Pediatric Vitreoretinal Diseases Not Associated with Prematurity

Abstract

Pediatric vitreoretinopathies pose unique surgical challenges because of the distinct anatomic and physiological features. The pars plana is not fully formed until approximately the age of 8 or 9 months, requiring instrument entry through the pars plicata for vitreous surgery in infants [1]. The vitreous gel may be atypically optically empty or syneretic in various pediatric diseases. Firmer vitreoretinal adhesion in children renders induction of posterior vitreous detachment difficult [2]. Rising and falling cytokines impact on progression of disease [3–5]. To operate safely, one must have a grasp of the unique characteristics that define pediatric vitreoretinal diseases. This chapter presents a review of several of the more important pediatric vitreoretinal pathologies.

Copyright © 2012 S. Karger AG, Basel

Familial Exudative Vitreoretinopathy

Familial exudative vitreoretinopathy (FEVR) is an inherited retinal vascular disorder characterized by an avascular peripheral retina, extraretinal fibrovascular proliferation, exudation, an abnormal vitreoretinal interface, and traction retinal detachment (fig. 1). Patients with the FEVR mutation may present with an avascular retinal periphery without exudation or vasoproliferative findings,

or with a clinically normal retina (incomplete penetrance although mutation present). The disease may be inherited in an autosomal-dominant, autosomal-recessive or X-linked manner. Family history can be instrumental in making a diagnosis. In 55% of cases there is no known family history of the disease, though on peripheral fundus examination vascular abnormalities are commonly uncovered in an asymptomatic parent. Earlier reports of retinopathy of prematurity (ROP) in fullterm infants were likely, in reality, infants with FEVR and a negative family history [6].

The clinical manifestations of FEVR include an avascular peripheral retina, neovascular buds at the junction of vascular and avascular retina, fibrovascular proliferation extending into the vitreous, and often a characteristic traction detachment producing a retinal fold which extends through the macula. Subretinal exudates, dragged retinal vessels, and retinal folds that can extend to the lens may also be seen. The clinical appearance may mimic ROP, but also Coats’ disease, Norrie disease, incontinentia pigmenti and retinoblastoma. The diagnosis is usually made by clinical examination, patient history, birth history, and family history. In its most severe forms, a total retinal detachment due to exudation and fibrovascular

proliferation can result and render diagnosis more challenging. FEVR is usually, but not invariably, bilateral and asymmetric. Fluorescein angiography will often unmask peripheral nonperfusion in a seemingly normal-appearing companion eye.

FEVR is a life-long disease with periods of exacerbation and remission. Ongoing examinations are necessary for appropriate management. Patients who present with symptomatic FEVR (strabismus, amblyopia, or leukocoria most commonly) in infancy and early childhood often have a poor prognosis. Treatment of FEVR depends on the severity of the pathology. Exudation, even if asymptomatic, is initially treated with laser ablation of the avascular retina. Fluorescein angiography can be useful to identify the extent of the avascular retina and guide peripheral ablation. Tractional retinal detachment may be managed by vitrectomy in some cases. Family members of suspected patients with FEVR should have a thorough peripheral retinal examination to aid in the diagnosis.

Persistent Fetal Vasculature Syndrome

Persistent fetal vasculature syndrome (PFVS), previously known as persistent hyperplastic primary vitreous (PHPV), refers to a spectrum of structural changes in which the hyaloid vessels and tunica vascular lentis (TVL) persist in an eye following birth. The hyaloid system, or primary vitreous, fills the vitreous cavity and is more than just the hyaloid vessel connecting the optic nerve to the posterior lens. The TVL extends both anterior and posterior to the lens, interweaving with the hyaloid system posteriorly and the ciliary processes as well. The hyaloid system typically regresses by 28–30 weeks of gestational age. Incomplete hyaloidal involution may result in posterior lens opacity of variable severity, and a number of characteristic potential posterior pole abnormalities. No distinct

genetic mutation has been associated for typical unilateral PFVS [7].

Ninety percent of the time PFVS is unilateral. Eyes with PFVS are typically, but not invariably, smaller compared to the normal fellow eye, with posterior lens opacity (fig. 2) and a stalk that connects the posterior lens to the optic disc. Anterior or posterior changes may predominate in a given eye. Visual potential is most dependent on the extent of posterior involvement (especially optic nerve and peripapillary retina) and the size of the eye. Retinal dysplasia is found in varying amounts in PFVS, and may limit visual function as well.

When an eye is normal in size and leukocoria is the prominent ocular finding, the most important differential diagnostic consideration is retinoblastoma. Ultrasonographic and/or radiographic imaging (CT or MRI) can be performed to detect intraocular calcifications and aid in the diagnosis.

Visual-evoked potentials (VEP) are useful, comparing an affected eye to its normal companion, when trying to determine visual potential of the affected eye. If the visual evoked potential is positive, it is reasonable to consider surgical repair. With minor eccentric lens opacity, lenssparing vitrectomy with interruption of the stalk is in order. Peripapillary retinal detachments will often resolve following vitrectomy, and the eye is allowed to grow more normally. Anatomic and visual results are variable following surgery, and depend not only on preoperative ocular anatomy but also timing of surgery, whether the lens was removed, and postoperative amblyopic therapy. Monocular precautions and the use of safety glasses lifelong are standard recommendations.

