Ординатура / Офтальмология / Английские материалы / The Retina and its Disorders_Besharse, Bok_2011

membrane as well as the extracellular matrix. Once the endothelial cells gain access to the extravascular space, they migrate and form new capillary sprouts. Mesenchymal cells are then recruited to form smooth muscle cells in arterioles and a new basement membrane is deposited to complete the process of angiogenesis. The resulting abnormal vessels lack structural integrity and are prone to leak fluid, leading to retinal edema. Further, the abnormal vessels often are associated with a fibrovascular membrane. This membrane can become adherent to both the retina and the posterior hyaloid face. As the vitreous contracts, the fibrovascular membrane can cause tractional forces on the retina, leading to retina edema, vitreous hemorrhages, retinal heterotropia, retinal tears, and tractional retinal detachments. Fortunately, the majority of DR follows a fairly predictable course; thus, screening examinations and prophylactic interventions can be implemented to reduce the devastating and potentially blinding consequences of advanced DR.

Classifications

The classification of DR is classically based on the severity of intraretinal microvascular changes and the presence or absence of retinal neovascularization. Thus, DR is divided into two main forms: nonproliferative and proliferative. NPDR is characterized by intraretinal microvascular changes which precede the proliferative phase. Proliferative diabetic retinopathy (PDR) is characterized by the presence of retinal neovascularization. These two classifications of DR (NPDR and PDR) have been useful for the analysis of treatment efficacy in the literature and serve as general indicators for treatment strategies. However, it should be noted that an individualized approach to the treatment of DR is prudent, as every patient with DR has a unique combination of findings, symptoms, and rate of progression.

Nonproliferative Diabetic Retinopathy

The retinal microvascular changes found in NPDR are, by definition, limited to the confines of the retina and do not extend beyond the innermost retinal layer – the internal limiting membrane. Characteristic findings in NPDR include microaneurysms, retinal hemorrhages, retinal edema, hard exudates, cotton-wool spots (CWSs), areas of capillary nonperfusion, intraretinal microvascular abnormalities (IRMAs), and venous beading. NPDR primarily causes visual decline through either capillary nonperfusion leading to macular ischemia, or through increased vascular permeability, resulting in macular edema.

The first visible sign of NPDR is the retinal capillary microaneurysm. Clinically, microaneurysms are identified as red dots from 15 to 60 mm in diameter (Figure 4).

Figure 4 (a) Severe non-proliferative diabetic retinopathy. Color fundus photograph and a red-free fundus photograph of the left eye of a patient with severe NPDR. The photographs demonstrate numerous diffusely scattered microaneurysms, dot-blot hemorrhages, and hard exudates. (b) Microaneurysms and retinal hemorrhages. Arteriovenous phase fluorescein angiogram image of the same left eye (a). The microaneurysms demonstrate marked early hyperfluorescence, whereas the retinal hemorrhages block fluorescein and thus appear hypofluorescent.

On histologic examination, microaneurysms are hypercellular saccular outpouchings of the capillary wall. They are often found in relation to areas of capillary nonperfusion. Postulated mechanisms behind microaneurysm formation include the release of vasoproliferative factors (e.g., VEGF) with endothelial cell proliferation, weakness of the capillary wall secondary to the loss of pericytes, abnormalities of the adjacent retina, and increased intracapillary pressure. Microaneurysms can be differentiated from punctate retinal hemorrhages, which are also seen in DR, through fluorescein angiography. Microaneurysms will demonstrate marked early hyperfluorescence against the darker choroidal background; whereas, retinal hemorrhages

will block fluorescein and thus appear hypofluorescent (Figure 4(b)). Late fluorescein angiography frames often demonstrate leakage emanating from microaneurysms as a result of the breakdown in the blood–retinal barrier. Individual microaneurysms typically appear and disappear over time. Microaneurysms often foreshadow progression of DR as an increase in microaneurysms often is associated with progression of DR.

