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NEOVASCULAR GLAUCOMA

Sohan Singh Hayreh, MD, PhD, DSc, FRCS, FRCOphthProfessor Emeritus of Ophthalmology, Department of Ophthalmology & Visual Sciences, Collegeof Medicine, University of Iowa, Iowa City, Iowa, USA

Abstract

NVG is a severely blinding, intractable disease. The objective of this review is to provide detailed

information on its basic and clinical aspects, to enable us to manage it logically. Therefore, its causes,

pathogenesis and pathology, methods of early diagnosis and management are discussed. To prevent

or reduce the extent of visual loss caused by NVG, the first essential is to have a high index of

suspicion of its development. The most common diseases responsible for development of NVG are

ischemic CRVO, diabetic retinopathy and ocular ischemic syndrome. In the management strategy,

the first priority should be to try to prevent its development by appropriate management of thecausative diseases. If NVG develops, early diagnosis is crucial to reduce the extent of visual loss.

Management of NVG primarily consists of controlling the high IOP by medical and/or surgical means

to minimize the visual loss. Currently we still do not have a satisfactory means of treating NVG and

preventing visual loss in the majority, in spite of multiple modes of medical and surgical options

advocated over the years and claims made. This review discusses pros and cons for the various

advocated treatments.

Keywords

Angle neovascularization; Carbonic anhydrase drugs; Central retinal vein occlusion;

Cyclophotocoagulation; Diabetic retinopathy; Intraocular pressure; Iris neovascularization;

Neovascular glaucoma; Ocular ischemic syndrome; Trabeculectomy; Glaucoma implants

1. INTRODUCTION

Neovascular glaucoma (NVG) is a blinding, intractable disease, difficult to manage and often

resulting in disastrous visual loss. For a logical understanding and scientific rationale for

management of any disease, one first has to know the basic issues involved and the scientifically

valid information available on the disease. To prevent or reduce the visual loss caused by NVG,

the first essential is to have a high index of suspicion of its development, i.e. to be aware of

the various ocular diseases in which it can develop. Once it develops, early diagnosis and

rational management are important to minimize the visual loss. Therefore, the objective of this

review on NVG is to discuss its causes, pathogenesis and pathology, methods of early diagnosis

and finally management.

Correspondence to: Professor S.S. Hayreh, Department of Ophthalmology and Visual Sciences, University Hospitals & Clinics, 200Hawkins Drive, Iowa City, Iowa 52242-1091, USA, Telephone No. 319-356-2947. Fax No. 319-353-7996 [email protected].

FURTHER READING

For comprehensive bibliography on he various topics, please consult the full bibliography given in the references listed above.

NIH Public AccessAuthor ManuscriptProg Retin Eye Res. Author manuscript; available in PMC 2010 May 17.

Published in final edited form as:

Prog Retin Eye Res. 2007 September ; 26(5): 470485. doi:10.1016/j.preteyeres.2007.06.001.

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2. CAUSES OF NEOVASCULAR GLAUCOMA (NVG)

These can be divided into two categories: (a) the most common causes, and (b) uncommon

causes.

2.1. Most common ocular causes of NVG

Diabetic retinopathy, ischemic central retinal vein occlusion (CRVO) and ocular ischemic

syndrome are by far the most common causes of NVG. There is little controversy about NVGin diabetic retinopathy. However, many of the concepts about NVG in various types of retinal

vascular occlusive diseases and ocular ischemic syndrome are controversial. In the Ocular

Vascular Clinic of the University of Iowa Hospitals and Clinics we have systematically

investigated the various retinal vascular occlusive diseases as well as ocular ischemic syndrome

in detail in longitudinal prospective studies since 1973; these studies have provided new

information, contradicting several of the conventional wisdoms on these disorders. Those

require detailed discussion in the interest of clarifying the confusion and controversies on these

important disorders (see below);

2.1.1. Diabetic retinopathyAssociation of NVG with diabetic retinopathy is a well-

established clinical entity, and a huge volume of literature has accumulated on this subject.

NVG is an advanced manifestation of diabetic retinopathy. NVG may occur without retinal or

optic disc neovascularization (NV), however, it is more commonly seen in association withproliferative diabetic retinopathy.

2.1.2. Retinal vascular occlusive diseasesNVG may occur in the setting of ischemicCRVO or more rarely following ischemic hemi-CRVO, simultaneous multiple branch retinal

vein occlusion involving large areas of the retina, or when venous occlusions are superimposed

upon a background of non-proliferative diabetic retinopathy. There are many unfounded

theories regarding NVG and vein occlusions. These have spawned controversy and some

confusion on the etiology, natural course and management of NVG in such patients. I have

discussed the various misconceptions elsewhere [Hayreh 2005]. I have included here an

abbreviated discussion of some of the most common misunderstandings relevant to NVG in

retinal vascular occlusive diseases.

2.1.2.1. Retinal vascular occlusive diseases associated with NVG

2.1.2.1. Retinal vascular occlusive diseases associated with NVG:2.1.2.1.1. Central retinal

vein occlusion (CRVO): There is a common notion among ophthalmologists that every eye

with CRVO is at risk of developing NVG. It is well established now that CRVO is of two

distinct types non-ischemic and ischemia CRVO, with very different clinical findings,

complications, course, prognoses and managements (Hayreh 1965,1976,1983,1994, 2003,

2005; Hayreh et al. 1983, 1990a).NVG is a complication only of ischemic CRVO(Hayreh et

al. 1983). Eyes with nonischemic CRVO do not develop ocular NV or NVG (Hayreh et al.

1983), unless there is associated diabetic retinopathy or ocular ischemic syndrome - the latter

two associated conditions being the sole cause of ocular NV in those eyes, which may wrongly

be attributed to nonischemic CRVO. Therefore, the first essential step in the management of

CRVO is to determine whether the CRVO is ischemic or non-ischemic. Hayreh et al.

(1990a) in their study investigated the various clinical tests that can help to differentiate thetwo types of CRVO. In almost all the published series, a criterion of 10 disc area of retinal

capillary obliteration has been used to classify CRVO as ischemic. However, studies by

Hayreh et al. (1990a) have shown that this is not at all a valid criterion. The presence ofisolated,

small, focal retinal capillary obliteration is compatible with nonischemic CRVO. The results

of a large multicenter CRVO study (The Central Retinal Vein Occlusion Group, 1995)

supported their conclusions. This multicenter study clearly showed that eyes with less than

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30 disc diameters of retinal capillary nonperfusion and no other risk factor are at low risk

for developing iris/angle neovascularization (i.e. ischemic CRVO), whereas eyes with 75 disc

diameters or more are at highest risk. Thus, 10 disc area of retinal capillary obliteration

on fluorescein angiography is totally unreliable parameter in differentiating ischemic from non-

ischemic CRVO. It can result in incorrect diagnosis, prognosis and management.

Hayreh et al. (1990a) in their study, to differentiate ischemic from non-ischemic CRVO during

the early acute phase, found a number of much more sensitive and specific diagnostic clinicaltests, which make such a differentiation accurately. They divided these tests into two

categories:

A. Functional tests: These consist of visual acuity, visual fields plotted with a Goldmann

perimeter, relative afferent pupillary defect and electroretinography. The following

table gives their sensitivity and specificity.

