Ординатура / Офтальмология / Учебные материалы / Retinal Vascular Disease Joussen Springer

562 III Pathology, Clinical Course and Treatment of Retinal Vascular Diseases

22 III

Fig. 22.4.1. Stages of Coats’ disease: a Early stage with typical telangiectasis of retinal vessels without exudates. b Early stage with localized telangiectasis, aneurysm-like abnormalities and lipid exudates. c Advanced stage with diffuse retinal vessel anomalies in the periphery of the retina, massive subretinal lipid exudates and with exudative retinal detachment.

d Late stage of Coats’ disease with solid subretinal lipid exudates and total retinal detachment

development of microaneurysms and finally capillary occlusions may be the result of endothelial cell death. Breakdown of the blood-retina barrier with extravasion of blood components explains the intraretinal and subretinal fluid, protein and lipid deposits and development of exudative retinal detachment. Histopathological examination of enucleated eyes shows thickening and hyalinization of the retinal vessel walls. The subretinal space contains exudates, cholesterol and cholesterol-laden macrophages [21].

22.4.2 Classification

According to the variety of clinical pictures, various classifications have been suggested. Coats’ disease is divided between type I disease with exudates without recognizable vascular abnormalities, type II disease with exudates and retinal telangiectasia and type III with local exudates around a solitary retinal angioma [4]. Coats’ type III disease is consistent with the description of von Hippel’s angiomatosis retinae. In type I disease fluorescein angiography also shows abnormal retinal vessels in the area of the exudates. Based on the proposal of Gomez-Morales, Shields published a more detailed clinical classification [6, 19]. Based on the clinical outcomes after

treatment of 124 eyes with Coats’ disease, he proposed a classification that implies treatment selection and prognosis of the eye. Stage 1 shows telangiectasia only (Fig. 22.4.1a). Stage 2 presents with telangiectasia with extrafoveal (stage IIA) or foveal exudation (stage 2B). In stage 3 additional exudative retinal detachment occurs. Stage 3 is divided into localized retinal detachment (stage 3A) and total retinal detachment (stage 3B). Stage 4 is characterized by total detachment and secondary glaucoma. Stage 5 is the end-stage disease with phthisis and blindness.

With respect to functional prognosis, a poor visual outcome (20/200 or worse) was found in none of the eyes with stage 1. However, in stage 2 and 3 significant visual impairment was observed in 53 % and 74 %, respectively. Finally all eyes with stage 4 and 5 Coats’ disease at presentation had a poor visual outcome.

This actual classification may be applicable for juvenile forms of Coats’ disease. The clinical course in adults is normally less severe and shows a slower progression. Therefore an additional differentiation between juvenile (onset before 30 years) and adult (after age of 30 years) forms of the disease might be necessary.

22.4.3 Differential Diagnosis

The differential diagnoses of Coats’ disease are listed in Table 22.4.1. In children, retinoblastoma is the most important differential diagnosis. Subretinal masses in Coats’ disease normally appear more yellowish, in retinoblastoma more white, but this criterion is not reliable (Fig. 22.4.2). Subretinal masses with secondary calcifications are more common in retinoblastoma. Retinal telangiectasis over the solid masses is more typical for Coats’ disease. A clear differentiation between these two entities is essential before the start of treatment. Vitreoretinal interventions are sometimes recommended in Coats’ disease. In retinoblastoma, however, intraocular surgery may end up with a local spreading of tumor cells into the orbit, worsening the overall prognosis. Diagnostic tools should be performed in unclear cases to allow correct diagnosis. Additional ultrasound examination and fluorescein angiography (Fig. 22.4.3) might be helpful to detect typical vessel abnormalities. Computer tomography allows the detection of calcifications and magnetic resonance imaging allows a better staging of the tumor extension in the eye [15].

An intraocular medulloepithelioma is a rare disease. It is a unilateral solitary tumor of the non-pig- mented epithelium of the ciliary body. It always presents in the first decade of life. Decreased vision, leukocoria, glaucoma, rubeosis iridis and hyphema are the most frequent findings at presentation [17]. A pathognomonic finding in medulloepithelioma is a cystic tumor, located in the ciliary body.

