SURVEY OF OPHTHALMOLOGY

VOLUME 22

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NUMBER 5

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MARCH-APRIL

1978

REVIEW Neovascularization (Rubeosis

of the Iris

Iridis)

SAMUEL GARTNER, M.D., AND PAUL HENKIND,

M.D., Ph.D.

Department of Ophthalmology, Albert Einstein College of Medicinelhfontefiore Hospital and Medical Center, Bronx, New York Abstract. This glaucoma that more frequent never primary,

is a review of neovascularization of the iris and the neovascular often follows. With the aging of our population, this has become a cause of blindness and enucleation of eyes. Iris neovascularization is but is always secondary to other ocular disorders. The pathology is described based on the study of 110globes. Diagnosis, pathogenesis and treatment are

discussed. (Surv Ophthalmol 22:291-312, 1978) Key words. diabetes glaucoma hemorrhagic glaucoma neovascularization of the iris iris neovascular elaucoma rubeosis iridis trauma . tumor vascular disease ??

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N

eovascularization has been called

of the rubeosis

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iris, which iridis since

1928, is a major calamity. Considering the large number of eyes that are lost because of complications that follow its appearance, this entity deserves more attention than it has received in the past. Neovascularization never starts as a primary condition of the iris, but is always secondary to any of a host of ocular and systemic disorders. It can cause an almost hopeless glaucoma. A large number of the affected eyes become so blind and painful that many are enucleated. The diagnosis is made more often by the ocular pathologist studying the specimen under the microscope than by the clinician examining the eye in life. Little is known of the pathogenesis of iris neovascularization and even its pathology has been only scantily described. Our present methods of treatment may preserve the globe, but they rarely save the vision. For this review, we surveyed the literature, 291

studied our clinical cases and the pathology of 110 globes that demonstrated neovascularization of the iris.

I. Incidence Neovascularization of the iris with its complications is a frequent cause for enucleation. Schulzelo4 found that of 870 enucleated eyes received in 1965 at the London Institute of Ophthalmology, 105 (12%) had iris neovascularization. Anderson et al. 152 reported that from 1964 to 1968 at the University of Toronto 460 eyes were enucleated; of those, 70 had iris neovascularization (15.2%). Neither author stated whether all the eyes were surgically removed for therapeutic reasons or obtained at autopsy. In a series of 737 consecutive autopsies from 1937-1970 in which the eyes were obtained at Montefiore Hospital we found 4 cases (0.5%) of neovascularization of the iris, while in a consecutive series of 380 eyes which

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SW Ophthalmol 22 (5) March-April 1978

GARTNER, HRNKIND

FIG. 1. A (top left). Schematic drawing of cross-section of normal iris and angle. B (top right). Stage 1 iris neovascularization. New thin-walled vessels appear in the iris near the pupillary border and at the root of the iris. C (bottom left). Stage 2 iris neovascularization. Thin-walled vessels have penetrated the anterior surface near the pupil and at the root of the iris. They will extend and the two sets will merge. New thin-walled vessels will also develop in the iris stroma. D (bottom right). Stage 3 iris neovascularization. New thin-walled vessels with a connective tissue support cover all or part of the anterior surface of the iris. The anterior surface becomes flattened. Ectropion uvea develops. The dilator muscle (shown by dots in A-C) is often lost. As this stage progresses, peripheral anterior synechiae develop, causing extensive attachment of the peripheral iris to the cornea.

were therapeutically enucleated during the same period we found 70 (18%). In our recent series (1970-1977) of 146 therapeutically enucleated eyes, there were 36 cases (20%) with neovascularization of the iris. In our series the average age of patients with iris neovascularization whose globes were enucleated following trauma was 35. In the group of non-traumatic cases the average age was 57 and this included a child of 5. Iris neovascularization is most often associated with older age groups. It is our impression that with the increase in the numbers of old people in the population, there has been an increase in the incidence of neovascularization of the iris. More people are living long enough to develop vascular disease and diabetes, conditions that often precede iris neovascularization.

II. History A clinical description of neovascularization of the iris was written by Bader’O in 1868. DeutschmarP in 1879 first noted the presence of iris vessels in “hemorrhagic glaucoma.” In

1888, NettleshipW described the clinical appearance of a 48-year-old man with diabetes and new-formed vessels from the retina extending into the vitreous. Several very much enlarged vessels were visible on the iris. This is probably the earliest note of neovascularization of the iris in association with diabetic retinopathy. CoatP in 1906 reported the clinical picture and histological appearance of central vein thrombosis and new vessels on the iris. Saluslos in 1928 clinically described three cases of new vessels on the iris in diabetes and, noting the red blush on the iris, he named it “rubeosis iridis diabetica.” This brought attention to the entity and considerable literature has since been published using this name. Later it was realized that diabetes was not the only cause of new vessel formation on the iris (we have found in the literature and in our cases 41 entities that may be associated with neovascularization of the iris); thus, the name was shortened to “rubeosis iridis.” The frequency of clinical diagnosis varies

NEOVASCULARIZATION

OF THE IRIS

with the examiner and the method of examination. Early techniques of studying the eye by loupe and lens found these cases only rarely. Slitlamp biomicroscopy improved the ability to perceive the new vessels. Fluorescein angiography of the iris demonstrates the new vessels when they are still not easily visible by any other method. Mitsui,Bo using fluorescein angiography, stated that he was able to detect neovascularization of the iris one month before he could see it at the slitlamp. However, the largest percentage of cases are still diagnosed in the eye pathology laboratory by histological study. It is interesting to see how in succeeding years larger numbers of cases of iris neovascularization have been diagnosed. In 1928, when Salus1o2 described it, the entity seemed rare. In 1935, Waite and Beetham, in a study of 2002 diabetic patients, did not report a single case of it. In 1958, Ohrta4 in a slitlamp study of 325 diabetics found 17 cases of iris neovascularization. MadsenT in 197 1, studied 123 patients with proliferative diabetic retinopathy, and found iris neovascularization in one-third of the eyes. With the improved techniques for examining the eye, it has become clear that there is an early stage of neovascularization, during which new vessels can be seen before the characteristic red blush is present. Therefore, the term, rubeosis iridis, describes the entity inadequately and should, as suggested by Walton and GranP be replaced by the term, neovascularization of the iris. Similarly, as Weiss and Shaffer121 have suggested, the glaucoma secondary to neovascularization, which for many years has been called “hemorrhagic glaucoma,” should now be called simply neovascular glaucoma. In the interest of establishing this more appropriate terminology, we have taken the liberty of using it throughout this review, even though in most of the literature cited, the terms “rubeosis iridis” and “hemorrhagic glaucoma” were used.

III. Clinical Picture of Neovascularization of the Iris The clinical course of iris neovascularization can be divided into three stages (Fig. 1). In the first stage, the new vessels appear separately in isolated areas at the pupillary zone and at the angle. It is not certain which area is affected first in many cases. When one patch of new vessels is detected a search

293

should be made for the others. They are fine tortuous red lines that course in an irregular manner over the surface of the iris; this is in contrast to the regular radial path of normal iris vessels. Gonioscopy is required to view the new vessels at the angle which’appear at the periphery of the iris and course over the angle onto the meshwork towards Schwalbe’s line. In the first stage the angle is of normal width. The first stage is usually brief, lasting only a few weeks or months following obstruction of the central retinal vein. On the other hand, diabetics may have neovascularization at the pupil which may last years without progression and without causing symptoms. Neovascularization of the iris may be difficult to detect in its earliest stages. The small new vessels are obscured in a dark iris and more obvious in a light-colored eye. The best chance to see an early stage of the condition is by frequent examination of patients after obstruction of the central retinal vein, as neovascularization of the iris will develop in so many of these cases. Repeated examination should be done at the slitlamp with high magnification and by gonioscopy. Fluorescein angiography of the iris may also be helpful for early detection. In the second stage, the isolated patches of vessels extend and merge until they cover the iris. When well-developed, they impart the red flush that gave the name, rubeosis iridis. The new vessels have thin walls so the blood column is visible, while the normal iris vessels have thick walls that obscure the blood in them. Most of the new vessels are narrow, but some enlarge. At this stage, the patient has no symptoms. Only if a spontaneous hyphema occurred would the patient be aware of an ocular disturbance. Later, peripheral anterior synechiae develop in scattered spots and finally become extensive. This marks the onset of the third stage with the dramatic appearance of pain due to the neovascular glaucoma. The pain brings the patient to the ophthalmologist who usually then makes the diagnosis for the first time, based on the finding of elevated tension in the range of 40 to 80 mm Hg and neovascularization of the iris with extensive peripheral anterior synechiae. This usually defies treatment and ends very often in enucleation. It is remarkable that the end picture is so similar no matter which cause initiated it.

