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

entry without damage to the retina is less than 1 mm in width compared to about 6 mm in the adult eye. Unlike in the adult, a retinal break can lead to an inoperable retinal detachment and blindness in an infant. The ridge/junction region often has retinal detachment incorporated into it. Therefore, in order to reduce the risk of causing an iatrogenic retinal break, the surgical strategy is to release vitreous traction rather than to remove the ridge or dissect preretinal tissue from it. In addition, injury to the lens can lead to cataract, amblyopia, and poor vision. Therefore, the timing of surgery is prior to that when the retina and ridge are pulled anteriorly to contact the posterior lens capsule.

Visual rehabilitation in preterm infants

Infants with ROP are more likely to be myopic and develop strabismus in childhood than full-term infants. The more severe the ROP, the greater the risk of developing high myopia. Infants who develop stage 5 ROP or total retinal detachment have very poor vision, and are usually legally blind (bilateral visual acuity <20/200) even after successful surgery to reattach the retina. Therefore, the goal in managing ROP is to prevent stage 5 ROP. Surgery at early stage 4 ROP often permit the retention of the lens which is important in visual development. Infants who have their lenses removed have compromised visual development and reduced visual acuity from aphakic amblyopia, even with optical means to correct aphakia.

Genetics Related to ROP

Based on retrospective analysis of monozygotic and dizygotic twins, a 70% variance in the susceptibility of ROP was found to be from genetic factors, suggesting that genetics plays a strong role in ROP. However, studies of candidate genes are not in agreement and suggest that a more complex situation exists, involving genetics and environmental factors such as nutrition, oxygen, and the health of the infant.

The Norrie disease gene produces the gene product, norrin, which is also a downstream ligand for receptors in the Wnt signaling pathway. Norrie disease is usually x- linked and causes visual and hearing loss. The Wnt pathway and norrin are important in retinal and vascular development. Genetic mutations in the Norrie disease gene [Xp11.2-11.3] were reported to account for 3% of the cases of advanced ROP, but were not found in a study in infants with severe ROP compared to control preterm infants with no or minimal ROP within a racially diverse population. Another study reported that mutations within the cysteine knot configuration of the Norrie disease gene

were associated with severe retinal dysplasia, whereas other polymorphisms within the gene had less severe vitreoretinopathies.

Severe ROP has been reported in infants with certain polymorphisms in the gene of vascular endothelial growth factor (VEGF), but the same polymorphisms have not been confirmed in other studies. Despite the finding that low serum insulin-like growth factor-1 (IGF-1) was associated with more severe ROP, one study failed to show a relationship between a prevalent polymorphism in the IGF-1 receptor and the presence of ROP. The role of genetics requires greater study and will continue to be elucidated along with the effect of environmental factors on gene function.

Pathophysiology of ROP

To understand ROP, it is helpful to understand the known processes in human retinal vascular development. It is believed that vasculogenesis or de novo development of the central vasculature around the optic nerve occurs from angioblasts, or endothelial cell (EC) precursors. Angioblasts lack markers commonly thought to be present on ECs such as CD31, CD34, and von Willebrand’s factor, but do express CD39 and CXCR4. Retinal vascular development is believed to be completed mainly through a process of angiogenesis, but the role of circulating endothelial precursors is being appreciated more. During angiogenesis, a front of migrating cells, astrocytes in cat or angioblasts in dog, sense physiologic hypoxia and express VEGF. The ensuing ECs are attracted to VEGF and migrate to create blood vessels. The VEGF signaling pathway has been found to regulate and integrate several cell processes important during sprouting angiogenesis. Whereas VEGF concentration is thought to regulate EC division rate, the presentation of VEGF, as in a gradient, may regulate filopodia formation of endothelial tip cells at the migrating front and direct the growth of ECs. The delta-like ligand 4/Notch1 (Dll4/Notch1) signaling pathway regulates VEGF-induced endothelial tip/stalk cells at the junction of vascular and avascular retina and permits ordered angiogenesis.