The retinal hemorrhages most commonly seen in NPDR include both dot-blot hemorrhages and retinal nerve fiber layer hemorrhages. Dot-blot hemorrhages are punctate, intraretinal hemorrhages that arise from the venous end of retinal capillaries and are located within the compact middle layers of the retina. These compact, vertically aligned, middle retinal layers confer upon the retinal hemorrhages their characteristic red, dot-blot appearance (Figure 4). Retinal nerve fiber layer hemorrhages arise from the more superficially located precapillary arterioles. The horizontal alignment of the retinal nerve fiber layer gives these hemorrhages their classic flame shape.

As discussed previously, another consequence of DR is excessive vascular permeability, which can result in retinal edema, usually in the macular region. Retinal edema is often accompanied by macular hard exudates, which are lipid deposits that accumulate in association with lipoprotein leakage from decompensated endothelial tight junctions. On clinical examination, hard exudates are yellowish intraretinal deposits often found at the border of edematous and nonedematous retinal tissue (Figure 4). Macular edema initially accumulates between the outer plexiform and inner nuclear layers. With chronic edema, the entire thickness of the retina becomes edematous and can assume a cystoid appearance. Retinal thickening secondary to macular edema is best detected by indirect slit-lamp biomicroscopy; in addition, optical coherence tomography (OCT), can be used to detect thickening and may be used to assess response to therapy (Figure 5).

CWSs, also known as soft exudates, may often be found in NPDR. CWSs are composed of accumulations of neuronal debris within the retinal nerve fiber layer. These result from disruption and stasis of axoplasmic flow. As CWSs heal, debris is removed from the nerve fiber layer by autolysis and phagocytosis. Clinically, CWSs are seen as yellowish, fluffy superficial lesions which obscure the underlying blood vessels. Interestingly, CWSs are only found in the postequatorial retina where the nerve fiber layer is of sufficient thickness to allow visualization of the CWSs.

As NPDR progresses, it can lead to the obliteration of retinal capillaries. These areas of capillary nonprofusion are seen on fluorescein angiography as patches of hypofluorescence. Adjacent to areas of nonperfusion, tortuous, hypercellular vessels often develop. It is difficult to determine whether these vessels are actually dilated preexisting capillaries or whether they represent new vessels forming within the retina. These vessels have been

Figure 5 Macular edema secondary to diabetic retinopathy. OCT (two images) demonstrating retinal thickening and cystoid intraretinal spaces created by extensive capillary leakage and secondary macular edema in a patient with severe NPDR.

referred to as IRMAs, a term which encompasses both possibilities. The main distinguishing features of IRMAs are their intraretinal location, failure to cross major retinal blood vessels, and absence of leakage on flouroscein angiography. As areas of capillary nonperfusion become extensive, it is common to see an increase in intraretinal hemorrhages or dilated segments of retinal veins (referred to as venous beading). The degree of retinal capillary nonperfusion is directly associated with the severity of IRMAs, intraretinal hemorrhages, and venous beading.

NPDR is further categorized into four levels of severity: mild, moderate, severe, and very severe (Table 1). The clinical extent of microaneurysms, retinal hemorrhages, venous beading, and IRMA determine the level of severity of nonproliferative disease. Mild and moderate NPDR are characterized by relatively few microaneurysms and intraretinal hemorrhages and only minimal venous changes or IRMA. Severe NPDR is characterized by diffuse intraretinal hemorrhages, two quadrants of venous beading, or moderate IRMA in at least one quadrant. If any two of these features are present, the retinopathy is considered to be very severe NPDR. The Early Treatment Diabetic Retinopathy Study (ETDRS) found that severe NPDR had a 15% chance of progression to high-risk PDR within 1 year. Very severe NPDR had a 45% chance of progression to high-risk PDR within 1 year.