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GARTNER, HENKIND

1978

The normal iris has a delicate stroma with a wavy anterior surface with open crypts which connect with tissue spaces, permitting aqueous to penetrate the stroma to supply it with nutrition and oxygen. As neovascularization of the iris develops, the iris becomes compacted, thin and flat with a loss of the normal iris markings, Ectropion uvea frequently develops as the anterior layer of new formed fibrovascular tissue contracts and pulls the pigment layer anteriorly. The pupillary border may be bowed forward. Ectropion uvea can occur in a few other conditions, e.g., with iris tumors and the iris nevus syndrome, and following surgery and injury. In these other conditions, ectropion is usually partial and localized to the involved zone. In neovascularization of the iris, it encircles the pupil. Whenever ectropion uvea involves the entire pupillary zone, it is safest to consider it secondary to neovascularization of the iris. In some cases, new vessels break through the pupillary border to form a vascularized pupillary membrane that may obstruct the pupil (occlusio pupillae) and, in some, the membrane and the iris adhere to the lens (seclusio pupillae). The pupil becomes fixed or has limited ability to expand or contract, perhaps due to two factors: a) scarring of the iris; and b) atrophy of the dilator and sphincter muscles. Cataract formation is common. The onset of glaucoma may accelerate its development. Hyphema may occur in 25% or more of patients with iris neovascularization. The most serious complication is the intractable glaucoma which develops as the peripheral iris becomes attached to the cornea. Anderson2 reported its occurrence in 75% of their patients with neovascularization of the iris. Spontaneous disappearance of the new vessels in iris neovascularization has been reported in a number of eyes.1’*‘07It has also been reported to disappear with various modalities of treatment.Be~72~geJ0’ It should be noted that these are clinical impressions without histological proof. What probably happens is that as scar tissue shrinks, it obscures the vessels. In the cases we have observed of apparent disappearance of the new vessels, the iridi had a flat, smooth and scarred appearance. The scar tissue may have hidden the new vessels. Reports of “vascular tufts”28J0*a8 and “microhemangiomas”gs at the pupillary border have appeared in the literature. It is

FIG. 2. Fluorescein angiography demonstrating leakage at the pupillary border in early neovascularization of the iris in a 6dyear-old diabetic. not certain whether these constitute separate entities or are a variation of neovascularization of the iris. Reese8’ expressed the opinion that primary hemangiomias of the iris are rare. He thinks that of nine reported cases of hemangiomata of the iris, most were either granulomas or were associated with malignant melanomas. He has seen only one case that he thought could possibly be classified as hemangioma of the iris. A. FLUORESCEIN

ANGIOGRAPHY

Fluorescein angiography may be used to examine the dynamics of iris circulation using techniques similar to those used in fundus angiography (Fig. 2). Not all of the normal iris vessels are seen with fluorescein angiography, as some of them are opaque. They are more readily seen in a light colored iris. Those that are visible course in a fairly regular radial direction. The diagnostic feature of new formed vessels is that they appear like irregular threads over the iris. Another important feature of neovascularization is the leakage that occurs from these new thin-walled vessels. This is usually seen as luminous dots along the pupillary border which increase in size and gradually coalesce to form a more-or-less complete ring. In these cases, fluorescein readily escapes into the aqueous. Bagessen l1 by this method examined 32 non-diabetics and 82 diabetics by fluorescein

NEOVASCULARIZATION

295

OF THE IRIS

after the obstruction of the central retinal vein. Months later neovascular glaucoma ensued. Imre69 performed tonography on 18 eyes with iris neovascularization. In 15 the aqueous outflow was reduced. In eight intraocular tension was reduced (4 to 12 mm Hg), in one it was normal, and in nine it was elevated. MadsenT noted that very low intraocular pressures were found in eyes with severe proliferative retinopathy in -which neovascular glaucoma later developed. He charted a case in which the eye was hypotonous for two years with iris neovascularization. In eight of 10 eyes, pressures of 10 mm Hg or less were found prior to the onset of glaucoma. B. BILATERAL INVOLVEMENT Neovascularization of the iris apparently Bilateral occurrence of neovascularization developed during the phase of hypotony. With the onset of central retinal vein occluof the iris is found most often in diabetics. The next most frequent occurrence is in sion, tension may become temporarily retinoblastoma patients. Other causes rarely lowered in the affected eye. One of our induce bilateral development. 0hrt,88 in a patients, a 56-year-old white male, had poorly study of 309 diabetics, found that 16 of the 21 controlled open angle glaucoma. One day he patients with iris neovascularization were noted decreased vision in one eye and exaffected bilaterally. HohP reported that amination revealed a “normal” intraocular among his 40 cases of iris neovascularization pressure and central retinal vein occlusion. in diabetics, two were bilateral. Madsen” The other eye still had elevated intraocular reported five bilateral cases among 58 cases tension. In a case of temporal arteritis with of diabetic iris neovascularization. BresnickZo bilateral occlusion of the central retinal reported two bilateral cases in seven arteries, Zion and Goodside’sa found an exdiabetics. tremely low uniocular tension of 2 to 4 mm Hg. Iris neovascularization later developed in C. LIFE EXPECTANCY IN DIABETICS WITH that eye. angiography. Twenty-seven of his diabetic patients had iris neovascularization. In the non-diabetics, leakage was seen in four patients, three of whom were over 50 years of age and one who was 33-years-old. Leakage, which was much more common in the diabetics, was seen in 25 of the 27 cases of iris neovascularization. In both diabetics and non-diabetics, leakage increased with age. Mitsui,Bo using fluorescein angiography, was able to diagnose iris neovascularization before it was visible at the slitlamp. By fluorescein angiography of the iris, VannaP found neovascularization that could not be seen biomicroscopically.

NEOVASCULAR

GLAUCOMA

A somewhat low life expectancy among patients with neovascular glaucoma must be expected because by the time the condition is present the primary disease which caused it is well advanced. Boniuk” noted that four of eight diabetic patients that he treated with cryotherapy for neovascularization of the iris died, three within one year after treatment and one 16 months after treatment. Since neovascularization of the iris is a late development in diabetes, it is likely that these patients also had vascular and kidney disease in an advanced state, which contributed to their mortality. D.

LOW

INTRAOCULAR

TENSION

AND

IRIS

NEOVASCULARIZATION

Moore*’ in 1924 reported that the intraocular tension was often low soon after thrombosis of the central retinal vein. Samuelslos in 1935 also found the globe to be frequently softer than normal immediately

IV. Causes of Iris Neovascularization A. REPORTS

OF SERIES

There are many causes for iris neovascularization. Table I lists possible etiologies; the order of the categories is strictly arbitrary. SchulzelM culled 27 causes from the literature. In his study of 105 eyes with neovascularization of the iris, he found thrombosis of the central retinal vein to be the leading cause (44 cases), and retinal detachment to be next most frequent (24 cases). Diabetes, surprisingly, was present in only three cases. Walton and GranP drew attention to the frequent finding of iris neovascularization with retinoblastoma. It occurred much more often when the tumor invaded the choroid or optic nerve. In 1971, Anderson et ~1.~ published a list of 28 causes of neovascularization of the iris. Hoskin$’ found 11 causes among his 100 cases; most common were diabetes (33 patients), central retinal

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TABLE 1 Causei of Neovascularization of the Iris* 1. Vascular disorders CENTRAL RETINAL VEIN OCCLUSION 16. 57, 103.108

2.

3.

4. 5.

6.