Role of Oxygen in Retinal Development

The oxygen level has been long recognized as important in the development of ROP. High unregulated oxygen at birth likely accounted for many of the early cases of ROP first described in the 1940s and 1950s. With improved oxygen monitoring and avoidance of hyperoxia, ROP virtually disappeared. However, as infants of younger gestational ages and lower birth weights survived, ROP re-emerged. Currently, it is recognized that fluctuations in oxygen, as well as high oxygen at birth, are important

risks for severe ROP. Although a multicenter clinical study (Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity) to test the effects of supplemental oxygen to prevent severe ROP found no adverse effect from supplemental oxygen and, perhaps, a benefit in a subgroup, some reports indicate that severe ROP is associated more commonly with infants who have had high oxygen saturations during their courses.

High oxygen early in development causes loss of perfused central capillaries and is the basis for the development of several animal models of oxygen-induced retinopathy (OIR) in cats, mice, beagles, and rats. One mechanism proposed is that hyperoxia inhibits basic fibroblast growth factor (bFGF)-induced angioblast differentiation into ECs in vitro. Although most models of OIR recapitulate this high constant hyperoxia, it is not relevant to what preterm infants experience in neonatal intensive care units (NICUs) in which oxygen is well regulated, in whom minute to minute fluctuations in oxygen have been measured rather than constant oxygen. Furthermore, almost all studies of the mechanisms of oxygen stress on retinal vessels have been performed using models that subject animals to high constant oxygen.

Animal Models of Severe ROP

Models of severe ROP take advantage of the fact that several species undergo retinal vascular development after birth. Furthermore, the newly developed capillaries are susceptible to oxygen stresses such that high oxygen will cause loss of capillaries. No model uses premature animals. In addition, no model develops stage 4 or 5 ROP (retinal detachment). The beagle OIR model comes closest to stage 4 ROP with the development of tractional retinal folds, but does not develop stage 5 ROP.

Mouse OIR (model of aggressive posterior ROP)

The mouse OIR model also uses high constant oxygen and is probably the most useful to study mechanisms of extreme oxygen insult by using genetically modified animals (Table 2 and Figure 7). This model may mimic aggressive posterior ROP (APROP, Figure 8), a less-common form of severe ROP, in which there are broad areas of central avascular retina. APROP may share the retinal oxygenation pattern as does the avascular hypoxic retina during relative hypoxia in the mouse OIR model. Fluorescein angiograms of infants with APROP demonstrated extensive capillary loss centrally that appeared similar to that seen in perfused retinas from the mouse OIR, and several studies have shown avascular retina in OIR models to be hypoxic.

Rat 50/10 OIR (model of peripheral severe ROP)

The rat 50/10 OIR model mimics the more common form of severe ROP, peripheral severe ROP (PSROP). Here,

Table 2 Mouse and 50/10 rat models of OIR

Constant high hyperoxia: Mouse OIR model of human APROP p12 Low retinal VEGF

Central avascular retina

p17 Intravitreous neovascular budding

Fluctuations in oxygen: Rat 50/10 OIR model of more common PSROP

p14 Rat 50/10 OIR; 32 weeks premature infant High retinal VEGF

p18 Rat 50/10 OIR; 35-37weeks premature infant

High VEGF164 and VEGFR2 signaling Intravitreous neovascularization

p30 Rat 50/10 OIR; 40 weeks preterm infant Intraretinal vascularization and regression of IVNV

