Christopher M. Andreoli
In 1969, Criswick and Schepens reported on six patients with abnormalities of the retina and vitreous that were clinically similar to retinopathy of prematurity (ROP) but without a history of prematurity or oxygen supplementation. Two of the patients were related by blood, and the other four patients were members of another family and were related by blood. Criswick and Schepens called this entity familial exudative vitreoretinopathy (FEVR; which is also known as Criswick-Schepens syndrome) because of the familial and exudative nature of the disease. Both FEVR and ROP are characterized by avascularity of the peripheral retina, which is especially evident on fluorescein angiography. In both diseases, reactive fibrovascular proliferations develop that may lead to cicatricial changes and retinal traction in the temporal periphery, resulting in dragged disks, ectopic maculae, retinal detachments, and falciform retinal folds. Visual loss is primarily due to retinal detachment.
FEVR is a vitreoretinal disorder that is clinically similar to ROP, except that there is usually a positive family history, and there is no history of prematurity or oxygen supplementation. The disease is often asymptomatic in the early stages and progresses very slowly. Based on funduscopic and fluorescein angiographic observations, Canny and Oliver developed a useful staging scheme. The three stages describe mild, moderate, and severe forms of FEVR, and each stage can be seen at any age.
Mild (Stage 1)
Moderate (Stage 2)
Severe (Stage 3)
Stage 1 describes the mild form of FEVR. Fundus examination during this stage reveals vitreoretinal changes in the periphery between the equator and the ora serrata, including the white-with-pressure and white-without-pressure signs, peripheral cystoid degeneration, and vitreous bands. There is a peripheral avascular zone that is difficult to see clinically. Exudation, neovascularization, and fibrovascular proliferation are not present at this initial stage. Fluorescein angiography demonstrates the peripheral avascular zone clearly (Fig. 141.1) that is present in the temporal periphery and can leak fluorescein. There is abnormal arborization of the vessels in the periphery that terminates along a scalloped or curvilinear border with the avascular zone. In cases with wider zones of peripheral avascularity, a wedge-shaped area of avascularization may be seen in the temporal meridian. Retinal pigment epithelial changes are often associated with this V-shaped zone of avascularization. In many individuals, the peripheral avascular zone persists into adult life without regression or progression to proliferation. This is in contrast to ROP in which the peripheral retina subsequently vascularizes.
FIGURE 141.1 Fluorescein angiogram demonstrates the peripheral avascular zone, vascular engorgement and telangiectasia, microaneurysms, and shunt vessels in stage-1 disease.
It is not known why the peripheral retina does not vascularize completely in FEVR. Whether this disease is a primary disorder affecting retinal vessel development[6,7] rather than a true vitreoretinopathy, as originally suggested by Criswick and Schepens, is still to be determined. Although congenital nonvascularization of the retinal periphery is the most common characteristic of the mildest phenotypes, vitreous changes are also noted in these patients. It also remains uncertain whether a secondary vasoocclusive process (e.g., associated with hematologic disease) contributes to the pathogenesis of FEVR. Laqua performed extensive hematologic examinations on one of his patients with FEVR and did not find any evidence of a hematologic disorder. Platelet dysfunction may play a role in FEVR, but this is still not fully determined.[8-10]
Stage 2 FEVR is the moderate form of the disease and represents the proliferative and exudative stage. In addition to the stage 1 findings already described, neovascularization, fibrovascular proliferation, and subretinal and intraretinal exudation are seen, especially in the temporal periphery (Figs 141.2 and 141.3). A localized traction retinal detachment may also be present. The fibrovascular lesions contract and exert traction on the retina, producing ectopic maculae and dragged disks (Fig. 141.4). A fluorescein angiogram shows neovascularization developing from the retinal vessels at the vascular-avascular border and growing anteriorly into the avascular retina. The temporal region of the retina is again the most common area for neovascularization. There is abrupt cessation of the retinal capillary network at the scalloped edge posterior to the fibrovascular mass. These terminal capillaries also leak fluorescein. Fibrovascular masses stain with fluorescein. Large feeder vessels may also be seen.
FIGURE 141.2 (a) The temporal periphery in stage-2 FEVR. Fibrovascular ridge and retinal exudation are seen. (b) Early fluorescein angiogram of the same area shows neovascularization at the vascular-avascular border. (c) Late fluorescein angiogram of the same area shows extensive leakage of the fluorescein dye.