GARTNER, HENKIND

1978

vein thrombosis (28 patients), iritis (11 patients), and carotid insufficiency (8 patients). In 1975, Yanoff and Fine’*’ listed

25 causes for iris neovascularization. There have been reports of the development of iris neovascularization following Central retinal artery occlusionzs* 57*lo8*lZO*12@ treatment with certain therapeutic modalities, Branch vein occlusions7 and these should be considered. Carroll and Carotid occlusive diseases73 68. lo’*lo8 Lande?’ reported a patient who developed Takayasu’s disease (Pulseless disease)81 neovascularization of the iris following laser Giant cell arteriti?, lZ7*Ia2 coreoplasty to enlarge a pupil, and Michels Carotid artery ligation”’ and RyarP reported that it occurred in 16 of Carotid-cavernous fistula’zl 100 eyes which had undergone vitrectomy. In Leber’s ciliary aneurysms104 neither case did the authors consider the Retrolental fibroplasiasa Sturge-Weber with choroidal hemangioma104 # therapeutic modality to be the causative factor. Carroll and Lander attributed the Ocular Diseases neovascularization of the iris to a longstandUVEITLC?‘~ lo4 ing retinal detachment; Michels and Ryan’s Endophthalmitis# patients also had ocular conditions that Sympathetic ophthalmia# predispose to iris neovascularization, esVogt-Koyanagi syndromes0 Retinal detachments’* ls8 pecially active proliferative retinopathy.7g Persistent hyperplastic vitreousn” However, until more is known, various new Coats’ disease2’* 64*lo4 treatment modalities should be considered as Eales’ diseaseI possible contributors to neovascularization of Pseudoexfoliation of lens capsule11s the iris. Essential iris atrophy In our series of 110 globes studied GLAUCOMA histologically, there were 21 patients with OPEN ANGLE GLAUCOMAs7* lo’*lz8 diabetes, 13 with glaucoma, 14 who had sufClosed angle glaucomas7* lo8 fered trauma, 10 with retinoblastoma, and 8 Secondary glaucoma# with central retinal vein occlusion. A variety Surgery and Radiation Therapy of other causes which were only found once or Retinal detachment surgeryg twice are not listed here. The frequency of Vitrectomy**‘B trauma as a cause may be due to the fact that Laser coreoplasty**24 our hospital sees many cases of severe ocular Cataract extraction# trauma. Glaucoma was also frequent in our Radiations2 series. We are not certain whether some of the TRAUMAS’ cases were primary or secondary to Systemic Diseases neovascularization of the iris. Some of the DIABETE9’9 es>lo2 globes were obtained with only limited Norrie’s diseases histories. In about 10% of our cases, we could Sickle cell disease’# not determine the original disease that subNeurofibromatosis# sequently caused neovascularization of the Lupus erythematosis#! iris. Marfan’s syndrome2 Review of the literature and examination of Neoplastic diseases our cases revealed 41 different entities (Table RETINOBLASTOMAIO’* X16,# I) that became complicated by the developMelanoma of choroida** Iso ment of neovascularization of the iris. Melanoma of irislo Metastatic carcinomas8* ‘I Reticulum cell sarcoma of ciliary bodyl’”

*Numbers refer to reference list at the end of this article. # indicates cases seen in our current series. Most frequent causes are capitalized. **Iris neovascularization has been seen in association with this therapeutic modality; it has not been established that the modality is a causative factor.

B.CENTRAL

RETINAL VEIN OBSTRUCTION

Eyes that suffer from closure of the central retinal vein often show signs of open angle glaucoma in the other eye. Glaucoma, as well as diabetes, increases the incidence of closure of the central retinal vein. After such closure, neovascularization of the iris may develop and is followed by neovascular glaucoma in a

297

NEOVASCULARIZATION OF THE IRIS

percentage variously estimated at 2530%. Glaucoma usually develops about three months after closure of the central retina1 vein. Braendstrup20 studied 13 1 cases of central vein thrombosis, of which 62 developed neovascular glaucoma. The time interval to the onset of glaucoma varied from less than one month to three or four years; it most often occurred in three months. Recently, Laatikinen and B1ach,s* using fluorescein angiography, differentiated two types of central retinal vein occlusion. Those associated with retina1 capillary occlusion were labeled ischemic and those without capillary occlusion, non-ischemic. Twentyfour eyes were identified by fluorescein angiography as ischemic type of central retina1 vein occlusion; all of these developed neovascularization of the iris, while none of 24 eyes which were non-ischemic did. The period of observation was up to 52 weeks with an average of 13 weeks after the onset of symptoms. This study adds evidence that retinal hypoxia is an important factor in inducing neovascularization of the iris.

D. DIABETES

Madsen” found iris neovascularization in about 5% of non-selected diabetics and in 43% of 68 patients with proliferative retinopathy. 0hrts4 studied 309 diabetics and found 21 (6.8%) with iris neovascularization, 16 of which were bilateral. In the group with proliferative retinopathy, the incidence of iris neovascularization was 64%. Bresnick et af.*Ostudied eight diabetics with proliferative retinopathy. With fluorescein angiography they demonstrated that the first development is closure of capillaries and arterioles in the retina, which they thought produced retina1 ischemia. That was followed by proliferative retinopathy. Seven of these eight patients developed iris neovascularization, two bilaterally. HohP6 reported 40 cases of neovascularization of the iris and glaucoma in diabetics. Half were juvenile onset and half maturity onset diabetes with an average age of onset of 20.8 years. All had proliferative retinopathy. One eye had central retina1 artery thrombosis, and another had central retinal vein thrombosis. Two had bilateral iris C. CENTRAL RETINAL ARTERY neovascularization. Ten of the eyes were OBSTRUCTION enucleated. Glaucoma simplex developed in Following obstruction of the central retina1 the contralateral eye in two patients. Iris neovascularization in a diabetic artery, a small percentage (l-2%) of patients develop neovascularization of the iris and appears most often after the development of neovascular glaucoma. The incidence is far proliferative retinopathy. The appearance of lower than that after obstruction of the cen- bilateral neovascularization in an adult marks tral retinal vein. However, the onset of that person as most likely to be diabetic. There is usually an interval of many years glaucoma takes place in a relatively shorter time. Perraut and Zimmermane4 reported six from the onset of neovascularization of the cases whose glaucoma appeared within nine iris in a diabetic before glaucoma develops. weeks after the arterial obstruction. Weiss Why it takes so much longer than in patients and Leopo1d’20 reported a clinical case in with obstruction of the central retina1 vein is not known. which obstruction of the central retina1 artery Madsen76 wrote that in about one-fourth of was followed eight weeks later by iris neovascularization and glaucoma. Wolter his diabetic patients the iris neovascularizaand Ryan’28 reported a patient with open’ tion apparently disappeared, and in many patients it remained unchanged for some angle glaucoma that was well controlled medically who had an acute closure of the years, or there were fluctuations in its severity. Twenty-four of the affected eyes that central retina1 artery. Iris neovascularization and glaucoma developed within six weeks. were followed for five years did not develop glaucoma. This observation is important to Histological examination revealed embolism of the central retina1 artery. Wo1ter129 keep in mind in evaluating any form of treatreported another case in a 92-year-old woman ment. with aphakia, who suffered an obstruction of E. GLAUCOMA the central retina1 artery. Two months later, The role of glaucoma in the development of iris neovascularization and glaucoma of the iris is probably developed. Histological examination dis- neovascularization closed embolism of both the central retina1 secondary. Both diabetes and glaucoma increase the incidence of central vein occlusion. artery and one long posterior ciliary artery.

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When neovascularization of the iris and glaucoma develop, it may be difficult in some cases to decide which disease came first. In all events, whenever a patient has central retinal vein obstruction or diabetes or neovascularization of the iris, a study should be made for glaucoma. Most reports of central vein thrombosis and diabetes mention the presence of open angle glaucoma. Smith and Ottlog studied the association of 120 eyes with iris neovascularization in one eye and angle closure glaucoma in the other; detailed histories and workups were available in 99 cases. Ten of the patients had neovascularization in one eye and angle closure glaucoma in the other. In most of their cases of iris neovascularization, the affected enucleated eyes had central retinal artery or vein occlusion. F. PROGRESSIVE

ESSENTIAL

IRIS ATROPHY

JampoP reported three cases of progressive essential iris atrophy, two of which had neovascularization of the iris. This was not seen by biomicroscopy, but was identified by fluorescein angiography. C. CAROTID ARTERY OCCLUSION

Huckman and Haass8 reported two cases of internal carotid artery occlusion with iris neovascularization. Ischemia of the iris is believed to occur as blood is shunted away from the eye in a retrograde fashion through the ophthalmic artery to the carotid siphon. They coined the phrase “ophthalmic steal.” H. CARCINOMA AND

METASTATIC

GARTNER, HENKIND

1978

TO THE EYE

ORBIT

Ferry and Font” reported 26 cases of carcinoma metastatic to the anterior segment of the eye. Ten of them had iris neovascularization. I. RETINOBLASTOMA