Functional tests Sensitivity Specificity

Visual acuity:

20/400 91% 88%

Peripheral visual fields*:

No I-2e 97% 73%

Defective I-4e 92% 87%

Defective V-4e 100% 100%

Relative afferent pupillary defect:

0.9 log units 80% 97%

Electroretinography:

b-wave amp.60% 80% 80%

*Visual field plotted with a Goldmann perimeter.

B. Morphological tests: These consist of ophthalmoscopy and fluorescein fundus

angiography. The study by Hayreh et al. (1990a) showed ophthalmoscopy to be

unreliable and most misleading test to differentiate the two types of CRVO at any

stage. Fluorescein fundus angiography has multiple limitations (discussed in detail in

that study) to provide satisfactory information about the retinal capillary obliteration

during the early acute stage, and it provided reliable information at best in 5060%

only.

Thus, their study showed that combined information provided by the six functional tests helps

to differentiate ischemic CRVO from nonischemic CRVO most reliably during the early acute

stage.

Based upon this and additional criteria, Hayreh et al. (1983) have demonstrated that every eye

with ischemic CRVO does not develop ocular NV and/or NVG. The cumulative risk in theirstudy of ocular NV in ischemic CRVO is illustrated in figure 1. It shows that the risk of

developing NVG in eyes with ischemic CRVO reaches a maximum of about 45% in aggregate

over several years the maximum risk being during the first 78 months only [Hayreh et al.

1983]. They also found that only 20% of all eyes with CRVO are of the ischemic type [Hayreh

et al. 1983; Hayreh 1994]. Therefore, the risk of an eye with CRVO developing NVG is not

100% but about 910% [Hayreh 2003]. This puts the threat of NVG in CRVO into proper

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perspective. However, if an ischemic CRVO is identified, one should have a high index of

suspicion for development of NVG.

2.1.2.1.2. Hemi-central retinal vein occlusion: Similar to CRVO, hemi-central retinal vein

occlusion (HCRVO) may be divided into ischemic and non-ischemic types, based upon clinical

findings [Hayreh and Hayreh 1980]. Like the CRVO, NVG is only a complication of the

ischemic hemi-CRVO and not in non-ischemic type. In one series, NVG developed in 3% (one

of 31) ischemic HCRVO eyes (Hayreh et al. 1983).

In general, the development of NVG in retinal vein occlusion depends upon the severity and

extent (area) of retinal ischemia (Hayreh et al. 1983; The Central Vein Occlusion Study

1997). Hemi-CRVO typically involved one hemisphere of the eye. Thus, the risk of developing

NVG due to sufficient stimulus in ischemic hemi-CRVO is very low.

2.1.2.2. Retinal vascular occlusive diseases not associated with NVG

2.1.2.2. Retinal vascular occlusive diseases not associated with NVG:2.1.2.2.1. Branch

retinal vein occlusion: There is a prevalent mistaken belief that branch retinal vein occlusion

can cause NVG. The principal factors in the development of ocular NV following retinal vein

occlusion are the severity and spatial extent (area) of retinal ischemia [Hayreh et al. 1983; The

Central Vein Occlusion Study 1997]. In the study by Hayreh et al. (1983) on ocular NV

associated with retinal vein occlusion, NONE of the 264 eyes with branch retinal vein occlusiondeveloped NVG. Their studies have indicated that it usually requires at least half or more of

the retina to be involved by ischemia to provide adequate neovascular stimulus. The vast

majority of major branch retinal vein occlusions involve smaller segments of the retinal

vasculature, typically a quarter or less of the retinal surface area. Concerns of development of

NVG in branch retinal vein occlusion may stem from equating ischemic CRVO with ischemic

changes seen following branch retinal vein occlusion, which represent different clinical entities

and scales of stimuli. Thus, there is little risk of NVG following typical or isolated branch

retinal vein occlusion.

2.1.2.2.2. Central retinal artery occlusion (CRAO): Some authors have proposed that CRAO,

similar to ischemic CRVO, may be followed by ocular NV and NVG. A review of all the

publications associating NVG with CRAO from 1874 to 1982 revealed a number of problems

with this contention (see details in Hayreh and Podhajsky 1982). Studies by Hayreh et al.

[Hayreh and Podhajsky 1982; Hayreh and Zimmerman 2007], which evaluated 248 eyes with

CRAO, have not shown development of NVG in CRAO. Thus, their studies have shown no

basis for development of NVG in CRAO (Hayreh and Podhajsky 1982). The reasons are:

i. Equating CRAO with ischemic CRVO is a fundamental mistake because they have

very different nature, cause, course and outcome. Published evidence indicates that

chronically hypoxic retina, e.g., in diabetic retinopathy and/or ischemic CRVO,

results in production and secretion of vasoproliferative factors such as VEGF, FGF

and others, but that necrotic or infarcted retina, which results from CRAO, does not.

Therefore, there is no scientific basis to expect solitary CRAO to produce ocular NV

[Hayreh and Podhajsky 1982]. Hayreh and Zimmerman (2007), in their study of 248

eyes with CRAO, found that none of the eyes with CRAO alone developed ocular

NV; however, in the setting of ocular ischemia or diabetic retinopathy, ocular NV

was rarely found in CRAO [Hayreh and Zimmerman 2007]. In this study on CRAO,

estimated probability of developing cilioretinal collaterals on the optic disc within 3

months was 32% (Hayreh SS, Zimmerman 2007); I have found that some of those

collaterals have been misdiagnosed as disc NV.

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ii. It is well established that an eye suffering from ocular ischemic syndrome is at high

risk of developing ocular NV, including NVG (Hayreh and Podhajsky 1982; Mizener

et al. 1997). These eyes are also at risk of developing CRAO and independently of

developing NVG (Hayreh and Podhajsky 1982; Mizener et al. 1997). Therefore, the

following scenarios may happen: Development of NVG in eyes with ocular ischemia

results in a rise of intraocular pressure (IOP). Blood flow in the central retinal artery

and retinal vascular bed depends upon the perfusion pressure (i.e. difference between

the mean retinal arterial blood pressure and the intraocular pressure). In an eye withocular ischemia, two things can happen at the same time: (i) a fall of mean blood

pressure in the central retinal artery due to ocular ischemia, and (ii) a rise of IOP due

to development of NVG. This is a fatal combination for the retinal and central retinal

artery circulation, resulting in the development of secondary CRAO. This sequence

of events is represented diagrammatically in figure 2. In addition to CRAO, these eyes

may also develop anterior ischemic optic neuropathy and choroidal infarction (Hayreh

and Podhajsky 1982; Mizener et al. 1997). It is also well established that blood

pressure falls during sleep (i.e. nocturnal arterial hypotension see below). When all

these factors are put together, it is not surprising that the visual loss due to CRAO in

these eyes is often discovered on waking up from sleep. In such cases, NVG has

wrongly been considered as an effect of CRAO, when in fact it is the cause of CRAO.

2.1.2.2.3. Branch retinal artery occlusion: In my study of more than 150 eyes with branchretinal artery occlusion, no eye developed any ocular NV, including NVG. The reason for not

developing NVG in these eyes is the same as discussed above in CRAO.