newborn rat pups are placed into an oxygen environment that cycles concentrations between 50% and 10% oxygen every 24 h for 14 days. The oxygen extremes in the rat 50/10 OIR model cause rat arterial oxygen levels to be similar to the transcutaneous oxygen levels measured in preterm infants who developed severe ROP. In addition, rather than constant oxygen used in other models, the 50/ 10 OIR model exposes pups to repeated fluctuations in oxygen, a risk factor for severe ROP. As in PSROP, in which there is reduced peripheral retinal vascularization and perfusion with minimal central nonperfusion, the rat 50/10 OIR model has mainly peripheral avascular retina and minimal central capillary loss (Figure 4(a)). The 50/10 OIR model reproducibly and consistently first develops avascular retina (analogous to human zone II ROP) and, subsequently, vessel tortuosity (analogous to human plus disease) and intravitreous neovascularization (analogous to human stage 3 ROP). All OIR models have regression of tortuosity and intravitreous neovascularization with later intraretinal vascularization; however, the beagle model takes the longest to regress.

Role of Avascular Retina

Although the size of the avascular retina does not always correlate with the presence of intravitreous neovascularization in animal models, multicenter clinical trials have shown that eyes with the largest peripheral retinal avascular zones have the worst outcomes from ROP. Furthermore, the avascular, hypoxic retina is believed to be a source of angiogenic

Figure 8 Preterm infant left eye with APROP after laser treatment showing pigmentation of laser to the right of image, plus disease, and vitreous hemorrhage inferior to optic nerve; Courtesy Sarah Moyer, CRA, OCT-C.

factors that cause pathologic intravitreous neovascularization in some models of ROP. What causes avascular retina remains largely unknown. Delayed retinal vascular development in B-cell lymphoma protein 2 (bcl2 –/–)-deficient mice that have a defect in protection against apoptosis supports the thinking that increased apoptosis of ECs or their precursors may contribute to avascular retina. Protection of newly formed capillaries from hyperoxia-induced endothelial death occurs by giving growth factors or nutritional supplements prior to the hyperoxic insult, and these protective agents largely prevent intravitreous neovascularization that would occur in the hypoxic phase of the mouse OIR model. The activation of nicotinamide adenine dinucleotide phosphate [NADPH] oxidase from repeated oxygen fluctuations in the rat 50/10 OIR model contributed to the avascular retina through apoptosis. Thus, the area of avascular retina appears to be one factor involved in the severity of human ROP, and apoptosis of ECs or their precursors may contribute to its size.

Role of Growth Factors

Molecular mechanisms of OIR have been identified mainly from the mouse OIR model, which mimics APROP, but does not mimic most cases of severe ROP.

Vascular Endothelial Growth Factor

VEGF is an important factor in retinal vascular development and is also neuroprotective. However, it is also one of the most important angiogenic factors involved in pathologic retinal and choroidal vascular diseases. Mice in OIR had reduced VEGF expression in association with capillary loss centrally when exposed to high constant hyperoxia. Subsequently, when placed into relative hypoxia that occurred in room air, VEGF messenger ribonucleic acid (mRNA) was overexpressed in association with the development of endothelial budding above the internal limiting membrane. If VEGF was given during hyperoxia, capillary loss could be reduced and, if agents to inhibit VEGF were given during relative hypoxia, endothelial budding into the vitreous was also reduced.

In the rat 50/10 OIR model, a relevant model of most cases of severe ROP in the US currently, neutralizing VEGF with an antibody made against VEGF164 reduced tortuosity (analogous to plus disease) and intravitreous neovascularization (analogous to stage 3 ROP). Too low a dose appeared to lead to a rebound in intravitreous neovascularization and persistence of the avascular retina.

Clinical trials are underway, testing intravitreous injections of antibodies to VEGF in severe ROP. There are concerns regarding the effect of dose based on animal studies described above, and the possible adverse effect of inhibiting VEGF in the developing preterm infant. VEGF is neuroprotective and besides the possible local effect on the retina, there is the potential adverse effect systemically from the absorption of the antibody into the bloodstream. Compared to the adult, an intravitreous drug in the newborn can achieve a higher concentration in the bloodstream and affect measurable outcomes, such as body weight gain in animal models. However, in some forms of severe ROP, such as APROP, there are few other options to prevent retinal detachment and permit the development of vision in these infants. Therefore, clinical trials are necessary and the data obtained will be important in developing improved treatments for severe ROP.