Walton and Grant116 examined histopathologically 88 eyes which were enucleated for retinoblastoma. Forty-four percent of them had neovascularization of the iris. It appears that of all the various conditions that cause iris neovascularization retinoblastoma has the highest frequency. Cheng-Minodaz8 confirmed the high incidence in retinoblastoma. In 14 cases of retinoblastoma enucleated at Montefiore Hospital, we found histological evidence of neovascularization of the iris in 10 (72%). Peripheral anterior syn-

echiae were not notable, occurring in only four cases. The marked discrepancy between the low reported incidence of iris neovascularization in uivo in retinqblastoma and the high incidence on histopathologic examination is interesting. J. MALIGNANT

MELANOMA

Schulzelo4 reported a 5% incidence of iris neovascularization in a series of patients with malignant melanoma. Cappin studied 308 cases of uveal melanoma in which he found 46 cases (15%) with iris neovascularization. At Montefiore Hospital, 71 eyes with choroidal melanoma were studied, among which four cases (6%) of iris neovascularization were found. YanofPao reported that one-third of choroidal melanomas are associated with glaucoma, but that neovascular glaucoma occurred in only 5%. The globes of two cases of iris melanoma were obtained at Montefiore Hospital. In both there was neovascularization of the iris, in one it was very extensive. Tumors stimulate new vessel formation. In the eye the same stimulating mechanism may affect the iris vessels, causing them to proliferate. K. PSEUDOEXFOLIATION

OF LENS CAPSULE

Vannasl’s claims to have found neovascularization of the iris in 75% of cases of pseudoexfoliation of the lens capsule. He was most successful in finding it by fluorescein angiography. It was a constant finding when glaucoma was present. He suggests that before cataract surgery fluorescein angiography should be performed to look for neovascularization. as it is often difficult to find in other ways and may explain some of the bleeding seen at cataract extraction. L. COATS’ DISEASE

Four cases of Coats’ Disease in adults were reported by Henkind and Morgan?’ All had iris neovascularization. In addition to the exudative retinopathy, three patients had retinal detachment, two had glaucoma, and one had a hypermature cataract. This is another example of the association of vascular disease of the retina with neovascularization of the iris. V. Special Features of Iris Anatomy A. SPONGY STRUCTURE

Normally the iris is a spongy structure with many open tissue spaces. Gregerson”’ studied

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in fine detail the free communication of not give a clue to its possible etiology. In most aqueous through the crypts and many small cases it is remarkable that the affected iris openings in the iris surface into open spaces in looks very similar regardless of cause. Only in the iris stroma. Hogan et ~1.~~described the diabetes is the diagnosis evident when there effect of injecting India ink into the anterior are typical cystoid changes in the iris pigment iris Even histologically, chamber. They found that ink enters the iris epithelium. through the crypts and other gaps in the sur- neovascularization may be missed, since the face and penetrates freely into the iris stroma. new vessels have scant support, and many collapse during preparation of the specimen. B. IRIS BLOOD VESSELS JocsorP demonstrated that far more new The blood supply to the ciliary body comes vessels were found in and on the iris by infrom two long posterior ciliary arteries and jecting the anterior ciliary arteries than were six or seven perforating branches from the evident on clinical or histological examinaanterior ciliary arteries. These anastomose to tion. Our own observations indicate that as form the greater arterial circle of the iris, one becomes accustomed to looking for all which is often located in the ciliary body. The the signs and sequelae of neovascularization blood supply to the iris comes from branches of the iris, it is diagnosed more frequently. Neovascularization starts separately in the of the greater arterial circle. In the ciliary body the vessels are similar to pupillary zone and in the periphery of the iris. those in the choroid, with a muscular coat in Later it extends to cover the entire iris. the arteries and a normal adventitia. A Neovascularization starts as endothelial budchange in the vessels takes place as they enter ding from capillaries or venules. The normal the iris. The arteries lose almost all their mus- blood vessels in the iris have extremely thick cle. Arteries and veins in the iris have walls from which new vessels might not easily remarkably thick walls of hyalinized connec- develop. However, at the pupillary zone and tive tissue, which may appear in histologic at the iris periphery there are many capillaries sections as a double layer; the inner and outer from which new vessels could readily grow. layers dense with intervening looser areolar Initially, the new vessels arise from normal tissue. Compared according to the diameter vessels in the iris stroma. With growth, there of their lumen, these vessels are among the is a tendency for them to form a layer on the thickest vessels in the body. Histologically, anterior surface of the iris and, similar to there is an unusual resemblance of artery and retinal neovascularization, the new vessels vein, making it difficult to identify which is start with thin walls and scant support (Fig. which. 3). Later, there is a proliferation of connecThe vessels follow a radial course toward tive tissue surrounding the vessels, which the pupil with slight irregular variation. There eventually may also cover the iris (Figs. 4-9). are limited anastomoses, mainly at the As the new connective tissue shrinks, the collarette-the lesser arterial circle of the iris. embedded vessels may be compressed and Clinically, the vessels at the collarette look hidden, giving the impression that they have much fuller early in life, while with aging they disappeared. At this stage, the iris becomes are reduced to irregular strands and fewer fibrotic and thinned, having lost its spongy anatomosing vessels. Capillaries are almost character, its surface markings and crypts. limited to the area between the collarette and The anterior and posterior iris surfaces the pupillary border, where they supply the become parallel. Figs. 8 and 9 illustrate variasphincter muscle. The remainder of the iris tions in the pathology of iris neovashas only a rare capillary. There are usually cularization. none in the region of the active dilator musEctropion uvea develops in many cases. cle. This is caused by the adhesion of the fibrovascular membrane on the surface of the iris to the pigment epithelium at the pupillary VI. Pathology border. As the connective tissue shrinks, it This part of our study was based on the pulls the pigment epithelium onto the anterior study of 110 globes, 99 of which were surface of the iris, a condition called ectroenucleated at Montefiore Hospital and 11 pion uvea. The pupillary zone of the iris may from other institutions. Histological study of be folded onto the anterior surface of the iris the iris with neovascularization usually does by the shrinkage of the tibrovascular mem-

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brane. This could bend the sphincter muscle into a IJ or J shape, a condition called ectropion of the sphincter (Fig. 9). Clinically, neovascularization of the iris is perceived as only a surface phenomenon. However, new iris vessels are not confined to the surface, for they originate from and penetrate the iris stroma and appear at all layers. Wherever they appear, the new vessels have thin walls in contrast to the normal

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thick-walled vessels. Rarely, new vessels perforate the pigment epithelium and grow behind the iris. More frequently, the new vessels extend across the pupil and produce pupillary membranes. In the angle, as new vessels grow, their connective tissue framework adheres to the cornea and iris creating peripheral anterior synechiae. The iris angle becomes “zipped up,” causing an intractable mechanical glaucoma.

FIG. 3. New blood vessels in periphery of the iris bridge the angle. There is connective tissue proliferation around the vessels.

FIG. 4. Many large new blood vessels at and near the angle which has been closed by peripheral anterior synechiae. The iris is fibrotic, its stroma is compressed and there is loss of the crypts. The anterior and posterior layers of iris have become almost parallel. The peripheral iris is necrotic. Patient is a 58-year-old diabetic with neovascular glaucoma.

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that Jocsons’ has also demonstrated glaucoma can develop when new vessels cover the trabecular meshwork without the formation of synechiae, but this is an uncommon phenomenon in our view. had previously found that Grant’6 neovascularization of the iris could raise the intraocular tension prior to gonioscopic closure of the angle. Our histologic study of such angles showed a connective tissue framework for these new vessels which undoubtedly affected the region of the

meshwork. We conclude that an “open” angle by gonioscopy cannot necessarily detect the early pathologic alterations which might embarrass aqueous drainage (Fig. 3). Posterior synechiae may develop. These are much less frequent than anterior synechiae. The posterior synechiae may be attached to the lens or to cyclitic membranes (Fig. 10). It is our impression that with neovascular glaucoma there often occurs a diminution in the number of normal thickwalled iris vessels.

FIG. 5. Extensive fibrosis with neovascularization on the iris surface. The angle is closed by peripheral anterior synechiae. There are focal infiltrates of inflammatory cells. Patient is 55 years old and has had poor vision since an accident at the age of 5 years.

FIG. 6. Neovascularization of the iris with large new vessels in the iris stroma. The patient had glaucoma and comeal ulceration with hypopyon. The anterior chamber and iris are heavily infiltrated with inflammatory cells.

