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

retinal explants. The rate of transcription of the iodopsin gene peaks late in the subjective day in constant darkness,3 h before the beginning of the subjective night, and mRNA levels peak early in the subjective night. The functional significance of the circadian rhythm of iodopsin mRNA is yet to be determined.

Ion channels in chicken cone photoreceptors are also subject to circadian regulation. There is a circadian rhythm in the affinity of the cone cyclic nucleotide-gated channel for cGMP, with highest affinity during the subjective night. In addition, L-type Ca2+ channels are regulated in a circadian fashion. The Ca2+ currents and immunoreactivity for a1C and a1D calcium channel subunits are greater at night than during the day. There is also a rhythm of a1D mRNA level. More details on rhythms of ion channels can be found elsewhere in this encyclopedia.

Conclusion

The chick retina is a remarkably rhythmic tissue, with robust circadian control of gene expression, metabolism, physiology, and melatonin synthesis. Most attention has been paid thus far to photoreceptor rhythms, but inner retinal neurons also express clock genes and are likely to be subject to circadian control. The ability to generate retinal cell cultures, which maintain their circadian properties and can be manipulated pharmacologically and genetically, suggests that the chick retina will continue to be a valuable model system for exploring the circadian organization of the retina.

Acknowledgments

The author is grateful to the past and present members of his laboratory, especially Rashidul Haque, Nikita Pozdeyev, Shyam Chaurasia, and Tamara Ivanova, and to David Klein and the members of his laboratory, who contributed greatly to the body of knowledge contained within this article. The author also thanks Gianluca Tosini for his collaborative contributions and for critical comments and suggestions on the article. Research in the author’s laboratory is funded by the National Institutes of Health EY004864 and EY06360, and by Research to Prevent Blindness.

See also: The Circadian Clock in the Retina Regulates Rod and Cone Pathways; Circadian Photoreception; Circadian Regulation of Ion Channels in Photoreceptors; Circadian Rhythms in the Fly’s Visual System; Fish Retinomotor Movements; Limulus Eyes and Their Circadian Regulation; Neurotransmitters and Receptors: Dopamine Receptors; Neurotransmitters and Receptors: Melatonin Receptors.

Further Reading

Bailey, M. J., Beremand, P. D., Hammer, R., et al. (2004). Transcriptional profiling of circadian patterns of mRNA expression in the chick retina. Journal of Biological Chemistry 279: 52247–52254.

Bellingham, J., Chaurasia, S. S., Melyan, Z., et al. (2006). Evolution of melanopsin photoreceptors: Discovery and characterization of a new melanopsin in nonmammalian vertebrates. PLoS Biology 4: e254.

Bailey, M. J., Chong, N. W., Xiong, J., and Cassone, V. M. (2002). Chickens’ Cry2: Molecular analysis of an avian cryptochrome in retinal and pineal photoreceptors. FEBS Letters 513: 169–174.

Bernard, M., Iuvone, P. M., Cassone, V. M., et al. (1997). Avian melatonin synthesis: Photic and circadian regulation of serotonin N-acetyltransferase mRNA in the chicken pineal gland and retina.

Journal of Neurochemistry 68: 213–224.

Chaurasia, S. S., Haque, R., Pozdeyev, N., Jackson, C. R., and Iuvone, P. M. (2006). Temporal coupling of cyclic AMP and Ca/calmodulin-stimulated adenylyl cyclase to the circadian clock in chick retinal photoreceptor cells. Journal of Neurochemistry 99: 1142–1150.

Chaurasia, S. S., Pozdeyev, N., Haque, R., et al. (2006). Circadian clockwork machinery in neural retina: Evidence for the presence of functional clock components in photoreceptor-enriched chick retinal cell cultures. Molecular Vision 12: 215–223.

Chaurasia, S. S., Rollag, M. D., Jiang, G., et al. (2005). Molecular cloning, localization and circadian expression of chicken melanopsin (Opn4): Differential regulation of expression in pineal and retinal cell types. Journal of Neurochemistry 92: 158–170.

Chong, N. W., Bernard, M., and Klein, D. C. (2000). Characterization of the chicken serotonin N-acetyltransferase gene. Activation via clock gene heterodimer/E box interaction. Journal of Biological Chemistry 275: 32991–32998.