Macular Edema

Macular edema is the most common cause of visual impairment in patients with NPDR. Due to the

Table 1 Classification of diabetic retinopathy

Nonproliferative diabetic retinopathy (NPDR)

Mild NPDR:

At least one microaneurysm

Criteria not met for other levels of DR

Moderate NPDR:

Hemorrhage/microaneurysm standard photograph #2A or

Soft exudates (cotton-wool spots), venous beading, and intraretinal microvascular abnormalities definitely present

Criteria not met for severe NPDR, very severe NPDR, or PDR

Severe NPDR:

Hemorrhage/microaneurysm standard photograph #2A in all four quadrants

or

Venous beading in at least two quadrants or

Intraretinal microvascular abnormalities standard photograph #8A in at least one quadrant

Very servere NPDR:

Any two or more of criteria for severe NPDR

Criteria not met for PDR

Proliferative diabetic retinopathy (PDR)

Early PDR:

New vessels

Criteria not met for high-risk PDR

High-risk PDR:

Neovascularization of the disk 1/4 to 1/3 disk area or

Neovascularization of the disk and vitreous or preretinal hemorrhage

or

Neovascularization elsewhere 1/2 disk area and vitreous or preretinal hemorrhage

Advanced PDR:

Posterior fundus obscured by preretinal or vitreous hemorrhage or

Center of macula detached

breakdown of the blood–retinal barrier, leakage of fluid and plasma constituents leads to retinal edema (Figure 6). If the retinal edema threatens the center of the fovea, there is a higher risk of visual loss. In the ETDRS, the 3-year risk of moderate visual loss was 32% (moderate visual loss was defined as a doubling of the initial visual angle or a decrease of three lines or more on a logarithmic visual acuity chart). The ETDRS investigators classified macular edema by its severity. More specifically, macular edema was defined as clinically significant macular edema (CSME) if any of the following features were present: (1) thickening of the retina at or within 500 mm of the center of the macula; (2) hard exudates at or within 500 mm of the center of the macula, if associated with thickening of the adjacent retina; or (3) a zone of thickening larger than one disk area if located within one disk diameter of the center of the macula (Table 2). Many of the current treatment paradigms for the management of diabetic

macular edema are derived from the ETDRS. The ETDRS demonstrated that eyes with CSME benefited from focal argon laser photocoagulation treatment when compared to untreated eyes in a control group. Furthermore, focal argon laser photocoagulation treatment for CSME reduced the risk of moderate visual loss, increased the chance of visual improvement, and was associated with only minor losses of visual field. Specifically, in patients with CSME involving the center of the macula, focal treatment reduced moderate visual loss by 60% after 3 years of follow-up. In patients with less than CSME, little difference was noted between the untreated and treated groups during the first 2 years of follow-up, after which there was a trend toward less frequent visual loss in the treated group.

Treatment patterns regarding CSME continue to evolve. In patients with refractory CSME, intravitreal administrations of corticosteroids have been shown to be beneficial. Intravitreal anti-VEGF agents have also been shown to improve CSME. Currently, several trials investigating corticosteroid use as well as anti-VEGF agents in the treatment of CSME are underway. Pars plana vitrectomy and detachment of the posterior hyaloid may also be useful for treating CSME. Surgical intervention may prove particularly beneficial when there is evidence of posterior hyaloidal traction and diffuse macular edema.

Proliferative Diabetic Retinopathy

As the degree of retinal ischemia increases, extensive hypofluorescent areas representing retinal nonperfusion are seen on fluorescein angiography. Eventually neovascularization may develop in an attempt to revascularize hypoxic retinal tissue. This neovascularization is the hallmark of PDR. It has been estimated that over one-quarter of the retina has to be nonperfused before PDR develops. PDR affects 5–10% of the diabetic population (Figure 7). Type I diabetics are at particular risk for PDR with an incidence of about 60% after 30 years. Although new vessels may arise from anywhere in the retina, neovascularization is particularly common on the optic disk itself (this location is termed new vessels on disk, or NVD). NVD is defined as neovascularization on or within one disk diameter of the optic nerve head. It can be differentiated from normal vessels by utilizing fluorescein angiography, which demonstrates profuse leakage in NVD but not in normal vasculature (Figure 8). Neovascularization of the retina found greater than one disk diameter from the optic nerve head is termed new vessels elsewhere, or NVE. NVE typically is found along the course of the major retinal vessels. The rate of growth of NVD or NVE is extremely variable. In some patients, neovascularization may show little change over many months, while in others definite changes in neovascularization may be seen in as little as 1–2 weeks. As neovascularization