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adjacent endothelial cells. Okamura and RoherP reported an electron of 4 cases of microscopic study neovascularization of the iris and found marked endothelial cell proliferation. ChengMindodaZS performed electron microscopy of iris of neovascularization in cases retinoblastoma. A striking feature which has received little attention is loss of the dilator muscle which occurs in many cases (Figs. 11 and 12). The cause may be related to the fibrosis of the iris or to the longstanding glaucoma. This requires further study. The sphincter muscle is most often preserved, though it usually undergoes some degree of atrophy. As a result

of fibrosis of the iris, loss of dilator muscle and partial atrophy of the sphincter muscle, the iris with advanced neovascularization has little or no mobility and poor reaction to light or accommodation. It is often’ fixed and dilated. In some advanced cases, there is marked iris atrophy with only a shadow of supporting tissue left. Localized areas of necrosis may occur, accounting for the frequent finding of inflammatory cell nodules. The pigment epithelium is best preserved in most cases, though it usually becomes thinner and flatter. Some of our cases showed many small thinwalled vessels in the ciliary body which we consider to be new-formed vessels. Atrophy

FIG. 9. The fibrovascular membrane on the anterior iris has folded the pupillary border on itself creating a J-shaped sphincter, with both ectropion uvea and ectropion of the sphincter. The iris is compacted and fibrotic.

FIG. 10. A new blood vessel penetrating the pigment epithelium and growing into a cyclitic membrane.

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FIG. 11. Neovascularization on the iris surface and in the stroma. There are peripheral anterior synechiae, loss of the dilator muscle and pigment migration into the iris.

FIG. 12. Neovascularization upon the surface and within the stroma of the iris. The dilator muscle is absent and the sphincter atrophic.

of the ciliary body was found in many of our cases of neovascularization of the iris. Anderson et al3 reported a series of 70 eyes with iris neovascularization. They stated: “Many had similar findings in the iris and ciliary body, differing only slightly in degree, for example, acute and chronic inflammatory cells, pigment epithelial degeneration with pigment dispersion and atrophy. The ciliary body showed some atrophy and fibrosis.” All their cases had severe posterior segment pathology.

VII. Extension of Cornea1 Endothelium and Descemet’s Membrane onto the Anterior Surface of the Iris: The Role of Neovascularization Cornea1 endothelium and Descemet’s membrane may, under certain conditions, extend from their normal position on the posterior cornea and grow over the anterior surface of the iris. This entity has also been

called “endothelialization of the anterior chamber.” Gartner et ~1.~’ in a retrospective study of 100 globes with neovascularization of the iris found 16 eyes that demonstrated this abnormality. In each case the iris displayed the typical histopathological features a neovascular membrane on the anterior surface and closure of the anterior chamber angle by peripheral anterior synechiae. The endothelium and Descemet’s membrane grew from the cornea onto the iris at the pseudo-angle formed by the attachment of the iris to the cornea and then extended for a variable distance onto the anterior surface of the iris (Fig. 13). This membrane was firmly attached to the iris by the fibrovascular membrane typical of neovascularization of the iris. Some of these globes also had ectropion uveae and pupillary membranes. The layer of new-formed Descemet’s mem-

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FIG. 13. Cornea1 endothelium and Descemet’s membrane have been reflected onto the iris surface at the pseudo-angle formed by peripheral anterior synechiae. Beneath the membrane is the typical neovascularization of the iris. (Reprinted from Gartner S, Taffet S, Friedman AH” with permission of the British Journal of Ophthalmology).

brane was thick and prominent and extended over most of the iris in six patients. In 10 cases, the membranes were thin and partial and were found only after a careful search when they extended only a short distance from the pseudo-angle in an early stage of development. Extension of Descemet’s membrane onto the anterior surface of the iris was first described by Wagenmann”’ in 1889. Parsonso and Cogans2 in their studies of glaucomatous eyes reported some globes with extension of Descemet’s membrane onto the iris which they noted occurred at the attachment of peripheral anterior synechiae. Colosi and Yanoffs’ found 22 cases of endothelialization of the anterior chamber in 100 consecutive enucleations. Iris neovascularization was present in nine of these eyes. Other casues of extension of the endothelium and Descemet’s membrane onto the iris occur with traumatic recession of the angle and with iris nodules. The accepted explanation for ectropion uveae is that contraction of the fibrovascular membrane in neovascularization of the iris pulls the iris pigment epithelium from the pupillary border onto the anterior iris surface. It seems likely that contraction of the

neovascular membrane attached to the cornea at the pseudo-angle can in the same way pull the endothelium onto the anterior iris surface, from which it may extend and secrete Descemet’s membrane.

VIII. Theories of the Pathogenesis of Iris Neovascularization The pathogenesis of iris neovascularization is at present unknown. However, there are a number of facts and theories that can be considered. AshtonS theorized that if the retina becomes hypoxic it produces a vasoformative material which diffuses anteriorly to stimulate new vessel formation in the iris. This theory is supported by the impression that vitrectomy in diabetics with lens extraction results in a greater incidence of iris neovascularization than occurs in those without lens extraction; this suggests that “the factor” can flow more readily anteriorly when not inhibited by the lens. Iris neovascularization is very apt to develop when there is severe vascular disease of the retina, particularly after closure of the central retinal vein and in diabetics who have proliferative retinopathy. It also occurs with closure of the central retinal artery and carotid artery defects. For example, Wolter12s

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studied histologically a case of iris neovascularization. He found occlusion of the central retinal artery and one long posterior ciliary artery. Schulzelo4 attributed iris neovascularization to chronic ischemia of the iris. Any mechanism that suddenly shuts off the major blood supply to the iris causes necrosis of the iris, but it does not necessarily lead to neovascularization. Imre,sg in a study of 18 cases of iris neovascularization found reduced aqueous flow in 15 of them. Oxygen reaches the iris from a number of sources. The normal blood supply to the iris can furnish only a fraction of its needs as there are remarkably few capillaries and these are concentrated at the sphincter area. The aqueous which bathes the iris probably derives much of its oxygen from the blood in the ciliary body. In some cases of iris neovascularization, the ciliary body is atrophic and the greater arterial circle is absent so aqueous secretion is deficient. An accessory source of oxygen may come from the retinal circulation. According to Bill,” the retinal vessels supply most of the oxygen needs of the retina while the choroidal circulation supplies most of the nutrition. Oxygen from the retina could diffuse through the vitreous to reach the aqueous. If the theory is correct, impairment of the retinal circulation in proliferative retinopathy or closure of the central artery and vein would cause a deficiency of oxygen reaching the aqueous from the retinal circulation. The iris vessels may react to hypoxia by developing neovascularization. The recent discovery that photocoagulation of the retina causes a recession of neovascularization of the iris is of interest. It can be explained that retinal destruction reduces its utilization of oxygen, allowing more oxygen to reach the iris. An appealing theory is that a tumor angiogenesis factor demonstrated by Gimbrone et u/.*~ is a chemical, probably a protein, which can induce neovascularization not only in the tumor but also some distance from it. A similar mechanism may explain why retinal vascular disease causes neovascularization of the iris.

IX.

Experimental Production of Iris Neovascularization

Several attempts have been made to duplicate iris neovascularization in an animal model, but none has succeeded in simulating

the human disease. Schulze104 produced what he felt was neovascularization of the iris in the rabbit by occluding both long posterior ciliary arteries. Anderson et al.,9 however, found rabbits to be poor experimental animals in which to induce the condition, because inflammatory reactions dilate the normal capillaries which are then difficult to distinguish from iris neovascularization. Anderson et al.,’ using a limbal suction cup, maintained elevated ocular tension for 8 hours in owl monkeys. Partial necrosis of the iris and ciliary processes occurred in most of the animals. A fibrovascular membrane developed on the iris in one monkey. Shabo et al.“’ developed a model of iris neovascularization by sensitizing monkeys to beef insulin with 3 weekly injections into the footpads of 1 cc insulin-Freund’s adjuvant mixture. On injecting insulin in’to the viteous, intraocular inflammation ensued and neovascularization of the iris developed associated with iris inflammation. This model can be criticized in that it does not duplicate the human situation in which inflammation is not the prime exciting factor. X. Therapy of Neovascularization of the

Iris The eye tolerates iris neovascularization until neovascular glaucoma sets in. This is a serious complication which is most difficult to manage, Pilocarpine and epinephrine are often tried, but usually have little effect. Diamox may be useful for a time. However, as more of the angle becomes occluded, medical therapy becomes less effective and is unsatisfactory in most cases. Samuels103 found that a surgical opening into the eye with iris neovascularization led to a hyphema and worsening of the glaucoma. Iridectomy and fistulizing operations have been of little value. A method was devised by Christensen and Meye?& in which they did cyclodialysis above and iridectomy of the upper half of the iris. A severe hyphema followed which took several weeks to clear. They operated on 8 eyes in 6 patients in this manner. Three eyes maintained vision of 20/200 or better for a minimum of 9 months. Five eyes had final vision of no light perception. reported 40 cases of iris HohP6 neovascularization in diabetics who developed glaucoma; 19 were controlled with diamox and other medication. One had