Congenital X-Linked Retinoschisis

Congenital X-linked retinoschisis (CXLRS) is predominantly inherited in an X-linked recessive distribution. It is the most common cause of juvenile macular degeneration in males affecting

5,000–25,000 live births worldwide. Affected individuals have a 96% incidence of a mutation in the XLRS1 gene, resulting in expression of an aberrant retinoschisin protein. Mothers are typically asymptomatic obligate carriers of the disease with normal retinal examinations and normal electroretinograms (ERG), but often have a positive family history of male members in the family with a history of vision loss [8].

Patients may present in infancy with a diagnosis of amblyopia, strabismus, or nystagmus, but most patients will present between 5 and 10 years of age with difficulties in school. The disease is characterized by structural deficits in the retinal layers resulting in foveal schisis and peripheral bullous schisis cavities most commonly affecting the inferior retinal periphery (fig. 3). Retinal splitting was previously thought to occur primarily in the nerve fiber layer. Analysis of the retinal layers by OCT has revealed that schisis occurs in all layers of the retina, most commonly in the outer plexiform layer. The finding on OCT of fine, coalescing extramacular intraretinal schisis cavities is referred to as lamellar schisis. Foveal schisis is seen in all forms of CXLRS, while lamellar and peripheral bullous schisis are variably present [9]. Electroretinography (ERG) typically shows an ‘electronegative’ waveform, consisting of a normal a-wave amplitude and selectively reduced b-wave amplitude.

Bullous peripheral schisis cavities may cause amblyopia when they extend superiorly to interrupt the visual axis. Disruption of the thin inner wall of schisis bullae may result in interruption of a retinal vessel and amblyogenic vitreous hemorrhage. Rhegmatogenous retinal detachment (RRD) is uncommon and may be difficult to diagnose in CXLRS.

The clinical course is variable with severity in visual loss ranging from 20/50 to no light perception. Currently, there is no treatment for foveal or lamellar schisis in CXLRS. Vitreoretinal surgery may be necessary when bullous CXLRS results in interruption of the visual axis or threatens to extend through the fovea, to address an

amblyogenic vitreous hemorrhage, and to repair combined schisis-RRD. Laser retinopexy can create a mechanical barrier to prevent progression of bullous retinal schisis, but there is risk of iatrogenic full-thickness retinal break. Correction of refractive errors and early intervention with amblyopia therapy are vital during the entire visual development of the child. Low-vision aids in conjunction with a low-vision specialist can be invaluable as the child gets older. Protective eyewear is recommended.

Coats’ Disease

Coats’ disease is typically a unilateral retinal vascular disorder (90%) occurring predominantly (up to 90%) in young males in the first decade of life. Inheritance is primarily sporadic. Mildly affected individuals can present late in adulthood, typically with vitreous hemorrhage in the setting of posterior vitreous detachment. Patients who are younger at presentation are affected more severely. No racial or ethnic predisposition or environmental factors have been linked to Coats’ disease [10].

Children typically will present with strabismus, leukocoria or poor vision on routine vision screening. Characteristic funduscopic findings in Coats’ disease are focal vascular telangiectasias and ‘light bulb-shaped’ aneurysmal dilatations (fig. 4). It is generally held that breakdown of the blood-retinal barrier of the capillary endothelium causes plasma leakage into vessel walls and ultimately form dilatations and telangiectasias. Continued leakage into nearby retinal tissue results in the characteristic intraretinal and subretinal cholesterol exudates, hemorrhage and subretinal fluid.

More severely affected patients have an associated serous detachment of the neurosensory retina which can be localized or total. Visual compromise occurs as a consequence of accumulation of exudative material in the macular area, secondary

Fig. 1. Fundus image of the retinal periphery in a child with FEVR. The peripheral retina is avascular, fibrosis is apparent at the vascular-avascular junction, with associated vascular proliferation and vitreous organization.

Fig. 2. Anterior segment image of an eye with PFVS demonstrating prominent ciliary processes and retrolenticular persistent hyaloidal vasculature.

Fig. 3. Fundus image of the fundus of a child with CXLRS. A retinal schisis bulla is visible inferiorly, with a demarcation line running from below the optic nerve just beneath the fovea. Foveal schisis is present as well.

Fig. 4. Peripheral fundus findings in a child with Coats’ disease demonstrating the classic telangiectatic vascular changes and associated subretinal accumulation of lipid exudate.

macular changes (RPE atrophy or subfoveal fibrosis), exudative detachment involving the macula, and amblyopia.

