A few words regarding examination complications are warranted. Complications are few and usually unimportant. The risk benefit ratio is tilted dramatically toward the value of the exams. But complications do occur, both from the dilating drugs and the physical exam. Reported complications include cardiopulmonary arrest, apnea, bradycardia, tachycardia, alternations in blood pressure, decreased oxygen saturation, inadvertent extubation, gastric reflux, and infection [115–120]. Most of these occur at a nuisance level, such as when bradycardia transiently appears and immediately responds to a short, less than 1 min, interruption of the exam. But rarely serious events do supervene. Such potential may need to be accounted for in developing screening criteria.

Finally, the extremely important clerical component to screening needs addressing. The best protocol fails if infants are not brought to the attention of the examiner. And this is a primarily clerical function. Several publications deal with these issues and suggest ways to deal with them [39, 40, 71, 121–123]. The critical nature of this cannot be overemphasized.

ROP itself. The statistics on premature birth are not encouraging [48]. The percent of VLBW infants is slowly increasing, having been 1.3% in 1990 and 1.5% in 2005. Public health success would provide the greatest social, economic, and medical benefit but unfortunately is often not well funded. Caring for one such infant can cost more than providing public health funding that could effectively prevent several early preterm births. This doesn’t even consider a lifetime of potential disability from developmental delay, cerebral palsy, and ROP. Maximizing neonatal care means mimicking the in utero environment as much as possible. Unfortunately that eludes our technology. Neonatal care is still primarily reactive and focused in a piecemeal fashion on organ support. We still do not know the optimal oxygenation that would minimize morbidity from all courses. Finally, several yet promising and several discarded preventative methods have so far failed completely to reduce the incidence and severity of ROP. Pharmacologic vitamin E supplementation and ambient light reduction failed to curtail ROP [34, 86–90]. Yet promising ideas include optimizing supplemental oxygen, VEGF manipulation, and IGF-1 manipulation, among others. These latter are in their infancy.

4.8  Management

Management of ROP involves prevention, various treatment options, and management of associated entities or complications. We can conveniently characterize these as prevention; interdiction; correction; and mitigation. Prevention includes any management method that reduces the incidence or severity of ROP. Interdiction involves peripheral retinal ablation by laser photocoagulation or cryotherapy which interdicts disease progression. Correction involves surgical approaches to cicatricial disease, essentially the management of retinal detachment. Finally, mitigation involves management of myopia, low vision, strabismus, amblyopia, and rarely cataract and glaucoma.

4.9  Prevention

Prevention can be subdivided into the prevention of premature birth, eliminating ROP at the source; optimizing neonatal care, eliminating ROP by facilitating normal physiologic maturation; and preventing or minimizing

4.10  Interdiction

The mainstay of interdictory management is peripheral retinal ablation, either with cryotherapy or with laser photocoagulation. This treatment was proven effective by the original CRYO-ROP trial with recent modifications by the ET-ROP Trial [32, 33, 35]. It is based on the theory that destruction of the retina anterior to the fibrovascular ridge of ROP will lower VEGF levels by eliminating ischemic signals and VEGF production by destroying cells that produce both VEGF inducing cytokines and VEGF itself [124]. Peripheral ablation diminishes both the stimulus and the ability to respond to the stimulus.

CRYO-ROP was a landmark trial that completely changed the clinical approach to ROP overnight. The study designers arbitrarily chose an intervention point based on their judgment and experience. This came to be known as threshold ROP. Researchers applied cryotherapy to the peripheral retina at this level of disease and the results were tabulated as either favorable or unfavorable. Both anatomic and visual results were assessed. It is important to note that a favorable result

was not necessarily a normal result. Favorable anatomic results ranged from normal maculas to macular heterotopia. Favorable visual results ranged from 20/20 to 20/100. Unfavorable results were macular fold or retinal detachment involving the macula and visual acuity from 20/200 or worse. Visual results were reported as both resolution and recognition acuities as they became measureable. Usually the anatomic results correlated with the visual results. A normal macula yielded good vision. A macular detachment yielded very poor vision. Interestingly the medium anatomic results i.e., macular heterotopia and macular fold yielded a surprisingly wide range of acuities [125–127] (Figs. 4.35 and 4.36). Of course cortical/brain development issues can also interfere with correlating retinal anatomy with vision.

