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

20.2.9 Late Changes

Retinopathy of prematurity (ROP) is a lifelong illness. Even after conclusion of the acute phase of ROP, further ocular problems can arise in all pre-term patients, e.g., refractive errors that appear not only following coagulation treatment, but also in cases of pre-term patients with serious retinal changes. Further ocular changes are increased incidence of strabismus and nystagmus, as well as retinal pigment changes, retinal distortion, vitreoretinal degenerations, retinal folds, retinal holes, and secondary glaucoma. Because late retinal detachments are rare, yearly check-ups are not necessary. However, risk patients should of course be informed of the possibility of a retinal detachment and its accompanying symptoms.

Cats and Tan [12] found over an observation period of 6 – 10 years that 55 % of children with regressive ROP developed ocular changes. Other studies have shown in 59 % [10], or rather 25 % [35], of cases, that even without ROP during the acute phase, changes can occur that require ophthalmic examination. Each of the possible late developments are given in detail below.

20.2.9.1 Risk of Myopia

Children born on their due date have an incidence of myopia of between 6 % and 9 % [32]. Data found in the literature in reference to the development of myopia in prematurely born infants is not homogenous. In children with ROP, an incidence of myopia of 16 – 50 % is given [76, 78]. The Cryo-ROP Study [22] found that the incidence of myopia rose with the increase in the stage of severity of ROP. Pre-term babies with an ROP Stage 3 under the threshold for

coagulation had a 40 – 62 % risk of developing myopia [20, 22].

Several authors have discovered a difference in the incidence of myopia, dependent upon development of ROP in cases of prematurely born babies under the threshold criteria for treatment. In two studies [12, 76] it was found that myopia developed in 50 % or rather 29 % of premature babies with ROP and in 16 % or rather 10 % of premature babies without ROP. Other authors found only a very small [20] or no difference [11].

New studies have shown that predominantly children with ROP Stage 3 have a higher risk for myopia [82, 91]. The incidence of a refractive error in children with a retinopathy < Stage 3 was not higher than for children born on time [82].

The reason for the development of myopia in prematurely born children is the subject of frequent debate. Myopia is usually attributed to changes in the axial length of the eye or to changes in the anterior portion of the eye. In eyes with a regressive retinopathy, the axial length is longer than normal [13], normal [103] or shorter [32, 67]. Changes in the anterior portion of the eye have been accounted for through an enlarged lens [41], a flatter anterior chamber [45] or an increase in corneal curvature [32].

20.2.9.2 Visual Acuity

Several studies came to the conclusion that visual acuity in prematurely born infants is reduced until at least the 12th year of life when compared with their full-term counterparts [32, 47]. Some studies found a functional difference between eyes with and without ROP [28, 69]. Other studies however, did not find this [22]. A recently published study found that prematurely born children at 10 years of age had reduced visual acuities compared to full term children, even when children who had ROP and neurological disorders were excluded [65]. Only 53 % of pre-term babies reached a visual acuity 0.7 (at 3.5 years of age) in contrast to 93 % of full-term children (at 4 years of age). Thirty-four percent of prematurely born children without ROP had a visual acuity of < 0.7 in contrast to pre-term babies with ROP, whose visual acuity was under 0.7 in 61 % of cases [47]. The cause for the reduced visual acuity appears to be the incomplete development of the fovea [50].

20.2.9.3 Strabismus

The incidence of strabismus is higher in premature babies than in full-term babies [30a]. In cases of fullterm babies the incidence of strabismus is 5 – 7 %. The incidence of strabismus fluctuates between 14 % and 47 % for premature babies with ROP and

between 10 % and 20 % for premature babies without ROP [12, 78, 98]. In some comparative studies, a higher strabismus risk exists following the occurrence of ROP [98]; on the other hand, other studies found no difference [55, 91]. A pseudo-strabismus can occur through a macular ectopy caused by a peripheral distortion of the retina (Annette von Dro- ste-Hülshoff syndrome) [1].

20.2.9.4 Glaucoma

A common (25 – 30 %) late development of Stage 5 is that of secondary glaucoma, first described by Blodi [4]. The secondary glaucoma develops from retinal fibrovascular proliferation that shifts the lens anteriorly, thereby narrowing the anterior chamber. Medical therapy with miotics [4] should be tried before surgery (lensectomy or iridectomy). Angle closure glaucoma is alarmingly common among older, prematurely born patients. The enlarged lens causes a pupillary block. This form of glaucoma is, as a rule, well handled through an iridectomy or a trabeculectomy. Sometimes, however, removal of the lens is required [85].