If left untreated, eyes with Coats’ disease deteriorate. Gomez Morales reported that 64% of

untreated patients who were followed for 5 years developed total retinal detachments and 32% developed secondary glaucoma [11]. Not uncommonly, advanced unilateral Coats’ disease must be differentiated from retinoblastoma. Funduscopic

(microvascular dilatations), ultrasonographic, and radiographic (CT or MRI) findings (intraocular calcification) can help in the diagnosis when serous detachment or disorganization is a prominent feature.

Fluorescein angiography is helpful in juvenile Coats’ disease in not only diagnosis but also identifying treatable areas. Discrete ‘light bulb-shaped’ aneurysmal vessels hyperfluoresence early and leak late into the subretinal space. In addition, normal-appearing areas of nonperfused retina are more effectively identified for treatment.

All abnormal vasculature and areas of nonperfusion are treated with photocoagulation or cryotherapy ablation. Multiple treatment sessions are often needed to adequately treat the abnormal vasculature initially. Recurrences may occur long after successful treatment. Consequently, children with Coats’ disease should be followed every 6 months to monitor for additional ablative therapy as needed. In cases of partial retinal detachment, scleral buckle may be performed with external drainage of subretinal fluid to facilitate peripheral retinal ablation and reduce exudative activity. Recently, Sun et al. [12] showed elevated levels of VEGF in Coats’ disease, which rapidly reduced after injection of pegaptanib sodium. Thus, they suggested that VEGF-mediated angiogenesis could play a role in Coats’ disease. Venkatesh et al.

References

[13] reported the treatment of two older children with Coats’ disease with intravitreal bevacizumab injections (1.25 mg/0.05 ml). These data suggest that anti-VEGF treatment may be useful for the treatment of Coats’ disease. But long-term visual outcomes of the use of anti-VEGF agents in children are unknown.

Conclusion

Pediatric vitreoretinopathies are a diverse group of pathologies. Pitfalls of surgical intervention in these diseases arise in part from a failure to understand the relevant anatomy and biochemistry. Examination under anesthesia with careful attention to detail and fluorescein angiography or ultrasonography when appropriate, can provide the pediatric vitreoretinal surgeon with crucial information before surgery. Overly aggressive surgical techniques, failure to recognize anterior or posterior retinal folds, or inadvertent intraoperative traction on vitreoretinal adhesions may result in iatrogenic retinal breaks with catastrophic consequences. A careful and conservative surgical approach is therefore particularly important when performing surgery in eyes with pediatric vitreoretinopathies.

1 Hairston RJ, Maguire AM, Vitale S, et al: Morphometric analysis of pars plana development in humans. Retina 1997;17: 135–138.

2Trese MT, Capone A: Surgical approaches to infant and childhood retinal diseases: invasive methods; in Hart-

nett ME (ed): Pediatric Retina. Philadelphia, Lippincott, Williams & Wilkins, 2005.

3 Drenser KA: Anti-angiogenic therapy in the management of retinopathy of prematurity. Dev Ophthalmol 2009;44:

89–97.

4 Sonmez K, Drenser KA, Capone A Jr, et al: Vitreous levels of stromal cell-derived factor 1 and vascular endothelial growth factor in patients with retinopathy of prematurity. Ophthalmology 2008;115: 1065–1071.

5 Wilkinson-Berka JL, Babic S, De Gooyer T, et al: Inhibition of platelet-derived growth factor promotes pericyte loss and angiogenesis in ischemic retinopathy. Am J Pathol 2004;164:1263–1273.

6Trese MT, Capone A Jr: Familial exudative vitreoretinopathy; in Hartnett ME, Trese MT, Capone A Jr, et al (eds): Pediatric Retina. Philadelphia, Lippincott, Williams & Wilkins, 2005.

7Trese MT, Capone A Jr: Persistent fetal vasculature syndrome (persistent hyperplastic primary vitreous); in Hartnett ME, Trese MT, Capone A Jr, et al (eds) Pediatric Retina. Philadelphia, Lippincott, Williams & Wilkins, 2005.

8Sieving PA, MacDonald IM, Trese MT: Congenital X-linked retinoschisis; in Hartnett ME, Trese MT, Capone A Jr, et al (eds): Pediatric Retina. Philadelphia, Lippincott, Williams & Wilkins, 2005.

9 Prenner JL, Capone A Jr, Ciaccia S, et al: Congenital X-linked retinoschisis classification system. Retina 2006;26(suppl): 61–64.

10Recchia FM, Capone A Jr, Trese MT Coats’ disease; in Hartnett ME, Trese MT, Capone A Jr, et al (eds): Pediatric Retina. Philadelphia, Lippincott, Williams & Wilkins, 2005.

11 Gomez Morales A: Coats’ disease. Natural history and results of treatment. Am J Ophthalmol 1965;60:855–864.

12 Sun Y, Jain A, Moshfeghi DM: Elevated vascular endothelial growth factor levels in Coats’ disease: rapid response to pegaptanib sodium. Graefes Arch Clin Exp Ophthalmol 2007;245:1387–1388.

13 Venkatesh P, Mandal S, Garg S: Management of Coats’ disease with bevacizumab in 2 patients. Can J Ophthalmol 2008;43: 245–246.