Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

Symptoms of decreased visual acuity, often attributable to macular fold or retinal detachment, may occur in infancy and through adolescence.

Clinical severity is highly variable. Alsheikheh and coworkers recently presented two consanguine families with seven members affected at different stages (Fig. 22.5.4) [1]. While patients 5 and 6 show

22 III subclinical disease, patients 2 and 3 present with retinal exudates indicating progression of the disease.

The clinical signs always include abrupt termination of the temporal retinal vasculature with scall-

oped borders (Fig. 22.5.5a, c). Fluorescein angiography confirms formation of a vascular-avascular border of variable distance from the ora serrata (Fig. 22.5.5b). The vessels just posterior to this zone may be tubularly dilated and straightened. At the avascular border, vessels end in arteriovenous anastomoses, which may leak fluorescein and from which neovascularization may develop. Vitreous hemorrhage is rare and signals the end stage of the natural course of the disease by retinal detachment and phthisis.

c

Fig. 22.5.5a, b. FEVR stage I. Peripheral avascular zone in an asymptomatic family member. Clinical appearance (a) and during fluorescence angiography (b) demonstrating arteriovenous anastomoses with leakage of fluorescein at the border of vascularization. c FEVR stage I. Peripheral avascular zone with obliterated retinal vessels, few subretinal exudates. d FEVR stage I. Dragging of the optic disk and retinal vessels toward the temporal periphery.

e FEVR stage II B. Peripheral neovascularization with small retinal bleeding and massive subretinal exudates. Peripheral vessels appear dilated.

Fig. 22.5.5. f Falciform retinal detachment with macular involvement. Toward the periphery, massive subretinal exudates. g FEVR stage IV B. Vitreous veils obscuring fundus view. Retina attached. h FEVR

stage V. Total retinal detachment, lens with pigment adhesion

III 22

f

Just anterior to the avascular border, a fibrovascular mass (cyclic membrane) may develop with prominent, large-caliber arterial and venous feeders associated with marked retinal exudates. Exudates have been found in 9 – 22 % of cases [2]. This mass may encompass the ciliary body and peripheral lens capsule.

Then, dragging of the macula, of the disk, and of retinal vessels can be seen in up to 50 % of gene carriers. Tractional forces can result in retinal folds extending from the temporal quadrant through the macula or in tractional retinal detachment. Rhegmatogenous retinal detachment can be masked by epiretinal membranes covering up the retinal round hole.

Other clinical signs include myopia, peripheral white-with-pressure and white-without-pressure (Fig. 22.5.5c), peripheral cystoid degeneration [11, 14, 35], peripheral vitreous snowflakes [6, 11, 37], and condensed vitreous bands. Rarely, areas of coarse pigmentary changes or retinoschisis [11] are found.

In more advanced stages the subretinal exudates increase in size (Fig. 22.5.5e).

Advanced traction is followed by retinal detachment starting from the temporal periphery. Whereas visual function is frequently only minimally restricted when the macula is attached, a significant visual loss is associated with macular detachment. The typical form of the detachment is a falciform tractional detachment starting from the temporal periphery potentially involving the macula (Fig. 22.5.5f).

With increasing severity of vitreous strains a combined tractional-rhegmatogenous form with complete detachment and severe membrane formation can occur (Fig. 22.5.5g). Although there is a tractional component to the detachment, retinal holes may coexist, leading to a combined tractional-rhegmato- genous form of the detachment.

Nouhuys reports FEVR as a common cause of juvenile rhegmatogenous retinal detachment [39]. While falciform folds and total retinal detachments with retrolental organizations occur mostly during the 1st decade of life, rhegmatogenous retinal detachment was mostly observed during the 2nd and 3rd decades of life.

The anterior segment structures are usually uninvolved. However, in end stages of severely affected

eyes with chronic retinal detachment, a cataract, band keratopathy, and glaucoma can be observed (Fig. 22.5.5h), all of which can be aggravated by previous surgical procedures.