FIGURE 141.3 The temporal periphery in stage 2 disease demonstrates intraretinal and subretinal exudation, pigmentary changes, and straightening of retinal vessels.
FIGURE 141.4 Patient with stage 2 FEVR with a dragged disk.
Stage 3 represents the advanced stage of FEVR. A cicatricial lesion in the temporal periphery pulls the retina and causes traction retinal detachments, falciform retinal folds, and rhegmatogenous retinal detachments. Massive intraretinal and subretinal exudation is present and can result in an exudative retinal detachment (Fig. 141.5). The exudative component of the disease may resemble Coats' disease and is different from ROP. The degree of exudation is usually less than in Coats' disease, and total retinal detachments from exudation are rare. Anterior segment changes, including cataract, iris atrophy, rubeosis iridis, and neovascular glaucoma, nonneovascular chronic angle-closure glaucoma, as well as band keratopathy can also occur.[3,12]
FIGURE 141.5 Stage 3 FEVR in a patient with retinal hemorrhage and severe exudative retinal detachment.
Retinal detachments are relatively common in FEVR and constitute the major cause of visual loss in these patients. The incidence of retinal detachment ranges between 20% and 32%.[2,13-15]Rhegmatogenous retinal detachment is common - between 25% and 63% of all retinal detachments in FEVR are of this type. A variety of retinal breaks have been observed, including round holes, horseshoe tears, and giant tears. Rhegmatogenous retinal detachments usually occur in the second and third decades of life. At least in the Japanese population, rhegmatogenous retinal detachments from FEVR appear to constitute a significant proportion of all rhegmatogenous retinal detachments in this age group. Hashimoto and associates showed that in 576 consecutive cases of all rhegmatogenous retinal detachments, 5% were in FEVR patients. When these authors looked at all rhegmatogenous retinal detachments in patients younger than 30 years of age, a surprising 12% were in patients with FEVR.
Retinal breaks in FEVR are thought to be caused by a combination of vitreoretinal traction and retinal atrophy. Vitreous bands and adhesions are seen even in the early stages of FEVR. Neovascularization and fibrovascular proliferation produce additional traction. The peripheral retina in FEVR patients is also avascular and atrophic. Atrophic holes are seen in the periphery in many of the cases. The combination of vitreoretinal traction and atrophic retina makes these eyes more susceptible to retinal tears.[2,15,16] The combined traction and rhegmatogenous retinal detachments that result tend to be surgically difficult to repair and often lead to proliferative vitreoretinopathy and require multiple procedures.[2,15,17] There is also one reported case of significant postoperative uveitis. Vitreous hemorrhage in FEVR patients is rare but may be an ominous sign; two cases described by van Nouhuys resulted in rapid progression to closed-funnel retinal detachments. In summary, the cases of retinal detachment in FEVR have many of the difficulties seen in combined traction-rhegmatogenous retinal detachment in young adults with predilection for proliferative vitreoretinopathy.
Falciform retinal folds are also relatively common and are found in 15-39% of the eyes with FEVR.[2,19] The folds usually extend from the optic nerve head to the temporal or inferotemporal periphery, at which point there are cicatricial connections to the mass of fibrous tissue at the peripheral retina and lens equator.[20,21] The distance between the peripheral retina and the lens equator is very short in the neonatal eye, and this accounts for the high frequency of adhesions anteriorly to the lens. The folds appear to be caused by severe traction of the retina resulting from the organization of peripheral neovascularization and formation of a fibrovascular mass. The folds usually occur in the first decade of life and do not show progression.
Traction retinal detachments are less common and occur at a rate of 6-10% in eyes with FEVR.[2,14] They usually occur before the age of 10 years and show very little progression. In the cases with isolated traction retinal detachment, vitrectomy alone may be effective. Massive Coats'-like exudation can cause total retinal detachments (Fig. 141.5), but in general, significant exudative retinal detachments appear to be rare.
FEVR is characterized by nonvascularization of the peripheral retina, familial occurrence (usually autosomal dominant, X-linked, or autosomal recessive), dragged disk and macula, retinal exudation, retinal detachment, and retinal folds. The clinical features are most similar to those of ROP and include peripheral nonvascularization, reactive fibrovascular proliferations, and cicatricial changes with severe traction on the retina. Important differentiating features are a family history of the disorder and no history of prematurity or oxygen supplementation. The peripheral avascular retina does not vascularize in FEVR, as it typically does in ROP, and exudation, which is common in FEVR, is very rare in ROP.