The results of the CRYO-ROP trial are well known to all. In essence, treatment reduced the unfavorable anatomic outcome from about 50% to 25% with a less dramatic reduction for unfavorable visual acuity results. Treatment was proven efficacious, intervention began en mass, and many babies were saved from ROP induced blindness. There are two noteworthy caveats about CRYO-ROP results. Firstly, the intervention point, i.e., threshold ROP, was not a tested parameter. It was an arbitrarily chosen parameter. It was a study constant, if you will, chosen by the designers to maximize the ability of the study to detect a treatment effect. The study question was whether cryotherapy improved outcomes, not whether threshold ROP was the correct intervention

point. The study tested CRYO versus no CRYO. It never tested any other intervention points. Threshold never should have been assigned the force of standard of care. It was never tested. Secondly, cryotherapy as applied according to CRYO-ROP protocols was not a panacea. At least 25% of treated infants developed an unfavorable outcome. And when zone I threshold ROP was analyzed, the unfavorable outcome rate rose to nearly 90%.

These two caveats formed the rationale for the ET-ROP trial. Since there was no magic about threshold and it was an untested, arbitrarily chosen, consensus, intervention point perhaps earlier intervention could be better. And since unfavorable treatment ­outcomes occurred despite intervention performed according to CRYO-ROP protocols, perhaps earlier intervention could reduce that rate and improve outcomes. That is exactly what ET-ROP accomplished. It proved earlier intervention was more efficacious and it redefined the intervention point. However, it also contained untested components. The biggest was the change from all cryotherapy in CRYO-ROP to laser photocoagulation in ET-ROP. The study was not designed to test this difference. The designers simply accepted an already empirically accepted treatment paradigm shift. So an untested but real question was and is – would laser if applied according to CRYOROP protocols improve CRYO-ROP results. There is indirect evidence that it would. ET-ROP included results on patients conventionally treated but with laser

Fig. 4.35  Visual acuity range in CRYO-ROP patients with macular heterotopia (Courtesy of V. Dobson)

TELLER ACUITY CARD GRATING

ACUITY AT 3-1 /2 YEARS

IN EYES WITH MACULAR HETEROTOPIA

4/93

Fig. 4.36  Visual acuity range in CRYO-ROP patients with macular fold (Courtesy of V. Dobson)

TELLER ACUITY CARD GRATING

ACUITY AT 3-1 /2 YEARS

IN EYES WITHRETINAL FOLD

4/93

i.e., zone II threshold ROP. The ET-ROP results were better in this category than those of CRYO-ROP. So ET-ROP proved earlier intervention at a new point in disease evolution was efficacious. But it indirectly suggested that laser was better than cryo. But that is an untested conclusion since ET-ROP was not set up to answer that question directly. So what is the current status for treatment? What are the indications for treatment? Intervention may now be performed on ROP as according to Table 4.9. We see the real refinement of ET-ROP over CRYO-ROP intervention points is the primacy of zone I disease and plus disease. Zone I intervention should occur earlier. Plus disease and not the extent of neovascularization is more critical.

In summary, CRYO-ROP tested a treatment hypothesis. ET-ROP accepted treatment for all and tested an intervention point hypothesis. In CRYOROP threshold was arbitrary and although a very good intervention point, ET-ROP proved there were better ones. Unlike CRYO-ROP, ET-ROP did not test a treatment hypothesis and is only suggestive that laser is superior to cryo. Finally, future studies may further refine our intervention parameters.