Table 2 Clinically significant macular edema as defined by ETDRS

Thickening of the retina 500mm from the center of the macula or

Hard exudates and adjacent retinal thickening 500 mm from macular center

or

Zone of retinal thickening at least 1 disk area in size located <1 disk diameter from the center of the macula

progresses, a white fibrous membrane composed of fibrocytes and glial cells accompanies the growth of the new vessels. As mentioned previously, this membrane can become adherent to both the retina and the posterior hyaloid face. As the vitreous contracts, the fibrovascular membrane can cause tractional forces on the retina, leading to retina edema, vitreous hemorrhages, retinal heterotropia, retinal tears, and tractional retinal detachments.

The main therapy used to prevent the devastating complications of PDR is the application of thermal laser photocoagulation in a panretinal pattern in order to induce neovascular regression. Numerous panretinal photocoagulation (PRP) application protocols exist.

The classification of PDR is determined by the location and size of the neovascularization, along with the presence or absence of vitreous hemorrhage (Table 1). The Diabetic Retinopathy Study (DRS) defined high-risk PDR as any one of the following: (1) mild NVD with vitreous or preretinal hemorrhage, (2) NVD 1/4 to 1/3 disk area with or without vitreous hemorrhage, (3) NVE 1/2 disk area with vitreous or preretinal hemorrhage. The DRS was designed to evaluate the effectiveness of photocoagulation for treating diabetic retinopathy. As complications from PDR can result in severe vision loss (SVL), the primary outcome measured in the DRS was SVL, defined as visual acuity of less than 5/200. The DRS found that PRP

Figure 7 High-risk PDR. Color fundus photo of the right eye of a patient with high-risk PDR. Patient has significant NVD and NVE. This patient also has several areas of preretinal hemorrhages. CWSs can be seen inferior to the optic disk.

Figure 8 Leakage of NVD and NVE on fluorescein angiography. Fluorescein angiogram of the same patient seen in Figure 7. This patient has developed severe NVD and NVE causing significant hyperfluorescences secondary to profuse vascular leakage.

produced a 50% reduction in the rates of SVL in eyes treated with PRP compared to untreated control eyes during a follow-up of over 5 years. Treated eyes with high-risk PDR achieved the greatest benefit; thus, the DRS recommended prompt PRP treatment of eyes with high-risk PDR because this group had the highest risk of SVL.

Surgical management of PDR can be employed in patients with severe, persistent vitreous hemorrhages, progressive tractional retinal detachments, combined tractional

and rhegmatogenous retinal detachments, and dense macular preretinal hemorrhages. Investigation into the use of anti-VEGF agents in the treatment of PDR is ongoing.

Screening for Diabetic Retinopathy

Proper screening for DR is critical as diabetic patients often do not experience visual disturbances until late in the disease course. Screening examinations allow for the prompt diagnosis and treatment of DR before the development of potentially blinding complications. In patients with type I diabetes, initiating screening examinations 3–5 years after diagnosis is recommended. In patients with type II diabetes, an initial examination upon diagnosis is recommended. Pregnant women with preexisting diabetes should undergo screening early in the first trimester. More frequent retinal evaluations are subsequently required during pregnancy and in the early postpartum period.

See also: Pathological Retinal Angiogenesis.

Further Reading

Aiello, L. M. (2003). Perspectives on diabetic retinopathy. American Journal of Ophthalmology 136: 122–135.

Centers for Disease Control and Prevention (2007). National Diabetes Fact Sheet. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf (accessed June 2009).

Diabetes Control and Complications Trial Research Group (1993). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The New England Journal of Medicine 329: 977–986.

