Classification of Central Retinal Vein Occlusion SOHAN SINGH HAYREH, MD, PhD, FRCS

Abstract: Our prospective clinical study of 360 eyes with central retinal vein occlusion (CRVO) and our experimental studies on CRVO in 54 eyes of rhesus monkeys have shown that CRVO consists of the following two distinct entities: (1) Nonischemic CRVO in which there is essentially a stasis of retinal venous circulation; we call it venous stasis retinopathy (VSR). (2) Ischemic CRVO: We call this hemorrhagic retinopathy (HR). Our' prospective clinical studies have revealed that it is absolutely essential to differentiate CRVO into VSR and HR because of their very different prognoses and management. VSR is a benign and self-limited condition, while HR is a severe, potentialiy blinding disorder. Lumping the two types of CRVO together as one disease has caused much confusion concerning the prognosis and management of CRVO. The basis of such a classification and differential diagnosis of VSR and HR is discussed at length. [Key words: central retinal vein, hemorrhagic retinopathy, occlusion, retinal vessels, venous stasis retinopathy.] Ophthalmology 90:458-474, 1983

Much confusion exists in the ophthalmic community regarding the prognosis and management of Central Retinal Vein Occlusion (CRVO), in spite of the facts that: CR VO has been known as a clinical disease for almost 150 years; that it is a common cause of visual disorder; and that a huge volume of literature has ac­cumulated on the subject. I have reviewed the subject in detail elsewhere. lOur studies indicate that the prin­cipal reason for this confusion has been the erroneous concept that CRVO is a single entity. In 1904 Coats2

first suggested that clinically these patients fell into two groups: those with marked deterioration of vision and poor prognosis, and those with much better vision and prognosis. Since then, some other authors have also sug­gested such a division3

-10 but, unfortunately, they have

been largely ignored by the ophthalmic community or, sometimes, even questioned. I 1,12

Our experimental and clinical studies, conducted over the past 20 years, have demonstrated clearly that CRVO

From the Ocular Vascular Clinic, Department of Ophthalmology, University of Iowa, Iowa City.

Presented at the Eighty·seventh Annual Meeting of the American Acad­emy of Ophthalmology, San Francisco, October 30-November 5, 1982.

Supported by Grant EY·1151 from the National Institutes of Health, Be· thesda, Maryland.

Reprint requests to S. S. Hayreh, MD, Department of Ophthalmology, University of Iowa Hospitals & Clinics, Iowa City, IA 52242.

comprises two distinct entItIes. The classification of CR VO presented in this paper is based on the following studies by us: I. Experimental studies: these were con­ducted in 54 eyes of rhesus monkeys13,14 and discussed in detail elsewhere. 1,14 2. Prospective clinical studies: 360 eyes with CRVO in 339 patients have been studied pro­spectively in detail. These studies reveal that CRVO con­sists of: (I) nonischemic CRVO and (2) ischemic CRVO.

EXPERIMENTAL AND CLINICAL STUDIES

The experimental studies provided fairly conclusive evidence for such a classification. 13,14 Clinically, the pat­tern of the disease in the two types is different l; in par­ticular, the fluorescein fundus angiographic pattern, complications, and course of the disease provide firm evidence for such a classification.

FLUORESCEIN FUNDUS ANGIOGRAPHIC PATIERN

This gives the most valuable information in the dif­ferentiation ofCRVO into its two types. In the nonisch­emic type, during the entire course of the disease an­giography shows no retinal capillary obliteration in the vast majority of eyes (Figs 2C, 5C, 6D); very occasionally an insignificant, patchy retinal capillary obliteration may be seen (Fig 4F) (usually at the site of an occasional cotton-wool spot that may be seen in a few eyes, or in the extreme peripheral part of the retina). In sharp con-

458 0161-6420/83/0500/0458/$1.65 © American Academy of Ophthalmology

· HA YREH • CLASSIFICATION OF CRVO

Fig 1. VSR-Case 1: right eye. A perfectly healthy 23-year-old man with no visual symptoms, was found to have VSR during routine eye examination on June 28, 1978. VA 6/6, normal visual fields and no abnormality on angiography. The retinal hemorrhages were mainly located in the peripheral fundus, best seen by indirect ophthalmoscopy. VSR resolved completely within one year and the eye was never symp­tomatic.