IGF-1 – IGF 1BP3

IGF-1 is important in the physical growth of the infant. However, IGF-1 levels that occur in utero are not maintained upon birth in preterm infants. Low serum IGF-1 was found to correlate with greater avascular retinal area in human preterm infants. Furthermore, transgenic mice expressing a growth hormone antagonist gene, or wild-type mice treated with an inhibitor to growth

hormone, had reduced intravitreous neovascularization in the mouse OIR model. IGF-1 was also found to be important for signaling through the mitogen-activated protein (MAP) kinase pathway, which is important in cell proliferation. In addition, VEGF and IGF-1 synergistically triggered the serine-threonine kinase, Akt, which is important in cell survival. Based on these findings, it is theorized that IGF-1, which is low in the preterm infant, is necessary for early retinal vascular survival and growth, but can result in later intravitreous neovascularization in ROP. However, the timing and dose of IGF-1 appear to be critical.

A hypoxia-regulated binding protein of IGF-1, IGF1BP3, was shown to be important in reducing hyperoxiainduced capillary loss and in promoting vascular regrowth into the retina in the mouse OIR model. IGF-BP3 was shown to promote differentiation of endothelial precursor cells into ECs and in promoting angiogenic processes, such as cell migration and tube formation.

Erythropoietin

Erythropoietin is angiogenic, erythropoietic, and neuroprotective. It is upregulated after the stabilization of hypoxia-inducible factor (HIF)-1a in response to hypoxia. In the mouse OIR model, hyperoxia reduces the expression of erythropoietin. The administration of exogenous erythropoietin prior to hyperoxia reduced capillary loss, whereas giving erythropoietin during relative hypoxia in room air enhanced pathologic neovascularization. Clinical studies have reported an association between the number of administrations of erythropoietin for anemia of prematurity and the prevalence of severe ROP and have found that recombinant erythropoietin is an independent risk factor for severe ROP.

HIF 1a

The stabilization of HIF1a occurs under hypoxic conditions or secondary to reactive oxygen species (ROS) generated from NADPH oxidase, nitric oxide, mitochondria, and other enzymes. HIF1a binds to the hypoxia response elements to cause transcription of several genes including angiogenic factors, VEGF, and erythropoietin. A knock-out to HIF 1a is lethal, but a knock-out to the HIF-1a-like factor (HLF)/HIF-2a provided evidence that erythropoietin was a major gene involved in intravitreous neovascularization after relative hypoxia from hyperoxia-induced capillary loss in the mouse OIR model.

Role of Oxidative Stress

Oxidative stress has been proposed to be important in the development of ROP because the retina is susceptible to oxidative damage given its high metabolic rate and rapid rate of oxygen consumption. In addition, the premature infant has a reduced ability to scavenge ROS, increasing

its vulnerability to oxidative stress. End products of ROS, lipid hydroperoxides, were increased in the 50/10 OIR model at time points corresponding to intravitreous neovascularization. When injected into the vitreous, these compounds caused intravitreous neovascularization in the rabbit. In addition, ROS can trigger signaling pathways relevant to apoptosis or angiogenesis, both important in the pathogenesis of ROP.

The treatment of pups in the 50/10 OIR model or humans with ROP using a broad antioxidant, N-acetylcysteine, failed to show a reduction in clock hours of intravitreous neovascularization, or the avascular retinal area. In a clinical trial in preterm infants, there was no difference in the incidence in ROP between those receiving N-acetylcysteine or control. However, reduction in ROS with preparations of vitamin E or liposomes containing the antioxidant enzyme, manganese superoxide dismutase, reduced OIR severity. Also, a meta-analysis of human preterm infants treated with vitamin E showed a significant reduction in severity of ROP. Reducing the activation of NADPH oxidase, an enzyme that produces ROS, can also reduce the size of the avascular areas and subsequent intravitreous neovascularization in certain OIR models.