Chong, N. W., Chaurasia, S. S., Haque, R., Klein, D. C., and Iuvone, P. M. (2003). Temporal-spatial characterization of chicken clock genes: Circadian expression in retina, pineal gland, and peripheral tissues.

Journal of Neurochemistry 85: 851–860.

Garbarino-Pico, E., Carpentieri, A. R., Contin, M. A., et al. (2004). Retinal ganglion cells are autonomous circadian oscillators synthesizing N-acetylserotonin during the day. Journal of Biological Chemistry 279: 51172–51181.

Guido, M. E., Pico, E. G., and Caputto, B. L. (2001). Circadian regulation of phospholipid metabolism in retinal photoreceptors and ganglion cells. Journal of Neurochemistry 76: 835–845.

Hamm, H. E. and Menaker, M. (1980). Retinal rhythms in chicks – circadian variation in melatonin and serotonin N-acetyltransferase.

Proceedings of the National Academy of Sciences of the United States of America 77: 4998–5002.

Haque, R., Chaurasia, S. S., Wessel, J. H., III, and Iuvone, P. M. (2002). Dual regulation of cryptochrome 1 mRNA expression in chicken retina by light and circadian oscillators. NeuroReport 13: 2247–2251.

Iuvone, P. M. and Alonso-Go´mez, A. L. (1998). Melatonin in the vertebrate retina. In: Christen, Y., Doly, M., and Droy-Lefaix, M.-T. (eds.) Retine, Luminiere, et Radiations, vol. 9, pp. 49–62. Paris: Irvinn.

Iuvone, P. M., Brown, A. D., Haque, R., et al. (2002). Retinal melatonin production: Role of proteasomal proteolysis in circadian and photic control of arylalkylamine N-acetyltransferase. Investigative Ophthalmology and Visual Science 43: 564–572.

Ivanova, T. N. and Iuvone, P. M. (2003). Circadian rhythm and photic control of cAMP level in chick retinal cell cultures: A mechanism for coupling the circadian oscillator to the melatonin-synthesizing enzyme, arylalkylamine N-acetyltransferase, in photoreceptor cells.

Brain Research 991: 96–103.

Iuvone, P. M., Tosini, G., Pozdeyev, N., et al. (2005). Circadian clocks, clock networks, arylalkylamine N-acetyltransferase, and melatonin in the retina. Progress in Retinal and Eye Research 24: 433–456.

Pierce, M. E., Sheshberadaran, H., Zhang, Z., et al. (1993). Circadian regulation of iodopsin gene expression in embryonic photoreceptors in retinal cell culture. Neuron 10: 579–584.

Pozdeyev, N., Taylor, C., Haque, R., et al. (2006). Photic regulation of arylalkylamine N-acetyltransferase binding to 14-3-3 proteins in retinal photoreceptor cells. Journal of Neuroscience 26: 9153–9161.

Central Retinal Vein Occlusion

S S Hayreh, University of Iowa, Iowa City, IA, USA

ã 2010 Elsevier Ltd. All rights reserved.

Glossary

Demographic – The statistical study of a population, including geographical distribution, sex and age composition, and birth and death rates.

Electroretinography – The recording of the changes in electric potential in the retina by stimulating it by light.

Fluorescein fundus angiography – The visualization of blood vessels in the interior of the eye following intravenous injection of fluorescein. Glaucoma – An eye disease caused by an increase in eye pressure, which causes changes in the optic nerve and loss of vision.

Hematological – Dealing with the blood and bloodforming tissues.

Histopathological – Dealing with the minute structure of diseased tissues.

Lamina cribrosa – The perforated portion of the back part of the white of the eye (sclera) through which nerve fibers from the retina exit.

Multifactorial – Related to, or arising through the action of many factors.

Neovascularization – The formation of abnormal new blood vessels.

Ophthalmoscopy – The examination of the interior of the eye with the instrument called ophthalmoscope.

Panretinal photocoagulation – The application of an intense beam of laser light to the entire retina. Pathogenesis – The mechanisms of development of a disease.

Perimeter – An apparatus used to test the visual field.

Retinal vein occlusion is the most common retinal vascular occlusive disorder. In general, there is a tendency to regards this as one disease; that is not only incorrect but also causes much confusion. From the point of view of pathogenesis, clinical picture, prognosis, and management, retinal vein occlusion in fact consists of six distinct clinical entities that are categorized as follows:

1.Central retinal vein occlusion (CRVO), which comprises

a.nonischemic CRVO, and

b.ischemic CRVO.