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cyclodiathermy which gave enough relief that the eye was retained, but vision was lost. Seven eyes were enucleated and 10 were lost to follow-up. Cyclocryotherapy has been more useful in lowering intraocular tension and relieving pain, but the improvement has often been temporary as pressure tends to rise after a few months. When used extensively it may cause atrophy of the globe. The procedure does nothing to open the occluded angle. Even when it is successful in lowering tension, it does little to restore vision. Using this modality, Feibel 4o treated 38 eyes with neovascular glaucoma. The followup period was at least 3 months; the majority was followed for 6 months or longer. Pain was controlled in most of the patients. Three eyes were later enucleated. Dense cataracts developed in 10 eyes. In only 3 eyes was vision better than 20/100. Boniuk17 reported very poor results with cyclocryotherapy in neovascular glaucoma: Of eight diabetic cases, six lost light perception in five months to live years, one had light perception and one could see hand movements; of nine non-diabetics, three lost light perception in two months to four years, one could count fingers at 1 ft., and two could see hand movements. One patient who saw 20/70 before treatment saw O.D. 20/40 and O.S. 20/30, three years after treatment. Boniuk suggested that the results are slightly better in the non-diabetic. He advised treatment with the Amoils unit with a nitrous oxide adaptor and with a retinal probe of 2.5 mm diameter. He gave 8 applications of 45 seconds 3 mm behind the limbus with the probe temperature 85” to 100”. Retrobular alcohol injection may relieve the pain, but does nothing to improve the dynamics of the aqueous and cannot help vision. Michels and Maumenee7* advise that it be done with 1 to 2 cc of 50% alcohol with 2% xylocaine. In 1971, Krill et aL6’ photocoagulated the retina of a patient with branch vein occlusion and macular edema. The retinal appearance and function improved. As an incidental finding, they reported the apparent disappearance of new blood vessels on the iris. No fluorescein studies were done. In 1975, Little et al.72 reported treating 15 eyes in 11 patients with neovascularization of the iris by panretinal photocoagulation. Twelve had total involution of the neovascularization. Three of the 15

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had regression of the synechiae and 3 had no change. Laatikainen@ in 1977 also reported a good effect with panretinal photocoagulation on iris neovascularization. Ten eyes were treated, eight of which had central retinal vein occlusion and six of which had neovascular glaucoma. All responded to treatment with decreases in intraocular tension. There was a decrease in iris neovascularization in all cases and in four none of the new vessels were visible. Fluorescein angiography showed persistence of new vessels in some cases, but less leakage. The followup period was 6 to 19 months with an average of 10 months. At Montefiore Hospital, Walsh and Gold (personal communication) have treated 15 cases in a similar manner. Treatment produced regression of the neovascularization, but not complete loss of the vessels. Leakage from the iris vessels was demonstrated by fluorescein angiography even after apparently successful treatment. However, there was clinical improvement for some time in most of the patients. Some with high tension had a reduction in tension which was then controllable with medication. Improvement in the appearance of the neovascularization of the iris occurred in most of the cases. There was recurrence of both the neovascularization and increase in tension in about half the cases after 1 to 2 years. They think that the ideal time for treatment would be when the neovascularization of the iris is definitely established, but while the angle remains open. It is essential that the iris can be dilated and a clear view of the fundus be available to deliver laser therapy or photocoagulation. The reports of this method of treatment are encouraging. More extensive and critical studies are needed to determine its value, as well as the optimum time for treatment. Regression of the new vessels on the iris have been reported following adrenalectomy,* hypophysectomy,“’ and pituitary stalk section.74 These are radical methods that have many undesirable side effects. While they received much publicity when they were first introduced they are now rarely utilized. Simmons et aLlo reported a method of treatment which they found effective before the angle was closed by synechiae. Argon laser applications were made using a Goldmann three mirror lens. The beam was

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directed at the new formed vessels as they cross the scleral spur. Treatment was confined to 180”, but since it was successful in this limited range, 360’ may be treated in future cases. In 13 eyes, with a follow-up of 22 months, 10 (77%) have been successfully prevented from developing progressive neovascular glaucoma. XI. Summary Neovascularization of the iris, a condition that develops secondary to a variety of ocular and systemic disorders, often results in neovascular glaucoma so severe as to require enucleation of the affected eye. Although the condition in its late stage was observed as early as 1868, it was difficult to diagnose by the loupe and lens and was, therefore, considered to be quite rare. Most often, the diagnosis was made by the pathologist after the eye was lost. The slitlamp and fluorescein angiographic techniques have recently made it possible to diagnose the condition more frequently and in its early stages, and also to increase our knowledge about the incidence and causes of the condition. Drawing on the literature and on findings from our own series, we have attempted to elucidate the clinical, pathological and anatomical features of iris neovascularization and also to review some theories of its pathogenesis and various approaches to its treatment. References 1. Amsler M, Verrey F, Huber A: Zur physiopathologie einer Gewebsflusigkeit. Schweiz Med Wschnschr 77:1321-1327, 1947 2. Anderson DM, Morin JD, Hunter WS: Can J Ophthalmol Rubeosis iridis. 6:183-188, 1971 3. Anderson DM, Morin JD: Experimental anterior segment necrosis and rubeosis iridis. Can J Ophthalmol 6:196-201, 1971 4. Anderson DR, Davis EB: Sensitivity of ocular tissues to acute pressure induced ischemia. Arch Ophthalmol93:267-274, 1975 5. Anderson RS, Warburg M: Norrie’s disease. Arch Ophthalmol 66:614-618, 1961 6. Armaly MF, Bagolou PJ: Diabetes mellitus and the eye. Arch Ophthalmol 77:485-502, 1967 7. Armstrong JR, Daily RK, Dobson HL, Girard LJ: The incidence of glaucoma in diabetes mellitus. Am J Ophthalmol 50:55-63, 1960 AG, Perry LD: 8. Asbury T, Spaulding

13. 14.

15.

16.

17.

18. 19.

20.

21.

22.

23.

24. 25. 26.

27. 28.

Glaucoma following occlusion of the central retinal artery. Trans Am Ophthalmol Sot 68:41-55, 1970 Ashton N: Retinal vascularization in health and disease. Am J Ophthalmol44:7-17, 1957 Bader C: The Natural and Morbid Changes of the Human Eye and Their Treatment. London, Trubner, 1868, p 394 Bagessen LH: Fluorescein angiography of the iris in diabetics and non-diabetics. Acta Ophthalmol 47:449-460, 1969 Baum JL, Wise GN: Experimental subretinal vascularization. Am J Ophthalmol 61:528-534, 1966 Becker B, Shaffer RN: Diagnosis and Therapy of the Glaucomas. St. Louis, C V Mosby Co. 1965, p 208 Bill A: Ocular Circulation in Adler’s Physiology of the Eye. St. Louis, Mosby, 5 ed. 1970, p 278-296 Bohringer HR: Sekundarglaukom met gefassneubildungen auf der iris. Ophthalmologica (Basel) 123:211-215, 1952 Boniuk M: Unilateral glaucoma associated with sickle-cell retinopathy. Trans Am Acad Ophthalmol Otolaryngol 68:316-328, 1964 Boniuk M: Cryotherapy in neovascular glaucoma. Trans Am Acad Ophthalmol Otolaryngol 78:337-343, 1974 Bonnet P: Rubeosis iridis. Ophthalmologica 118:575-588, 1949 Braendtrup P: Central vein thrombosis and hemorrhagic glaucoma. Acta Ophthalmol Suppl 35:1-162, 1950 Bresnick GH, DeVenecia G, Myers FL, et al: Retinal ischemia in diabetic retinopathy. Arch Ophthalmol 93:1300-1310, 1975 Busacca A: Biomicroscopie et Histopathologie de I’Oeil V. 2: Zurich, Schweitzer Druck, 1964, French Translation, p 182 Cappin JM: Malignant melanoma and rubeosis iridis. Br J Ophthalmol 57:8 15-824, 1973 Cheng-Minoda K: Retinoblastoma and iris neovascularization. Jap J Ophthalmol 15:215-222, 1971 Carroll RP, Lander MB: Pinwheel rubeosis iridis following argon laser coreoplasty. Ann Ophthalmol 7:357-360, 1975 Christensen L, Meyer SL: Neovascular glaucoma. Trans Am Acad Ophthalmol Otolaryngol 79:372-375, 1975 Coats G: Further cases of thrombosis of the central retinal vein. Roy Lond Ophthalmol Hosp Rep 16:516, 1906 Coats G: Forms of retinal disease with massive exudation. Roy Lond Ophthalmol Hosp Rep 18:440-525, 1909 Coats G: Pathology of obstruction of the central artery of the retina. Roy Lond Ophthalmol Hosp Rep 19:45 (Part I), 1913

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29. Cobb B: Vascular tufts at the pupillary Trans Ophthalmol Sot UK margin: 88:211-221, 1968 30. Cobb B, Shilling JS, Chisholm IH: Vascular tufts at the pupillary margin in myotonic dystrophy. Am J Ophthalmol 69:573-582,

1958 48. Gregersen E: The tissue spaces in the human iris and their communication with the anterior chamber by way of the iridic crypts.

