Ординатура / Офтальмология / Английские материалы / Retinal and Vitreoretinal Diseases and Surgery_Boyd, Cortez, Sabates_2010

78.Ramchandran RS, Fekrat S, Stinnett SS, Jaffe GJ. Fluocinolone acetonide sustained drug delivery device for chronic central retinal vein occlusion: 12-month results. Am J Ophthalmol 2008;146(2):285-91.

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82.Wingate RJ, Beaumont PE. Intravitreal triamcinolone and elevated intraocular pressure. Aust N Z J Ophthalmol 1999;27(6):431-2.

83.Gewaily D, Greenberg PB. Intravitreal steroids versus observation for macular edema secondary to central retinal vein occlusion. Cochrane Database Syst Rev 2009(1):CD007324.

84.McAllister IL, Constable IJ. Laser-induced chorioretinal venous anastomosis for treatment of nonischemic central retinal vein occlusion. Arch Ophthalmol 1995;113(4):456-62.

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Retinopathy of prematurity (ROP) is a vitreoretinal proliferative disease in premature infants that may cause severe or complete visual impairment, and it is a major cause of reversible blindness worldwide. The two largest multicenter cohort studies report similar incidence of the disease, CRY-ROP Study of 65.8%, and ETROP Study of 68% among infants <1251 g, reassuring it remains a common important problem in the neonatal intensive care unit.1

The fundamental process underlying the development of ROP is incomplete vascularization of the retina and the ophthalmoscopic findings derive from this abnormal development. ROP is characterized by the proliferation of fibrovascular tissue at the border of vascular and avascular retina, giving rise to the various stages of ROP2 (Figure 1).

Figure 1: This picture shows a dense white membrane emerging from the optic disc with a retina fold on the macula area as a secuelae of an ROP stage IV b.

Multicenter trials have defined the manner in which ROP is screened, monitored and treated.

The Multicentre Trial of Cryotherapy for RetinopathyofPrematurity(CRYO-ROP)Study for the first time established the beneficial effect of cryotherapy of peripheral avascular retina on eyes with threshold ROP. Threshold ROP is defined as 5 contiguous or 8 cumulative clock hours of stage 3 ROP in zone I or II, in the presence of plus disease (dilated and tortuous posterior pole vessels). This has demonstrated to significantly reduce by half the progression to an unfavorable outcome such as macular dragging, retinal detachment or retrolental cicatrizal formation. Of the 9751 infants enrolled at 23 centers in the USA of birth weight less than 1251g, 291 that progressed to threshold disease participated and were randomly assigned to have either cryotherapy in one eye or no cryotherapy in the fellow eye.3

Cryotherapy was shown to significantly reduce both functional and structural primary outcomes of threshold ROP in treated versus control eyes throughout the follow-up (Figure 2). Unfavorable structural outcome, defined as posterior retinal detachment, retinal fold involving the macula or retrolental tissue, was proven to be reduced to 45.8% at 12 months. Consistent with CRYO-ROP previous reports, the beneficial effects of structural outcome persisted long-term, and at 15 year followup 30% of treated eyes had unfavorable outcome versus 51% of control eyes.4

Figure 2: Extensive Cryoablation in Peripheral Retina.

Visual function for near and distance acuity was assessed monocularly, and the attempted procedure showed that treated eyes had significantly better visual acuity than control. For the 5 1⁄2 year outcome visual acuity showed a reduction in unfavorable outcomes of 47.1% in treated versus 61.7% in control eyes.5 Unfavorable visual acuity outcomes at 15 years was found in 44.7% of treated versus 64.3% of control eyes.

Treatment at threshold in the CRYO-ROP resulted in approximately a 50% reduction in the rate of retinal detachment. CRYO-ROP showed that 44.4% of eyes with history of severe ROP had a visual acuity at 10 years of age of 20/200 or worse, and of those only

45.5% had visual acuity 20/40 or better. With the hope of improving the rate of unfavorable outcome, the indications for treatment were questioned and the need to identify earlier treatment criteria for the eyes at highest risk for developing threshold ROP and/or unfavorable visual or structural outcome in the absence of treatment was discussed.

Data of 828 infants with birth weight less than 1251g in 26 participating center in the USA were collected for the Early Treatment for Retinopathy of Prematurity (ETROP) study from 2000 to 2002, designed to detect if some eyes with ROP of less than threshold could benefit from retinal ablation therapy. In the study infants were randomized to early peripheral retinal ablation or standard treatment (follow-up until regression or treatment at threshold disease) if they developed prethreshold ROP, which was defined as any ROP in zone I that was less than threshold, or in zone II stage 2 with plus disease and stage 3 without plus disease, or zone II stage 3 with plus disease but fewer than threshold. A risk analysis program based on natural history data from CRYO-ROP study (RMROP2) was used; if the risk progression to unfavorable outcome in absence of treatment was <15%, the eye was termed “high-risk pre-threshold”, and randomization occurred. Eyes with >15% risk according to RM-ROP2 were termed “low-risk pre-threshold” and followed.6

Functional outcome was measured monocularly with as used in CRYO-ROP, and showed a reduction in unfavorable outcomes with earlier treatment, from 19.8% to 14.3%. Structural examinations were performed at 6 and9months,withunfavorableresultsreduced from 15.6% in conventionally treated to 9.0% in high-risk pre-threshold treated eyes, at 9 months, with outcomes stable at the 2 year follow-up.