Light was proposed to be important in ROP development through photooxidation of polyunsaturated fatty acids within photoreceptor outer segments. On the other hand, during the dark, photoreceptors are more metabolically active. A clinical trial testing the effect of light or shade on the development of ROP showed no significant difference.

Future Treatment Considerations

There are difficulties in studying treatments for ROP in developing infants. Preterm infants with severe ROP often have other developmental and health problems, making it difficult to assess long-term complications of a drug in clinical trials. Inhibiting the bioactivity of VEGF has been reported to be beneficial in adult diseases, such as proliferative diabetic retinopathy, but this strategy has been reported to interfere with neuronal and endothelial survival in some animal models, and these are issues of concern in the developing preterm infant. Inhibition of ROS may be detrimental to the preterm infant, whose abilities to combat infection are limited. A reduction in inspired oxygen concentration may also be detrimental to the developing preterm infant brain and long-term effects of such reductions are unknown. The timing and dose of neuroprotective agents such as erythropoietin and growth factors are critical but vary among individual infants, so that an agent may worsen rather than lessen ROP severity. Currently, the optimal time or dose of an agent cannot be

safely determined for an individual infant. However, the current standard of care laser treatment for severe ROP does not address vascular development that is ongoing in the developing human preterm infant. Better treatments for severe ROP are needed.

See also: Anatomy and Regulation of the Optic Nerve Blood Flow; Choroidal Neovascularization; Evolution of Opsins; Genetic Dissection of Invertebrate Phototransduction; Microvillar and Ciliary Photoreceptors in Molluskan Eyes.

Further Reading

Capone, A., Jr., Hartnett, M. E., and Trese, M. T. (2005). Treatment of retinopathy of prematurity: Peripheral retinal ablation and vitreoretinal surgery. In: Hartnett, M. E., Trese, M. T., Capone, A., Keats, B., and Steidl, S. (eds.) Pediatric Retina, pp. 417–424. Philadelphia, PA:

Lippincott Williams and Wilkins.

Chen, J., Connor, K. M., Aderman, C. M., and Smith, L. E. (2008). Erythropoietin deficiency decreases vascular stability in mice. Journal of Clinical Investigation 118: 526–533.

Coats, D. K. (2005). Retinopathy of prematurity: Involution, factors predisposing to retinal detachment, and expected utility of preemptive surgical reintervention. Transactions of the American Ophthalmological Society 103: 281–312.

Geisen, P., Peterson, L. J., Martiniuk, D., et al. (2008). Neutralizing antibody to VEGF reduces intravitreous neovascularization and does not interfere with vascularization of avascular retina in an ROP model.

Molecular Vision 14: 345–357.

Hartnett, M. E. (2003). Examination and diagnosis in the pediatric patient. In: Steidl, S. M. and Hartnett, M. E. (eds.) Clinical Pathways in Vitreoretinal Disease, pp. 341–373. New York: Thieme Medical Publishers.

Hartnett, M. E. and Toth C. A. (2010). Retinopathy of prematurity. In: Levin L. and Albert, D. (eds.) Ocular Disease: Mechanisms and Management. London: Elsevier.

Hartnett, M. E., Trese, M. T., Capone, A., Keats, B., and Steidl, S. (eds.) (2005) Pediatric Retina. Philadelphia, PA: Lippincott Williams and Wilkins.

Hartnett, M. E., Martiniuk, D., Byfield, G., Zeng, G., and Bautch, V. (2008). Neutralizing VEGF decreases tortuosity and alters endothelial cell division orientation in arterioles and veins in rat model of ROP: Relevance to plus disease. Investigative Ophthalmology and Visual Science 49: 3107–3117.

Hasegawa, T., McLeod, D. S., Prow, T., et al. (2008). Vascular precursors in developing human retina. Investigative Ophthalmology and Visual Science 49: 2178–2192.