1970 3 1. Cogan DC? Applied anatomy and physiology of the cornea. Trans Am Acad Ophthalmol Otolaryngol 55:329-359, 195 1 T: Growth and 32. Cogan DG, Kuwabara

molecular dextran fractions from the anterior chamber and iridic stroma of rabbit eyes.

regenerative potential of Descemet’s membrane. Trans Am Acad Ophthalmol Otolaryngol 91:87%X94, 1971 33. Coleman SL, Green R, Patz A: Vascular tufts of pupillary margin of iris. Am J Ophthalmol 83:881-883, 1977 34. Colosi NJ, Yanoff M: Reactive cornea1 en-

dothelialization. Am J Ophthalmol 83:219-223, 1977 35. Cristiansson J: Glaucoma simplex in diabetes mellitus. Acta Ophthalmol 43:224-234, 1965 36. Dietrich CE, Witmer R, Franz HE: Arch Klin Ophthalmol 182:32 l-340, 197 1 37. Deutschman R: Zur pathologischen

anatomie

des haemorrhagischen

Albrecht von Graefes 25:163-172, 1879

Arch

glaucoms. Ophthalmol

38. Duke JR, Kennedy JJ: Metastatic carcinoma of the iris and ciliary body. Arch Ophthalmol 60:1092-l 103, 1958 39. Ellett EC: Metastatic carcinoma of the

choroid. III. Rubeosis iridis with melanoma of the choroid and secondary glaucoma. Am J Ophthalmol 27:726-731,

74:862-867,

Acta Ophthalmol 37:35-48, 1959 50. Gregersen E: Structural variations

of the crypts and bridge trabeculae of the human iris. Acta Ophthalmol 37:119-124, 1959 5 1. Gregersen E: The tubular tissue spaces surrounding the endothelial channels of the human iridic vessels. Acta Ophthalmol 37:199-208, 1959 52. Harbitz F: Bilateral carotid arteritis. Pathol Lab Med 1:499-510, 1926

Evaluation J

of

Ophthalmol

1972

4 1. Ferry AP, Font RL: Carcinoma metastatic to the eye and orbit. (I) Arch Ophthalmol 92:276-286, 1974. (II) Arch Ophthalmol 93~472-486, 1975 42. Fralick FB: Rubeosis iridis diabetica. Am J Ophthalmol 28:123-138, 1945 43. Gartner S: Ocular pathology of diabetes. Am J Ophthalmol 33:727-740, 1950 44. Gartner S, Taffet S, Friedman AH: The

association of rubeosis iridis with endothelialisation of the anterior chamber. Br J Ophthalmol 61:267-27 1, 1977 45. Grant WM: Management of Neovascular Glaucoma. Symposium on Ocular Therapy V. 7. St Louis, CV Mosby 1974, pp 36-61

46. Gimbrone MA, Leapman SB, Cotran RS, Folkman J: Tumor angiogenesis; Iris neovascularization at a distance from experimental intraocular tumors. J Nat Can Inst 50:219-228, 1973 47. Gregersen E: The spongy structure of the human iris. Acta Ophthalmol 36:522-535,

Arch

53. Henkind P: Circulation in the iris and ciliary processes. Br J Ophthalmol 49:6-10, 1965 54. Henkind P, Morgan G: Peripheral retinal angioma with exudative retinopathy in adults (Coats’s lesion). Br J Ophthalmol 50:2-l 1, 1966 55. Hogan MJ, Alvardo A Jr, Weddell JE: Histology of the Human Eye. Philadelphia, W. B. Saunders, 1971, p 202-223 56. Hohl RD, Barnett DM: Diabetic hemorrhagic glaucoma. Diabetes 19:944-947, 1970 57. Hoskins HD: Neovascular glaucoma. Trans Am Acad Ophthalmol Otolaryngol 78: 330-333, 1974 58. Huckman MS, Haas J: Reversed flow

through the ophthalmic artery as a cause of rubeosis iridis. Am J Ophthalmol

1944

40. Feibel RM, Bigger JF: Rubeosis iridis and

neovascular glaucoma: cyclocryotherapy. Am

Acta Ophthalmol 36:819-928, 1958 49. Gregersen E: Elimination of high-and-low

74:1094-1099, 1972 59. Imre G: Rubeosis iridis. Acta Medica Scientarum Hungaricae 27:205-207, 1970 60. Jampol LM, Rosser MJ, Sears ML: Unusual

61.

62. 63. 64.

aspects of progressive essential iris atrophy. Am J Ophthalmol 77:353-357, 1974 Jocson VL: Microvascular injection studies in rubeosis iridis and neovascular glaucoma. Am J Ophthalmol 83:508-517, 1977 Jones RF: Glaucoma following radiotherapy. Br J Ophthalmol 42:636-638, 1958 King MJ: Retrolental fibroplasia. A clinical study of two hundred and thirty-eight cases. Arch Ophthalmol 43:694-711, 1950 Kinsey VE, Palm E: Posterior and anterior chamber aqueous humor formation. Arch

Ophthalmol 53:330-344, 1955 65. Kiss F: Der Blutkreislauf des Auges. Ophthalmologica (Basel) 106:225-240, 1943 66. Knox DL: Ischemic ocular inflammation.

Am J Ophthalmol 60:995-1002, 1965 67. Krill AE, Archer D, Newell FW: Photocoagulation in complications secondary to branch vein occlusion. Am J Ophthalmol 85:48-58, 197 1 68. Laatikainen L, Blach RK: Behaviour of the

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iris vasculature in central retinal vein occlusion. Br J Ophthalmol 61:272-277, 1977 69. Laatikaine L: Preliminary report on effect of retinal panphotocoagulation on rubeosis iridis and neovascular glaucoma. Br J Ophthalmol 61:278-283,

1977

70. Lauring L: Anterior chamber membranes. Am J Ophthalmol 6&308-312, 1969 71. Lee P, Field R: Hypophyseal stalk section and intraocular pressure. Am J Ophthalmol 62:1 l-16, 1966 72. Little HL, Rosenthal R, Dellaporta A,

301-307, 1971 88. Okamura P, Rohen JW: Elektronmikrosckopischer untersuchugen tiber die rubeosis iridis. Albrecht von Graefes Arch Klin Ophthalmol 182:53-75, 1971 89. Oosterhuis JA, Loewere-Sieger D, Van Goal

J: Treatment adrenalectomy.

of diabetic Acta

retinopathy Ophthalmol

by 41:

365-376, 1963 90. Opin A: Embolie de l’artere centrale de la Arch retine et glaucoma secondaire. Ophthalmol 44:321-341, 1927 91. Ostler HB: Pulseless disease. Am J

Jacobson DR: The effect of panretinal photocoagulation on rubeosis iridis. Am J Ophthalmol 81:804-809, 1976 73. Mackenzie W: A Practical Treatise on Diseases of the Eye. London, Longman, Brown, Green and Longman, 1854, p 893 74. Madsen PH: Haemorrhagic glaucoma. Comparative study in diabetic and non-diabetic patients. Br J Ophthalmol 55:444-450, 1971 75. Madsen PH: Rubeosis of the iris and haemorrhagic glaucoma in patients with proliferative diabetic retinopathy. Br J

Ophthalmol 43:583-589, 1957 92. Parsons JH: The Pathology of the Eye, Vol I, Part I, London, Hodder and Stoughton, 1904, p 200 93. Pei-Fei Lee, McMeel JW, Schepens C, Field RA: A new classification of diabetic retinopathy. Am J Ophthalmol 62:207-219, 1966 94. Perraut LE, Zimmerman LE: The occurrence of glaucoma following occlusion of the central retinal artery. Arch Ophthalmol