2.1.3. Ocular ischemic syndromeOcular ischemic syndrome is a serious but

uncommon blinding condition. It is a frustrating condition for the ophthalmologist. The visual

prognosis and treatment outcomes are poor. There is no well-established treatment. Moreover,

it may be overlooked or misdiagnosed, primarily because of its diverse and sometimes subtle

presentation. Ocular ischemic syndrome can also masquerade several other ocular conditions.

Mizener et al. (1997) in their study, on ocular ischemic syndrome in 39 eyes, found a variable

range in the symptoms, signs, and course of the disease. Hayreh and Podhajsky (1982) have

discussed its pathogenesis in detail. Ocular ischemic syndrome is caused by reduction of global

blood flow to the eyeball, which can produce anterior and/or posterior segment ischemia.

Anterior segment ischemia results in development of iris and angle NV and NVG. Most patients

with ocular ischemic syndrome have severe carotid artery occlusive disease, but not all; it can

be associated with vascular occlusive disease of the aortic arch, or of the ophthalmic, central

retinal or ciliary arteries. It is not uncommon in clinical practice to find that carotid artery

disease is ruled out as the cause of ocular ischemia based on findings of absence of occlusion

or severe stenosis of the internal carotid artery on carotid Doppler. However, carotid Doppler

evaluates only the artery in the neck and not above or below that, where it may be markedly

stenosed. Hayreh and Dass (1962), in their anatomical studies on the ophthalmic artery, found

on rare occasions that the ophthalmic artery was markedly stenosed at its origin, while the

internal carotid artery was unobstructed and fully patent. Cerebral angiography or magnetic

resonance angiography may be necessary to provide information which carotid Doppler cannot

demonstrate, such as a significant stenosis in the carotid siphon or ophthalmic artery.

In the study of Mizener et al. (1997) on ocular ischemic syndrome, the prevalence of diabetes

mellitus in these patients was much higher than in the comparable general population.

Conventionally, retinal ischemia in the form of extensive retinal capillary non-perfusion (as

seen for example in ischemic CRVO and diabetic retinopathy) is considered the exciting factor

for the development of anterior segment NV and NVG. However, in that study, no patient with

ocular ischemic syndrome and ocular NV had retinal capillary non-perfusion on fluorescein

fundus angiography, not even those with diabetes mellitus. In contrast, in their studies in eyes

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with ocular ischemic syndrome, they have invariably found evidence of uveal vascular

insufficiency [Hayreh and Podhajsky 1982; Mizener et al. 1997]. This was further confirmed

by an experimental study in rhesus monkeys, where anterior segment NV (similar to that seen

with ocular ischemic syndrome) developed with uveal ischemia alone, without any retinal

ischemia (Hayreh and Baines 1973). These data suggest that uveal ischemia may be an

important contributing factor for the NV seen in ocular ischemic syndrome.

2.2. Uncommon ocular causes of NVGThe following is a list of the diseases in which NVG has been reported sometimes. In many of

them, the associated retinal ischemia seems to be the most likely factor for ocular NV.

2.2.1. Ocular radiationThere are large number of reports of development of NVGfollowing radiation for a variety of ocular and orbital lesions, e.g., iris melanoma (Shields et

al. 2003), posterior uveal melanomas (Shields et al. 2002), choroidal metastatic tumors (Tsina

et al. 2005), retinoblastoma (Kingston et al. 1996), orbital lymphoma (Bhatia et al. 2002), and

nasal and paranasal malignancies (Takeda et al. 1999). In ocular radiation, in most eyes the

main factor responsible for the development of NVG most likely is the development of

secondary radiation retinopathy, in which there is development of retinal capillary non-

perfusion and retinal ischemia.

2.2.1. Ocular tumorsNVG has been reported in association with prior to treatment in ring

melanoma of the anterior uvea (Allaire et al. 1997), adenocarcinoma of the nonpigmented

ciliary epithelium (Terasaki et al. 2001), medulloepithelioma (Singh et al. 2001), circumscribed

choroidal hemangioma (Shields et al. 2001a), metastatic cutaneous melanoma to the vitreous

(Gunduz et al. 1998), retinoblastoma (De Potter 2002), and metastatic malignant lymphoma

(Matsui et al. 2005).

2.2.3. UveitisDevelopment of NVG has been observed following anterior as well asposterior uveitis. It is not known whether the stimulus for NV is from the inflammation or

related secreted cellular products or may be a complication of underlying systemic diseases

associated with uveitis, e.g., Whipples disease (Nishimura et al. 1998), Crohns disease

(Salmon et al. 2000) and Behets disease (Elgin et al. 2004).

2.2.4. Miscellaneous retinal diseasesThese include retinal vasculitisper se or when

it is associated with systemic diseases, such as Crohns disease (Salmon et al. 2000) and

Behets disease (Elgin et al. 2004). Other miscellaneous retinal conditions which may be

associated with development of NVG include Coats disease (Shields et al. 2001b,c), Eales

disease (Atmaca et al. 2002; Perentes et al. 2002), frosted branch angiitis (Seo et al. 1998),

giant cell astrocytoma of the retina (Gunduz et al. 1999), peripheral retinal detachment (Barile

et al. 1998), and X-linked retinoschisis (Rosenfeld et al. 1998). Similarly other system diseases,

for example, cryoglobulinemia and Churg-Strauss syndrome, by causing retinal vascular

occlusion can be associated with NVG

3. PATHOGENESIS AND PATHOLOGY OF NVG

There is a large volume of literature on the subject of angiogenesis and NV and is beyond thescope of this discussion. However, a brief summary of the most pertinent information

concerning ocular NV and NVG, especially to its clinical aspects, is warranted. Chen et al.

(Chen et al. 1999) reported that increase in the inflammatory cytokine interleukin (IL) - 6 in

aqueous humor correlated spatially and temporally with the grade of iris NV in patients of

NVG secondary to CRVO. They postulated that the increased level of IL-6 might have a

putative role, along with other angiogenic factors in angiogenesis of NVG.

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Since 1996, several studies have implicated vascular endothelial growth factor (VEGF) as an

important and likely the predominant factor in the pathogenesis of intraocular NV and NVG

(Peer et al. 1996, 1998; Sone et al. 1996; Tolentino et al. 1996; Kozawa et al. 1998; Tripathi

et al. 1998; Atmaca et al. 2002; Hu et al. 2002). Boyd et al. (2002) found a close temporal

correlation between aqueous VEGF levels and the course of iris NV and permeability in

ischemic CRVO, indicating that increased aqueous VEGF level may predict the need for

treatment. Itakura et al. (2004) reported that in proliferative diabetic retinopathy a high VEGF

level was maintained in the vitreous cavity after vitrectomy. They stated that their resultssuggest that there is persistent secretion of VEGF into the vitreous cavity even after vitrectomy

in these eyes. This observation is supported by the experimental findings of ocular NV in rhesus

monkeys, where Virdi and Hayreh (1982) found a correlation between retinal vascular leakage

and the development of ocular NV.