20.2.9.5Regressive Late Changes in the Retina

In most eyes, where the premature retinopathy did not reach threshold for treatment, the changes spontaneously resolve without consequence. However, it is possible that regressive vitreoretinal changes remain, for example, blood vessel distortion with macular shift, retinal dragging (Fig. 20.2.11), retinal folds and chorioretinal scarring (Fig. 20.2.12), peripheral blood vessel changes, peripheral avascular areas, diffuse retinal pigment-epithelial lumping

(Fig. 20.2.12), and seldomly retinal holes [51, 52]. The frequency of the distinct regressive changes varies between 2.9 % and 12.3 % [23, 35, 81]. In addition, changes to the vitreoretinal traction can consequently give rise to retinal foramina and retinal detachments later in life [71, 102]. This type of retinal detachment typically occurs in puberty. A suc-

cessful treatment method for this type of detachment III 20 is a pars plana vitrectomy [57].

20.2.9.6 Differential Diagnosis

The differential diagnoses of ROP are dependent on the respective stage of ROP. The earlier stages are changes involving peripheral avascular retina, as in familial exudative vitreoretinopathy, incontinentia pigmenti (Bloch-Sulzberger syndrome) or Norrie disease. The later stages are associated with a leukocoria, such as congenital cataract, persistent hyperplastic primary vitreous (PHPV), retinoblastoma, ocular Toxocara infection, Coats’ disease, uveitis and vitreal hemorrhages.

20.2.9.7 Outlook

Through the improved neonatal medicine, more and more prematurely born children are surviving at even younger ages. These pre-term children have a higher risk for retinal changes. The Cryo-ROP Study clearly showed that, through optimal screening, premature babies who received coagulation treatment at particular stages achieved a visual improvement and the rate of blindness was reduced. Because this disease is very rare, it makes sense to provide care for these babies in specialized centers.

20.2.9.8 Future Treatment Possibilities

Currently, there is no clinically established medical therapy with a localized anti-angiogenetic effect to prevent ROP. The main area interest at the moment in research is in blocking VEGF (vascular endothelial growth factor), angiopoietin or PEDF (pigment epi-

20 III thelial derivated factor) (see Chapter 20.1).

In industrialized nations, ROP is still the cause of blindness in 6 – 20 % of children [38, 101]. In contrast to other diseases, it is currently possible to have all children pass through an effective screening protocol, and in this way catch the advanced retinal changes early enough for appropriate treatment. The time of this screening differs for the health system of each country, and is dependent on the stage of development of the neonatal system and socioeconomic conditions of the country. Through optimal care of pre-term babies, blindness can be mostly avoided.

However, the delayed effects of the regressing retinal changes call for intensive follow-up of patients. Unfortunately, despite treatment at the optimal moment, a retinal detachment can occur in a few eyes at an acute stage. It is important in these cases to search for further possible causes such as blood transfusions, increased oxygen variability, anemia, and fetofetal transfusion syndrome. The possibility of treatment of ROP through medication, thereby avoiding surgical procedures, would be desirable for the future.

In order to make ROP an avoidable illness, more research is necessary. Knowledge of the disease mechanism would allow us to avoid the factors causing the problem or it would allow for treatment of the factors in advance of the disease.

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P. Quiram, M. Lai, M. Trese

20 III

Core Messages

Eyes with previous laser ablation have improved anatomic and functional outcomes compared to eyes without previous peripheral ablation

Stage 4A retinopathy of prematurity (ROP) often progresses to Stage 4B/5, which has a poor visual prognosis. Stage 4A detachments

20.3.1Introduction: Preoperative Evaluation and Timing of Surgical Intervention

Children who require surgical intervention for retinal detachment secondary to retinopathy of prematurity (ROP) can be divided into two groups: those who have had peripheral ablation and those who have not. The ideal situation for a child who has achieved retinal detachment is to have had previous peripheral ablation (Fig. 20.3.1). If a child needs laser intervention, they will usually reach that point between 32 and 46 weeks postmenstrual age with the peak occurring somewhere between 35 and 37 weeks postmenstrual age based on the data from the Cryo-

should be repaired before progression to Stage 4B/5

The anatomy of an infant’s eyes poses unique surgical challenges in that the pars plana is not developed and strong vitreoretinal adhesions exist Preoperative evaluation by visual evoked potential (VEP) is typically performed to assess visual potential in eyes with Stage 5 ROP

therapy for Retinopathy of Prematurity Study and the Early Treatment for Retinopathy of Prematurity Study [4].