The results of this study showed it was possible to identify characteristics of ROP that predict high-risk eyes for retinal detachment and blindness (Figure 3), therefore most likely to benefit from early peripheral retinal ablation, while minimizing treatment of pre-threshold eyes likely to show spontaneous regression of

ROP. Ocular complications rates were similar inbothgroups,whereassystemiccomplications were higher following treatment at high-risk pre-threshold, attributed to receiving retinal ablative therapy at an earlier postmenstrual age.

Therefore, with the ETROP it was established the beneficial effect of treatment at high-risk pre-threshold ROP on structural outcome and visual acuity outcome provides further support for retinal ablative therapy for eyes with:

•Type I ROP defined as: zone I, any stage with plus disease; zone I, stage 3 ROP without plus disease; or zone II, stages 2 or 3 with plus disease.

The analysis supported a “wait and watch” with continued serial examinations, as opposed to peripheral retinal ablation, (unless eyes progress to type I ROP or threshold), for eyes with:

•Type II ROP defined as: zone I, stage 1 and 2 without plus disease, or zone II, stage 3 without plus disease.7

Screening

Babies born at or before 32 weeks gestational age, or weighing 1500g or less, or weighing between 1500 and 2000g requiring supplemental oxygen, or with unstable course and who are thought to be at high risk, should be screened for ROP by an ophthalmologist with expertise in this matter. Clinical studies suggest screening should begin 4-6 weeks post-natal age or within the 31st or 33rd week of postconceptional or postmenstrual age (whichever is later) to detect the onset of threshold disease. Indirect ophthalmoscopy with a 28 or 20 D lens under wide pupil dilation is the gold standard for screening. Subsequent review should be at 1-2-weekly intervals, depending on severity, until retinal vascularization reaches zone 3 or until 45 weeks of postmenstrual age.

Screening with digital imaging with wide angle retinal fundus camera (RetCam) is now used as an alternative method, as shown in the photographic screening for ROP study (photo-ROP) where remote interpretation of digital fundus images is a useful adjunct to conventional bedside ROP screening by indirect ophthalmoscopy, with an excellent diagnostic sensitivity when image quality is high.8

Laser Treatment

In spite of new advances in the understanding of the treatment of ROP, the basic tools available have not changed dramatically. Since 1980`s retinal ablation therapy anterior to the fibrovascular ridge has been proven to be successful method of treating active ROP.

Cryotherapy was first used as an effective treatment for preventing progression of ROP. However, cryotherapy may be associated with significant systemic an ocular complications, such as postoperative lid edema hemorrhage, laceration and chemosis of conjunctiva, myopia and preretinal and vitreous hemorrhage. The need for conjunctival dissection, the technical difficulty of placement of the cryo-probe for

posterior zone 2 or 1 and the nitrogen tank not readily portable, has made most ophthalmologists to use laser therapy rather than retinal cryoablation.9 When used, cryotherapy is applied in contiguous single spots to the avascular retina in 360 degrees anterior to the ridge until whitening of the retina is observed. Today, indications for cryopexy instead of laser in ROP include poor fundus visibility, lack of availability of laser and lack of expertise in laser of the treating ophthalmologist.

The CRYO-ROP trial showed that ablation of peripheral avascular retina with cryotherapy was of benefit in threshold ROP. Laser photocoagulation of avascular retina has replaced cryotherapy as the established treatment for ROP in most centers for various reasons. Although no randomized trial has been conducted on the scale of the CRYO-ROP study, smaller studies have shown laser treatment to be at least as effective as cryotherapy in treatment of active ROP. NagE, Connelly et al published a 10-year follow-up randomized trial comparing laser photocoagulation with cryotherapy for threshold ROP. Outcomes showed that compared with cryotherapy, eyes treated with laser photocoagulation were 5.2 times more likely to have a 20/50 or better BCVA, and eyes treated with cryotherapy were 7.2 time more likely to develop retinal dragging compared to laser treatment. This 10-year follow-up is the largest of its kind and shows the superiority of laser, in better structural and functional outcome, over cryotherapy.10

Laser photocoagulation with confluent or near confluent application of burns using indirect ophthalmoscopy has gained wide acceptance and is the gold standard for ablation of the avascular retina in ROP. Indirect

ophthalmoscopic laser is considered to be technically easier, induces less inflammation and stress on the neonate, and to be at least equivalent to cryotherapy in terms of outcome.11