trast to that, in the ischemic type, the development of a significant retinal capillary obliteration is universal; it may vary from mild to moderate to almost total cap­illary obliteration (Figs 7F, 8C, 9C, 90, lOC, WE, lIE, 12C, 12F). Retinal capillary obliteration is not specific to the ischemic type of CRVO, but is also seen in dia­betic retinopathy, Eales' disease, postradiation retinop­athy, pulseless disease, sickle cell retinopathy, retrolental fibroplasia, and a number of other types of retinopathy. The common factor in all these conditions is retinal ischemia; retinal capillary obliteration is a hallmark of retinal ischemia. 14

COMPLICATIONS

In our series of 78 eyes with the ischemic type of CRVO, about 75% developed one or another type of ocular neovascularization (NV) within about two years from the onset of the disease. 15 By contrast, not one of the 280 eyes with nonischemic CRVO developed any ocular NY. 15 It is well established now that ocular NY (ie, of the iris, angle, disc and retina, and neovascular glaucoma) is typically a manifestation of ischemia, in this case, retinal ischemia. Similar ocular NV is seen in other types of retinopathy associated with retinal isch­emia (see above).

COURSE OF DISEASE

Nonischemic CRVO. This usually runs a benign course, being a self-limited condition. The macular edema is almost invariably the primary cause of visual disturbance and a chronic persistent macular edema re­sults in permanent macular changes (eg, cystoid macular degeneration and/or premacular gliosis) and consequent central scotoma. Otherwise the retinopathy resolves,

usually leaving either little visual disturbance (ie, central scotoma) or in over half of them none at all.

Ischemic CRVO. This, on the other hand, is a ma­lignant disease with about half of the eyes ultimately developing neovascular glaucoma and consequent blindness and even loss of the eye. A certain proportion of the eyes develop recurrent vitreous hemorrhage, which also results in blindness. None of the eyes ever recovers normal visual function, and there is almost always severe visual loss.

RELATIVE FREQUENCY OF TWO TYPES OF CRVO

In our series of 360 eyes studied prospectively for CRVO, 78 eyes were of the ischemic type and 282 eyes of the nonischemic type; this gives a ratio of 22% and 78%, respectively. I have calculated this ratio every year for the past four years, and all along it has fluctuated within a very narrow range of 75 to 80% for the non­ischemic type and 20 to 25% for the ischemic type. This consistency strongly suggests that the above ratio is fairly accurate. It could be argued that this does not represent a true ratio between the two types since our clinic is entirely a referral, tertiary care center. My impression is that the actual incidence of non ischemic CRVO may be even higher than our ratio suggests, because nonisch­emic CRVO may remain completely asymptomatic dur­ing its entire course or may never progress beyond a mild, vague blurring of vision, so that the patient may never seek ophthalmic advice or may not be referred by the primary ophthalmologist. This is suggested by the periodic detection of either symptom-less disease or footprints of an old resolved asymptomatic disease (eg, retinociliary collaterals on the optic disc, macular changes, perivenous sheathing) during a routine eye ex­amination. Ischemic CRVO, by contrast, is always as­sociated with marked visual loss, and the patient is much more likely to seek ophthalmic advice, and to be referred for opinion to our Ocular Vascular Clinic. Thus, it seems most likely that nonischemic CRVO may exist in more than 75-80% of CRVO cases, and ischemic CRVO in less than 20-25%. This suggests that in at least 75-80% ofCRVO cases the disease is benign, and treatment like panretinal laser photocoagulation is contraindicated, because no study has so far shown conclusively that such treatment helps the visual prognosis in chronic macular edema.

An analogy can very well be drawn between tumors and CRVO. Tumors are divided into benign and ma­lignant tumors, and the severity of lesion varies from mild to severe in both types. Most tumors can be divided easily into benign and malignant types once adequate clinical and other information is available. In a number of cases, however, differentiation between benign and malignant tumors is not possible to begin with, in spite of all the clinical and diagnostic information available, and it is only a follow-up of the cases that finally settles the diagnosis. In some cases the benign tumor may

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Fig 2. VSR-Case 2: right eye. A 31-year-old healthy man developed slowly progressive blurred vision six weeks before we saw him on July 26, 1976; the eye had VA 6/21 , enlarged blind spot (A) with centhu distortion on Amsler chart, optic disc and macular edema with extensive peripheral retinal hemorrhages (B), and dilated retinal capillaries with microaneurysms on angiography (C). Within one year VSR resolved completely. D shows a normal fundus on July 26, 1977, with no abnormality on angiography.

change to a malignant tumor. Similarly, CR VO consists ofa benign form (nonischemic CRVO) and a malignant form (ischemic CRVO)-in both types the severity of the disease varies from mild to severe. In our series, about 10% of the cases could not be classified on an initial examination, but on a follow-up of three to six months the true nature of the disease emerged. Also 7% of eyes with VSR later changed to HR.