The main reason for visual loss with high IOP in NVG is ischemia of the optic nerve head and/

or retina. Blood flow in the various intraocular vascular beds can be calculated by using the

following formula:

According to this formula and assuming no change in vascular resistance, a rise of IOP reduces

the perfusion pressure and thus decreases the blood flow in the retina, choroid and optic nerve

head. Therefore, the higher the IOP and the lower the blood pressure, the greater is the reduction

of blood flow, and the worse the ischemic damage to the optic nerve head and retina,

particularly the former. Thus, in the management of NVG, although lowering the IOP is crucial,

one also has to make sure that the treatment does not lower the systemic arterial blood pressure.

Iris and angle NV almost invariably develops before the pressure rises. This is associated with

the development of a fibrovascular membrane on the anterior surface of the iris and iridocorneal

angle of anterior chamber. Membrane development is followed by development of progressive

anterior synechiae, and angle closure, and precipitous rise of IOP, which may be of fairly acute

onset. In some of the eyes, anterior segment NV may be associated with development of

hyphema, which may contribute or precipitate an acute rise of IOP. It is worth rememberingthat the iridocorneal membrane may be difficult to visualize and that the angle may appear to

be open and the IOP elevated before synechiae develop.

4. DIAGNOSIS OF NVG

Advanced NVG is straightforward to diagnose. However, early in the course, NVG may present

subtle findings and one must have a high index of suspicion of its development in the settings

of various diseases discussed above (particularly ischemic CRVO, diabetic retinopathy and

ocular ischemic syndrome). In addition, a careful examination of the iris and angle of the

anterior chamber is essential, before the pupil is dilated and any drops put in the eye. Once the

pupil is dilated, it may not be easy to find the NV. During the early stages, iris NV is essentially

at the pupil margin and is very fine and delicate in character. Similarly, careful gonioscopy is

essential to detect early angle NV and early anterior synechiae. The anterior chamber in these

eyes often shows the presence of flare. Some time a few cells may be seen in the anterior

chamber, which may erroneously be diagnosed as a sign of uveitis. Fluorescein iris angiography

can be helpful in some doubtful cases because it shows leakage of fluorescein which is normally

not seen. However, in a fully developed NVG with very high IOP, the clinical picture may be

dramatically different; the eye may be painful and, when the IOP goes very high fairly fast,

there is usually corneal epithelial edema which can make examination for iris and angle NV

difficult.

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5. DIFFERENTIAL DIAGNOSIS

From time to time, NVG has been confused with other ocular conditions. For example, eyes

with severe non-granulomatous uveitis with dilated iris vessels and proteinous aqueous and

high IOP can be misdiagnosed to have NVG. There are some eyes where normal iris vessels

are seen easily, particularly in blue eyes, which may be mistaken for iris NV or even angle NV

when the vessels are seen near the root of the iris. Eyes with carotid-cavernous fistula

erroneously may be diagnosed to have NVG because of the blood in Schlemms canal, andelevated IOP.

6. MANAGEMENT OF NVG

This is highly challenging, unpredictable, difficult and controversial. It involves several

considerations, including the following:

1. Most importantly, it is essential to have a high index of suspicion of its development

in the various diseases discussed above (particularly ischemic CRVO, diabetic

retinopathy and ocular ischemic syndrome). Early treatment of those underlying

diseases can reduce the development of NVG.

2. A high index of suspicion of its development is also important for early diagnosis and

treatment to prevent irreversible visual loss.

3. Once NVG develops and the IOP is high, the major aspect of management is control

of high IOP, which is almost invariably the main factor in irreversible and massive

visual loss, rather than the original disease, which induced NVG.

Sivak-Callcott et al. (2001) conducted a review of the literature to evaluate evidence-based

recommendations for treatment of NVG. They stated: The current standard of care includes

retinal ablation and control of increased intraocular pressure with medical and surgical

therapy. They concluded: The current literature on neovascular glaucoma has few articles

that provide strong evidence in support of therapy recommendations based on the data that

provided strong evidence in support of clinical recommendation.

We can divide the management of NVG into two categories: (1) management of the underlying

disease and (2) management of high IOP when it develops.

6.1. Management of the underlying disease associated with NVG

As discussed above, the main diseases, which are responsible for inducing NVG, are diabetic

retinopathy, ischemic CRVO and ocular ischemic syndrome. Management of these 3

conditions is discussed.

6.1.1. Management of diabetic retinopathy to prevent development of NVG

There is strong evidence that panretinal photocoagulation (PRP) is the treatment of choice for

prevention of development of NVG in diabetic retinopathy (The Diabetic Retinopathy Study

Research Group 1976). Recently, Bandello et al. (2006), in a series of nine patients, reported

that intravitreal triamcinolone before PRP may be useful in improving the effect of PRP in

eyes with proliferative diabetic retinopathy by reducing NV and retinal thickening.

6.1.2. Management of ischemic CRVO to prevent development of NVGNVG isthe most dreaded and blinding complication of ischemic CRVO. Unlike diabetic retinopathy,

management of ischemic CRVO to prevent NVG is highly controversial. One reason for this

longstanding controversy is that application of PRP for ischemic CRVO has been advocated

by some based primarily upon the limited similarities in retinal vascular changes in diabetic

retinopathy and ischemic CRVO. The controversy is increasingly confused since the role of

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growth factors in ischemic retinal disease has been elucidated. Clinically and in therapeutic

response to PRP, ischemic CRVO and proliferative diabetic retinopathy behave very

differently in nature and course (Hayreh 2003; Hayreh et al. 1990b).

6.1.2.1. Role of PRP in NVG due to ischemic CRVO: The theoretical justification advocated

for PRP in ischemic CRVO is, as in diabetic retinopathy, to prevent development of ocular NV

and NVG. Some time ago, Hayreh et al. (1990b) reviewed the literature on the subject, and

found flaws in most of the studies claiming beneficial effects of PRP in ischemic CRVO. Forexample, Magargal and co-workers (1981, 1982) claimed that not one of the 100 eyes treated

by them with PRP developed NVG attributable to ischemic CRVO and iris neovascularization

subsequently regressed in each case (Magargal et al. 1982). They concluded that Prophylactic

PRP in high-risk ischemic CRVO eyes appears to eliminate virtually the devastating

complications of NVG (Magargal et al. 1982). Yet no subsequent study has been able to

confirm their enthusiastic claim.

Hayreh et al. (1990b) conducted the first long-term (10-year) prospective, planned study of

argon laser PRP in a large group of ischemic CRVO eyes. They started this study in 1977, soon

after the publication of the Diabetic Retinopathy Study (The Diabetic Retinopathy Study

Research Group 1976) in 1976, which showed the beneficial effect of PRP in proliferative

diabetic retinopathy. Their hypothesis at the start of the study was that they would find a similar

beneficial response in ischemic CRVO, since both retinopathies share common features ofretinal capillary non-perfusion and ocular NV. However, on completion of their study, on

comparing the lasered eyes with the non-lasered eyes, they found to their complete surprise

that there wasNO statistically significant difference between the two groups in the incidence

of development of angle NV, NVG, retinal and/or optic disc NV, or vitreous hemorrhage, or

in visual acuity (in Fig. 3 both eyes developed iris NV in spite of PRP) (Hayreh et al. 1990b).