In addition to ROP, possible alternative differential diagnoses of patients having peripheral retinal nonvascularization with neovascular proliferation include sickle-cell trait and disease as well as other hemoglobinopathies, Eales' disease, incontinentia pigmenti, and autosomal dominant neovascularization as described by Gitter and co-workers. Diseases causing dragged disks, ectopic maculae, and falciform retinal folds also need to be considered, especially hereditary falciform retinal folds, persistent hyperplastic primary vitreous/persistent fetal vasculature, Toxocara canis infection, Norrie disease, and incontinentia pigmenti.[19,25,26] Causes of peripheral retinal fibrous or exudative mass lesion include Coats' disease, angiomatosis of the retina, Toxocara canis infection, and pars planitis.[7,16]
FEVR is a genetically heterogeneous disease with autosomal dominant, autosomal recessive, and X-linked inheritance possible with variable clinical expression. Multiple loci and genes have been implicated. Penetrance is variable, depending on the method of diagnosis. When using fluorescein angiography to determine clinical status, penetrance is reported to be 100% because all affected individuals have a sector of avascular peripheral retina. When using examination of the retina with an indirect ophthalmoscope through a dilated pupil to determine clinical status, penetrance is considered to be ?90%. When using reduced vision or other clinical symptoms to determine clinical status, penetrance as low as 10% has been reported.
The first locus discovered, EVR1, contains the FZD-4 gene encoding the Wnt receptor Frizzled-4.[28,29] Mutations in FZD-4 are responsible for autosomal dominant forms of FEVR. This gene maps to the long arm of human chromosome 11 at locus 11q13-23. Multiple families have been discovered to have novel missense and nonsense mutations in this gene causing a similar FEVR phenotype.[28,30-34] The FZD-4 family of genes encode for the Frizzled family of seven-pass transmembrane receptors that bind to multiple ligands including the Wnt family of proteins. This receptor-ligand pair is implicated in development, cell proliferation, and carcinogenesis.[29,35] A missense mutation in FZD4 has been reported in a single case of advanced ROP.
The second FEVR locus, EVR-2, has been found to contain the same gene responsible for Norrie disease (ND) and has been shown to be mutated in cases of X-linked FEVR.[37,38] ND is clinically characterized by bilateral retrolental grayish-yellow fibrovascular masses. This has traditionally been thought to arise from primary retinal dysplasia. With age, the disease progresses to include cataract, posterior and anterior synechiae, iris atrophy, corneal opacification, band keratopathy, and blindness with phthisis bulbi. Mutations in the Norrie gene (NDP) on the human X chromosome at locus Xp11.4 which encodes ND protein (Norrin), have been shown to cause a spectrum of diseases including ND (nonsense mutation) and X-linked FEVR (missense mutations). There are also reported cases suggesting a role of this gene in the pathogenesis of persistent hyperplastic primary vitreous/persistent fetal vasculature, Coats' disease, and advanced ROP. These diseases all appear to share abnormalities in retinal vasculature.
There is some evidence that a genotype-phenotype relationship exists with mutations in NDP. It is suggested that missense mutations affecting the carboxy terminus of the protein result in a less severe phenotype manisfested as X-linked FEVR.[37,41] However, there is also significant phenotypic variation within families carrying the same NDP mutation.[37,42] Allen et al suggests that all phenotypes associated with a defect in NDP should be classified as ND with a range of expressivity, and that X-linked FEVR should be reserved for any cases which do not involve a defect in NDP.
Xu et al established Norrin as a ligand for Frizzled-4, a presumptive Wnt receptor. They propose that Norrin-Frizzled-4 binding serves as a signaling system involved in vascular development. Both FZD-4 and NDP knockout mice have been shown to display increased retinal vascular permeability with an increased number of fenestrated blood vessels as well as persistence of hyaloid vasculature.[44,45]
A third locus, EVR3, segregating with a large kindred demonstrating autosomal dominant FEVR has been identified on chromosome 11 at locus 11p12-13. The gene is currently unidentified.