2.Hemi-central retinal vein occlusion (HCRVO), which comprises

a.nonischemic HCRVO, and

b.ischemic HCRVO.

3.Branch retinal vein occlusion, which includes

a.major BRVO, and

b.macular BRVO.

It is beyond the scope of this article to discuss all the six types of retinal vein occlusion; hence, we restrict our discussion only to CRVO. Over the last 150 years, a large volume of literature has accumulated on the subject of CRVO. The objective of this article is to provide a brief review of the current state of our knowledge on the subject.

Pathogenesis

A good understanding of the pathogenesis of a disease is fundamental to a full grasp of the clinical features of the disease and its logical management. There is almost a universal tendency to blame one or two factors as causative factor(s) in the development of CRVO, but association does not necessarily mean there is a cause-and-effect relationship. Available evidence strongly suggests that the pathogenesis of CRVO, like many other ocular vascular occlusive disorders, is a multifactorial process. It seems that some risk factors predispose an individual or an eye to CRVO (predisposing risk factors), while others act as the final insult and produce clinically evident disease (precipitating risk factor(s)). Only when an eye and an individual have the critical number of risk factors required for the development of CRVO, does the CRVO develop. This must explain why bilateral CRVO is rare. Once this basic concept of multifactorial causation is understood, one can attach appropriate significance to the various risk factors. The various risk factors for CRVO may be divided into the following three categories:

Local. Two local factors are particularly important:

1.The central retinal vein and central retinal artery lie in the center of the optic nerve, surrounded by a fibrous tissue envelope (Figure 1). In elderly persons, sclerotic changes in the central retinal artery and the fibrous tissue envelope compress the thinwalled central retinal vein, resulting in narrowing of its lumen. This produces circulatory stasis. According to Virchow’s triad, slowing down of the blood stream causes stagnation thrombosis.

FTE

CRA

CRV

FTE

CRV

CRA

Figure 2 Schematic representation of blood supply of the optic nerve. A, arachnoid; C, choroid; CRA, central retinal artery; Col. Br., collateral branches from other orbital arteries to the optic nerve; CRV, central retinal vein; D, dura; LC, lamina cribrosa; ON, optic nerve; PCA, posterior ciliary artery; PR, prelaminar region; R, retina; S, sclera; SAS, subarachnoid space. Adapted from Hayreh, S. S. (1974). Transactions – American Academy of Ophthalmology and Otolaryngology 78: OP240–OP254, with permission from American Academy of Ophthalmology.

Figure 1 Histological sections (Masson’s trichrome staining) showing the central retinal vessels and surrounding fibrous tissue envelope, as seen in a transverse section of the central part of the retrolaminar region of the optic nerve, in a normal rhesus monkey (above) and in a rhesus monkey with experimental arterial hypertension, atheroselerosis, and glaucoma (below). CRA, Central retinal artery; CRV, central retinal vein; FTE, fibrous tissue envelope.

2.It is well established that CRVO is significantly more common in patients with raised intraocular pressure (IOP) and glaucoma.

Systemic. A significant association of CRVO has been reported with arterial hypertension, diabetes mellitus, cardiovascular disease, atherosclerosis, and thyroid disease.

Hematological. The literature is full of reports of hematological abnormalities in CRVO. The author recently critically reviewed the literature dealing with these and found no definite pattern – often the negative findings outweighed the positive ones. The idea of hematologic factors playing a role in CRVO is essentially based on the assumption that those hematological disorders, which play a role in development of systemic venous thrombosis (e.g., deep vein thrombosis), must also do so in CRVO. All the available evidence, however, indicates that the hematologic risk factor responsible for major systemic venous thrombosis occurs only sporadically in CRVO. Furthermore, CRVO is extremely rare in patients with systemic venous thrombosis. Moreover, the presence of a particular hematologic disorder in a patient does not necessarily mean it has a cause-and- effect relationship with CRVO. In view of this, there is no particular reason for conducting a detailed hematological investigation in all patients with CRVO.