There are two major classification systems according to the angiographic and funduscopic findings:

22 III The Miyakabo and Hashimoto classification [24], according to the angiographic appearance, is as follows:

Type I: Avascular zone less than two disk diameters in width from the ora serrata, focal arteriovenous shunts, no neovascularization

Type II: Avascular zone greater than two diameters and more arteriovenous shunts

Type III: V-shaped notch in the avascular zone between the superior and inferior temporal arcades

Type IV: Additionally neovascularization including sea fans

Type V: Cicatricial disease

Miyakabo’s classification focuses on early retinal vasculature changes. Fibrovascular proliferations of advanced FEVR and its complications are better described by Pendergast [28].

Pendergast and Trese [28] classify FEVR into five clinical stages as follows (Fig. 22.5.6a, b):

Pendergast’s staging may be helpful for treatment considerations as all stages with exudates require treatment.

It is important to note that eyes without retinal exudates are only rarely affected by progressive disease.

Retinal folds manifesting in infancy or childhood may progress rapidly, slowly, or remain stable, depending on the presence of vascular leakage. Falciform retinal detachment unaccompanied by retinal exudation is usually stable.

Visual loss after the 2nd or 3rd decade of life is rare and usually relates to the development of rhegmatogenous retinal detachment or late peripheral exudation. Occasionally a fibrous macular pucker can cause traction and visual loss [13].

In a series of 170 eyes from 16 pedigrees [40], retinal exudates were found in 9 %, retinal neovascularization in 11 %, a peripheral fibrovascular mass in 6 %, macular ectopia in 49 %, retinal fold in 8 %, retinal detachment in 21 % and vitreous hemorrhage in 2 %.

22.5.5 Differential Diagnosis

The differential diagnosis of FEVR includes a variety of peripheral vascular disease in childhood and differs as to the stage of the disease (Table 22.5.1, Fig. 22.5.7).

22.5 Familial Exudative Vitreoretinopathy

Table 22.5.1. Differential diagnosis

FEVR, familial exudative vitreoretinopathy; ROP, retinopathy of prematurity; IP, incontinentia pigmenti; PHPV, persistent fetal vitreous; f, female; m, male; AD, autosomal dominant; X-R, X-linked recessive; X-D, X-linked dominant.

Fig. 22.5.7. Differential diagnosis

575

III 22

If a systemic association and premature birth are excluded, ROP, incontinentia pigmenti and Norrie’s disease can be excluded with great likelihood.

This differentiation can be supplemented by other characteristics. Incontinentia pigmenti affects only female newborns. Norrie’s disease demonstrates a primary retinal neuronal affection which can be shown by means of electrophysiology. Furthermore,

subretinal exudates are not typically seen in Norrie’s disease [7].

In contrast to ROP, changes in FEVR follow a different time course. In ROP there is the tendency to either progress to cicatricial stages or to abort and vascularize the periphery, whereas the avascular zone in FEVR and eventual retinal exudation remains a permanent feature throughout life.

Where there is peripheral vascular sheathing in the absence of a peripheral avascular zone and the temporal dragging of the disk or vasculature, Eales disease should be considered.

Coats’ disease may resemble FEVR stages with subretinal deposits; however, it does not usually exhibit the vascular dragging or falciform detachment.

22 III If the peripheral temporal traction in FEVR increases anterior-posteriorly, the clinical picture of a persistent fetal vitreous (PHPV) can be resembled. PHPV, however, is usually unilateral and the changes are predominantly in the lower part of the retina. Retinal folds in PHPV occur in conjunction with remnants of the hyaloid vascular system and may exhibit retinal dysplasia. No such association is found in FEVR.

Whereas PHPV results from abnormal development of the tunica vasculosa lentis and vitreous in the 7th or 8th weeks of gestation, the pathogenesis of FEVR appears to be a consequence of disturbed development of the retinal vasculature in the last months of gestation.