Table 4.9  Indications for treatment in acute ROP

Zone I, any stage ROP with plus

Zone I, stage 3 ROP, no plus

Zone II, stage 2 or 3 ROP with plus

Peripheral retinal ablation is not without complications and side effects. Those effects in escalating seriousness­ include lid and conjunctival edema, minor peripheral vision reduction, inflammation, hemorrhage, uveitis, choroidal or exudative retinal detachments, hyphema, cataract, glaucoma, anterior segment ischemia, macular burn, and central retinal artery occlusion [35, 128–140]. The expected side effects such as edema and peripheral vision constriction occur in nearly all patients but are minor issues. Vision threatening or vision damaging complications are very infrequent. A reasonable estimate of the latter is 2–3%.

4.11  Corrective Therapy

Corrective management centers on the repair of retinal detachments. Partial detachment, macular detachment, and total retinal detachment are all subject to corrective therapy. Partial detachments are divided in ROP similarly to any disease; those with the macula not detached i.e., on and those with the macula detached i.e., off. The CRYO-ROP and ET-ROP trials classified those as stage 4a and stage 4b. Total retinal detachment is classified as stage 5.

There are several single center reports and separate analyses from both CRYO-ROP and ET-ROP [141– 149]. In general, single centers report better results

than the large trials, but they agree on reporting some success in stage 4a detachments but poor results in stage 4b and stage 5 detachments. ET-ROP provides an excellent source of the most recent and robust data and is therefore worth repeating [150]. ET-ROP investigators found 89 eyes in 63 patients with retinal detachments with follow-up available for 78 eyes in 56 patients. Eighteen detachments were unclassified, but the rest were classified as stage 4a-30 eyes, stage 4b-14 eyes, and stage 5–16 eyes. Surgical repair resulted in some visual success in stage 4a (21%), but stage 4b and stage 5 visual results were dismal. Stage 5 surgical intervention in eleven eyes resulted in six NLP, 3 LP, and two low vision card acuities. Corrective therapy remains heroic with poor results. Unfortunately little else can be offered for retinal detachment. The question remains whether surgery is preferable to nothing. The answer may be an extremely guarded yes. Clearly prevention and interdiction is where our resources must be directed.

4.12  Mitigation

This portion of ROP management deals with mitigating or minimizing the directly associated sequelae/ complications­ of the disease or the indirect associations. The former concerns myopia, strabismus, amblyopia,

cataract, glaucoma, and late retinal detachment. The latter includes neurologic visual impairment such as cortical blindness, optic atrophy, and nystagmus.

Myopia by far is the most common sequelae of ROP. Mild disease is associated with a slightly increased risk of myopia and essentially no increased risk of high myopia. However, in serious ROP the levels­ of both myopia and high myopia are increased dramatically [151, 152] (Figs. 4.37 and 4.38). There has been a concern that treated eyes may be more prone to high myopia than untreated eyes. However, the ET-ROP trial found that earlier treatment at high risk prethreshold did not place eyes at more risk of this than conventionally treated eyes [153]. Therefore there is no increased risk of myopia associated with earlier treatment. Nonetheless early and repeated cycloplegic refractions are necessary in this population.

Anisometropia, amblyopia, and strabismus also occur with some regularity in patients with ROP. The incidence of these problems follows the same pattern as myopia. Mild ROP may increase the risk for these problems slightly, but serious ROP dramatically increases risk [154–155]. Interestingly, the ET-ROP report suggested that although the strabismus rate was very high, spontaneous resolution in the first 9 months was also high [156]. Clearly, strabismus and amblyopia are important and frequently manifest problems. Standard treatment of glasses, amblyopia therapy, and surgery will be necessary in a large number of children with serious ROP. But

EYES WITH MYOPIA:

ZONE OF ROP

Fig. 4.37  MYOPIA vs. ROP zone (Courtesy of V. Dobson)