McColm, J. R. and Hartnett, M. E. (2005). Retinopathy of prematurity: Current understanding based on clinical trials and animal models. In: Hartnett, M. E., Trese, M. T., Capone, A., Keats, B., and Steidl, S.

(eds.) Pediatric Retina, pp. 387–410. Philadelphia, PA: Lippincott Williams and Wilkins.

McLeod, D. S., Hasegawa, T., Prow, T., Merges, C., and Lutty, G. (2006). The initial fetal human retinal vasculature develops by vasculogenesis. Developmental Dynamics 235: 3336–3347.

Penn, J. S., Henry, M. M., and Tolman, B. L. (1994). Exposure to alternating hypoxia and hyperoxia causes severe

proliferative retinopathy in the newborn rat. Pediatric Research 36: 724–731.

Penn, J. S., Madan, A., Caldwell, R. B., et al. (2008). Vascular endothelial growth factor in eye disease. Progress in Retina and Eye Research 27: 331–371.

Saito, Y., Uppal, A., Byfield, G., Budd, S., and Hartnett, M. E. (2008). Activated NADPH oxidase from supplemental oxygen induces neovascularization independent of VEGF in retinopathy of prematurity model. Investigative Ophthalmology and Visual Science

49: 1591–1598.

Smith, L. E. H., Wesolowshi, E., McLellan, A., et al. (1994). Oxygen induced retinopathy in the mouse. Investigative Ophthalmology and Visual Science 35: 101–111.

Stone, J., Itin, A., Alon, T., et al. (1995). Development of retinal vasculature is mediated by hypoxia-induced vascular endothelial

growth factor (VEGF) expression by neuroglia. Journal of Neuroscience 15: 4738–4747.

Relevant Websites

http://www.iom.edu – Institute of Medicine Statement on Prematurity. http://www.nei.nih.gov – National Eye Institute statement on ROP.

Glossary

Retinopexy – A Laseror cryotherapy-induced chorioretinal adhesion surrounding a retinal break as prophylaxis for or during surgical treatment of rhegmatogenous retinal detachment.

Rhegma (Greek) – A rupture, rent, or fracture.

Rhegmatogenous retinal detachment –

A separation of the neurosensory retina from the retinal pigment epithelium associated with a fullthickness hole, break, or tear in the retina. The detachment occurs secondary to the passage of vitreous fluid through the break.

Tamponade – The plugging on a retinal break so that fluid can no longer pass through it (e.g., with a gas bubble).

Vitreous – Pertaining to the vitreous body of the eye located in the posterior chamber of the eye.

Rhegmatogenous retinal detachment (RRD) is defined as a separation of the neurosensory retina from the underlying retinal pigment epithelium (RPE) due to accumulation of subretinal fluid (SRF) via one or more full-thickness retinal breaks. With an incidence of 1 in 10 000 among the general population, RRD is relatively uncommon but remains an important cause of vision loss. In 1918, Jules Gonin recognized the importance of retinal breaks in the etiology of RRD and transformed the prognosis of this previously untreatable, blinding condition. Using thermocautery to seal retinal breaks, he demonstrated successful retinal reattachment in 30–40% of his cases. Modern vitreoretinal surgery can now achieve a final retinal reattachment rate of >95%.

Pathophysiology

Under physiological conditions, retinal attachment is principally maintained by the following mechanical and metabolic factors: (1) fluid or intraocular pressure (IOP) differentials (hydrostatic and osmotic forces); (2) glue-like interphotoreceptor matrix at the photoreceptor outer segment and RPE interface; and (3) RPE pump (NAþ–Kþ adenosine triphosphate (ATP)ase metabolic pump transporting ions and fluid across the subretinal space).

For RRD to occur, the following factors need to be present to overcome the attaching forces: (1) fullthickness retinal break in the neurosensory retina and

(2) vitreous liquefaction and vitreoretinal traction. Vitreoretinal traction may coexist at the site of the retinal break, and varies depending on the type of break.