Site of Occlusion in CRVO

Based on histopathological studies, there is a widespread misconception that the site of occlusion in CRVO is invariably at the lamina cribrosa. However, all the available anatomical, experimental, and clinical evidence (particularly fluorescein fundus angiography) shows that the actual site of occlusion in the central retinal vein is typically in the optic nerve, at a variable distance posterior to the lamina cribrosa, and not at the lamina cribrosa (Figure 2). The farther back the site of occlusion, the more collaterals are available, and the less severe is the retinal venous stasis. Thus, in nonischemic CRVO the site of occlusion most likely is farther back in the optic nerve, whereas in ischemic CRVO it is closer to the lamina cribrosa.

Demographic Characteristics

CRVO is more common in middle-aged and elderly persons, and patients with ischemic CRVO tend to be older than those with nonischemic CRVO. Contrary to the prevalent impression, CRVO is not at all rare in young persons, and the incidence in persons under the age of 45 years has been reported as high as 18%. Thus, no age is immune. In our series of 620 consecutive CRVO cases, 81% were nonischemic and 19% ischemic CRVO. The Kaplan– Meier estimate of the cumulative proportion of eyes that developed nonischemic CRVO in the fellow eye is about 6% within 1 year and 7% within 5 years from onset in the first eye; for ischemic CRVO it is 5.6% at 2.8 years.

Clinical Features

With regard to symptoms, patients with nonischemic CRVO may have no symptoms and it may be detected as an incidental finding on a routine ophthalmic examination. Retinal venous stasis with mild retinal hemorrhages per se is asymptomatic. Occasionally there may be a history of episodes of transient visual blurring before constant visual deterioration. Almost invariably, it becomes symptomatic only when there is involvement of the foveal region by development of macular edema (Figures 3 and 4) and rarely by hemorrhages. Therefore, the most common complaint is gradual development of central visual blurring, usually more marked on waking up in the morning, improving to a variable extent after a few hours or in the afternoon. In ischemic CRVO, on the other hand, there is always marked deterioration of vision.

While the diagnosis of CRVO is not difficult because of its classical clinical features (Figures 5 and 6), the main problem is differentiation of nonischemic from ischemic CRVO, which is crucial for the correct management of CRVO. This is because nonischemic CRVO is a comparatively benign condition, with permanent central

Figure 4 Late phase of fluorescein fundus angiogram of an eye with nonischemic CRVO showing classical petaloid pattern of cystoid macular edema.

(a)

(b)

Figure 5 Fundus photograph (a) and fluorescein fundus angiogram showing intact retinal capillary network (b) of an eye with nonischemic CRVO. Reproduced from Hayreh, S. S. (1994).

Indian Journal Ophthalmology 42: 109–132.

scotoma as the major complication in some eyes, but no ocular neovascularization (NV). In sharp contrast to this, ischemic CRVO is a blinding disease, with high risk of development of anterior segment NV, particularly neovascular glaucoma, which often results in blindness or even loss of the eye. Thus, the two types of CRVO can be compared to benign and malignant tumors.

Differentiation of Ischemic from Nonischemic CRVO

Ophthalmologists have almost universally used ophthalmoscopic and fluorescein angiographic appearances to evaluate and manage CRVO and to differentiate ischemic from nonischemic CRVO. However, these two morphological tests have much lower sensitivity and specificity to differentiate the two types of CRVO compared to the four functional tests – visual acuity, peripheral visual fields plotted with a Goldmann perimeter, relative afferent

(a)

(b)

Figure 6 Fundus photograph (a) and fluorescein fundus angiogram showing complete nonperfusion of retinal capillary network (b) of an eye with ischemic CRVO. Reproduced from Hayreh et al. (1983). Ocular neovascularization with retinal vascular occlusion III. Incidence of ocular neovascularization with retinal vein occlusion. Ophthalmology 90: 488–506.

pupillary defect, and electroretinography. Table 1 gives sensitivity and specificity of various functional tests to differentiate ischemic from nonischemic CRVO.

On fluorescein fundus angiography, to differentiate ischemic from nonischemic CRVO, the presence of a 10 disk area or more retinal capillary obliteration has been regarded as the gold standard in practically all the reported studies, but there are several serious problems with this criterion, including the following:

1.During the early, acute stages of CRVO, to provide reliable information on retinal capillary obliteration, angiography has many serious limitations, including extensive retinal hemorrhages, poor-quality angiograms, inability to perform angiography for a variety of reasons, the time lag of several weeks after the onset of CRVO before retinal capillary obliteration is visible, and other limitations. A study showed that fluorescein angiography provided reliable information at best in only

50–60% of cases during the early, acute phase, which is clinically unsatisfactory for early management.