22.5.6Treatment Recommendations Including Follow-up

Essentials

Gene carriers suffering no visual impairment should be observed for progression of the disease into the 3rd decade of life

There is no evidence for a prophylactic treatment of the avascular periphery

Photocoagulation or cryotherapy are obligatory to regress peripheral subretinal exudates through destruction of abnormal vessels Retinotomies must be avoided as they are likely to result in proliferative vitreoretinopathy (PVR)

As discussed above a rapid progression of the disease is uncommon unless active leakage is involved.

The majority of gene carriers suffer no visual impairment and the condition is only diagnosed by chance. Out of this group, adult patients in which a peripheral avascular zone was found without other changes do not require treatment.

Similarly temporal dragging of the disk and the macula without detachment or peripheral traction may explain a reduction in macular function but should not be treated.

Children with symptomatic siblings, themselves exhibiting stage I or II disease, should be monitored carefully. Usually observation without treatment is justified in the absence of prominent exudates.

The effect of laser photocoagulation or cryotherapy in neonatal disease has not been investigated. Ablation of the avascular retinal zone in children as young as 4 years of age did not stimulate retinal vessels to advance beyond the avascular border [11].

Absolute indications for laser treatment include subretinal exudates, funduscopically visible peripheral neovascularization (Fig. 22.5.1b), and abnormal peripheral vessels with subretinal exudates (Fig. 22.5.1a).

Relative indications for treatment include treatments of fellow eyes which exhibit fewer severe peripheral changes, and stable falciform folds.

22.5.6.1General Recommendations for Laser Photocoagulation in FEVR

Essentials

Argon green or krypton red can be used according to the surgeon’s preference

Spot size and exposure time will differ according to the respective clinical appearance, usually 200 – 350 mW, 200 μm, 200 – 1,000 ms

Subretinal exudates can only be addressed by direct laser coagulation of the leaky vessels

Large subretinal exudates may take several months to regress. Six to 8 weeks after completion of the laser treatment, the treated area should be reexamined for persistence of neovascularization (Fig. 22.5.1c)

Re-treatment is indicated in case of insufficient regression of neovascularization, persistent pathological peripheral vessels, or persistent subretinal deposits

There is no rationale for panretinal photocoagulation as depicted in Fig. 22.5.1d

If the retinal periphery cannot be inspected (e.g., media opacities, epiretinal membranes, or vitreous hemorrhage), it is necessary to perform a vitrectomy and decide intraoperatively on laser treatment (Fig. 22.5.8a–c)

Similar to laser photocoagulation, cryotherapy does induce regression of neovascularization, as evidenced by permanent replacement by a fibrous scar [40]. However, transscleral cryoapplication may be ineffective due to thick subretinal exudates. One may then consider endocryocoagulation. It is mandatory to freeze the abnormal vessels two to three times successively to reliably achieve tissue destruction.

Follow-up examinations are recommended since progression is reported in spite of laser coagulation: In a series of 15 eyes with active extraretinal vascularization and an attached retina, it was reported that

a

b

c

Fig. 22.5.8. a Vitrectomy of peripheral vitreous strands under indentation. Vitreous membranes are very adherent and cannot be peeled, but have to be sharply dissected. Subretinal exudates and abnormally dilated overlaying vessels are seen. b After removal of peripheral epiretinal membranes, a retinal round hole (circle) was detected associated with rhegmatogenous retinal detachment. c Fundus view after extensive peripheral photocoagulation. Remnants of vitreous strands can be seen after vitrectomy and peeling

8 (53 %) of 15 eyes treated with peripheral laser required no further treatment [28]. Seven (47 %) out of 15 eyes progressed to retinal detachment requiring vitreoretinal surgery.

A surgical approach becomes necessary if vitreous traction causes detachment involving the macula or if persistent vitreous hemorrhage prevents necessary laser treatment of peripheral neovascularization.