Diabetes Control and Complications Trial Research Group (1995). Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial.

Ophthalmology 102: 647–661.

Diabetic Retinopathy Study Research Group (1981). Photocoagulation treatment of proliferative diabetic retinopathy: clinical application of Diabetic Retinopathy Study (DRS) findings. DRS report 8.

Ophthalmology 88: 583–600.

Early Treatment Diabetic Retinopathy Study Research Group (1987). Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. ETDRS report 2. Ophthalmology 94: 761–774.

Early Treatment Diabetic Retinopathy Study Research Group (1991). Early photocoagulation for diabetic retinopathy. ETDRS report 9.

Ophthalmology 98: 766–785.

Early Treatment Diabetic Retinopathy Study Research Group (1995). Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline. ETDRS Report 19. Archives of Ophthalmology 113: 1144–1155.

Kanski, J. J. (2007). Clinical Ophthalmology, 6th edn. Philadelphia, PA: Butterworth Heinemann-Elsevier.

Klein, R., Klein, B. E., Moss, S. E., Davis, M. D., and DeMets, D. L. (1984a). The Wisconsin Epidemiologic Study of Diabetic Retinopathy: II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Archives of Ophthalmology 102: 520–526.

Klein, R., Klein, B. E., Moss, S. E., Davis, M. D., and DeMets, D. L. (1984b). The Wisconsin Epidemiologic Study of Diabetic Retinopathy: III. Prevalence and risk of diabetic retinopathy when age at

diagnosis is 30 or more years. Archives of Ophthalmology 102: 527–532.

Preferred Practice Patters Committee (2003). Retina Panel. Diabetic Retinopathy. San Francisco: American Academy of Ophthalmology; November 2003.

Ryan, S. J., Hinton, D. R., Schachat, A. P., and Wilkinson, C. P. (2006). Retina. 4th edn. Philadelphia, PA: Mosby-Elsevier.

United Kingdom Prospective Diabetes Study Group (1998a). Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of

complications in patients with type 2 diabetes. UKPDS 33. Lancet 352: 837–853.

United Kingdom Prospective Diabetes Study Group (1998b). Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes. UKPDS 38. British Medical Journal 317: 703–713.

UpToDate (2008). Prevention and treatment of diabetic retinopathy. http://www.uptodate.com/online/content/topic.do? topicKey=diabetes/12336&selectedTitle=1~90&source=search_result (accessed June 2009).

Glossary

Aggressive posterior retinopathy of prematurity (APROP) – Severe ROP manifesting at young ages in zone 1 with flat neovascularization. Outcomes may be poor with conventional management.

Avascular retina – Retina that lacks blood vessel growth in the inner capillary plexus.

Intravitreous neovascularization – Endothelial budding or blood vessels that grow above the inner limiting membrane of the neurosensory retina into the vitreous.

Oxygen-induced retinopathy – Includes a number of models of recently born animals of species that complete retinal vascular development after birth. Exposure to oxygen stresses varies depending on the model but shares the features of first avascular retina followed by intravitreous neovascularization.

Peripheral severe ROP (PSROP) – It refers to zone II, stage 2–3 ROP, plus disease, in this article. Plus disease – A feature of severe ROP, it refers to the dilation and tortuosity of retinal arterioles and veins. Postgestational age – The age measured in weeks that is the sum of the gestational age (age of preterm infant from conception or last menstrual period) and the chronologic age (age since the birth of the infant). For example, a 24-week gestational age infant

who was born 16 weeks ago would have a postgestational age of 40 weeks. Similar terms used include postmenstrual age, postconceptual age,

or corrected age.

Retinal detachment – A fluid develops between the photoreceptor outer segments and the retinal pigment epithelium. A traction retinal detachment occurs by vitreous tractional forces, a rhegmatogenous retinal detachment because of a break in the retina, and a serous retinal detachment from exudation often as a result of inflammation or leaky vessels, and is sometimes seen after treatment for severe ROP.