Vitreous surgery intervention becomes necessary when the eye progresses to Stage 4A ROP, where a macula-on retinal detachment is present. Stage 4A retinal detachment customarily begins at the ridge tissue between the avascular and vascularized retina (Fig. 20.3.2). Natural history data from the Cryotherapy for Retinopathy of Prematurity Study suggests that Stage 4A retinal detachment presenting at a postmenstrual age of less than 46 weeks tends to be progressive in a large percentage of eyes. Data accu-

Fig. 20.3.1. Fundus photo demonstrating laser ablation of avascular retina up to, but not including, the ridge

Fig. 20.3.2. Fundus photo demonstrating tractional retinal detachment at the ridge between vascular (left) and avascular retina (right)

mulated by Coats suggests that the peak incidence of retina detachment is at 41 weeks postmenstrual age [2]. There are several factors that have been identified that predict which infants will progress to Stage 4 retinopathy of prematurity. These factors include 6 clock hours of ridge elevation, 2 clock hours of plus disease, and the presence of vitreous haze. Vitreous organization can be a very significant indicator of an impending retinal detachment [6].

20.3.2 Eyes with Peripheral Ablation

Children requiring surgery for Stage 4A retinopathy of prematurity who underwent peripheral ablation are less likely to have vascularly active eyes, defined as plus disease and patent neovascular fronds. Surgery for Stage 4 detachments with previous peripheral retinal ablation is typically performed between 38 and 42 weeks postmenstrual age [1]. In eyes with active vascular proliferation and areas of untreated avascular retina, laser ablation is performed before surgery to decrease the risk of bleeding during vitreous surgery. In a long-term series with a 4-year fol- low-up, eyes with Stage 4B or 5 ROP with adequate peripheral ablation demonstrated a 76 % reattachment rate of the posterior pole and 72 % of patients had at least light perception [19]. In addition, 15 % of patients achieved a visual acuity of 20/300 or better.

The assessment of vascular activity is very important and can be managed by three potential mechanisms. First, at the child’s due date, 40 weeks postmenstrual age, endogenous TGF is produced that downregulates vascular endothelial growth factor [10, 20]. Second, if additional areas of avascular non-treated retina are present, additional laser may help return the eye to a vascularly quiet state. Finally, it may be possible to use pharmacologic agents, such as anti-VEGF agents, to control this vascular activity. At the time of preparation of this chapter, very little data is available for that mode of treatment.

20.3.3 Eyes Without Peripheral Ablation

Eyes that have not had peripheral ablation have a much lower anatomic and visual success rate. Many eyes that have not had peripheral ablation tend to progress to Stage 4B (macula-off) or Stage 5 (total) retinal detachment [3]. Furthermore, retinal detachment repair in eyes without adequate peripheral ablation results in a 50 % reattachment rate [16, 17]. In addition, in eyes that reattached, only 30 % had visual improvement. It is important when assessing the child preoperatively for retinal detachment to realize that the tempo of disease can be tempered by

the child’s race. Caucasian children tend to have a more aggressive retinopathy of prematurity and are more likely to progress to retinal detachment. Hispanic children within and outside the United States seem to have a more aggressive form of retinopathy of prematurity. In contrast, African Americans have a reduced chance of progressing to retinal detach-

ment [14]. ROP is a bilateral disease and 85 % of chil- III 20 dren will develop bilateral retinal detachment even

though one eye may precede the other [11]. We have also reported that if retinal detachment does not appear by 50 weeks postmenstrual age, it most likely will not occur.

20.3.4 Treatment of Retinal Detachment

20.3.4.1 Scleral Buckling

In the past, scleral buckling has been used for the treatment of non-rhegmatogenous retinal detachment of retinopathy of prematurity [5, 18]. With the advent of lens-sparing vitrectomy for retinopathy of prematurity, we have found that scleral buckling is rarely appropriate. Scleral buckling has many disadvantages in that it requires a second operation to segment the buckle to not inhibit eye growth. It induces a very large amount of myopia (up to 12 diopters) and very rarely has good vision been reported following buckling procedures for even 4A retinopathy of prematurity. Presently, scleral buckling is not recommended for Stage 4A retinopathy of prematurity, although placement of radial elements has been employed for peripheral 4A detachments.

20.3.4.2 Lens-Sparing Vitrectomy

Because the macula is uninvolved, patients with Stage 4A ROP who undergo successful retina reattachment can potentially have good visual acuity. If the native lens can be spared during retinal reattachment, the risk of amblyopia secondary to significant anisometropia can be minimized, further increasing the visual potential. Therefore, lens-sparing vitrectomy is the procedure of choice for Stage 4A ROP. Originally described by Maguire and Trese, this procedure can be performed when there is less than 6 clock hours of retina-lens touch [9].

