT] or magnetic resonance imaging [MRI]) may help confirm the diagnosis­ [20, 57].

Von Hippel’s angiomatosis retinae is an important consideration because of its systemic association with renal cell carcinoma, pheochromocytoma, and vascular tumors of the central nervous system and viscera. Typically, this phakomatous lesion appears as a yellow or reddish balloon-like mass with a feeding arteriole and a draining venule. It is bilateral in 30–50% of cases, becomes symptomatic in early adulthood, and may be inherited in an autosomal dominant fashion. Genetic testing is currently available.

Familial exudative vitreoretinopathy (FEVR) and retinopathy of prematurity (ROP) may produce peripheral retinal vascular abnormalities. In contrast to Coats’ disease, however, the vascular changes seen in FEVR and ROP are located predominantly at the vitreoretinal interface (not intraretinally, as in Coats’ disease) and usually occur bilaterally. Additional diagnostic clues include a family history of FEVR or blindness or a history of premature birth. Persistence of fetal vasculature (PFV, formerly known as persistence of primary hyperplastic vitreous [PHPV]) occurs congenitally in a microphthalmic eye. Ocular toxocariasis may be suspected by history of contact with puppies and confirmed by serologic testing.

Intravenous fluorescein angiography is helpful in children with Coats’ disease, both for diagnosis and for identification of treatable areas. Retinal telangiectasias produce the characteristic “light-bulb” appearance and fluoresce dramatically (Fig. 10.1b). Capillaries may appear dilated, but more often are occluded and are replaced by large arteriovenous shunts within areas of nonperfused retina [6, 19]. In the late phases of the angiogram, fluorescein dye may leak from aneurysmal vessels to produce a pattern of cystoid macular edema or to pool in the subretinal space [13].

Ultrasonography allows safe and effective evaluation of cases of leukocoria in which Coats’ disease is suspected but uncertain. Findings grow more specific with progression of disease and include: poorly mobile retinal detachment; convolution and looping of the

peripheral retina; dispersed subretinal cholesterol opacities exhibiting constant slow convection movements; and absence of mass lesion or calcification [58].

CT facilitates the differentiation of Coats’ disease from retinoblastoma. Intraocular calcifications are much more common in retinoblastoma and are readily seen radiographically. Partially calcified nodules may occur in Coats’ disease, but almost exclusively in phthisical eyes [28, 59]. More typical CT findings in Coats’ disease are a homogeneous opacification of the vitreous cavity, homogeneous subretinal densities, distinct retinal detachment, and lack of subretinal enhancement following administration of iodinated contrast dye [20, 60].

MRI offers greater tissue delineation and allows definitive differentiation of solid intraocular tumors (i.e., noncalcific or minimally calcified exophytic retinoblastoma) from nonneoplastic conditions causing retinal detachment. In Coats’ disease, there is hyperintensity of the subretinal space in T1-weighted images, hyperintensity [57], or hypointensity [61] of the subretinal space in T2-weighted images, and linear enhancement of retinal detachment following infusion of gadolinium contrast dye. Variation in MRI findings likely relate to the variability of composition of subretinal exudate and to the degree of retinal detachment [61].

Analysis of subretinal fluid obtained intraoperatively by fine-needle aspiration may confirm the diagnosis of Coats’ disease and permit safe and more thorough drainage. Colorless plates of cholesterol crystals, large pig- ment-laden cells, and fat-laden macrophages are observed in cases of Coats’ disease, but are not seen in retinoblastoma [62, 63]. Fine-needle aspiration is not recommended as part of routine evaluation, however, because of the risk of seeding the orbit with malignant cells in cases of retinoblastoma. Measurement of levels of lactate dehydrogenase in the aqueous humor have been studied, but this practice is not recommended because of the wide and nonspecific range of results [20, 64–66].

10.8  Management

Given the discouraging natural history of Coats’ disease, early treatment, preferably at the time of diagnosis, is advisable. The primary objective of treatment is eradication of all abnormal vasculature and areas of nonperfusion, thereby preventing progression of disease and preserving vision.

Initial therapy of Coats’ disease with antibiotics, corticosteroids, vitamins, and X-ray irradiation proved unsuccessful [67]. In 1943, Guyton and McGovern reported successful obliteration of exudate with the application of diathermy coagulation [68]. In the 1960s, direct photocoagulation, with xenon arc or argon laser, was used with encouraging results [15].

In many cases of early Coats’ disease, elimination of telangiectasias and aneurysms will inhibit further exudation, induce resorption of already-formed exudate [12, 19], and lead to resolution of serous detachments [53]. Interestingly, photocoagulation of peripheral vascular lesion may lead to a reduction or disappearance of macular exudates (Fig. 10.4) [7, 23, 39]. Favorable results are more likely to be obtained in early stages of disease (involvement of only one or two retinal quadrants), and in cases in which treatment can be applied over areas of vascular, rather than exudative, changes [7]. Multiple ablative treatments are often required to contain the vascular activity completely [18, 19], and recurrences may be seen over a decade following successful treatment [17]. In anticipation of recurrence, patients with Coats’ disease should be examined semiannually.

In their experience with 124 eyes with Coats’ disease, Shields et al. observed anatomic stabilization or improvement (defined as diminution or resorption of telangiectasias, exudate, or subretinal fluid) in threefourths of cases. Only one-fifth, however, achieved vision of better than 20/200. Sixteen percent required enucleation, most commonly for neovascular glaucoma. Older children and those presenting with retinal telangiectasias only (Shields Stage 1) or with minimal extrafoveal exudation (Shields Stage 2A) are most likely to achieve vision of 20/200 or better. Visual outcomes of less than 20/200 are most often attributable to persistent retinal detachment, macular exudates, and subfoveal fibrosis and are more likely in eyes with extensive disease [17].

Cryotherapy, either alone or in combination with laser photocoagulation, has proven effective especially in advanced cases with significant exudation [19]. Complications of cryotherapy include posterior subcapsular cataract, proliferative vitreoretinopathy, and total retinal detachment [4, 13]. In light of the risk of retinal detachment, it is advisable that no more than two quadrants be treated in one session.

In cases of partial retinal detachment, initial reappositioning of the retina to the retinal pigment epithelium may be accomplished by drainage of subretinal fluid,