A subretinal mass in children may be caused by a choroidal hemangioma, sometimes associated with the Sturge-Weber syndrome. Clinical features of

a

Fig. 22.4.2. In children, retinoblastoma is the most important differential diagnosis. Advanced Coats’ disease with intraand subretinal exudates (a) might be confused with a diffuse infiltrating retinoblastoma (b). Typical vessel anomalies and more yellow subretinal exudates are more common in Coats’ disease (c). Differentiation to solid

subretinal masses in retinoblastoma (d) c might be difficult

Coats’ disease may be mimicked by leukemic infiltrations of the choroid and the retina and by inflammatory diseases. Space occupying lesions like astrocy-

Eales disease

Diabetic retinopathy

Radiation retinopathy

Retinal vasculitis

b

d

tomic hamartoma may be misdiagnosed as Coats’ disease. Astrocytomas are a common finding in tuberouse sclerosis and less frequent in neurofibromatosis. A careful search will reveal other stigmata of these diseases. Hereditary conditions that may simulate Coats’ disease are incontinentia pigmenti and Norrie disease. Gender gives a hint in these two diseases: Norrie disease occurs only in boys and incontinentia pigmenti only in girls.

Despite some clinical similarities, specific findings or the medical history allow differential diagnosis. Retinopathy of prematurity has a typical medical history and is often bilateral. This is also valid for, e.g., familial exudative vitreoretinopathy and uveitis. Persistent hyperplastic primary vitreous is associated with microphthalmos in most cases. Blood analysis showing high levels of serum antibodies against specific antigens may be helpful for the diagnosis of uveitis and infections. In adults Coats’ disease may be misdiagnosed as central retinal vein occlusion or branch retinal vein occlusion.

Using standard fluorescein angiography is of little diagnostic value in young children. Imaging of the peripherally located retinal changes can only rarely be achieved in children. Introduction of wide-field fluorescein angiography systems in recent years allows the viewing of peripheral findings under general anesthesia in very young children (Fig. 22.4.3). Typical findings in Coats’ disease are relatively slow filling of the peripheral capillary changes in the early phase, sometimes combined with an early hypofluorescence due to the subretinal lipid exudates

(Fig. 22.4.3). Capillary occlusions and increased filling of aneurysms and capillary ectasia can be seen in the arteriovenous phase. An increasing focal or diffuse exudation can be seen in the late arteriovenous and in the late phase. Identification of retinal ischemia and areas of pathologically altered retinal vessel anomalies are important indicators toward considering treatment of the eye.

22.4.4 Treatment

The goal of treatment is the control of exudation by the pathological retinal vessels and to prevent further progression to visually threatening complications. Additional treatment of retinal ischemia is essential to prevent secondary complications. Effective therapy in stage 1 or 2 disease is destruction of the affected retinal vessels and ischemic retina by indirect laser photocoagulation or cryotherapy [13, 14]. Regression of the lipid deposits may take weeks to months, even after successful coagulation therapy. Repeated treatment may be successful even in more advanced stage 3 disease (Fig. 22.4.4). After initial coagulation therapy a partial regression of exudative changes can be achieved and may allow further coagulation therapy of the remaining retinal vessel anomalies several weeks later (Fig. 22.4.4). Finally a complete destruction of the abnormal vessels and a confluent coagulation of the ischemic retina should be achieved by thermal coagulation. It might be necessary to perform direct coagulation of the vessels or to use cryotherapy in triple freeze-thaw technique to control advanced

Fig. 22.4.4. a Advanced Coats’ disease before and directly after laser coagulation of the retinal vessel abnormalities in the periphery. b Finding before a stepwise confluent laser coagulation of the affected retinal vessels.

c Reattached retina and regression of the subretinal exudates 10 months after the first laser therapy. d Further regression and improved visual acuity 15 months after additional laser therapy

a

c

22.4 Coats’ Disease 565

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b

d

stages. External surgical drainage of the subretinal fluid and the exudates, followed by photoor cryocoagulation, may be an option in cases showing retinal vessel abnormalities at the posterior pole or in cases with a bullous exudative retinal detachment [1]. Vitreoretinal procedures using maneuvers to reattach the retina by internal drainage of the subretinal fluid and lipid deposits, endocoagulation of the affected vessels and gas or silicone oil tamponade have been recommended [8, 9]. Cases with particular paramacular involvement showed an improvement of the visual acuity after vitrectomy and enucleation could be avoided in eight of nine eyes [8]. Nevertheless, the rank of vitrectomy in the therapy of Coats’ disease is still controversial. In children, exclusion of retinoblastoma before surgery, attached vitreous as a surgical problem and the high rate of proliferative vitreoretinopathy remain a challenge and should be considered before a vitrectomy is taken into account.