2.Most importantly, a criterion of a 10 disk area or more of retinal capillary obliteration has been widely advocated as the definitive yardstick for diagnosis of ischemic CRVO. However, this is an invalid criterion to differentiate nonischemic from ischemic CRVO. A multicenter study showed that eyes with <30 disk diameters of nonperfusion and no other risk factor are at low risk for iris/angle NV (i.e., ischemic CRVO), ‘whereas eyes with 75 disk diameters or more are at highest risk’.

As regards ophthalmoscopy, there is a marked overlap between the two types of CRVO and virtually a continuous evolution of ophthalmoscopic lesions (i.e., retinal hemorrhages, venous dilatation, and cotton-wool spots, etc.; Figures 5(a) and 6(a)), which makes it hard to use this to differentiate the two types of CRVO.

A study showed that to differentiate the two types of CRVO, the overall order of reliability of various tests is as follows:

1.Relative afferent pupillary defect. In unilateral CRVO, when the fellow eye is normal.

2.Electroretinography. This is the next best test and it can be done even when the fellow eye is not normal, as in bilateral CRVO.

3.Relative afferent pupillary defect combined with electroretinography. This proved to be the most reliable (in 97%).

4.Peripheral visual fields plotted with a Goldmann perimeter. This is next in order and better than visual acuity. Since central scotoma is present in all CRVO eyes, that does not help in differentiation.

5.Visual acuity. This is also helpful in many cases.

6.Fluorescein angiography. This proved to be much worse than any of the functional tests in early stages.

7.Ophthalmoscopy. This is the least reliable and most misleading parameter of all.

Thus, we can conclude that no single test has 100% sensitivity and specificity to differentiate the two types of CRVO during the early, acute phase, such that no single test can be considered a gold standard; however, combined information from all the six tests is almost always reliable. The four functional tests overall are much superior to the two morphologic tests.

Course of CRVO

Both types of CRVO run a self-limited course, taking from a few weeks to many years for the retinopathy to resolve. In the meantime, some of these eyes can develop various complications, including those discussed below.

Complications

The main complications of the two types of CRVO are as follows:

1.Macular edema. This is the most common complication in both types of CRVO (Figures 3 and 4). However, it does not affect eyes with mild nonischemic CRVO. Chronic macular edema later on may produce cystoid macular degeneration (Figure 3(a)), macular pigmentary degeneration (very much resembling age-related macular degeneration; Figure 7), and/or epiretinal membrane – all resulting in central scotoma.

2.Ocular NV. This is the most dreaded complication of CRVO and a complication of ischemic CRVO alone. It is extremely important to note that ocular NV is almost never seen in nonischemic CRVO, unless it is associated with diabetic retinopathy or ocular ischemia.

The cumulative probability of developing various types of ocular NV in ischemic CRVO is shown

Table 1 Sensitive and specify of various functions tests to differentiate ischemic from nonischemic CRVO

From Hayreh, S. S., Klugman, M. R., Beri, M., Kimura, A. E., and Podhajsky, P. (1990). Differentiation of ischemic from nonischemic central retinal vein occlusion during the early acute phase. Graefe’s Archive for Clinical and Experimental Ophthalmology 228: 201–217.

Figure 7 Fundus photograph of an eye with resolved nonischemic CRVO, showing macular pigmentary degeneration and retinociliary collaterals on the optic disk, as the permanent, residual changes.

Cumulative chance of developing in %

Time in days

graphically in Figure 8, which provides five very important pieces of information for management of CRVO:

a.Not every eye fulfilling the criteria given above for ischemic CRVO develops ocular NV.

b.When ocular NV does develop, the most common site is the anterior segment, much less frequently the posterior segment.

c.The greatest risk of developing anterior segment NV is during the first 7–8 months, after which the risk falls dramatically, to minimal. The old concept of 100-day glaucoma has no validity.

d.The maximum risk of developing neovascular glaucoma is about 50% – not 100%, as often stated.

e.About one-third of eyes with iris NV and about onequarter of eyes with both iris and angle NV, contrary to the prevalent impression, never progress to develop neovascular glaucoma.

In order to place the overall incidence of ocular NV, particularly of neovascular glaucoma in CRVO, in true perspective, it is essential to point out two important facts:

i.ischemic CRVO constitutes only one-fifth of all CRVO cases (see above);

ii.neovascular glaucoma, the most dreaded complication of CRVO, is seen at the maximum in about 50% of ischemic CRVO cases only.