Clinical Background

Epidemiology

The Institute of Medicine reported that preterm births were up 30% from 1981 and now account for 12.5% of

all births in the US. Furthermore, developing countries are witnessing an increase in retinopathy of prematurity (ROP); therefore, ROP has now become a leading cause of childhood blindness worldwide. A report from a national registry of children in the US (Babies Count) found that ROP was the earliest cause of visual impairment and one of the three most prevalent conditions to cause visual impairment along with cortical visual impairment and optic nerve hypoplasia. ROP of any stage affects approximately 16 000 infants yearly in the US. Most early stages of ROP resolve, but about 1100 infants require treatment. Even with treatment, blindness occurs in 550 infants per year. In the US, ROP is seen more commonly in Caucasians than African-Americans, but once severe ROP occurs, the outcomes appear similar. Asians also have an increased risk of ROP. ROP has been reported in preterm infants of larger birth weight and older gestational ages in developing nations compared to those in the US, possibly because of variations in ethnic groups, regulation and monitoring of oxygen delivery, and the availability of prenatal care.

Clinical Classification of ROP

Based on the International Classification of ROP (ICROP), it is characterized by several parameters: zone, stage, extent of stage, and the presence of plus disease.

The zone of ROP is the retinal area supplied by the retinal vasculature and is an indicator of the extent of retinal vascular development (Figure 1(a)). Zone I is the smallest, having the largest area of avascular retina. Zone II has a greater area of retinal vascularization than zone I, and less than zone III. When vascularization completely extends to the ora serrata, it is termed complete vascularization. The risk of a poor visual outcome is greatest when severe ROP occurs in zone I (Figure 1(b)) and is still substantial in zone II. The risks of severe ROP and poor vision are rare when retinal vascularization extends into zone III. There are five stages of ROP. Stages 1 through 3 are the acute forms of ROP and are named for the appearance of the retina at the junction of vascular and avascular retina. A line (stage 1) or ridge (stage 2, Figure 2(a)) can often regress and vascularization of the previously avascular retina can occur. Stage 3 ROP has intravitreous neovascularization, a feature of severe ROP (Figure 2(b)). Stages 4 (Figure 2(c); also see Figures 6(a)) and 5 (Figures 2(d) and 2(e)) define partial or complete retinal detachment, respectively, and are associated with vitreous and fibrovascular changes. The extent of ROP indicates the number of clock hours of a stage. Plus disease

is the presence of dilated and tortuous retinal vessels in two or more quadrants around the optic nerve and is a feature of severe ROP (Figure 3).

There is a useful distinction to note between retinal drawings and images of dissected retinal flat mounts. The retina covers the inner sphere of the eyeball and, when dissected, must be cut with relaxing incisions in order to flatten it onto a microscope slide. The result is a cloverleaf appearance (Figure 4(a)). However, clinicians and surgeons represent the retina as a round clock face and use clock hours to describe the location of pathologic features on the retina determined in clinical examinations (Figure 4(b)).

Zone II

Zone III

Zone I

(a)

Management of ROP

Based on the American Academy of Pediatrics and American Academy of Ophthalmology, infants born at or younger than 30 weeks gestational age or less than 1500 g birth weight are screened for retinal vascular development

(e)

Figure 2 Images taken with wide-angle viewing system (Retcam, Clarity) of infant left eyes with (a) stage 2 ROP with early ridge and (b) stage 3 ROP with areas of intravitreous neovascularization (arrow) and hemorrhage adjacent to avascular retina (3–5 o’clock in image). Images of infant right eye with (c) early stage 4A ROP and (d) stage 5 ROP showing total retinal detachment with white pupil. (e) Diagram showing cross section of possible retinal appearances in stage 5 ROP; Figures 2(a), 2(b), and 2(c) courtesy Sarah Moyer, CRA, OCT-C. Figure 2(e) from Schepens’ Retinal Detachment and Allied Diseases, 2nd edn (eds. Schepens, Hartnett, and Hirose) copyright 2000. Butterworth-Heinemann, Boston, MA: Figure 26-19, p. 534.