22.4.5 Future Prospects

In future, anti-angiogenic drugs might play a role in the therapy of Coats’ disease. At the moment it is not clear whether or not any of these drugs, currently used for the therapy of age related macular degeneration, would help patients with Coats’ disease. The anti-angiogenic effect of these drugs might be a general problem for the use in children. The inclusion of children in controlled prospective studies on the efficacy of anti-angiogenic drugs in Coats’ disease might be problematic.

Regular control examinations after successful therapy of Coats’ disease are mandatory. New vessel abnormalities in prior unaffected retinal areas may develop and early treatment of these abnormalities is necessary to prevent further late complications [13, 20].

References

1.Adam R, Kertes P, Lam WC (2007) Observations on the management of coats’ disease: less is more. Br J Ophthalmol 91:303 – 306

2.Beby F, Roche O, Burillon C, Denis P (2005) Coats’ disease and bilateral cataract in a child with Turner syndrome: a case report. Graefes Arch Clin Exp Ophthalmol 243:1291 – 1293

3.Black GC, Perveen R, Bonshek R, Cahill M, Clayton-Smith J, Lloyd IC, McLeod D (1999) Coats’ disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for norrin in retinal angiogenesis. Hum Mol Genet 8:2031 – 2035

4.Coats G (1908) Forms of retinal disease with massive exudation. R Lond Ophthalmic Hosp Rep 17:440

5.Genkova P, Toncheva D, Tzoneva M, Konstantinov I (1986) Deletion of 13q12.1 in a child with Coats disease. Acta Paediatr Hung 27:141 – 143

6.Gomez Morales A (1965) Coats’ disease. Natural history and results of treatment. Am J Ophthalmol 60:855 – 865

7.Khan JA, Ide CH, Strickland MP (1988) Coats’-type retinitis pigmentosa. Surv Ophthalmol 32:317 – 332

8.Krause L, Kreusel KM, Jandeck C, Kellner U, Foerster MH (2001) Vitrektomie bei fortgeschrittenem Morbus Coats. [Vitrectomy in advanced Coats disease.] Ophthalmologe 98:387 – 390

9.Kreusel KM, Krause L, Broskamp G, Jandeck C, Foerster MH (2001) Pars plana vitrectomy and endocryocoagulation for paracentral Coats’ disease. Retina 21:270 – 271

16.Schuman JS, Lieberman KV, Friedman AH, Berger M, Schoeneman MJ (1985) Senior-Loken syndrome (familial renalretinal dystrophy) and Coats’ disease. Am J Ophthalmol 100:822 – 827

17.Shields JA, Eagle RC Jr, Shields CL, Potter PD (1996) Congenital neoplasms of the nonpigmented ciliary epithelium (medulloepithelioma). Ophthalmology 103:1998 – 2006

18.Shields JA, Shields CL, Honavar SG, Demirci H (2001a) Clinical variations and complications of Coats disease in 150 cases: the 2000 Sanford Gifford Memorial Lecture. Am J Ophthalmol 131:561 – 571

19.Shields JA, Shields CL, Honavar SG, Demirci H, Cater J (2001b) Classification and management of Coats disease: the 2000 Proctor Lecture. Am J Ophthalmol 131:572 – 583

20.Shienbaum G, Tasman WS (2006) Coats disease: a lifetime disease. Retina 26:422 – 424

21.Tripathi R, Ashton N (1971) Electron microscopical study of Coat’s disease. Br J Ophthalmol 55:289 – 301

Core Messages

Familial exudative vitreoretinopathy FEVR) is an inherited, bilateral peripheral vascular disease in children with no association to prematurity

