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

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Core Messages

Retinopathy of prematurity (ROP) is a mostly bilateral vascular disease in pre-term babies, associated with lower birth weight and younger gestational age

First presentation is an avascular retina in Zone I, II or III in combination with five different stages of retinopathy. Progression of the pathological changes may lead to a complete retinal detachment

If fibrovascular proliferation occurs at the border of avascular and vascularized retina, treatment is indicated if a certain amount of clock hours are involved, or “plus disease” is present. Treatment of the avascular area is performed either by laser or cryotherapy. If Stage 4 or 5 occurs, retinal surgery may improve outcome The main goal of treatment is to prevent progression of fibrovascular proliferation and to avoid retinal detachment

to 28 % [84]. The birth weight of these infants was approximately 400 – 500 g.

Retinopathy of prematurity occurs yearly in the USA in 14,000 – 16,000 premature infants weighing less than 1,250 g. Seven to 9 % of these children will require treatment. Despite treatment 3 – 4 % of these children will become legally blind every year (visual

20 III acuity 20/200). In Switzerland and Holland 3 – 5 % of all premature infants will develop blindness due to ROP [6, 95].

20.2.2Explanation of Important Terms, The International Classification and the Cryo-ROP Study

Retinopathy of prematurity (ROP):

Failure of the peripheral retina to vascularize

Retinal changes at the border of vascular and avascular retina Fibrovascular proliferation (Stage 3) at the border of vascu-

lar and avascular retina Complete retinal detachment

The following is an attempt to describe some definitions that are required to understand this and other publications, including the International Classification, the Cryo-ROP study, and the Screening and Therapy Criteria recommended.

20.2.2.1 Terms Used to Describe Age

Gestational age: Duration of the pregnancy counted in weeks from the first day of the last menstruation

Postnatal age: Age of child since birth Postmenstrual age: Sum of the gestational age and the postnatal age

20.2.2.2 International Classification

The international classification of ROP was developed in 1984 and expanded in 1987 [51, 52]. This classification was accepted worldwide as a standard and made comparisons between different centers possible as well as promoting multicenter studies. The classification assists in describing the retinopathy and includes localization of the retinal involvement in zones, defining the extent of the involvement by clock hours, grading the stage or severity of retinopathy at the junction of the vascularized and avascular retina, and noting the presence or absence of dilated and tortuous posterior pole vessels (plus disease).

In July 2005 a revised international classification was published. It combined the original ICROP system and the additional changes made by a group of 15 ophthalmologists from 6 countries [53].

The location of the disease was described by

Fig. 20.2.1. Zones: the location of the disease is described by defining three concentric zones of retina, which are centered on the optic disk

defining three concentric zones of retina, which are centered on the optic disk (Fig. 20.2.1).

For the practical approach, Zone I was defined by using a 25or 28-diopter condensing lens. The approximate temporal extent of Zone I can be determined by placing the nasal edge of the optic disk at one edge of the field of view; the limit of Zone I is at the temporal field of view.

20.2.2.2.1 Zones

Zone I: Encloses a circular area centered around the optic disk with a radius equivalent to two times the distance from the optic nerve to the fovea

Zone II: Extends centrifugally from the edge of Zone I to the nasal ora serrata

Zone III: The residual crescent of the retina anterior to Zone II

The extent of the disease is recorded as hours of the clock (1 – 12) or as 30 degree sectors. The five stages describe the abnormal vascular response at the junction of the vascularized and avascular retina (Figs. 20.2.2 – 20.2.7) [51, 52].

20.2.2.2.2 Stages

Stage 1: Demarcation line

A flat, white line within the plana of the retina that separates the avascular retina anteriorly from the vascularized retina posteriorly (Fig. 20.2.2).

Fig. 20.2.2. Stage 1, distinct demarcation line

Fig. 20.2.4. Stage 3+, ridge with extraretinal proliferation

Stage 2: Ridge

A prominent line that has height and width and extends above the plane of the retina. The ridge may change from white to pink and vessels may

leave the plane of the retina to enter it. Small isolated tufts may be seen posterior to this ridge structure (popcorn)

(Fig. 20.2.3).