Some ophthalmologists argue that all cases of CR VO represent the same disease process, being mild in some and severe in others, so that the only difference is the severity of the disease. II The same could be said of tu­mors, but benign and malignant tumors differ markedly in their course, complications, and management and

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prognosis. This is equally true of the two types ofCRVO. Lumping the two types ofCRVO together as one disease has caused much confusion on the prognosis and man­agement of CRVO.

OBJECTIONS TO DIVISION OF CRVO INTO ISCHEMIC AND NON ISCHEMIC TYPES

Some investigators have argued that such a division ofCRVO is unjustified I 1 .12; the latest are Green and co­workers. 12 Their study needs detailed comment to place

HA YREH • CLASSIFICATION OF CRVO

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Fig 3. VSR-Case 3: right eye. A 39-year-old healthy man was seen on May 10, 1973, complaining of slightly blurred vision for two weeks. The eye had VA 6/7 .5+, enlarged blind spot (A), markedly swollen disc with engorged retinal veins and hemorrhages (B, see color plate), and dilated capillaries with microaneurysms on angiography (C). VSR completely resolved by November 9, 1973, with normal V A and visual fields.

it in its true perspective. Their conclusions are based purely on a histopathologic study of29 eyes with CRVO, with no worthwhile information available on the visual acuity, visual fields, ophthalmoscopic findings, nor, above all, about the results of fluorescein fundus an­giography from the onset of the disease up to the time of enucleation of the eyes. As discussed later, the dif­ferential diagnosis between the two types is based only on the combination of information from all four clinical parameters mentioned on p. 465. Green et al l2 were perfectly justified from their studies in believing that their findings are "inconsistent with the theory of the two forms of CRVO," but their conclusions about CR VO as a whole are totally unjustified, because at least 28 of the 29 eyes in their series were of the ischemic type; one eye (no. 1) was probably of the nonischemic type. Most of the eyes were enucleated because of neo­vascular glaucoma, and 82.8% of the eyes in their series had ocular NV -all of these definite signs of ischemic CRVO. Since eyes with nonischemic CRVO never de­velop serious complications requiring enucleation, the choice of histopathology as the method of investigation inevitably excludes almost all eyes with non ischemic CR VO and hopelessly biases the sample. Evidently they studied eyes with ischemic CRVO and to extrapolate from that the clinical pattern and pathogenesis ofCRVO as a whole was unwarranted. Green et al '2 also argued that in their series all except seven eyes showed no isch­emic changes of the inner retina, and they put this for­ward as conclusive evidence against the theory of two forms of CRVO, thus denying the existence of an isch­emic form of CRVO. It is well established that all eyes with neovascular glaucoma have extensive retinal cap­illary obliteration. Twenty-three of the eyes in their se­ries had evidence of neovascular glaucoma and the other one had disc NV, so that all these eyes must have had

extensive retinal capillary obliteration and consequently retinal ischemia. The fact that the authors claimed they found no inner retinal ischemia in the vast majority of the eyes indicates that routine histopathologic exami­nation does not give reliable information about the ret­inal ischemia present in these eyes. This represents a serious limitation in their examination techniques. This has also been shown by the histopathologic findings in our experimental studies. Green et al '2 repeatedly cited studies in retinal branch vein occlusion in support of their conclusions. It must be stressed, however, that CRVO and branch retinal vein occlusion are not iden­tical processes pathogenetically. In branch retinal vein occlusions we are dealing with a closed system, so that primary retinal vein occlusion does produce secondary retinal ischemia by interfering with the arterial inflow, while in CRVO this is not always the case. Therefore, it is unjustified to extrapolate from branch vein occlu­sion findings to CRVO in toto.

Furthermore, in personal discussion Dr. Green main­tained that he found it inconceivable that retinal isch­emia can develop in the absence of histopathologically demonstrable arterial occlusion. This simply reflects a lack of basic understanding of the hemodynamics of the ocular circulation in vivo. Ocular blood flow can be calculated by the following formula:

Perfusion pressure (Mean Arterial Pressure - Venous Pressure)

Peripheral Vascular Resistance

Mean arterial blood pressure = diastolic BP + 113 (systolic minus diastolic BP). Venous pressure = about the in­traocular pressure.