Unlike inherited diseases, expression of FEVR may be asymmetrical between the two eyes The clinical course is slowly progressive, and

rarely stable. Its presentation may be confined to a peripheral avascular zone and a reduced angle kappa or it may lead to a falciform or a rhegmatogenous retinal detachment

Retinal exudates and a peripheral fibrovascular mass result from the leakiness of peripheral vessels forming aneurysms, tubular dilatation,

and neovascularization, indicating a progressive disease. Such abnormalities must be destroyed by laser or cryotherapy to stop exudation. Usually repetitive applications of retinopexy are necessary

The main goal of treatment is the occlusion of abnormal retinal vessels to avoid complications such as tractional retinal detachment and regrowth of vitreous membranes

The involvement of Wnt signaling in the pathogenesis of FEVR is currently under discussion. Frizzled-4 (Fz4), a presumptive Wnt receptor, and Norrin, the protein product of Norrie’s disease gene, function as a ligand-receptor pair

22.5.1 History

Familial exudative vitreoretinopathy (FEVR) was first described by Criswick and Schepens in 1969 in six children as a peripheral vitreoretinopathy similar to retinopathy of prematurity (ROP) yet with familial occurrence [11].

Three stages of the disease were described by Gow and Oliver in 1971, who pointed out the inheritance and the vascular pathogenesis [17]. Later Canny and Oliver confirmed the vascular origin and described a peripheral avascular zone as demonstrated by fluorescein angiogram as a pathognomonic sign of the early stages of the disease [6]. Similarly, Ober and Bird emphasized the role of fluorescein angiography in identifying subclinical cases [27]. The gene was first identified by Li in 1992 [20, 21].

To date, a total of about 340 cases in more than 60 families have been reported in the literature.

22.5.2 Special Pathological Features

Essentials

Failure of the (temporal) peripheral retina to vascularize

Abnormal existing vessels and neovascularization

Subretinal deposits as a result of increased vascular leakage

Greaseproof-paper-like vitreous membranes

FEVR is a disorder of the peripheral retinal vessels often associated with vitreous traction. Systemic associations are absent and no association with prematurity is found.

Despite earlier theories that emphasized vitreoretinal changes, it is now clear that the fundamental abnormality in FEVR is the leakiness of the abnormal peripheral retinal vessels [6, 12, 19].

Preexisting vessels dilate and form bulb like and tubular dilatations at their peripheral ends, which later become leaky. Large peripheral avascular zones correlate with the presence of neovascularization at

its border and the development of peripheral fibrovascular masses [24].

Subretinal exudates signal a risk of disease progression. The abnormal peripheral vessels are leaky and considerable amounts of fluid and protein extravasate from these vessels, resulting in deposition of subretinal lipid and exudates. It is likely that the majority of leakage derives from the abnormally dilated and straightened second order vessels in the periphery and not from neovascularization. Figure 22.5.1a demonstrates that subretinal deposits can be found in the presence of abnormal vessels without formation of neovascularization.

Thus, peripheral ischemia, neovascularization and the abnormal vasculature combine to produce the pathology in FEVR.

Demonstration of hematoserological defects and abnormal platelet aggregation in affected members of two families [8] has not been confirmed by subsequent studies [4, 40].

Histopathology reveals similarities to other peripheral vasculopathies such as Coats’ disease. Onion- skin-like vitreous membranes are typical of FEVR. Histopathological characteristics of FEVR comprise the following (Figs. 22.5.2, 22.5.3f):

Thickened retina containing dilated, teleangiectatic blood vessels

Vessel walls are thickened and may demonstrate a perivascular infiltrate [3, 12]

Intraretinal [3] and subretinal [26] inflammation may be present

Cellular and acellular vitreous membranes sprout from the retina [5]. They must be cut from the retina and cannot be peeled off the retina

There is no retinal dysplasia

The failure of vascularization of the peripheral retina is the unifying feature seen in all affected individuals. A small avascular crescent usually remains asymptomatic. The visual problems in FEVR result

g

avascular border or of the fibrovascular mass that may occur just anterior to it. Mostly vitreoretinal traction is located in the temporal periphery, the area of the most apparent ischemia.