and the presence of ROP. The screening examination is performed 4–6 weeks after birth (chronologic age) or at 31 weeks postgestational age, whichever is older. (The postgestational age is the gestational age þ chronologic age from birth in weeks and is similar in meaning to postmenstrual, postconceptual, or corrected ages). At any

Figure 3 Plus disease (dilated and tortuous vessels in all four quadrants around optic nerve) of right eye in infant with severe ROP; Courtesy Sarah Moyer, CRA, OCT-C.

examination, the risk of a bad outcome depends on the presence of plus disease or stage 3 ROP (both features of severe ROP). Severe ROP develops at about 35–37 weeks postgestational age, regardless of the gestational age or birth weight of the infant.

At the screening examination, the extent of retinal vascular development is determined (i.e., the zone of ROP), along with the presence and stage of ROP and presence of pre-plus or plus disease. (Pre-plus is less severe than plus disease and alerts the clinician to follow the infant closely.) If ROP is not severe, follow-up examinations are performed until full vascularization of the retina occurs or until severe ROP develops, at which time the treatment for acute neovascular ROP is performed.

Treatment of ROP

Acute neovascular stages

Based on the Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) and Early Treatment for Retinopathy of Prematurity (ETROP) studies, the treatment for ROP is strongly considered for infants with type 1 prethreshold ROP and almost always performed for infants with threshold ROP (Table 1). Laser is preferred to cryotherapy because it causes less inflammation, is less destructive, and is less often associated with myopia. The laser is applied to the peripheral avascular retina (Figure 5). Infants are then followed up weekly for regression of severe ROP or for the development of progressive stage 4 ROP.

Fibrovascular stages/retinal detachment

Stage 4 ROP refers to partial retinal detachment and develops as a result of fibrovascular changes and

Threshold ROP (CRYO-ROP) (risk of unfavorable outcome approaches 50%)

Zone I or II, stage 3

(5 contiguous or 8 total clock hours with plus disease*)

Type 1 prethreshold (risk

of unfavorable outcome is15% – ETROP)

Zone I, any stage with plus disease*

Zone I, stage 3 without plus disease*

Zone II, stage 2 or 3 with plus disease*

Figure 4 (a) Retinal flat mount stained with Alexa Fluor 568 conjugated isolectin B4 lectin (lectin-B4) to demonstrate vasculature from postnatal day 14 rat pup from the rat 50/10 oxygen-induced retinopathy model. (b) Artist’s drawing of retina with clock hour delineations, often used clinically to localize regions of pathology on the retina. Innermost circle at vortex vein ampullae indicates equator of the globe; middle circle indicates ora serrata; and outermost circle indicates pars plana region

in adult.

vitreoretinal traction that particularly occur at the junction of vascular and avascular retina and optic nerve to lead to retinal detachment (Figure 6(a)). The timing of the development of stage 4 ROP is often between 37 and 44 weeks postgestational age and represents a change

Figure 5 Type 1 prethreshold ROP (zone II, stage 2 severe ROP) after laser; it shows white spots from recently delivered laser to avascular retina and skipped areas between laser spots that will need to be filled in with laser in the left eye.

from neovascular to fibrovascular changes. Once progressive stage 4 ROP is diagnosed, surgery, preferably with a lens-sparing vitrectomy (Figure 6(b)), is performed to release vitreous tractional forces that detach the retina. The main forces addressed are those around the optic nerve, between the ridge and anterior aspect of the eye and lens, between the ridge and optic nerve, between the ridge and ora serrata, and from ridge to ridge (Figure 6(b)). The retina then reattaches in the postoperative period (Figure 6(c)), although the ridge and pulled-up retina often persist. Occasionally, a scleral buckle is performed, often when a break, that is, rhegmatogenous component, is present.

The decision to operate must be carefully considered in the preterm infant eye because there are surgical difficulties that make operating on an infant eye different from operating on an adult one. The infant eye is about twothirds the diameter of the adult eye and the region of safe