Thus, a fall in the perfusion pressure can occur to a marked degree with a fall in systemic BP, and this is

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Fig 4. VSR-Case 4: left eye. A 56-year-old man woke up with blurred vision one week before seen by us on November 24, 1980. VA 6/12, visual fields as shown in A, and multiple scattered retinal hemorrhages with optic disc and macular edema (B, see color plate). VA and visual fields further deteriorated on follow-up (On July 6, 1981 visual fields as shown in C). On February 1'2, 1982, VSR almost resolved and the eye had VA 6/60, large central scotoma with normal peripheral fields (D), premacular gliosis and a few retinal hemorrhages (E, see color plate), and angiography showed (F) a few small patches of retinal capillary obliteration (in areas of cotton-wool spots).

well known to occur during sleep and in many other conditions. This explains why many ocular vascular ac­cidents are discovered on waking up in the morning (eg, CRVO, anterior ischemic optic neuropathy, and some cases of central retinal artery occlusion), and yet fluo­rescein fundus angiography performed the same day does not always reveal a filling defect. This is because a transient collapse of blood vessels can occur due to a fall of perfusion pressure without any organic vascular occlusion; this occurs in far more cases than is appre­ciated by persons not specifically studying vascular dis­orders. Thus, the fact that Green et al12 did not find

462

organic arterial occlusion in many eyes in their series, in no way rules out ischemic damage. In fact, our ex­perimental studies suggested transient retinal ischemia superadded to CR VO as the major cause of ischemic CRVO. 14 With the elevated retinal venous pressure in CRVO, a comparatively moderate fall of mean arterial blood pressure would markedly interfere with the retinal arterial inflow and consequently would produce tran­sient retinal ischemia.

Thus, histologic studies, while very useful in providing information about the morphologic changes present at the time the eye is enucleated, do not give all the in-

HA YREH • CLASSIFICATION OF CRVO

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Fig 5. VSR-Case 5: left eye. A healthy 34-year-old man suddenly developed blurred vision in last week of January 1981. When seen on May 29, 1981, the eye had VA 6/12, a central scotoma and enlarged blind spot (A), fairly marked retinal hemorrhages with mild macular edema (B, see color plate), and no retinal capillary obliteration on angiography. On January 4, 1982, when retinal hemorrhages had resolved markedly, angiography showed multiple microaneurysms (C). When seen on June 26, 1982, the eye had VA 6/18, a small central scotoma with I2e and normal peripheral fields, and retinal hemorrhages had resolved leaving a foveal cyst and some microcystic macular edema (D, see color plate).

formation, because of several serious limitations in the method, some of which are mentioned above. To theo­rize from histologic studies of a biased sample about the disease process going on in the living eye, particularly when little clinical information is available and the eye is enucleated months or years after the onset of the dis­ease process (with superadded effects of secondary com­plications), is misleading and unwarranted.

TERMINOLOGY

The two types of CR VO have been given different names, some of them completely erroneous.

ISCHEMIC CRVO

These cases are usually called simply "CRVO," and sometimes "severe CRVO"ll or "ischemic type."6,10 I have used the term "hemorrhagic retinopathy" (HR) because it is a good descriptive term of considerable antiquity (first used by Liebreich l6 in 1855, and later on by Leberl?).

NONISCHEMIC CRVO

Until recently these cases were described by various terms like "partial," "incomplete," "imminent," "threatened," "incipient," or "impending" CRVO. Our studies indicate that, on the contrary, CRVO is usually complete in these cases; evidence to that effect also exists in the literature. 3

,4 A large number of these eyes have

been followed for years-up to 30 years by Moore3-

without progressing to HR. In our series of 280 eyes with this type of CRVO, 93% on a follow-up of up to ten years have not changed into HR. If these eyes had in fact had "imminent" CRVO, the vast majority must certainly have changed to HR within days or weeks. But they did not, a fact that strongly refutes the concept of the occlusion being partial, incomplete, imminent, threatened, incipient, or impending. Other terms used in the literature have been "mild CRVO"ll or "hyper­permeability-response-macular-edema-type, "6,10 the lat­ter term being misleading and incorrect, because not only do a number of these eyes never develop macular edema nor show any evidence of fluorescein leak on angiography, but also macular edema is universal and much more marked in HR-macular edema is second­ary to hyperpermeability of retinal capillaries in CRVO. I have designated this type "venous stasis retinopathy" (VSR) because it simply represents a venous stasis of the retinal vascular bed. Keams and Hollenhorst l8 first used the term VSR and felt that this was a specific condition seen only in patients with internal carotid artery (ICA) stenosis or occlusion and that it was due to retinal hy­poxia. However, they commented that "venous stasis retinopathy may also be mistaken for an impending occlusion of the central retinal vein". Our studies in­dicate that the vast majority of the VSR cases described by Keams and Hollenhorstl8 were no different from nonischemic CRVO. This is because in their series (1) 95% of patients with unilateral ICA stenosis or occlusion and (2) over 90% of their cases with low central retinal artery pressure showed no VSR-ifretinal hypoxia (sec­ondary to ICA stenosis or occlusion) and VSR were