Full-thickness retinal breaks are classified as tractional tears, round holes, or dialyses.

Retinal tractional tears (also known as U, horseshoe, or flap tears) develop following posterior vitreous detachment (PVD) and are the most common causes of RRD. They occur at sites of enhanced vitreoretinal adhesion, such as in peripheral retinal lattice degeneration, chorioretinal scars, or at the posterior edge of the vitreous base. Persistent vitreous traction exerted on the flap of a tear promotes rapid, continuous recruitment of liquefied vitreous into the subretinal space and progression to retinal detachment, which usually occurs more rapidly than with a round hole or dialysis (where there is no posterior vitreous separation).

Retinal hole formation is not usually associated with overt vitreous traction. This is caused by localized retinal atrophy and occurs more commonly in myopic patients. The pathophysiology of progression from retinal hole to RRD is not entirely clear, as 5–10% of postmortem eyes have full-thickness retinal holes without RRD.

Retinal dialyses are circumferential retinal breaks occurring along the ora serrata with concurrent avulsion of the overlying vitreous base. There is often a history of ocular trauma, although spontaneous cases are not uncommon.

Clinical Features

Symptoms

Many patients present acutely with classic symptoms of flashing lights (photopsia) and visual floaters in the affected eye, usually resulting from PVD. Photopsia lasts for seconds, is more noticeable in dim light conditions, may be precipitated by ocular movements, and commonly occurs in the temporal field but is not localizing. Floaters in the visual field vary from a solitary floater (e.g., Weiss ring formation) to innumerable minute dark spots (pigment or hemorrhage in vitreous). As an RRD develops and progresses, patients may notice peripheral visualfield loss, which is often described as a black curtain,

shadow, or half-moon. Central vision is lost if SRF spreads to involve the macula and detaches the fovea.

In a minority of patients, RRD may be asymptomatic. Typically, this occurs in young myopic patients with atrophic round holes who often present late only when the detachment encroaches the macula.

Signs

Nonspecific signs of RRD may include reduced visual acuity, relative afferent pupillary defect, mild anterior uveitis, and low IOP compared to the fellow eye. Up to 2% of patients may present with raised IOP or Schwartz–Matsuo syndrome. This typically occurs in young patients with chronic RRD, and is due to rod photoreceptor outer segments passing into the anterior chamber and blocking trabecular outflow. A positive Shaffer’s sign, defined as the presence of tobacco dust or pigment granules in the anterior vitreous, is highly predictive of a retinal break particularly when associated with any of the above symptoms.

Stereoscopic fundal examination reveals an elevated neurosensory retina in the area of the detachment, with reduced visibility of underlying choroidal markings. The detached retina has a convex configuration and may have a corrugated surface due to intraretinal edema. This is in contrast to tractional non-RRD, which has a concave configuration.

In addition, one or more full-thickness retinal breaks may be visible as evidenced by discontinuity of the retinal surface. These typically occur anterior to the equator. Visualization of the type, number, and distribution of all retinal breaks is important for surgical planning. This is best achieved with the aid of indirect ophthalmoscopy and scleral indentation. However, this may be difficult in the presence of media opacities. Identification of break type in RRD is crucial, as it determines the choice of appropriate surgical technique for repair.

Break type – identification

Retinal tears

1.Horseshoe or U-shaped tear (may be irregular;

Figure 1).

2.Persistent point of vitreous traction present at anterior edge of flap.

3.Giant retinal tear (GRT) is a circumferential retinal tear of 3 or more clock hours.

4.Avulsion of the anterior flap of a retinal tear may result in a round break with overlying retinal operculum. A tear with an operculum that is fully separated from the retina is known as a fully operculated round hole (FORH).

5.Retina is visible anterior to break.

Retinal round holes

1.Round atrophic hole without overlying retinal operculum (Figure 2).

2.May be associated with retinal degeneration (e.g., peripheral lattice degeneration).

3.Retina is visible anterior to break.