Stage 3: Ridge with extraretinal fibrovascular proliferation

Extraretinal, fibrovascular proliferative tissue or neovascularization extends from the ridge into the vitreous. The severity

Fig. 20.2.3. Stage 2, ridge between the avascular and vascularized retina

Fig. 20.2.5. Stage 4, peripheral retinal detachment in Zone I

can be subdivided into mild, moderate, or severe depending on the extent of the extraretinal fibrovascular tissue infiltrating the vitreous (Fig. 20.2.4).

Stage 4: Partial retinal detachment

a)Extrafoveal (Fig. 20.2.5)

b)Partial retinal detachment including

the fovea

Stage 5: Total retinal detachment

Complete retinal detachment, mostly tractional and funnel shaped. The configuration of the funnel is described in anterior and posterior parts with an open or closed funnel (Fig. 20.2.6).

20 III

Fig. 20.2.6. Stage 5, complete retinal detachment

Fig. 20.2.7. Plus disease in four quadrants

20.2.2.2.3 Plus Disease

Increased venous dilatation and arteriolar tortuosity of the posterior pole in at least two quadrants. This may later increase in severity to include iris vessel engorgement, poor pupillary dilatation, and vitreous haze. A “+” symbol is added to the ROP stage number (Fig. 20.2.7).

20.2.2.2.4 Pre-Plus Disease

Vascular abnormalities of the posterior pole that are insufficient for “plus disease” but demonstrate more arterial tortuosity and more venous dilatation than normal.

20.2.2.3 Cryo-ROP Study

The multicenter Cryo-ROP study was initiated by the National Institute of Health (NIH) [16]. The following terms were defined in the Cryo-ROP Study and the ETROP Study [29] and are considered when judging the indications for therapy and the results of therapy in all subsequent studies.

20.2.2.3.1 Threshold ROP (Stage for Treatment)

Stage 3 in Zone I or Zone II with extraretinal fibrovascular proliferations of at least 5 continuous or 8 cumulative clock hours with “plus disease”

20.2.2.3.2 Pre-threshold ROP

Zone I: Any stage

Zone II: Stage 2 with “plus disease”; Stage 3 less than “threshold”

20.2.2.3.3Pre-threshold Classification Used for ETROP Study

Type 1 (high risk pre-threshold)

Zone I: Any stage with “plus disease”; Stage 3 without “plus disease”

Zone II: Stage 2 or 3 with “plus disease”

Type 2 (low risk)

Zone I: Stage 1 or 2 without “plus disease” Zone II: Stage 3 without “plus disease”

20.2.2.3.4 Unfavorable Retinal Outcome

Stage 4B (Partial retinal detachment), retinoschisis, or folds – all with foveal involvement Stage 5 (Total retinal detachment), total retino-

schisis, or retrolental membrane

20.2.2.3.5 Unfavorable Visual Outcome

Distance visual acuity 20/200

20.2.3 Guidelines for Screening

The aim of all guidelines is to define a screening procedure in order to catch all premature babies whose retinopathy requires treatment [14]. Factors that must also be considered when proposing such guidelines are patient discomfort, the ophthalmologist’s time, as well as financial costs, all of which need to be

kept as low as possible without endangering the health of the patient or quality of care. In the UK just under 2 % of babies screened require treatment and it takes 39 – 55 examinations to detect a single case requiring treatment [7, 42].

Different countries have different screening guidelines for the examination of pre-term infants, but the inclusion criteria for treatment and the first examination are nearly all the same. The screening protocol used at every neonatal intensive care unit should be based on the official recommendations of the country. All at-risk infants should be identified and examined at the appropriate time (Table 20.2.1).

In the United States and Canada the birth weight is the most important measurable factor. In Germany and the European countries, ultrasound is regularly performed during pregnancy to monitor the size of the baby and therefore size is used to calculate the precise gestational age. In Germany and the European countries the gestational age is the most important factor and the screening guidelines are based on this.