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Fig 6. VSR-Case 6: left eye. A 53-year-oldman woke up with blurred vision 3 weeks before being seen by us on January 7, 1974. The eye had VA 6/15, visual fields as shown in 6A, and extensive retinal hemorrhages (8). VSR resolved completely by July \9, 1976, with VA 6/6, no visual field defect, normal fundus (C) and angiography showed no abnormality (0).

cause and effect, surely the incidence of VSR in these cases should have been much higher. In our series of 280 eyes with VSR: (1) mild to severe leA disease was seen in only 8%, (2) some patients with unilateral leA stenosis had VSR only on the side with normal leA, and (3) there was no correlation between the severity of leA disease and the presence and/or severity of VSR. Keams et al19 reported resolution of VSR in a patient after carotid artery bypass surgery and claimed that the resolution reflected the increased perfusion to the retina. In our series of 280 eyes with VSR, about half of the eyes have already resolved spontaneously, some in as short a period as two to three months from the time of onset of VSR. Not only that, but four eyes developed VSR two weeks, two months, two years, and 3If2 years

464

after carotid endarterectomy and with perfectly normal blood flow. Thus, it can be concluded that leA occlusive disease and VSR are not cause and effect, but are two independent manifestations of severe generalized ath­erosclerosis. In 118 patients with retinal vein occlusion, Paton20 found a high incidence of atheroma (as judged from a history of ischemic heart disease, cerebrovascular disease, or intermittent claudication) and carotid artery disease; hypertension and/or atheroma were present in 81 % of his cases. In their prospective study of 225 pa­tients with transient cerebral ischemic attacks, after a follow-up of 3 to 14 years (average 5.5 years), Toole et al. 21 found that the majority of these patients eventually succumbed to myocardial infarction. Generalized severe atherosclerosis in carotid arteries produces carotid artery

HA YREH • CLASSIFICATION OF CRVO

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Fig 7. HR-Case 1: left eye. A 53-year-old man suffered sudden transient blurring of vision in the eye ten days before and then three days later noticed sudden marked deterioration of vision on waking up in the morning. When seen on October 12, 1976, the eye had Y A of count fingers at 5 ft, a centrocecal scotoma (A), retinal hemorrhages, and mUltiple cotton-wool spots with optic disc and macular edema (8, see color plate), and intact retinal capillaries on angiography (C). When seen on December 6, 1976, the Y A was count fingers at I ft, there was a large, dense centrocecal scotoma (D), increase in retinal hemorrhages and cotton-wool spots (E, see color plate), and extensive retinal capillary obliteration (F), with iris and angle NY seen. On New Year's Day 1977 developed neovascular glaucoma (intraocular pressure 70 mmHg), the eye was treated with cyc1ocryotherapy and resulted in a phthisical blind eye.

disease; in the coronary arteries it produces myocardial infarction, and in the central retinal artery it produces secondary CRVO. Since most patients with carotid ar­tery disease suffer from myocardial infarction, this in no way means that carotid artery disease and myocardial infarction are cause and effect; the same logic applies to carotid artery disease and VSR. Evidently, all three conditions are simply independent manifestations of severe generalized atherosclerosis.

DIFFERENTIAL DIAGNOSIS OF VSRANDHR

This subject is discussed in detail elsewhere. I The di­agnosis ofVSR or HR is arrived at only by a combination of information obtained from: (1) Visual acuity (V A), (2) visual fields, (3) ophthalmoscopy (both direct and indirect), and (4) fluorescein fundus angiography.

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It should never be based on anyone of these inves­tigations alone. Figures 1 to 6 illustrate these features of VSR and Figures 7 to 12 of HR. The findings usually depend upon the severity of the condition. Briefly, these are as follows:

VISUAL ACUITY

In VSR, the VA may be normal or only mildly to moderately defective, and it is rarely 6/120 or count fingers (CF) (depending upon the severity of macular edema). In HR, on the other hand, there is always a marked visual deterioration, with a VA usually less than 6/60 and generally CF or worse.