With the development of current vitreous surgery instrumentation and the appreciation that vitrectomy can be performed through the pars plicata in very young children where the para plana is not developed, the pathologic process causing the retinal detachment can be directly accessed (Fig. 20.3.3). In our experience, two-port vitrectomy is advantageous, allowing us to manipulate the eye in the small

orbital space present in these children. The entry sites are chosen to maximize the surgical approach to the detached retina, and are verified by scleral depression to be free of retinal tissue. The sclerotomies are made in the pars plicata approximately one-half millimeter posterior to the limbus with the microvitreoretinal blade directed parallel to the

20 III visual axis to avoid lens injury (Fig. 20.3.3). We use a 19 gauge wide-angle high flow light pipe, 20 gauge vitreous cutter, and a 20 gauge infusion spatula to perform dissections. Although 25 gauge instrumentation theoretically has an advantage in that it is smaller, it is slow in removing formed vitreous and it is difficult to remove heavy proliferative tissue. In addition, manipulation of the three port 25 gauge instrumentation is more difficult with the small orbit and runs the risk of additional damage to the lens. The rigidity of the 20 gauge instrumentation allows better manipulation of the eye. The surgical goal is to free the ridge tissue from sheets of tissue that extend to the lens (Fig. 20.3.4), the ora serrata (Fig. 20.3.5), ridge to ridge (Fig. 20.3.6) and posteriorly to the area of the optic nerve stalk (Fig. 20.3.7). With all of these tractional forces removed, the reattachment rates are quite high (approximately 90 %).

Encouraging anatomic and functional outcomes have been achieved with lens-sparing vitrectomy. Three studies show an anatomic reattachment rate of

Fig. 20.3.4. Fundus photo demonstrating sheets of proliferation extending from the ridge anteriorly toward the lens

Fig. 20.3.3. Lens sparing vitrectomy entry site. Illustration of angle of entry through the pars plicata and area of influence in which lens sparing vitrectomy can be performed

Fig. 20.3.6. Fundus photo demonstrating proliferative stalk tissue extending from the optic nerve anteriorly to intersect with ridge to ridge proliferative tissue

Fig. 20.3.7. Fundus photo demonstrating sheet of proliferation extending from ridge to ridge creating a funnel-shaped detachment

approximately 90 % in patients with Stage 4A ROP undergoing lens-sparing vitrectomy. One study by Capone and Trese showed that 90 % of eyes had retinal reattachment and fixation behavior at their last visit, with a mean follow-up period of 12 months [1]. Hubbard and colleagues reported similar anatomic success, with 84 % of the eyes showing complete retinal reattachment after a median follow-up period of 13 months [8]. In another long-term study, patients with formal visual acuity testing between ages 1.8 and 6.3 years of age had a mean visual acuity of 20/58 (range 20/200 to 20/20), with 48 % of the eyes achieving visual acuities of 20/40 or better [13].

20.3.4.3Management of Stage 4B Retinopathy of Prematurity

Although peripheral ablation can be effective in stopping the progression of threshold ROP, retinal detachments can occur despite appropriate aggressive treatment. Even with close observation and treatment, some eyes will progress to Stage 4B. Compared to Stage 4A, Stage 4B retinal detachments have a much different prognosis with 72 % achieving partial or complete retinal reattachment. Visually, 15 % of eyes achieve 20/60 to 20/300 vision, 30 % achieve 20/60 to 20/800 vision, and 48 % achieve 20/60 to 20/ 1900 vision, which is what the authors feel is ambulatory vision. In a study by Droste and Trese, 72 % achieved 20/60 to light perception vision, but 28 % of eyes resulted in no light perception vision. In this study, the majority of eyes were treated with cryotherapy, which can increase effusive detachment and result in worse visual results.

Tractional 4B detachments can present in multiple conformations with asymmetric traction of posteri-

20.3.4.4Management of Stage 5 Retinopathy of Prematurity

Stage 5 retinopathy of prematurity is hopefully uncommon in hospitals that implement an appropriate screening schedule. However, Stage 5 eyes still appear, even today, particularly in developing countries. These eyes customarily have large amounts of subretinal blood and may or may not have had additional peripheral ablation. Previous studies suggest that some of the eyes may not have light perception preoperatively. To assess light perception, an awake visual evoked potential (VEP) may be used to assess the eye’s light perception status; however, false negative responses are possible. Most Stage 5 retinal detachments fall into one of three configurations: an open anterior and posterior funnel, open anterior and closed posterior funnel, and closed anterior and posterior funnel [16]. Less commonly, a closed anterior and open posterior funnel may be present. These configurations are somewhat predictive in terms of anatomic results in that a closed-closed funnel has a worse prognosis than an open-open funnel.

The surgical approach in Stage 5 ROP is typically lensectomy followed by vitrectomy and membrane peeling, as described above. Techniques that take advantage of vitreous anatomy such as bimanual dissection and lamellar dissection of vitreous sheets can be very helpful in removal of layers of vitreous in an unusual retinal anatomy. Viscoelastic dissection can be used to open the funnel under low pressure and flatten retinal folds and compartmentalize