Vitreous hemorrhage is rare, but indicates a high risk of retinal detachment and phthisis in the end

stage of the disease. Early vitrectomy should be con- III 22 sidered. This allows for release of vitreous traction as

well as treatment of the neovascularization triggering the hemorrhage.

22.5.6.2 Indications for Vitrectomy in FEVR

Essentials

Progressive falciform detachment

Progressing peripheral traction detachment threatening the macula

Recent visual loss due to macular-off detachment

Persistent vitreous hemorrhage (> 8 weeks) or recent hemorrhage if retinal situation is unclear

Vitreous onion-skin-like veils interfering with central vision

Rhegmatogenous retinal detachment, when the retinal hole is obscured by peripheral epiretinal fibrosis

PVR re-detachment

So far, surgical management of the complications has produced some encouraging results [12, 16, 23, 28, 34, 40].

Pars plana vitrectomy has been successfully applied in traction macular detachments, even in young patients [28]. In patients with vitreous hemorrhage and/or tractional retinal detachment a reattachment rate of 75 % was achieved [34].

Nouhuys [38] describes the expected visual acuity after vitrectomy to be better than 20/80 in 72 % of cases (Fig. 22.5.9). If an increase or at least stabilization of the initial visual acuity is considered a success, 11 out of 15 reported cases were successful in his series.

22.5.6.3General Recommendations for Vitrectomy in FEVR

Essentials

A three-port approach is generally used The lens must be removed in children to be able to address the most peripheral retinal changes. (This is in contrast to [23])

Fig. 22.5.10. Stable retinal fold after scleral buckle surgery (encircling band) and reduction of the peripheral traction

Vitreous veils of FEVR are structured in an onion-skin-like fashion, parchment-like consistency and there is little retinal traction. Such vitreous veils cannot be peeled off the retina but must be cut from the retina Additional buckling procedures (encircling band) may be helpful in releasing peripheral traction (Fig. 22.5.10)

Retinotomies should be avoided, since blood ocular barrier breakdown is typical and associated with a high risk of PVR (see below)

Usually no vitreous substitute other than buffered saline solution is required. In cases with increased risk of PVR (e.g., in case of redetachment or large retinal holes) or in eyes with aqueous insufficiency (cyclitic membrane), silicone oil is needed

As discussed earlier in this chapter, there is considerable recurrence of vitreous membranes forming an onion-skin-like pattern. Further, the role of inflammatory cells, which have been found in surgically removed membranes (Fig. 22.5.3f), is unknown.

It is an open question whether the recurrent greaseproof-paper-like vitreous membranes can be prevented by internal limiting membrane (ILM) peeling. However, these specific membranes seem to be anchored in or sprout deep from the retina. In this case ILM peeling would not be able to prevent regrowth of the membrane and could potentially even damage the retinal structure.

In tractional detachments, scleral buckling might be helpful in releasing some of the traction without performing a retinotomy (Figs. 22.5.10 – 22.5.12). Pendergast described an attachment rate of 62 %, with 10 (35 %) eyes achieving vision of 20/100 or better after pars plana vitrectomy and/or scleral buckling [28].

Buckle surgery or silicone tamponade alone [22] does not improve the vascular pathology and thus has to be supplemented by photocoagulation of peripheral neovascularization or abnormal vessels triggering the disease process [12].

Falciform folds and falciform retinal detachments are unspecific but common features of advanced FEVR. In the treatment, special considerations should be respected.

22.5.6.4Surgical Approach to Falciform Detachment in FEVR (Figs. 22.5.11, 22.5.12)

Essentials

Treatment of the falciform detachment involving the macular area causing visual deterioration should be not be attempted, since visual improvement is unlikely

Relaxing retinotomies lead to formation of PVR membranes, PVR development and progression to re-detachment and potential loss of remaining vision

Vitrectomy is performed to release peripheral vitreous traction and can be supported by an encircling band

Stabilization is a more realistic aim and is to be addressed by occlusion of abnormal retinal vessels (Fig. 22.5.11e)