A fourth locus, EVR4, contains the LRP5 gene which encodes a Wnt co-receptor, low-density lipoprotein receptor-related protein-5 (LRP5). Mutations in this gene cause an autosomal dominant form of FEVR.[47,48] This gene is located on chromosome 11 at locus 11q13, distinct from EVR1 (FZD-4) and EVR3. It has been shown that mutations in this same gene can cause an autosomal recessive form of FEVR as well. Frizzled-4 and LRP5 act as a functional receptor pair in the Wnt signaling pathway.
Toomes has suggested a fourth autosomal dominant locus distinct from EVR1, EVR3, and EVR4. Autosomal recessive pedigrees have also been described; however, an underlying genetic defect has not been determined.
Genetic sequence analysis is available on a research basis for NDP, FZD-4, and LRP. Because the autosomal dominant, autosomal recessive, and X-linked forms of FEVR cannot be distinguished clinically, determining the mode of inheritance for a particular family can be difficult, and for the simplex case, may not be possible.
Histopathologic studies of six eyes enucleated for end-stage FEVR have been reported.[53-56] These eyes were enucleated for phthisis, neovascular glaucoma, acute angle closure, and possible retinoblastoma (in a 6-week-old infant). Many of the histopathologic findings are those typically associated with chronic retinal detachments, neovascular glaucoma, and phthisis bulbi. This discussion concentrates on the findings unique to FEVR. No pathology of either stage 1 or stage 2 disease is available.
Retinal detachment and prominent preretinal and vitreal membrane formation are seen in all cases. Brockhurst and colleagues observed a thick, acellular, preretinal membrane consisting of amorphous material. This membrane is seen just posterior to the ora serrata and extends posteriorly. Glazer and associates showed by electron microscopy that the membranes consist of fibrovascular tissue with astrocytes. Multiple adhesions to the retina cause large retinal folds. Acellular fibrous membrane with pigment is also seen in the vitreous. Van Nouhuys' case of the 6-week-old infant with possible retinoblastoma shows the preretinal membrane to extend much more anteriorly and attach to the lens capsule. Intraretinal and subretinal exudation is also seen, but the degree of exudation and the extent of telangiectatic vessels are less than those usually seen in Coats' disease. Nicholson and Galvis observed areas of necrosis and acute inflammation surrounding the fibrovascular tissue in the temporal periphery of the retina.
PREVENTION AND TREATMENT
The major cause of visual loss in cases of FEVR is retinal detachment. When retinal detachments occur in eyes with FEVR, they tend to be complicated and difficult to repair, often requiring multiple surgical procedures.[2,57,58] Some of the detachments are similar to those seen in ROP. Retinal detachments are more difficult and have the worst prognosis in younger children; rhegmatogenous retinal detachment in an adolescent FEVR patient has high likelihood of proliferative vitreoretinopathy and redetachment. The key to retinal detachment repair in FEVR patients is to release the peripheral vitreoretinal traction using meticulous membrane dissection and scleral buckling.
As in ROP, the goal is to try to prevent the detachments of the retina seen in stage 3, advanced FEVR. Early examination (including dilated fundus examination with scleral depression) of children who have a positive family history is mandatory in identifying those with early proliferative changes. The neovascular and fibrovascular process can then be treated by prophylactic photocoagulation or cryotherapy. There are very few descriptions of FEVR in neonates and infants, and early examination will also give us a better understanding of how FEVR presents in this population. The application of retinoablative procedures to the avascular retina alone or together with the neovascular frond appears to be effective in aborting the proliferative process.[2,59] As in treated cases of ROP, the destruction of the proliferative process is thought to diminish the subsequent cicatricial process that leads to retinal detachment. A randomized study to test the effectiveness of prophylactic cryotherapy or photocoagulation would be difficult to carry out because of the rarity and slow progression of the disease. It is currently not clear whether we can prevent the retinal detachments that occur quite early in life, since stage 3 FEVR can be already present in very young patients.
Presence of the cicatricial process makes the direct detection of subtle retinal detachments difficult. Vitreous cells and haze, poor mydriasis, aqueous cells and flare, and posterior synechiae are all signs of retinal detachment in a FEVR patient. Ultrasonography is an important test in the diagnosis of retinal detachments in cases with media opacities. An increase in angle kappa is evidence of increasing peripheral traction. The role of electrophysiologic testing is uncertain.
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