This study did show, however, a statistically significant (p=0.04) difference in the incidence

of iris NV between the two groups, with iris NV less prevalent in the lasered group than in the

non-lasered group, but only when the PRP was performed within 3 months after the onset of

CRVO; however, iris NVper se is of little clinical importance for the following reasons: (a)

in one third of the eyes it does not progress to NVG (Fig. 1), and (b) in that study there was no

significant difference in development of NVG between the lasered and control groups in spite

of that difference in iris NV (Hayreh et al. 1983). The most important finding of this PRP study

in ischemic CRVO was the statistically significant difference in the loss of peripheral visualfields between the lasered and non-lasered eyes - the lasered group suffered a significantly

(p0.03) greater loss than the non-lasered group (Fig. 3). This showed that ischemic CRVO

cannot be equated to diabetic retinopathy; Hayreh et al. (1990b) discussed the reasons for this

disparity in response to PRP in the two diseases.

A multicenter prospective clinical trial by the Central Vein Occlusion Study (CVOS) group

investigated the role of PRP in ischemic CRVO (The Central Retinal Vein Occlusion Group

1995) to find out whether PRP prevents progression of iris/angle NV to NVG. The authors

recommended careful observation with frequent follow-up examinations in the early months

(including undilated slit-lamp examination of the iris and gonioscopy) and prompt PRP of eyes

in which 2clock iris/angle NV develops. Such a multicenter, multimillion-dollar study

conducted under the aegis of the National Institutes of Health carries tremendous prestige, and

the ophthalmic community considers its recommendations the gold standard in themanagement of ischemic CRVO. It is extremely important to place the results of this study in

its true perspective; to do that, I pointed out the various flaws in the study and its conclusions

(Hayreh 1996); briefly, they are as follows.

i. Their baseline data (Central Vein Occlusion Study Group 1993) suggest that they had

a mixture of ischemic and non-ischemic CRVO eyes in their designated two types of

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CRVO (i.e. perfused and nonperfused CRVO). Since ocular NV and NVG are a

complication of ischemic CRVO but NOT of non-ischemic CRVO, information

derived from such a mixture is likely to be inaccurate.

ii. Much more importantly, they treated all patients with iris NV, and did not randomize

them to treatment or no treatment groups. That fact puts a serious cloud over its

use of iris NV as an outcome measure for development of NVG. As shown by our

study, approximately one third of the eyes with iris NV and treated with PRP would

never have developed NVG (Fig. 1) (Hayreh et al. 1983). Treating all patients with

iris NV strongly biased their results in favor of PRP. Also, in our study on PRP in

ischemic CRVO, although eyes with PRP showed significantly (p=0.04) less

prevalent iris NV in the PRP group as compared to the control group, there was no

statistically significant difference between the two groups in angle NV and NVG

(Hayreh et al. 1990b).

iii. Most importantly, on a risk/benefit ratio, it is essential to find out if a therapy has

deleterious side effects. In the CVOS no visual fields were plotted so that information

on the highly damaging effect of PRP on peripheral visual fields was missed. Our

longitudinal studies in a large cohort of ischemic CRVO eyes have shown that,

although all eyes have central scotoma, they almost invariably have normal peripheral

visual fields. In our study (Hayreh et al. 1990b) on PRP in ischemic CRVO, we found

a statistically significant (p0.03) worsening of peripheral visual fields, with markedloss in eyes treated with PRP as compared to those in the control non-lasered group;

figure 3 includes some examples. After all, peripheral visual fields constitute a very

important component of our visual function; our daily navigational capacity depends

essentially upon them. Eyes with ischemic CRVO almost always have a large

permanent central scotoma, resulting in poor central visual acuity. Following PRP,

the large central scotoma combined with severe loss of peripheral visual fields may

virtually blind the eye. This is a seriously blinding complication of PRP in ischemic

CRVO.

It could be argued that this is simply my opinion (Hayreh 1996) about the CVOS; but the Editor

of Ophthalmology (where this study was published) sent my comments to the authors of the

CVOS Group and in their response (Central Vein Occlusion Study Group 1996) they agreed

with all the concerns I had raised. Nevertheless, the ophthalmic community, unfortunately, stillconsiders that study as the gold standard.

6.2. Management of ocular ischemic syndrome to prevent development of NVG

Management of ocular ischemic syndrome remains difficult and controversial. Reduction of

blood flow to the eyeball can produce anterior and/or posterior segment ischemia (see Fig. 2).

Anterior segment ischemia manifests as NV and NVG. As discussed above, in the ocular

ischemic syndrome studies of Hayreh and Podhajsky (1982) and Mizener et al. (1997), no

patient with ocular ischemic syndrome and ocular NV had retinal capillary non-perfusion on

fluorescein fundus angiography, even those with diabetes mellitus; however, those studies

invariably found evidence of uveal vascular insufficiency. Therefore, the conventional use of

PRP for anterior segment NV and NVG in diabetic retinopathy cannot be extrapolated to ocular

ischemic syndrome. Moreover, rise of IOP following PRP may further compromise the already

highly precarious ocular and optic nerve head circulation and result in severe visual loss due

to development of anterior ischemic optic neuropathy (Brown 1986) or retinal ischemia.

Since internal carotid artery occlusive disease is the most common cause of ocular ischemic

syndrome, carotid endarterectomy seems a logical management. However, the benefit of

carotid endarterectomy in patients with ocular ischemic syndrome is unknown and

controversial. I reviewed the multiple reports in the literature dealing with this topic. Those

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described that, following carotid endarterectomy or internal-external carotid anastomosing

procedure, there was stabilization of vision if initial vision was good, regression of iris NV,

and, rarely, improvement in already poor vision (Mizener et al. 1997). Some studies showed

that selected patients with asymptomatic severe carotid artery disease might benefit from

carotid endarterectomy (Thompson 1993). In the study by Mizener et al. (1997), most patients

with ocular ischemic syndrome who underwent carotid endarterectomy had poor vision and

visual outcome was unchanged by the surgery. However, clinical decisions for carotid

endarterectomy are usually driven by the patients entire clinical picture, as determined byneurologists and vascular surgeons.

Since, in ocular ischemic syndrome, perfusion pressure in the various ocular vascular beds is

low, lowering IOP to as low a level as possible is crucial to improve the blood flow (Fig. 2),

and thereby to prevent visual loss from various types of ocular vascular occlusion (including

CRAO and anterior ischemic optic neuropathy) and/or glaucoma.

6.2.1. Role of nocturnal arterial hypotension in visual loss in ocular ischemic

syndrome and NVGStudies dealing with 24-hour ambulatory blood pressure monitoringin ocular and optic nerve head ischemic disorders have shown that nocturnal arterial

hypotension plays an important role in their pathogeneses, by lowering the perfusion pressure

during sleep (Hayreh et al. 1994, 1999b; Hayreh 1999). These studies also showed that

aggressive antihypertensive therapy, particularly administration of blood pressure loweringdrugs in the evening or at bedtime, can result in marked nocturnal arterial hypotension, which

may precipitate ischemic visual loss. For example, 73% of patients with non-arteritic anterior

ischemic optic neuropathy gave a history of discovering the visual loss on waking up from

sleep (Hayreh et al. 1997). Similarly, in the study by Mizener et al. (1997) on ocular ischemic

syndrome, some patients reported discovery of visual loss on waking up from sleep in the

morning. Therefore, in patients with ocular ischemic syndrome, it is important to avoid

nocturnal arterial hypotension. A study by Hayreh et al. (1999a) showed that topical beta-

blockers eye drops produced significant nocturnal arterial hypotension. Therefore, it would be

advisable to avoid beta-blocker eye drops for lowering the IOP in these patients. In patients

who develop NVG from any cause, it is also important to avoid development of nocturnal

arterial hypotension, to prevent visual loss. Unfortunately, the important role played by

nocturnal arterial hypotension has not been stressed in the prevention of ocular ischemic

conditions and NVG.