Laser treatment is applied to the avascular retina immediately anterior to the ridge of extraretinal fibrovascular proliferation and extending to the ora serrata for 360 degrees in all cases (Figure 4 A-B). A moderately intense gray-white burn is the desired target intensity, and often ranges from a power of 150mW to 400mW and duration of 0.2 to 0.3 seconds. Focus on retina is essential to decrease the risk of laser absorption by other tissues rather than retina. The number and density of laser burns required for a complete treatment has remained controversial and can have a profound effect on ability to halt progression. Many reports have described burn spacing placed 0.5-1 burn width apart (near confluent), with some describing patterns of less than or equal to one-half burn widths (scatter laser pattern). Less dense laser treatment or “skip areas” may lead to higher rates of treatment failure and need for retreatment. As comfort increased with these techniques, a trend towards more dense treatment has been observed. Recent reports have suggested a more complete destruction of the avascular retina with continuous laser photoablation show improved results. Banach et al compared the outcome in two consecutive groups of patients treated with two different laser photocoagulation patterns, dense versus less dense. The rate of progression in the near confluent laser treatment group was only 3.6% overall compared to 29% in the less dense pattern12, concluding a dense pattern may reduce the rate of progression and the rate of re-treatment of the disease.13

Figure 4 A-B: A) Indirect Argon laser treatment in retinopahty of prematurity. B) Laser Application spots in Peripheral Area of Retina. The goal of this treatment is to destroy the retina that is deprived of retinal vessels. This helps to shrink the new vessels and prevents the formation of dense scars that usually follow.

Recent studies show the average number of spots applied has increased by 265% to 2163 applications per eye, which reflects the changing philosophy towards increased laser burn density in the avascular retina as the accepted burn pattern approaches near confluence.14

Tennant and Macnamara report the mean number of burns range from approximately 950 for zone II and over 2000 for zone I disease15, and vary considerably depending on the posterior extent of the ridge, but more than the number of burns is the adequate coverage. There is no direct correlation between covered area and number of laser burns

B

applied as the size of the laser burn varies

depending on the distance of the aspheric lens from the eye, dioptric power of lens, burn intensity and duration.

It can be performed under general anesthesia with intubation or under intravenous sedation or with local anesthesia, depending on surgeon`s preference and infant`s medical condition. Treatment is carried out using an indirect laser system with a 28 D or 20 D

hand held aspheric lens, under wide pupil dilation using sclera depression after topical anesthesia applied to the eye and placement of a lid speculum. The most common complication is “skip areas” leading to continued abnormalvascularitywithprogressiontoretinal detachment. Retreatment may be necessary in eyes with persistent plus disease, active stage 3 disease and localized tractional detachment, in which a scleral buckling procedure can be performed in the latter. When retreatment is necessary, it is applied confluently to previously untreated areas which show continued activity, and applying laser in vascular retina over the fibrovascular ridge is useful.16 Despite timely and thorough laser some infants will have poor anatomic and visual prognosis due to retinal detachment.

Other complications of laser therapy are rare and include inadvertent macular burns, anterior segment ischemia, cataract, burns in cornea, iris or tunica vasculosa lentis, vitreous an choroidal hemorrhage. Diode red (810nm) is preferable to argon green (514nm) in treating ROP because of reduced risk of cataract. Long-term adverse effects include peripheral visual field loss and possibly an increased risk of late-onset retinal detachment because of tears at the edge of treatment scars in the presence of abnormal vitreous traction. Laser therapy may increase the tendency toward myopia, however, multiple studies report a relationship between ROP and myopia.

Immediately after laser treatment, steroid drops, mydriatics and topical antibiotic may be applied. Follow-up examinations should be scheduled every 1-2 weeks until regression

of plus disease and fibrovascular proliferation occurs.

Additional Therapy

It has been established that ROP is directly related to the release of angiogenic factors such as vascular endothelial growth factor (VEGF), which is also a trigger for neovascularization in proliferative retinopathies. With the use of intravitreal injections of anti-VEGF drugs as medical treatment for ocular diseases caused by neovascularization, the use of antiangiogenics for treatment of ROP opens the minds of new investigations were this therapy can be considered as an optional treatment when gold standard is not effective.

Although some authors have reported treatment of ROP with antiangiogenics as a primary therapy. Mintz-Hittner et al reported a case series of 22 eyes that never received laser, treated successfully with one intravitreal injection of bevacizumab in stage 3 ROP, concluding the use of bevacizumab (with no laser therapy) was safe and effective in this small case series.17 Likewise, Quiroz-Mercado et al reported the use of intravitreal injection of bevacizumab in 18 eyes in different stages of ROP who had either no response to conventional laser therapy or difficult to treat because of poor visualization or at highrisk pre-threshold or threshold, and found neovascular regression in 17, concluding the use of bevacizumab may be promising in the treatment of patients with ROP18, but further studies need to be performed to determine safety and long-term results.