This means that the overall incidence of neovascular glaucoma in all CRVO cases is no more than 10% at the most – a key fact in any consideration of the management of CRVO.

3. Vitreous hemorrhage. In CRVO, this may be either secondary to retinal/optic disk NV or due to rupture of

Figure 9 Fundus photograph of an eye with nonischemic CRVO in a patient on aspirin, showing extensive retinal hemorrhages.

the retinal blood through the internal limiting membrane, particularly in eyes with many subinternal limiting membrane hemorrhages (Figures 9–11). Therefore, it is important to be aware that the presence of vitreous hemorrhages in CRVO does not always mean that there is retinal/ disk NV.

4. Cilioretinal artery occlusion. The major cause of serious visual loss in nonischemic CRVO is the development of associated transient occlusion of a cilioretinal artery due to hemodynamic block and not due to any thrombosis in the artery (Figures 12 and 13). This is particularly so when the artery supplies a large sector of the retina (Figure 13) or supplies the entire maculopapillar bundle (resulting in a large absolute centrocecal defect).

Figure 10 Fundus photograph of an eye with nonischemic CRVO in a patient on anticoagulant therapy, showing extensive retinal hemorrhages. Reproduced from Hayreh, S. S. (2006). Retina 26: S51–S62, with permission from Wolters Kluwer.

Figure 11 Fundus photograph of an eye with ischemic CRVO in a patient on anticoagulant therapy, showing extensive preretinal hemorrhages.

5. Conversion of nonischemic CRVO to ischemic CRVO.

Figure 14, based on study of 620 consecutive CRVO eyes, shows Kaplan–Meier survival curves for cumulative probability of conversion of nonischemic CRVO to the ischemic type. This change can happen either overnight or gradually.

Management of CRVO

In the management of CRVO, the first, most crucial step is to determine whether one is dealing with nonischemic or ischemic CRVO because of their very different nature, prognosis, visual outcome, and management. Lack of such differentiation has resulted in major controversies on CRVO.

Figure 12 Fundus photograph of an eye with nonischemic CRVO and retinal infarct in a narrow strip below the foveola due to associated cilioretinal artery occlusion. Reproduced from Hayreh, S. S., Fraterrigo, L., and Jonas, J. (2008). Central retinal vein occlusion associated with cilioretinal artery occlusion. Retina 28: 581–594, with permission from Wolters Kluwer.

Figure 13 Fundus photograph of an eye with nonischemic CRVO and retinal infarct involving most of the lower half of the retina due to associated cilioretinal artery occlusion. Reproduced from Hayreh, S. S., Fraterrigo, L., and Jonas, J. (2008). Central retinal vein occlusion associated with cilioretinal artery occlusion. Retina 28: 581–594, with permission from Wolters Kluwer.

Over the years, many treatments have been advocated enthusiastically and success claimed. A review of the treatment options, which have been championed from time to time, reveals that they vary from the logical to the totally absurd. The most important consideration when evaluating any proposed therapy for any disease is

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All episodes

Onset age <45

Onset age 45−64

Onset age 65 or older

to determine whether it is based on incontrovertible scientific facts and rationale. Treatments without such a logical foundation prove not only useless but also sometimes harmful. Most of the reported studies have been based on retrospective collection of information or on limited personal experience and, therefore, have a variety of limitations which make it hard to evaluate the claimed benefits; the limitations include lumping together of central and branch retinal vein occlusion, no differentiation of ischemic and nonischemic CRVO or use of invalid criteria to do so, therapies having no scientific validity, flawed study designs, and personal biases. All the proposed therapies must then be carefully scrutinized.

The main treatments advocated for CRVO can be divided into three categories, namely medical, surgical, and panretinal photocoagulation (PRP), which are discussed below.