6.3. Management of inflammatory diseases associated with NVG

Eyes with uveitis and retinal vasculitis are at risk of developing NVG (see above). Thus, their

appropriate management is important to prevent development of NVG. The treatment depends

upon cause of these inflammatory diseases. In most of the eyes with uveitis, use of topical

steroids and mydriatics are primary management; however, some of patients with uveitis

require systemic corticosteroids or other immunosuppressive therapies. For retinal vasculitis,

usually systemic corticosteroids are required, although some advocate using subtenon or

intravitreal steroids. Since most of these patients have an associated systemic disease,

management of that is also essential.

6.4. MANAGEMENT OF THE HIGH IOP IN NVGThis can be done by medical or surgical methods.

6.4.1. Medical therapiesThese are primarily meant to lower the IOP in eyes with NVG.

However, more recently, other medical therapies aimed at treating intraocular NV have been

reported.

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6.4.1.1. Medical treatments to control of high IOP: Different medical strategies have been

tried to control NVG and the high IOP. This is invariably the first step to prevent visual loss

and relieve pain or discomfort associated with NVG. IOP is lowered invariably by means of

various aqueous suppressants (beta-blockers, alpha adrenergics, and carbonic anhydrase

inhibitors). There is no role for cholinergic eye drops. Prostaglandins may not be of much help

because they work by increasing the uveal outflow, which may be covered by a membrane. At

the same time, it is helpful to give topical steroids to reduce any inflammatory component that

may be present.

6.4.1.2. Anti-VEGF therapy: As discussed above, there is evidence now that VEGF is an

important factor in the pathogenesis of ocular NV and NVG. There are a large numbers of

reports about the use of anti-VEGF therapy for choroidal neovascularization associated with

age-related macular degeneration; however, only a few recent reports deal with its use in ocular

NV and NVG, essentially with Bevacizumab (Avastin).

Most of the published reports deal with anti-VEGF therapy in ocular NV associated with

proliferative diabetic retinopathy (Avery et al. 2006; Davidorf et al. 2006; Mason et al. 2006;

Oshima et al. 2006; Spaide et al. 2006). Regression of retinal and iris NV (Avery et al. 2006

in 45 eyes), retinal and optic disc NV (Mason et al. 2006 in 3 patients), retinal NV (Spaide et

al. 2006 in 2 patients), and iris NV (Davidorf et al. 2006 in one eye; Oshima et al. 2006 in 7

eyes) have been reported. Spaide et al. (2006) had to re-inject after 3 months because ofreactivation of retinal NV. Grisanti et al. (2006) gave intracameral injection of 1.0 mg

bevacizumab in 6 eyes with iris NV and claimed a decrease in leakage from the iris vessels on

angiography. All the reports published so far show only a short-term beneficial effect of this

treatment.

There is much less information about the role of anti-VEGF therapy in ocular NV and NVG

associated with CRVO. Genaidy et al. (2002), in an experimental study on retinal vein

occlusion in monkeys, found that intravitreal anti-VEGF therapy did not affect the development

of iris NV. Iliev et al. (2006) gave intravitreal Avastin in 6 eyes with NVG associated with

CRVO and reported marked regression of anterior segment NV within 48 hours in all and a

substantial fall of IOP in 3 eyes, while the other 3 eyes required cyclophotocoagulation to

control IOP on a follow-up of 416 weeks. Kahook et al. (2006) gave intravitreal bevacizumab

(1.0 mg) to a patient with NVG following CRVO and reported IOP improved within 2 days.

Thus, so far the published experience is in only in a small number of eyes, except that of Avery

et al. (2006), with extremely short follow-up and limited information on IOP control in NVG,

other than that iris NV responded. As yet, there is no study providing definite information for

long-term control of ocular NV and NVG and complications of the anti-VEGF therapy. As

usual, there is invariably an initial marked enthusiasm with a new therapy in a disease with

poor prognosis; it is only a long-term experience, which provides realistic information.

Moreover, the success rate of this therapy in NVG may also depend upon the cause of NVG.

For example, ocular NV and NVG associated with diabetic retinopathy are not as aggressive

and sudden in onset as in ischemic CRVO, and that may influence the success and failure rates

of this mode of treatment. Unfortunately, no such information is available in the reported series

so far. However, a decrease in iris and angle NV can permit safer surgical intervention.

6.4.1.3. Corticosteroid therapy: Jonas et al. (2001) in 4 eyes with NVG gave intravitreal

injection of 20 mg of crystalline triamcinolone acetonide and found the mean IOP decreased

from 26.5 12.1 mm Hg to 21.7511.3 mmHg; however, in one of the eyes with IOP of 40

mm Hg, there was no change although iris NV decreased.

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In conclusion, so far, information on anti-VEGF and corticosteroid therapy in NVG is available

from only a few anecdotal reports, and no worthwhile conclusions can be drawn about their

beneficial effect in controlling IOP and preventing visual loss, and their complications. The

primary medical management still remains the use of drugs that lower the IOP.

6.4.2. Surgical methods to control high IOPIf medical methods do not control IOPin NVG, then one has to resort to surgery. A variety of such methods have been advocated with

differing claims, as is evident from the following. In these eyes, there is no role for lasertrabeculoplasty because there is no visible trabecular meshwork.

6.4.2.1. Cycloablation: This has been oldest of the surgical procedures used to try to control

high IOP in NVG. Various such methods have been used for this purpose. The objective of

this mode of treatment is to try to reduce the formation of aqueous by partially destroying the

ciliary body. Initially cyclodiathermy was the most popular mode of doing that but this

frequently had post-operative complications. That was later replaced by cyclocryotherapy,

which has much less post-operative complications. Another similar procedure advocated in the

past was cyclo-electrolysis. However, since 1997 (Bloom et al. 1997), for cycloablation various

cyclophotocoagulation methods have been advocated.

6.4.2.1.1. Cyclophotocoagulation: A report on cyclophotocoagulation by the American

Academy of Ophthalmology showed that transscleral cyclophotocoagulation with noncontactNd:YAG and semiconductor diode laser is useful in acute-onset NVG (Pastor et al. 2001).