22.5.3Genetics and Molecular Mechanisms

Essentials

Autosomal dominant or recessive trait

Complete penetrance

Variable phenotypic expression

Chr 11q13, principal locus EVR1 Wnt signaling is demonstrated to be involved

FEVR is most commonly inherited as an autosomal dominant trait [18, 31]. However, a few families with an X-linked recessive form of FEVR [9, 10, 32] as well as one family with an autosomal recessive pattern of inheritance [33] have been reported. Isolated cases of sporadic or idiopathic cases of FEVR have been noted by Miyakubo [24].

Fig. 22.5.3 (Contin.) after resection of the vitreous strands. The retinal surface is covered by a tightly adherent pucker forming a pseudomacular hole. d2 A closer view demonstrates insertion of the vitreous strands near the vessel arcades. Several thin membranes are piled up forming onion-skin-like structures. e After preparation of the membranes covering the macula, peripheral remnants have to be dissected but cannot be peeled off because of their insertion into the retinal tissue. Old laser scars are visible. f Histology section of the dissected membranes demonstrates fibrosed tissue intertwined with inflammatory cells. H&E. g Fundus view after extensive membrane peeling. The status remained stable without tamponade for several years

The disease exhibits complete penetrance (almost 100 %) with a highly variable phenotypic expression [27]. Many individuals demonstrate an asymptomatic expression of the disease, then only apparent on fluorescein angiography.

Figure 22.5.4 demonstrates two families from Syria of known consanguinity [1]. Different stages of the disease were seen in all six children of the families. Traction and distortion of the macula or optic disk was seen in 11 out of 12 eyes. The father demonstrated asymptomatic disease with temporal peripheral degenerations and atypical vessels.

The gene for autosomal dominant FEVR was mapped on chromosome 11q13-q23 with its principal locus (EVR1) in four northern European families [20, 25] and an Asian family [29]. To date, two autosomal dominant loci have been mapped. EVR1 on chromosome 11q was the first FEVR locus to be identified [20, 21] and verified in further families. The gene encoding Wnt receptor frizzled-4, FZD4 (MIM604579) was recently reported as the EVR1 gene [30]. The discovery that FEVR can be caused by mutations in the Wnt receptor FZD4 highlighted proteins involved in the Wnt-signaling pathway as candidate FEVR genes. Toomes et al. describe mutations in a second gene at the EVR1 locus, low-density-lipoprotein receptor-related protein 5 (LRP5), a Wnt coreceptor, which is one such candidate gene [36].

Xu et al. recently reported the vascular development in the retina and inner ear to be controlled by Norrin and Frizzled-4, a high-affinity ligand-receptor pair [41]. As described above, one form of FEVR is caused by defects in Frizzled-4 (Fz4), a presumptive Wnt receptor. Norrin, the protein product of Norrie’s disease gene, is a secreted protein of unknown biochemical function. In a mouse model the authors were able to prove that Norrin and Fz4 function as a ligandreceptor pair based on: (1) the similarity in vascular phenotypes caused by Norrin and Fz4 mutations in humans and mice, (2) the specificity and high affinity of Norrin-Fz4 binding, (3) the high efficiency with which Norrin induces Fz4and Lrp-dependent activation of the classical Wnt pathway, and (4) the signaling defects displayed by disease-associated variants of Norrin and Fz4. These data define a Norrin-Fz4 signaling system that plays a central role in vascular development in the eye and indicate that ligands unrelated to Wnts can act through Fz receptors.

At present, the cell types that express Norrin and Fz4 are not well defined in the retina. It is interesting, however, that linkage and candidate gene analysis have shown X-linked FEVR to be allelic to Norrie’s disease [9, 15, 32]: A number of mutations in Norrie’s

disease gene have been found in families with X- linked FEVR [15, 32].

Further effort is required to more closely define the cellular and subcellular localization of the proteins involved in the disease process leading to specific phenotypes, and more effort is required to develop new therapeutic targets.

22.5.4 Clinical Course of the Disease

Essentials

Peripheral avascular zone (mostly temporal)

Temporal dragging of disk and vessels (reduced angel kappa)

Subretinal exudates indicate progressive disease

Falciform tractional retinal detachment

The disorder is bilateral but often asymmetric. The majority of gene carriers suffer no visual impairment. Early manifestation (childhood) heralds progression. In the first years of life exotropia may be one of the first symptoms.