VISUAL FIELDS

A careful recording of both the central and peripheral visual fields is extremely helpful in the differential di­agnosis. (All our visual fields are done with a Goldmann

466

Fig 8. HR-Case 2: left eye. A 36-year-old man developed sudden onset of blurred vision on morning of November 27,1977. When seen by us on January 3, 1978, the eye had V A of count fingers in peripheral field only, a large dense centrocecal scotoma (A), extensive retinal hemorrhages with some cotton-wool spots (B), and on angiography extensive retinal capillary obliteration (C). The eye had panretinal argon laser photocoagulation (3014 spots of 500 ,,). When seen on April 7, 1978, the eye had developed iris and angle NY with neovas­cular glaucoma; was treated with cyclocryotherapy and resulted in phthisical blind eye.

perimeter.) Unfortunately, the importance of this has not been stressed in the past.

Central fields. In VSR there may be no defect or a relative or absolute central scotoma (depending upon the severity of macular edema); in some cases of VSR, although 12e of the Goldmann perimeter may reveal no abnormality of the central field, testing on the Amsler grid chart reveals a central visual abnormality (Fig 2A). In HR there is almost always a large dense central or centrocecal scotoma.

Peripheral fields. With a Goldmann perimeter, in VSR these are normal; the 12e target is usually seen and 14e always. In HR, I2e target is almost never seen and in a number of them not even 14e, and the peripheral fields are frequently abnormal with smaller targets. Since there is a high prevalence of open-angle glaucoma in eyes with CRVO, it is important that glaucomatous vi­sual loss is not attributed to CRVO. Similarly, other purely coincidental ocular lesions, eg, senile macular degeneration and cataracts, must be excluded as the cause of visual disorder.

HAYREH • CLASSIFICATION OF CRVO

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Fig 9. HR-Case 3: right eye. A 57-year-old man developed suddenly blurred vision four weeks before we saw him on July 10, 1979. The eye had VA of count fingers close by, absolute large centrocecal scotoma (A), widely scattered retinal hemorrhages with cotton-wool spots (B), almost total retinal capillary obliteration (C), and early iris and angle NV. The eye had pan retinal argon laser photocoagulation (1725 spots of 500 microns) that day. On August 10, 1979, developed retinal and disc NV (D) and a vitreous hemorrhage was detected on September 7, 1979. On August 29, 1980, the eye developed neovascular glaucoma, had cyclocryotherapy and became phthisical and blind.

OPHTHALMOSCOPY

It cannot be stressed too strongly that indirect ophthalmoscopy must be a routine method of exami­nation in all these cases, because it provides most useful information in the diagnosis and differentiation of these cases. (For example see in Figs 1, 2B).

The fundus changes depend not only on the type of CRVO (VSR or HR) but also on the severity and du­ration of the disease in each type, because retinal hem­orrhages and other changes tend to resolve with time­if this fact is not borne in mind it could lead to erroneous diagnosis. Moreover, the diagnosis should not be based entirely on ophthalmoscopic findings.

Venous stasis retinopathy: During the early stages. Figures 1 to 6 represent progressive increase in severity of the ophthalmoscopic findings during the early stages of VSR. The retinal veins are always engorged. The number of retinal hemorrhages varies markedly; usually there are few hemorrhages, most numerous in the pe­ripheral retina (Figs 1, 2B), but in rarer severe cases the posterior part of the retina may show considerable hem­orrhages (Figs 5B, 6B) and the appearance may be con­fused with that of HR. Cotton-wool spots are usually absent or only an occasional spot may be seen in the posterior pole. The macular region may show no edema in eyes with normal VA but in eyes with blurred vision there is almost always edema with or without microcysts.

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The optic disc is usually edematous. If a cilioretinal ar­tery is present a localized retinal infarct may be present in its distribution 1.22 and may be responsible for the vi­sual symptoms.

The fundus appearance (particularly on indirect ophthalmoscopy) is so typical in the vast majority of cases that once one is familiar with it, the diagnosis is usually quite easy.

During the late stages. In about 6-12 months or longer, the ophthalmoscopic findings change consider­ably as compared to the early stages. The retinal hem­orrhages may resolve completely or considerably, with the peripheral hemorrhages, particularly in the temporal periphery, last to disappear. The macular region may return to normal, or may show some pigmentary dis­turbances, or may develop cystoid macular edema and progress to cystoid degeneration, macular cyst, or hole or in some cases to premacular gliosis (Figs 4E, 5D); occasionally a well-defined serous detachment of the macular retina with retinal pigment epithelial degener­ative changes may be seen. Perivenous sheathing of