Fig. 20.2.8. Vessels growing over the ridge into the avascular retina

First Examination: At 4 – 6 weeks of postnatal age (but not before 31 weeks postgestational age)

Follow-up Examinations (German Guidelines):

The time of the follow-up examination is dependent upon the respective retinal finding

Follow-up

After 1 week: III 20

Vascularization in Zone I or central Zone II with or without ROP

Vascularization in Zone II with ROP Stage 2 or 3 Every ROP with plus disease

More regular check-ups should be performed in eyes with “aggressive posterior disease” and/or in eyes with very immature retina

After 2 weeks:

Vascularization in peripheral Zone II without ROP or with ROP Stage 1

Vascularization in Zone III with or without ROP

Longer intervals:

If after several examinations regression occurs

After the calculated date of birth

End of follow-up:

If the retina is completely vascularized

If an obvious regression of the peripheral retinal changes occurs, but only after the calculated date of birth

(Fig. 20.2.8)

An initial examination performed in the sixth postnatal week is sufficient [18, 21, 30, 60, 86]. Retinopathies requiring treatment prior to the 6th week of life, so called “rush types,” are very rare in the literature [39, 77]. Different studies [30, 46, 58, 86] have shown that the time for the development of Stage 3 ROP is prolonged for infants born very early (e.g., 23 – 25 weeks gestational age) compared to infants born at gestational age 28 – 30 weeks.

Stage 3 ROP is described only once in the literature in a child born at 26 weeks gestational age [18] . In all other instances it did not develop before 31 weeks postmenstrual age [18]. The latest occurrence of a Stage 3 ROP was recognized at 44 – 47 weeks postmenstrual age [30, 46, 54]. Reynolds et al. [89] combined the data of the Cryo-ROP and Light ROP Studies. In these two studies the occurrence of “prethreshold” and “threshold” was not before

mydriasis (e.g., 2.5 % phenylephrine + 0.5 % tropicamide, one drop, 2 – 3 times, 5 – 10 min apart).

A second person should hold the child. After the installation of anesthetic eyedrops a lid speculum is inserted. A binocular ophthalmoscope is used and together with a localizator or muscle hook the bulbus can be rotated and indented so that the peripheral retina becomes visible (Fig. 20.2.9).

First the examiner should examine the anterior eye, noting pupil wideness, a possible tunica vasculosa lentis or a rubeosis iridis. During the retinal examination, the border of vascularization should be determined and the vessels should be checked for possible plus disease.

Documentation of the eye findings with details regarding stage and zone is important. The time of the next follow-up, a possible treatment, or the end of the screening should be recorded.

20.2.4Indications for Coagulation Treatment

The indications for treatment vary slightly between countries, but all rely on the results of the Cryo-ROP Study and since 2003 based additionally on the result of the ETROP Study.

Indications for Coagulation treatment in Germany is indicated when:

In isolated cases an earlier treatment can be indicated (for example, in instances of swift progression and/or early distortion of the retina)

Should the findings indicate that treatment is necessary, the treatment should follow within days of the examination.

Through the screening criteria of the guidelines, it may be possible that subtle retinal changes may be diagnosed later than they actually occurred. It is, however, not important to recognize a diminishing Stage 1 or 2 that does not carry any therapeutic consequences. The goal of a screening is to detect all children who need treatment. For the later screenings (after the acute phase of ROP) for the detection of amblyopia, myopia or strabismus, it is not important to know if a lower stage of ROP occurred. There is no difference in the incidence of visual problems to premature children without ROP or to children born on term [82]. And there is no difference in the visual outcome of 10-year-old preterm children with ROP Stage 1 or without ROP [65].

20.2.5Incidence of ROP and Incidence of Treatment

The incidence of any stage of ROP for children of 1,500 g in the literature is between 27 % and 40 % [7, 17, 30, 33, 46, 56, 88, 94]. After reaching “threshold,” treatment is necessary in 1.4 – 10.8 % [7, 17, 30, 33, 46, 57, 88, 94]. Many studies in previous years show that the incidence of ROP and the treatment incidence have diminished [9, 31, 92]. In contrast, other authors found no change in the incidence of ROP, but recognized a lower birth weight and younger gestational age in affected patients [64] (Table 20.2.2).

Table 20.2.2. Incidence of ROP and treatment in different studies

20.2.6 Zone I Disease

A vascularization border in Zone I during the first examination is very rare. In the Cryo-ROP study only 5 % had Zone I disease, and 33 % of these eyes needed treatment during follow-up. The unfavorable outcome in this group was 78 %. The risk of an “unfavorable outcome” was 8.24 times higher in eyes with Zone I disease [17]. Recently performed studies indicated a better anatomical outcome after laser treatment. The unfavorable outcome was 15 – 36 % in these studies [2, 34].

In the German guidelines and the ETROP Study, recommendations are made to treat retinopathies found with vascularization in Zone I together with blood vessel anomalies [14, 29]. In the ETROP Study Zone I disease occurred in 40 %. The unfavorable outcome was reduced due to earlier treatment from 53.8 % to 29.6 % when compared to conventional treatment strategies.