Cyclophotocoagulation with a diode laser compared to cyclocryoablation has the advantage

that it causes less pain and is better tolerated by the patients; however, in my experience it takes

longer to lower the IOP. Oguri et al. (1998) reported that diode laser transscleral

cyclophotocoagulation appears to be as effective as free-running mode Nd:YAG laser

transscleral cyclophotocoagulation and better than continuous-wave mode Nd:YAG laser

transscleral cyclophotocoagulation for treating NVG. However, there are reports of

complications of laser cyclophotocoagulation, the most common being hypotony. Yap-Veloso

et al. (1998) reported that 26% of eyes had severe long-term complications, including loss of

vision (22%), corneal decompensation (2%), and phthisis bulbi (2%). Development of

necrotizing scleritis 10 months after diode laser cyclophotocoagulation for NVG has been

reported (Shen et al. 2004). Delgado et al. (2003) reported that use of noncontact transscleral

neodymium:yttrium-aluminum-garnet cyclophotocoagulation for NVG in 115 eyes, while

providing long-term IOP reduction, was associated with complications that included

inflammation, visual loss, and hypotony, and that repeat treatments may be necessary to main

good control of IOP.

6.4.2.2. Filtering surgery: The most common filtering procedure tried has been

trabeculectomy combined with or without mitomycin C or 5-fluororacil. Elgin et al. (2006)

claimed that trabeculectomy with mitomycin C combined with direct cauterization of

peripheral iris in NVG decreased the incidence of both intraoperative bleeding and early

postoperative hyphema, and provided reduction of IOP and the number of antiglaucomatous

medications in 96% at one week, 86% at one month, 83% at 3 months and 66% at 6 months,

in cases with a 6-month follow-up period. Kiuchi et al. (2006) found that pars plana vitrectomy,

followed by PRP and trabeculectomy with mitomycin C in eyes with NVG associated withdiabetic retinopathy effectively reduced the elevated IOP. Kono et al. (2005) performed pars

plana vitrectomy combined with filtering surgery and claimed success in control of IOP for

more than 12 months. By contrast, Mietz et al. (1999) found that trabeculectomy without

antimetabolites failed to control IOP in 80% of eyes with NVG. Thus, there are conflicting

claims, and it seems the effectiveness of these procedures decreases with time. There are several

limitations in the reported studies to provide definite information for long-term control of IOP.

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For example, in all of them the follow-up was only 12 months or less. Moreover, the success

rate of these procedures in NVG may also depend upon the cause of NVG. For example, NVG

associated with diabetic retinopathy is not as aggressive and sudden in onset as in ischemic

CRVO, and that may influence the success and failure rates of these procedures. Unfortunately,

no such information is available in the reported series, where NVG from various causes were

usually lumped together.

6.4.2.3. Glaucoma drainage devices: Glaucoma drainage devices have been considered as anoption in the management of NVG where there is a high risk of failure from conventional

filtering surgery. Various drainage devices used have been Molteno implant, Baerveldt

implant, Ahmed glaucoma valve and Krupin valve. Different reports make conflicting claims

about the success of different devices to control IOP in NVG. For example, Every et al.

(2006) in a prospective study of 145 eyes followed up for a mean of 3.3 years found Molteno

implant to control the IOP at 21 mm Hg up to 5 years, but the success rate progressively

decreased from one year onwards. Failure to control IOP was significantly correlated with

persistent iris NV. Broadway et al. (2001) found that, in the long term, Molteno implant tended

to fare poorly in NVG. Krishna et al. (2001) claimed that the 350-mm(2) Baerveldt glaucoma

implants are a safe and effective treatment for intermediate-term IOP control in patients with

NVG. According to Yalvac et al. (2006), the Ahmed glaucoma valve and Molteno single-plate

implant were successful for early and intermediate-term of IOP control but in the long term

both implants failed to achieve control of IOP. Hong et al. (2005) recently reviewed theliterature on various glaucoma drainage devices and compared their success rate in controlling

IOP. They concluded that the Moltino implant, Baerveldt implant, Ahmed glaucoma valve and

Krupin valve showed no statistically significant difference in either the percentage change in

IOP or the overall surgical success rate at the last follow up. One has to bear in mind that each

glaucoma drainage device has its own complications and limitations. Placing a glaucoma

drainage device in an eye with 360 degrees of synechiae is technically challenging and the

fibrovascular membrane can encase the tube.

6.4.2.4. Photodynamic therapy: In 1984, in an experimental study in rhesus monkeys with

iris NV, Packer et al. (1984) reported marked reduction of leakage from iris NV on fluorescein

angiography after photodynamic therapy, but the effect was temporary and required repeated

application to control iris NV. Parodi and Iacono (2005) recently reported that photodynamic

therapy might be a promising approach for NVG. In their series of 16 eyes with NVG, there

was a 39% decrease in IOP overall and treatment did not control IOP satisfactorily in 31%.

6.4.3. Management of painful blind eyesTo make the eye feel comfortable, it is

advisable to try first topical corticosteroids, cycloplegics, cyclodestruction, and even alcohol

injection. If all else fails, as a last resort one may consider enucleation. Our policy is to try to

avoid doing enucleation whenever possible, because even a blind eye is less bothersome in the

long run (if cosmetically acceptable) than to maintain an artificial eye and socket. Some

ophthalmologists advocate doing evisceration of such eyes.

While control of IOP helps to prevent visual loss in NVG, one has to keep in mind that visual

outcome also depends upon the severity of underlying ocular disease and postoperative

complications. Thus, successful control of IOP does not always correspond with visual

outcome in NVG.

6.5. OUR MANAGEMENT REGIMENS OF NVG

Finally, based on our studies on NVG in CRVO and ocular ischemic syndrome, in the Ocular

Vascular Clinic at the University of Iowa Hospitals and Clinics, since 1973, I will discuss our

management regimen of NVG.

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6.5.1. In ischemic CRVO and NVGAs discussed above, PRP study by Hayreh et al.(1990b) in ischemic CRVO showed no significant difference in the development of NVG

between the treated and the control group. I discussed above the serious flaws with the

conclusions of the multicenter CVOS about the role of PRP (Hayreh 1996). Naturally, the

question arises: if none of the advocated treatments is beneficial in ischemic CRVO, how

should patients with ischemic CRVO be managed? I have discussed this topic in detail

elsewhere (Hayreh 2003).

For a logical management of any disease, one has first to understand the basic issue involved

and the available information, which should act as guidelines. In ischemic CRVO, to reiterate

briefly what has been said above, we currently have the following definite information:

1. A maximum of about 45% of ischemic CRVO patients are likely to develop NVG

and 55% are never going to develop it (Fig. 1) [Hayreh et al. 1983].

2. The risk of developing NVG exists mainly during the first 78 months of the disease

(about 40% - Fig. 1) (Hayreh et al. 1983). After that, the risk falls dramatically to

about 5% or less. Therefore, the crucial period to monitor these patents closely is the

first 78 months (Hayreh et al. 1983).

3. The multi-center CRVO photocoagulation study showed that prophylactic PRP in

ischemic CRVO does not prevent iris and angle NV (The Central Retinal Vein

Occlusion Group 1995).

4. PRP study by Hayreh et al. (1990b) showed that eyes subjected to PRP usually suffer

marked loss of peripheral visual fields (Fig. 3). Combined with the large pre-existing

central scotoma in these eyes, that marked peripheral visual field loss can make these

eyes virtually blind.

5. There is no convincing scientific evidence that PRP usually helps prevent

development of NVG in ischemic CRVO, in spite of claims to that effect (The Central

Retinal Vein Occlusion Group 1995).