Medical Treatments

These include anticoagulants, aspirin or other antiplatelet agents, ocular hypotensive therapy, hemodilution, systemic or intravitreal corticosteroids, intravitreal anti-VEGF (VEGF, vascular endothelial growth factor) drugs, systemic acetazolamide, and antihypertensive therapy. Of these, either aspirin or anticoagulants have been most widely used, based on the impression that a treatment which is beneficial for systemic venous thrombosis is also good for CRVO; however, the two conditions are totally different etiologically and pathogenetically. Neither anticoagulants nor aspirin has any scientific rationale in the management of CRVO. They increase retinal

hemorrhages (Figures 9–11, and 15), thereby adversely influencing the visual outcome. Moreover, patients already on those drugs for other reasons do develop CRVO, indicating that they do not prevent an eye from developing CRVO. The so-called blood-and-thunder or tomato-ketchup fundus appearance described in CRVO is usually an iatrogenic phenomenon resulting from the use of aspirin or anticoagulants; it is not usually seen in regular CRVO. There is no scientific rationale for the commonly used ocular hypotensive therapy in CRVO eyes with normal IOP; however, if the fellow uninvolved eye has ocular hypertension or glaucoma (which is common), that eye must be treated to reduce the chances of its developing CRVO – thus, it is mostly the wrong eye (i.e., with CRVO) which is being treated. Recently, intravitreal corticosteroids and intravitreal anti-VEGF drugs have been widely advocated, primarily to manage macular edema; however, it is important to stress that the treatment with these agents is simply helping to reduce or eliminate macular edema transiently to prevent long-term permanent macular changes (Figures 3 and 7); it is not a cure for the CRVO, which has to take its own natural course. Moreover, both drugs require repeated intravitreal injections to maintain effectiveness and can have some side effects. As regards the rest of treatment modalities, there is not much scientifically valid evidence of beneficial effects.

Surgical or Invasive Treatments

These include (1) surgical decompression of the central retinal vein, (2) fibrinolytic therapy, and (3) laser-induced

chorioretinal venous anastomosis for treatment of nonischemic CRVO, which are detailed below:

1.Surgical decompression of central retinal vein. It has been claimed that a procedure called radial optic neurotomy, in which a radial cut in the optic nerve head, from the vitreous side, extending all the way down to the lamina cribrosa and adjacent sclera, is beneficial. This procedure not only has no scientific rationale but also can actually be deleterious – it involves cutting thousands of optic nerve fibers, which results in visual loss in the distribution of the cut nerve fibers.

2.Fibrinolytic therapy. Currently, the most widely promoted procedure of this type is vitrectomy with branch retinal vein cannulation and infusion of tissue plasminogen activator (t-PA). This procedure lacks scientific rationale and can be associated with complications; beneficial claims made for it seem unwarranted.

3.Laser-induced chorioretinal venous anastomosis for treatment of nonischemic CRVO. This procedure has many immediate and late complications, which heavily outweigh any dubious benefits. Therefore, it is not a safe and effective mode of treatment for a condition which has a fairly good outcome if simply left alone (see below).

Panretinal Photocoagulation

Currently, PRP is almost universally considered the treatment of choice in CRVO to prevent development of ocular NV, and macular grid photocoagulation for the management of macular edema. The rationale for usefulness of PRP in CRVO is based primarily on its beneficial effect seen in proliferative diabetic retinopathy.

1.Macular grid photocoagulation for macular edema. A multicenter clinical trial showed no difference between treated and untreated eyes in visual acuity at any point during the follow-up period. This indicated that there is no role for this treatment in CRVO.

2.PRP for prevention of ocular NV. The theoretical justification for PRP in ischemic CRVO is to prevent development of ocular NVand associated blinding complications of neovascular glaucoma and/or vitreous hemorrhage. As discussed above, ocular NVand neovascular glaucoma are seen only in ischemic CRVO. Since nonischemic CRVO does not develop these complications, there is absolutely no indication or justification for PRP in nonischemic CRVO.

Two large prospective studies have been conducted to evaluate the role of PRP in ischemic CRVO. The first study, based on 123 eyes with ischemic CRVO (47 had PRP and 76 no PRP), showed no statistically significant difference between the two groups in the incidence of development of angle NV, neovascular glaucoma, retinal and/or optic disk NV, or vitreous hemorrhage, or in visual acuity. What it did show was that the PRP group suffered a statistically significant ( p 0.03) greater loss of peripheral visual fields than the nonlaser group (Figure 16).

The second study investigated the role of PRP in ischemic CRVO by a multicenter clinical trial in 181 eyes (90 had immediate prophylactic PRP, and 91 no PRP). The purpose of that study was twofold – first to determine whether prophylactic PRP prevents development of iris and angle NV, and second whether PRP prevents progression of iris/angle NV to neovascular glaucoma. In answer to the first question, the study