20.2.7 Treatment Modalities

Contrast Sensitivity Testing [25] resulted in a significant difference between the groups, in favor of the treated eyes. The visual field of eyes with Stage 3+ was reduced by only an additional 7 % after cryocoagulation as compared to similar eyes that did not receive treatment. However, the visual field in all eyes with an advanced retinopathy (Stage 3+), regardless of treatment, was significantly reduced in comparison to eyes without ROP [26].

As a further treatment option, indirect laser coagulation (diode laser, argon laser) has been available for several years. These coagulation methods were established as a therapy for ROP [8, 49, 73] and due to the better anatomic, functional and refractive results [8, 34, 58] in comparison to cryo-coagulation, have been supported as the therapy of choice. Due to the wavelength, the diode laser (l = 800 – 900 nm) has more advantages than the argon laser (l = 488 and 514 nm). In cases of tunica vasculosa lentis, due to reduced absorption by the blood vessels there is less heat produced and therefore a smaller risk of induced cataract.

20.2.7.1.1 Timing of Treatment

Treatment carried out promptly after reaching the “threshold” criteria leads to a better anatomical result than a delayed coagulation [44]. It is due to this finding that the definition “within days” has been used in the German Guidelines for Ophthalmic

20 III Screening of Preterm Babies [14]. Due to the possibility of successful treatment and the very narrow time frame for the optimal therapy, it is important that all affected children be examined in timely fashion.

The large ETROP Study that appeared in December 2003, with 26 study centers and 401 randomized children, showed significantly better anatomical and functional results for treatment given at “pre-thresh- old” in comparison to treatment given after reaching threshold criteria. These results were further divided according to the vascularization border. Eyes with a vascularization border in Zone I and a Stage 3 benefit the most from early treatment. An “unfavorable outcome” was recorded in 30.8 % of the early treatment group in contrast to 53.8 % of the conventionally treated group. In view of their results the authors recommended early coagulation treatment in cases of Zone I disease and every ROP stage with “plus disease,” in cases of a vascularization border in Zone I and Stage 3 with or without “plus disease” and in cases of a vascularization border in Zone II with additional presentation of Stage 2 or 3 with “plus disease.“

20.2.7.1.2Laser Treatment Versus Cryo-Coagulation

In the Cryo-ROP Study [24] an “unfavorable outcome” was described in 31 % of cases after 3 months and after 10 years follow-up in 27 % of cases. In the later study comparing laser and cryo-coagulation, an “unfavorable outcome” was given to 8 % of laser treated eyes and to 19 % of cryo-coagulated eyes. Several other authors have also compared the different results from laser and cryo-treatment [58, 75, 79, 80, 105]. In these studies, a better anatomical result could be achieved with laser treatment than with cryo-coagulation.

Some studies have shown a higher probability of cryo-coagulated eyes developing blood vessel distortion [58, 75]. The reasons for this are, however, not clear. It is postulated that the different coagulation methods cause different damage to the tissue. The cryo-coagulation changes the retina to a thin glial scar with accompanying pigment epithelial atrophy, removal of Bruch’s membrane and atrophy of the choroid capillary layer [106]. Wallow et al. [107] described the histological findings after laser treat-

ment in monkeys. In comparison to cryo-coagula- tion, the inner retinal layers were not damaged. In addition, a more severe breakdown of the blood-reti- nal barrier was described following cryo-coagula- tion than after laser treatment [73]. The macula-pig- ment epitheliopathy, which has been described by several authors following cryo-coagulation, most probably occurs due to this breakdown. Interestingly enough, this observation has not been made following laser coagulation [38, 44, 79, 93]. These changes could also account for the reduced vision [79, 93]. The macula-pigment epitheliopathy can also occur together with a macula ectopy, macular folds or retinal detachment [38].

For eyes having a visual acuity of 20/40, the publication of the Laser Study Group [58] showed a significant visual improvement for the laser treated eyes in comparison to the cryo-coagulated eyes.

In a prospective study, White and Repka [108] also proved a better visual result following laser treatment. The results from Jandeck et al. [58] showed that laser treated eyes reached a visual acuity of 20/ 200 significantly more often. A visual acuity of 20/25 was achieved in 39.2 % of the laser treated eyes and in 17.6 % of the cryo-coagulated eyes. Two other study groups [80, 93], in a comparative retrospective study, showed a better visual result after laser treatment in comparison to cryo-coagulation.