468

Fig 10. HR-Case 4: right eye. A 38-year-old man, with arterial hy­pertension and one myocardial infarction, suddenly developed blurred vision on November 2, 1978, worsening a week later. When seen by us on November 14, 1978, the eye had VA 6/120, dense centrocecal and peripheral scotomata (A), extensive cotton-wool spots with only moderate numbers of retinal hemorrhages (B, see color plate) and on angiography extensive retinal capillary obliteration, except in the mac­ular region (C). The eye developed retinal NV nasally by January 22, 1979. When seen on May 14, 1982, the eye had VA 6/12 (the only eye out of 78 eyes with HR in our series to have such good vision because of sparing of macular capillaries) without macular degener­ation, optic atrophy, retinal NY, and no retinal hemorrhages (D, see color plate, E).

major retinal veins may develop (Figs 2D, 6C). The optic disc may look normal; however, a number of eyes de­velop retinociliary collaterals (Fig 4E). The process of resolution in different eyes varies markedly, with com­plete resolution in some within two to three months while in others peripheral retinal hemorrhages and mi­crocystic macular edema may occasionally still be seen years after the onset of YSR. It is difficult to predict the speed of resolution from the initial appearance of the fundus.

Hemorrhagic retinopathy: During the early stages. This is shown in Figures 7 to 12. If a patient is seen within a day or so of the onset of HR, the fundus ap­pearance may be similar to that in early YSR, except that the visual loss is out of proportion to the fundus changes. A typical fundus appearance usually develops after a few days. The retinal veins are markedly en­gorged. The retinal hemorrhages are usually extensive, although in a few cases the hemorrhages may be no more extensive than those seen in YSR (Fig 11 B), thus con­fusing the issue. Cotton-wool spots are almost always

HA YREH • CLASSIFICATION OF CRVO

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Fig II. HR-Case 5: right eye. A 71-year-old man suddenly developed marked blurred vision on January 29, 1981. When seen on February 2, 1981, the eye had VA of count fingers at 10 ft, a centrocecal scotoma (A), moderate scattered retinal hemorrhages with a few resolving cotton­wool spots (B, see color plate) and on angiography no appreciable retinal capillary obliteration except in areas of cotton-wool spots (C). Patient was lost to follow-up until March 19, 1982, when the eye had VA 6/120, a central scotoma (D), retinal hemorrhages almost disappeared, with macular degeneration and two very fine spots of disc and retinal NV and diffusely scattered retinal capillary obliteration (E). When seen in October 1982, he had developed vitreous hemorrhage.

seen at some stage of the disease and their number varies at various stages of the disease and in different eyes. Rarely, instead of the patchy retinal ischemia (ie, cotton­wool spots), most of the posterior pole may appear markedly ischemic and pale with "boxcarring" of the blood column in small retinal vessels. The optic disc is edematous and quite often free of hemorrhages and pale. The macular region usually shows extensive hemor­rhages and marked edema.

During the late stages. As in VSR, in about 6 to 12 months or longer, the fundus presents a significantly

different appearance from the initial stages. The retinal hemorrhages may resolve markedly and the cotton-wool spots usually disappear. If an eye is seen for the first time at this stage without any definite history of onset, the ophthalmoscopic findings may be interpreted as VSR (Figs lOD, 12E). The retinal veins frequently show perivenous sheathing. The macular region almost always shows degenerative changes with pigmentary distur­bances and sometimes premacular gliosis or scarring (Figs lOD, 12E). The optic disc may be pale and usually shows retinociliary colleratals. A few eyes may develop

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OPHTHALMOLOGY • MAY 1983 • VOLUME 90 • NUMBER 5

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Fig 12. HR-Case 6: left eye. A 32-year-old man, with renal failure and arterial hypertension, gave a history of visual deterioration for four months-gradually progressive for initial two months, and was started on Coumadin by local ophthalmologist for "CRVO." When seen on May II, 1981 VA was count fingers at 2 ft, with absolute centrocecal scotoma (A), extensive retinal and preretinal hemorrhages (B, see color plate) and scattered retinal capillary obliteration on angiography (C). Coumadin was stopped. On April 2, 1982, the VA was the same, visual field defect more extensive (D), markedly resolved retinal hemorrhages with cystoid degeneration of the macula (E, see color plate), and extensive retinal capillary obliteration (F). When seen on October II, 1982, the eye had developed marked iris and angle NV with early peripheral anterior synechiae and extensive peripheral retinal NV.

disc and/or retinal NV (Figs 90, lIE) which may result in preretinal and/or vitreous hemorrhage.

FLUORESCEIN FUNDUS ANGIOGRAPHY

Particular attention should be paid to the extent of retinal capillary obliteration because it is a hallmark of retinal ischemia.