6. The retinopathy in ischemic CRVO runs a self-limited course, and after a variable

length of time, it usually burns itself out and resolves spontaneously, with permanent

residual retinal damage. Once that happens, the stimulus for NV disappears and

consequently the anterior segment NV spontaneously starts to regress. Virdi andHayreh (1982) showed that in their experimental study also. This highly important

fact is usually not appreciated in the management of these eyes. An understanding of

this important fact must change our approach to the management of ischemic CRVO

and associated anterior segment NV. We need to babysit these eyes during the

period when they are at maximum risk of developing NVG, i.e. the first 78 months

(Fig. 1). From my own experience, I can safely say that baby sitting is generally

not a pleasant experience for either the ophthalmologist or the anxious patient, but in

the end, it pays off by preserving the peripheral visual fields in the majority.

The most important fact to bear in mind in the management of NVG in ischemic CRVO is that

the primary factor, which is going to completely blind these eyes, is the high IOP, producing

optic nerve head damage, and NOT the ischemic CRVOper se. If one can keep the IOP under

control by any means available, one can keep their peripheral visual fields intact.In the lightof these facts, I follow the following regimen with these patients:

a. I follow them every 23 weeks in my clinic for the first 78 months, to watch for any

evidence of anterior segment NV and rise of IOP, as well as doing gonioscopy. Every

2 months or so, I do a complete ophthalmic evaluation and visual field plotting with

a Goldman perimeter.

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b. If an eye develops moderate to marked anterior segment NV, I start topical

corticosteroid therapy, because there is evidence that steroids inhibit angiogenesis

and NV. (Warning: Topical corticosteroids in steroid responders may cause the IOP

to go high and that may be misdiagnosed as NVG. Performing gonioscopy would

prevent such a mistake. I am not aware of any information whether in eyes with

completely closed angle, use of topical steroid therapy may have similar IOP raising

effect or not.)

c. If the IOP goes above 21 mmHg, I start topical ocular hypotensive therapy. If need

be, I may add oral carbonic anhydrase inhibitors also. Most of the time, this medical

treatment regimen is enough to keep the IOP under satisfactory control.

d. If the IOP goes very high and is not controlled by the medical regimen, then we do

graduated cycloablation (previously by graduated cyclocryotherapy and more

recently by cyclophotocoagulation with diode laser). This, combined with medical

therapy, can control the IOP in majority of the eyes. Some eyes require repeated

cycloablation to keep the IOP under control. The universal impression that

cycloablation invariably results in hypotony and phthisis bulbi is based on aggressive

360 application at one sitting. Our study showed that a graduated cycloablation over

a period of time, titrated according to the IOP, is generally not associated with

hypotony or phthisis bulbi. There are a few cases where we have put glaucoma

drainage devices to manage elevated IOP in eyes with closed angle and very minimalor no NV.

With this treatment regimen, I have been able to tide many of these eyes over the first

78 months, or until the retinopathy starts to resolve and the stimulus for anterior

segment NV subsides. After that, these eyes start to settle down. However, a few eyes

very rapidly go into fulminant NVG and no amount of any treatment can control the

IOP. In our studies on PRP (Hayreh et al. 1990b) some eyes developed fulminant

NVG in spite of early and extensive PRP of up to about 3,500 burns; they finally

became totally blind and even developed phthisis bulbi.

e. If the eyes do not develop NVG during the first 7 months, their risk thereafter is

minimal (Fig. 1). Therefore, after that, I follow them every 3 months or so, depending

upon the state of the eye. I have found that some of the eyes that do not develop NVG

may develop disc or retinal NV at a much later stage (Fig. 1). If that happens, then I

do advocate the PRP, since by that time the retinal edema and hemorrhages are much

less or even absent, and consequently PRP is not so destructive to the peripheral visual

fields as during the early stages when there are extensive retinal hemorrhages and

marked retinal edema.

6.5.2. In ocular ischemic syndromeAs in NVG due to any cause, our first priority isto lower the IOP to prevent further visual loss, particularly since in these eyes perfusion

pressure in the ocular vascular bed is already low (Fig. 2). To do that, we use IOP lowering

eye drops, along with topical steroids, and if need be add systemic carbonic anhydrase

inhibitors. We avoid using beta-blocker eye drops because of their arterial hypotensive effect

(Hayreh et al. 1999a). Cycloplegics may be useful to decrease ciliary pain and prevent posterior

synechiae. If the IOP is uncontrolled with these measures, as with extensive peripheral anteriorsynechiae formation, or the medications are not tolerated, we do graduated cycloablation (see

above) in addition to the above measures. Out of 30 eyes in our study (Mizener et al. 1997),

18 developed NVG but only four patients required cycloablation. In our series, only one eye

developed phthisis bulbi, and this blind, painful eye required a retrobulbar alcohol injection

after cycloablation failed to give relief.

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7. CONCLUSIONS AND FUTURE DIRECTIONS

NVG is a severely blinding disease. To prevent or reduce the extent of visual loss caused by

NVG, the first essential is to have a high index of suspicion of its development; if NVG

develops, early diagnosis and aggressive control of high IOP is crucial to minimize the visual

loss. The most common diseases responsible for development of NVG are ischemic CRVO,

diabetic retinopathy and ocular ischemic syndrome. In the management strategy, the first

priority should be to try to prevent its development by appropriate management of the causativediseases.

Currently there is no satisfactory means of treating NVG and preventing visual loss in the

majority, in spite of multiple modes of medical and surgical options advocated over the years

and claims made. Currently our ability to prevent NVG and treat it is not satisfactory. For that,

the primary aim of our future research should be prevention of the development of anterior

segment NV and NVG. Primarily advances in basic sciences, which enable us to understand

the disease process, make advances in medicine. As a clinical scientist, I have found that once

one understands the basic scientific facts about a disease and its pathogenesis, one can almost

mathematically calculate whether a particular treatment is going to work or not. Unfortunately,

the major problem in clinical medicine has been lack of adequate knowledge of those basic

scientific facts about the disease process among clinicians who invariably manage them and

advocate various therapies. Not infrequently, with the best of intentions, treatment methodswithout any scientific rationale are advocated which in the long run not only do not work but

even can be harmful. Thus, in the management of NVG, we first need scientifically valid means

of management of the main diseases, which cause NVG, i.e. ischemic CRVO, diabetic

retinopathy and ocular ischemic syndrome. While conventionally PRP has been advocated for

the prevention and management of NVG in these diseases, as discussed above, apart from its

effectiveness in diabetic retinopathy, it has been shown that not only it may not be effective in

preventing NVG in ischemic CRVO and ocular ischemic syndrome but also it can cause further

visual loss. After all, PRP is basically a destructive procedure. Currently there is considerable

interest in the anti-VEGF drugs for management of ocular NV in age-related macular

degeneration, but, so far, we have little long-term worthwhile information in a large series of

patients about its effectiveness in prevention or control of NVG or ocular NV elsewhere.

Various medical means to control high IOP are usually only temporary measures. Claims about

the success of various surgical means to control IOP in NVG have not yet been substantiatedin the long run. Thus, we are still far from having a satisfactory management method to prevent

and treat NVG, to prevent visual loss.

Acknowledgments

I am grateful to my colleagues Drs. Wallace L.M. Alward, Young H. Kwon and Stephen R. Russell for valuable

suggestions.

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