Ophthalmology – Familial Exudative Vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is a rare inherited retinal vascular disorder in which abnormal development of the retinal circulation leaves an area of peripheral avascular retina. The resulting peripheral retinal ischemia can stimulate neovascularization, exudation, fibrosis, vitreoretinal traction, retinal folds, macular ectopia, and tractional retinal detachment. Advanced disease may also produce cataract, neovascular glaucoma, and band keratopathy.

FEVR is usually bilateral, but the two eyes can be strikingly asymmetric. Disease severity varies enormously, even among members of the same family and between the two eyes of a single patient. Many affected individuals remain asymptomatic throughout life, whereas others develop severe visual loss or complete blindness in infancy. Importantly, FEVR can progress even after many years of apparent stability.

Epidemiology and Genetics

The true incidence and prevalence are unknown because many affected individuals have mild disease and remain undiagnosed. Molecular and family studies suggest that a very large proportion of affected people may be asymptomatic.

The most common inheritance pattern is autosomal dominant, although autosomal recessive and X-linked forms also occur. Penetrance is high when careful peripheral retinal examination and fluorescein angiography are used, but clinical expression is extremely variable.

Several genes involved in the Norrin–β-catenin signaling pathway have been associated with FEVR. Important genes include FZD4, NDP, LRP5, and TSPAN12. This pathway is essential for normal retinal vascular development.

Mutations in NDP can also cause Norrie disease, an X-linked disorder characterized by severe congenital retinal disease and sometimes hearing loss and developmental abnormalities.

Patients with LRP5-associated FEVR may have reduced bone mass, so systemic skeletal assessment may occasionally be relevant.

Pathophysiology

The primary abnormality in FEVR is incomplete peripheral retinal vascularization. Defective signaling in pathways responsible for retinal vasogenesis leaves an avascular peripheral retina, most commonly temporally.

This avascular retina becomes relatively ischemic and can stimulate production of angiogenic factors. Secondary changes may include abnormal vascular branching, arteriovenous shunts, neovascularization, lipid exudation, and fibrovascular proliferation.

As fibrovascular tissue contracts, it produces vitreoretinal traction, which can drag the macula and optic disc temporally, create retinal folds, and eventually cause tractional retinal detachment. Some eyes may also develop retinal breaks and combined tractional-rhegmatogenous detachment.

Clinical Presentation

A detailed history should include a family history of retinal disease, visual loss, retinal detachment, or childhood blindness. It is also important to ask about prematurity and neonatal oxygen exposure, because retinopathy of prematurity can closely resemble FEVR.

Many affected individuals are asymptomatic and are diagnosed only after examination of family members of a known case.

Infants with severe disease may present with poor fixation and following, pendular nystagmus, strabismus, or leukocoria caused by extensive retinal detachment or heavy lipid exudation.

Older children and adults may present with gradual or sudden visual loss due to retinal detachment, retinal folds, vitreous hemorrhage, or macular ectopia.

Some patients develop apparent exotropia because temporal displacement of the macula produces a large positive angle kappa, creating pseudoexotropia.

Physical Examination

Visual acuity ranges from normal to profound visual loss. A complete dilated retinal examination with careful peripheral evaluation and scleral depression is essential.

The hallmark finding is a peripheral avascular zone, usually most prominent temporally but sometimes extending circumferentially.

At the vascular-avascular junction, retinal vessels may have a brush-like appearance, excessive branching, dilation, tortuosity, or abnormal peripheral looping.

Additional findings can include peripheral neovascularization, vitreous hemorrhage, subretinal lipid exudation, vitreoretinal fibrosis, retinal folds, macular ectopia, temporal dragging of the retina and optic disc, and tractional retinal detachment.

Fluorescein Angiography

Fluorescein angiography, preferably with wide-field peripheral imaging, is one of the most useful diagnostic tests.

Typical angiographic abnormalities include abrupt termination of the peripheral capillary bed, avascular peripheral retina, abnormal peripheral vessel branching, arteriovenous shunts, vascular tortuosity, leakage from abnormal peripheral vessels, and temporal dragging of retinal vessels.

Wide-field angiography is particularly valuable because clinically subtle disease may become obvious only when the far peripheral circulation is examined.

Differential Diagnosis

The condition that most closely resembles FEVR is retinopathy of prematurity (ROP). The distinction depends heavily on history. ROP occurs in premature infants, particularly those with a history of neonatal intensive care and oxygen exposure, whereas FEVR may occur in full-term infants and often has a positive family history.

Other differential diagnoses include persistent fetal vasculature, Norrie disease, X-linked retinoschisis, incontinentia pigmenti, Coats disease, pars planitis, and ocular toxocariasis.

The combination of a peripheral avascular retina, asymmetric bilateral disease, and a positive family history strongly supports FEVR.

Treatment

Treatment is determined by the stage and activity of disease.

Eyes with peripheral avascular retina alone, without neovascularization, exudation, or traction, are usually observed.

When significant peripheral neovascularization or exudation develops, laser photocoagulation to the avascular peripheral retina is commonly used. Cryotherapy can also be considered when laser treatment is technically difficult.

The goal is to reduce ischemic drive and prevent progression to fibrovascular traction and retinal detachment.

Anti-VEGF agents have been used in selected cases with severe exudative or neovascular disease, but their role requires caution because rapid regression of neovascular tissue may potentially increase fibrovascular contraction and traction. They are therefore generally considered adjunctive rather than routine therapy.

Surgical Management

Eyes with retinal detachment require treatment according to the extent and mechanism of traction.

Mild tractional detachment that does not involve the fovea may sometimes be managed with scleral buckling.

More advanced tractional retinal detachment generally requires pars plana vitrectomy, often with membrane dissection and other vitreoretinal techniques. Complex cases may require combined vitrectomy and scleral buckle procedures.

Surgery can be technically difficult because of abnormal peripheral vasculature and extensive vitreoretinal adhesions.

Follow-up

Long-term monitoring is essential because FEVR can remain stable for years and subsequently reactivate or progress.

Patients with only peripheral avascularity and no active complications may sometimes be followed annually.

Patients with neovascularization, exudation, or traction require much closer follow-up, particularly during periods of active treatment.

Children require particularly careful surveillance because progression can occur rapidly and because retinal pathology may interfere with visual development and cause amblyopia or strabismus.

Family Screening and Genetic Counseling

Because FEVR is inherited and may be clinically subtle, first-degree relatives should undergo retinal examination, often including wide-field fluorescein angiography when indicated.

Genetic counseling should be offered according to the identified or suspected mode of inheritance. Molecular testing can be helpful for confirming the diagnosis and screening family members, although a negative genetic test does not exclude FEVR because not all causative genes are known.

Prognosis

The prognosis is highly variable. Patients with mild peripheral vascular abnormalities may maintain normal vision throughout life, whereas those presenting in infancy with extensive retinal detachment generally have a poorer visual prognosis.

Early recognition of neovascularization and exudation before significant retinal traction develops provides the best opportunity to preserve useful vision.

Even apparently stable patients require lifelong follow-up because progression can occur after prolonged periods of inactivity.

Complications

Major complications include peripheral neovascularization, vitreous hemorrhage, lipid exudation, arteriovenous malformations, vitreoretinal fibrosis, falciform retinal folds, macular ectopia, retinal tears, tractional or combined retinal detachment, cataract, neovascular glaucoma, and blindness.