470

Venous stasis retinopathy: During the early stages. There is marked retinal venous stasis, usually with mi­croaneurysms and dilated capillaries on the optic disc and adjacent retina (Fig 2C). There is no retinal capillary obliteration except in the area of a cotton-wool spot (Fig 4F). The fluorescein stains the retina, maximally along the retinal veins; in eyes with macular edema a fluores­cent star develops and the optic disc stains.

HA YREH • CLASSIFICATION OF CRVO

During the late stages. With the resolution of VSR, angiography may show no abnormality, but if macular edema is present a typical pattern of cystoid macular edema is seen. There is no significant retinal capillary obliteration; however, an occasional eye may show mi­croaneurysms (Fig 5C) and/or some localized small spots of capillary obliteration posteriorly (Fig 4F) or in the extreme periphery. In a few cases the perifoveal ret­inal capillary arcade may be broken. No retinal or disc NV is seen. The optic disc may show retinociliary col­laterals and may stain for considerable time.

Hemorrhagic retinop~thy: During the early stages. Extensive retinal hemorrhages may mask the retinal vascular bed so that no definite information can be ob­tained except that there is marked retinal venous stasis. If the retinal hemorrhages are not extensive, the retinal capillaries may show extensive nonperfusion (Figs 7F, 8C, 9C, 10C, 12C), although in a few cases seen very early after the onset ofHR, the retinal capillary bed may fill normally (Figs 7C, 11 C), thus misleading one to be­lieve that the eye has VSR; in this latter group, within three to six months retinal capillary obliteration be­comes apparent. There is a marked staining of the retina and optic disc.· ,

During the late stages. The classical findings include generalized extensive retinal capillary obliteration, arteriovenous shunts, microaneurysms (Figs 10E, 11 E, 12F) and, in some cases, retinal and/or disc NV (Figs 10E, 11 E). The macular region shows pigmentary de­generation (Figs WE, lIE, 12F) and the optic disc shows retinociliary collaterals, when present. There is a marked fluorescein leak with retinal staining.

There are a few pitfalls in routine fluorescein fundus angiography:

1. Extensive retinal hemorrhages or other causes may result in a poor angiogram.

2. The conventional fundus camera covers only a 25 0 -30 0 field, so that most angiograms give information only about the posterior pole. In a number of eyes, the peripheral fundus shows extensive retinal capillary oblit­eration, not detected on a routine angiography, and ob­viously this causes serious problems in differential di­agnosis.

OTHER SIGNS HELPFUL IN DIFFERENTIAL DIAGNOSIS OF VSR AND HR

In addition to the above mentioned criteria, other clinical parameters may provide valuable information. The most important of these is the presence or absence of anterior segment NY, ie, iris and angle NV and neo­vascular glaucoma. 15 Mild iris NV occasionally may be seen in eyes with VSR, but in HR it is much more extensive and frequent (about 213 of the eyes develop it within two years). I have not seen angle NV with VSR but it is seen almost as frequently as iris NV in HR. Neovascular glaucoma is not seen in VSR but is a def-

inite sign of HR and is seen in about half of the eyes within two years. Disc and retinal NV are also signs of HR although seen much less frequently than anterior segment NV. Thus, the presence of ocular NV is a sign of HR. Very occasionally eyes with VSR and associated ICA occlusions may develop ocular NY due to the ca­rotid artery disease,23 and these eyes should not be con­fused with HR; ICA occlusion or severe stenosis as the cause of ocular NV is a well-established fact ..

Another promising test, which we are investigating prospectively, is the recording of the electroretinogram (ERG) in patients with CRVO. Eyes with HR, because of associated retinal ischemia, show a low amplitude of b-wave, and in some eyes almost a flat ERG, whereas in VSR it is usually not so, since there is no significant retinal ischemia. This has also been suggested by a few previous studies. Thus, the ERG and other electro­physiological tests may prove to be very useful in dif­ferential diagnosis of HR and VSR.

In conclusion, if all these criteria are borne in mind differential diagnosis between VSR and HR can be made without difficulty in 80-90% of the cases. No doubt there are some problem cases that fall in the gray zone between the two types where it may be almost impossible to make a differential diagnosis at the beginning, but a follow-up of about three to six months will usually settle the issue.

ACKNOWLEDGMENTS

The author is grateful to his wife for her help in the prep­aration of this manuscript, to Miss Laura Scheetz for her sec­retarial assistance, to Mrs. Ginny Colston and Mrs. Mariam Leinen for drawing the visual fields, and to our photography department for the illustrations.

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Fig3B Fig4B

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FigSD Fig7B

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HAYREH • CLASSIFICATION OF CRVO

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Fig 12B Fig 12E

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