20.2.7.2 Treatment Principles

In both treatment methods, the avascular area peripheral to the border is coagulated. In order to avoid hemorrhaging, the border should not be treated. In cryo-coagulation, the entire avascular retina is confluently destroyed. In indirect laser coagulation, the treatment should be close to the ridge and the laser burns should not be separated by more than 1/4 laser beam width from one another (Fig. 20.2.10). Moving out into the periphery, the distance between burns can be increased to 1 width of the laser beam. It is recommended that a 20 diopter or 2.2 diopter condensing lens be used in conjunction with a head-mounted ophthalmoscope. The necessary number of laser burns is dependent on the size of the avascular area and the condensing lens used and can be between 600 and 2,000 burns. Consequently, the treatment of one eye can take between 20 and 40 min.

In eyes with an advanced tunica vasculosa lentis and corresponding reduced function of the laser beam, coagulation with a transscleral diode laser should be considered.

Fig. 20.2.10. Fresh laser-coagulation burns in the avascular periphery of a Stage 3 ROP

20.2.7.3 Treatment in Stages 4 and 5

The treatment of advanced stages of ROP is still controversial. In the guidelines no recommendations are given for these stages, because no controlled studies of retinal surgery in these cases are available.

The surgery part is covered in Chapter 20.3 by Quiram, Lai, and Tresee

20.2.8 Conservative Therapy

Several conservative therapies for the treatment, or rather the prophylactic treatment of, severe ROP stages have been researched. However, no method has yet been proven to be effective.

20.2.8.1 Vitamin E

The Vitamin E supplement (tocopherol) used prophylactically against the development of ROP is controversial. In a prospective, randomized, doublemasked study, that compared vitamin E with a placebo, no significant difference was found with regard to the incidence of ROP between treatment and control group [15]. Other studies [87] showed that through a vitamin E supplement, a delay in the development of a Stage 3 was apparent and, consequently, the risk of blindness was reduced.

20.2.8.2 STOP-ROP Study

In the multicenter STOP-ROP (Supplemental Therapeutic Oxygen for Threshold ROP) Study [100],

infants with retinal changes meeting “pre-threshold” were randomly placed in two groups. The study group received additional oxygen, in order that the oxygen saturation reached 96 – 99 %. For the group with additional oxygen, a reduction in the advancement of the findings from “threshold” to “prethreshold” was achieved in 48.5 %. In the group with-

out additional oxygen, the reduction rate of the III 20 advancement was 40.9 %.

This difference was, however, not significant. The period of time required to reach the “threshold” criteria was simply lengthened through additional oxygen supplementation. For a subgroup from “prethreshold” without additional “plus disease” a significant reduction in the advancement of the disease to “threshold” was illustrated through the additional oxygen supplementation (from 46 % in the conventional group to 32 % in the study group). The negative effects of additional oxygen were, however, a worsening of the chronic lung disease and a longer and more cost intensive hospital stay.

In earlier studies by Gaynon et al. [36] and Seiberth et al. [97], a distinct reduction in the incidence of threshold cases was found through therapy of additional oxygen. Currently no general recommendation can be given regarding additional oxygen therapy.

20.2.8.3 Light-ROP Study

An earlier theory regarding the pathogenesis of ROP involves damage to cells through free radicals. Through light exposure, an increased number of free radicals are released. The multicenter, randomized study “Light Reduction in Retinopathy of Prematurity” (LIGHT-ROP) [88] was carried out to investigate the higher incidence of ROP that occurs under circumstances of unnatural light exposure in the neonatal intensive situation. In this study, prematurely born infants were given sunglasses (reducing visible light by 97 % and UV light by 100 %) within a maximal time span of 24 h after birth. The sunglasses were worn up until the first fundus examination (at 4 postnatal weeks of age or 31 postmenstrual weeks). The study, with 410 patients, comprising the largest randomized study of its kind, showed that a reduction of light cannot reduce the incidence of retinopathy in high-risk children.

20.2.8.4 Surfactant

Five Cochrane Reviews evaluated trials of surfactant. In these trials prophylactic surfactant was given to high-risk pre-term babies at, or shortly after, birth to prevent RDS (respiratory distress syndrome). The