Patients should be followed up for regression of subretinal fluid and retinal reattachment every 3 – 6 months during the first

2 years after surgery

Ambulatory vision can improve despite persistent falciform fold, when subretinal exudates of the posterior retina are absorbed (Fig. 22.5.12c)

22.5 Familial Exudative Vitreoretinopathy 579

Although advanced stages of FEVR seem difficult to treat and success has been limited, it still is worthwhile trying if only to delay blindness. We report here on a girl who first reported to the clinic at age of 5 years with a severe visual loss after non-resolv- ing vitreous bleeding of her „only eye“ (Fig. 22.5.3a). She had a history of retinal detachment at an earlier

age, but vision was reported to be better than 20/40 III 22 before the bleeding. After vitrectomy, vision im-

proved up to 20/40 again, but deteriorated due to rebleeding and persistent neovascularization and subretinal exudates. We were unable to destroy peripheral leaking retinal vessels with the lens in place. Thus, 3 months after the initial vitrectomy we decided to remove the still clear lens and repeat coagulation of the now more readily accessible peripheral vessels. Figure 22.5.3b and c demonstrate the resection of tight vitreous strands. The retinal surface was covered with tight membranes (Fig. 22.5.3d I, II), which inserted near the vessel arcades and in the periphery. In the macular area the membranes formed a pseudohole. Membranes were carefully dissected (Fig. 22.5.3e, g). Without the need for a permanent tamponade the situation remained stable thereafter with a corrected visual acuity of 20/40.

22 III

c

Fig. 22.5.12. a OD: VA 20/40, peripheral photocoagulation, stable for several years.

b OS: VA 20/800, stage IVA, falciform detachment involving the macula. c OS: VA 20/400, after encircling band and vitrectomy. Stable situation, falciform fold still present

22.5.7Treatment Options Under Investigation

In contrast to several other vascular abnormalities resulting in increased vascular leakage, there are no current clinical trials on pharmacological treatment options. As indicated for the prophylactic laser treatment there is no evidence that the disease progress could be stopped. If the high rate of stable disease and the small risk of relentless progression are considered, it is unlikely that clinical trials will be initiated in the field and the necessity of a pathophysiology based treatment approach remains questionable.

Nevertheless, there could be a potential benefit from anti-inflammatory drugs not only by stabilizing the retinal vasculature and potentially reducing leakage, but also by regressing and preventing the perivascular inflammatory infiltrates, which are also seen in the vitreous membranes in histological examination. Still the benefit of such drugs in preventing regrowth of vitreous strains remains to be elucidated.

As the pathological mechanisms are still being investigated in more detail, to date no approaches have been reported to develop specific antibodies targeting Norrin or Fz4 or to selectively inhibit sub-

sets of receptors and ligands in the Wnt/Fz signaling cascades.

Acknowledgements. Figure 22.5.4 was generously provided by Drs. A. Alsheikheh, W. Lieb, and F. Grehn, Department of Ophthalmology, University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg.

This chapter is devoted to the memory of Prof. Klaus Heimann, who has treated many FEVR patients and with his experience has greatly improved today’s surgical approach. Most of the figures in this chapter are derived from Prof. Heimann’s clinical collection.

References

1.Alsheikheh A, Lieb W, Grehn F (2004) Criswick-Schepens- Syndrom – Familiäre exsudative Vitreoretinopathie. Ophthalmologe 101:914 – 918

2.Benson WE (1995) Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc 93:473 – 521

3.Boldrey EE, Egbert P, Gass JD, Friberg T (1985) The histopathology of familial exudative vitreoretinopathy: a report of two cases. Arch Ophthalmol 103:238 – 241

4.Bopp S, Wagner T, Laqua H (1989) Keine Störung der arachidonsäureinduzierten Thrombozytenaggregation bei familiar exsudativer Vitreoretinopathie. Klin Monatsbl Augenheilkd 194:13 – 15

5.Brockhurst RJ, Albert DM (1981) Pathologic findings in