Figure 1 Right eye. Retinal tear in the superotemporal retinal periphery causing an acute macular-sparing retinal detachment. HST, horseshoe tear; RRD, rhegmatogenous retinal detachment.

Figure 2 Left eye. Retinal round hole in the inferotemporal retinal periphery causing a chronic macular-sparing retinal detachment. A demarcation line (arrowhead) indicates several months of stasis and nonprogression of the retinal detachment. Proliferative vitreoretinopathy in the form of subretinal band formation is consistent with the chronicity of the detachment. RH, round hole; PVR, proliferative vitreoretinopathy.

Retinal dialyses

1.Circumferential retinal break at the ora serrata without a PVD (Figure 3).

2.No visible retina anterior to retinal break.

Lincoff first described the principles of predicting retinal break location, taking into account the effect of gravity on the spread of SRF from the primary break and the resultant topography of an RRD. This is influenced by anatomical limits such as the disc, the ora serrata, and any chorioretinal adhesions that might be present.

Break localization – principles based on topography of RRD

Superotemporal and superonasal

1.SRF descends on the same side of break toward the disc, then revolves around the inferior pole of the disc and rises on the opposite side.

2.SRF may rise as high on the opposite side of the disc as the level of the primary retinal break, but never as high as the fluid level on the primary side.

3.The primary break will be found within 1.5 clock hours of the highest border of the detachment in 98% cases.

Midline (12 o’clock meridian) and total detachments

1.Detachments that cross the 12 o’clock meridian originate from breaks at or near 12 o’clock.

2.These detachments can become total.

3.In subtotal detachments, if the break is slightly to one side of 12 o’clock, the fluid front will be more extensive on the side coincidental with the break.

4.The more posterior the break, the more it can deviate from 12 o’clock position and still cause a detachment that will cross the vertical meridian.

Figure 3 Right eye. Retinal dialysis (arrowhead) in the inferotemporal retinal periphery causing a macular-sparing retinal detachment.

Therefore, contour edges of the detachment are of less localizing value.

Inferior

1.The SRF that arises from breaks below the level of the optic disc develops first around the break and then advances toward the disc and macula, rising higher on that side of the disc where the break lies.

2.The break need only be 1 or 2 mm from the 6 o’clock position for it to cause a difference in fluid levels.

3.When the levels are equal, the hole is at the 6 o’clock meridian.

4.Such detachments are never bullous.

Chronic RRD

The distinction between an acute and chronic RRD is important, as it may determine both the urgency of treatment and prognosis. Signs of chronicity are:

1.Retinal atrophy – retina may be thinned and atrophic.

2.Intraretinal cysts – these can develop in long-standing RRD, typically those over 12 months duration. At the time of surgery, they can be left undisturbed as they do not usually interfere with retinal reattachment and can subsequently collapse.

3.Subretinal demarcation lines – also known as high watermarks or tidemarks, these develop at the advancing front of the RRD as a result of proliferation of RPE cells. Their presence simply indicates a period of stasis of the RRD at the point of the demarcation line. However, it does not confer the strength of a chorioretinal scar that is generated by retinopexy; thus, RRD progression may still occur.

4.Proliferative vitreoretinopathy (PVR) (Figure 4) – This is a process of cellular proliferation and fibrocellular membrane contraction that complicates between 5% and 12% of all RRD, and is the most common reason for final failure of RRD surgery. PVR has a higher incidence in RRD secondary to GRTs (16–41%) and in eyes sustaining penetrating trauma (10–45%). Once PVR has developed, visual recovery is usually limited despite improving anatomical surgical success rates. The location and extent of epiretinal or subretinal proliferation have been classified by the Retina Society Terminology Committee in 1991 (Table 1).

Differential Diagnoses

RRD must be distinguished from other causes of retinal or choroidal elevation. Differential diagnoses include PVD, exudative RD, tractional RD, retinoschisis, choroidal lesions, and artifacts (Table 2).