Ophthalmol 55:368-371, 1971 76. Marsh RJ, Easty PL, Jones BR: Iritis and

61:845-867, 1959 95. Perry HD, Yanoff M, Scheie HG: Rubeosis

iris atrophy in herpes zoster ophthalmicus. Am J Ophthalmol 78:255-261, 1974 77. Marvas J: Biomicroscopie de la Chambre Anterieure de Iris et du Corps Ciliare. Paris,

Masson et Cie, 1928, p 10 78. Michels RG: Maumenee AE: Retrobulbar alcohol injection in seeing eyes. Trans Am Acad Ophthalmol 1973

Otolaryngol

77:164-167,

79. Michels RG, Ryan SJ: Results and complica-

tions of 100 consecutive cases of pars plana vitrectomy. Am J Ophthalmol80:24-29, 1975 80. Mitsui Y, Matsubara M, Kanagawa M: Fluorescence irido cornea1 photography. Br J Ophthalmol 53:505-512, 1969 8 1. Moore RF: Retinal Venous Thrombosis. Lon-

don, George Putnam and Sons, 1924 82. Nettleship E: Embolism of central artery of retina, microscopic examination, Roy Lond Ophthalmol Hosp Rep 8:9, 1874 83. Nettleship E: Chronic retinitis with formation of blood vessels in the vitreous in a patient with diabetes. One eye lost by result of chronic iritis accompanied by the formation of large vessels in the iris. Trans Ophtbalmol Sot UK 8:159-161, 1888 84. Ohrt V: Rubeosis iridis diabetica. Acta Ophthalmol 36:556-558, 1958 85. Ohrt V: Glaucoma due to rubeosis

iridis diabetica. Ophthalmologica (Basel) 142: 356-364, 1961 86. Ohrt V: Rubeosis iridis diabetica. Dan Med Bull 2:17-19, 1964 87. Ohrt V: The frequency of rubeosis iridis in diabetic patients. Acta Ophthalmol 49:

in Fuchs heterochromic iridocylitis. Arch Ophthalmol 93:337-339, 1975 96. Reese AB: Deep chamber glaucoma due to the formation of a cuticular production in the filtration angle. Am J Ophthalmol 27:1193-1205, 1944 97. Reese AB: Tumors of the Eye and Adnexa. Washington, D.C., Armed Forces Inst. of Pathology, 1956, p 149 98. Rosen E, Lyons D: Microhemangiomas at the pupillary border. Am J Ophthalmol 67:846-853, 1969 99. Rosenthal AR, Little HL: The use of pan-

retinal photocoagulation for rubeosis iridis. (Wilmer Residents Meeting, Baltimore, Md., April 1975). International Ophthalmological Reporter, Westport, Conn., Intercontinental Pub., 1975, p 1 100. Ross JVM: Bilateral occlusion of the central retinal artery complicated by bilateral secondary glaucoma. Eye Ear Nose Throat Mon 29:561, 1950 101. Saari M: Morphological basis of diffusion through the iris vessels in the dynamics of aqueous humor. Acta Ophthalmol Supp 123:26-29, 102. Salus R:

1974

Rubeosis iridis diabetica. Eine bisher unbekannte diabetische irisverlnderung. Med Klin 24:256-258, 1928 103. Samuels B: Pathologic changes in the anterior half of the globe in obstruction in central vein of retina. Arch Ophthalmol 13:404-418, 1935 104. Schulze RR: Rubeosis iridis. Am J Ophthalmol 63:487-495,

1967

311

NEOVASCULARIZATION OF THE IRIS

105. Shabo AL, Maxwell DS, Shintaku IP, et al.: Experimental immunogenic rubeosis iridis. Invest Ophthalmol 16:343-352,

1977

107. Simmons RJ, Dueker DK, Kimbrough RL, Aiello LM: Goniophotocoagulation for Trans Acad glaucoma. neovascular Ophthalmol Otolaryngol

83:80-89,

1977

108. Smith JL: Unilateral glaucoma in carotid occlusive disease. JAMA 182:683-684, 1963 109. Smith ME, Ott FT: Rubeosis iridis and angle closure glaucoma. Int primary Ophthalmol Clin 2, No 3, 1971, p 161-170

110 Sullivan reticulum

ST, Dallow RL: Intraocular cell sarcoma. Ann Ophthalmol

9:401-406,

1977

111. Swan KC, Raaf J: Changes in the eye and orbit following carotid ligation. Trans Am Ophthalmol Sot 49:435-444, 1951 112. Tamura T: Electron microscopic study on the small blood vessels in rubeosis iridis diabetica. Jap J Ophthalmol 13:65-78, 1969 113. Vannas A: Fluorescein angiography of the vessels of the iris in pseudoexfoliation of the lens capsule, capsular glaucoma and some other forms of glaucoma. Acta Ophthalmol Supp 105:9-75, 1969 A: Neubildung von glas114. Wagenmann hauteger substanz an der linsenkapsel und an der Descemet’s schen membran. Albrecht von Graefes Arch Klin Ophtbalmol 35:172-196, 1889

115. Waite J, Beetham W: The visual mechanism in diabetes mellitus. N Engl J Med 212:367-379, 428-443, 1935 116. Walton DS, Grant WM: Retinoblastoma iris neovascularization. and Am J Ophthalmol 65:598-599,

1968

117 Waring GO, Laibson PR, Rodriquez M: Clinical and pathological alterations of Descemet’s membrane. Surv Ophthalmol l&325-366,

1974

118 Weinbaum S: Ein fall von glaukoma hamorrhagicum mit thrombose der vena centralis retinae und ectropion uvea. Albrecht von Graefes Arch Klin Ophthalmol 38:191, 1892 119. Weiglin E: The blood circulation of the retina and the uvea. Adv Ophthalmol25:1-27, 1972

120. Weiss DI, Leopold IH: Prognosis of secondary glaucoma following retinal artery occlusion. Am J Ophthalmol 51:793-796, 1961 121. Weiss DI, Shaffer RN, Nehrenberg TR: Neovascular glaucoma complicating carotid cavernous fistula. Arch Ophthalmol 69:304-307,

1963

122. Wilson WA, Irvine SR: Pathological changes following disruption of blood supply to iris and ciliary body. Trans Am Acad Ophthalmol Otolaryngol

59:501-502,

1955

123. Wise GN: Retinal neovascularization. Am Ophthalmol Sot 54:729-826,

Trans 1956

124. Wolff SM, Zimmerman LE: Chronic seconAm J Ophthalmol glaucoma. darv 54:547-363, 1962 Phillips RL: Secondary 125. Wolter JR, glaucoma following occlusion of the central retinal artery. Am J Ophthalmol47:335-340, 1959

126. Wolter JR, Fechner PH: Glass membranes on the anterior iris surface. Am J Ophthalmol 53~235-243,

1962

JR, 127. Wolter glaucoma in

Phillips cranial

Ophthalmol 59:626-634,

RL: Secondary arteritis. Am J 1965

128. Wolter JR, Ryan RW: Atheromatous embolism of the central retinal artery. Arch Ophthalmol 87:301-304,

1972

129. Wolter JR: Double embolism of the central retinal artery and long posterior ciliary artery secondary hemorrhagic followed by glaucoma. Am J Ophthalmol 73: 651-657, 1972

130. Yanoff M: Mechanisms of glaucoma in eyes with uveal melanoma. Int Ophthalmol Clin 12: 51, 1972

131. Yanoff M, Fine BS: Ocular pathology. Hagerstown, Md, Harper and Row, 1.975, p 339 132. Zion V, Goodside V: Anterior segment ischemia with ischemic optic neuropathy. Surv Ophthalmol 19: 19-30, 1974 133. Zollinger R: Ueber das vorkommen von Gefassneubildungen auf der iris. Ophthalmologica (Basel) 123:216-219,

1952

This work was supported in part by NIH Grant #EYOOO613 Reprint requests should be addressed to: Samuel Gartner, M.D., Dept. of Ophthalmology, MonteBore Hospital and Medical Center, 111 E. 210 St., Bronx, NY 10467

Outline I. Incidence

II. History III. Clinical picture of neovascularization of the iris A. Fluorescein angiography B. Bilateral involvement C. Life expectancy with neovascular glaucoma D. Low intraocular tension and iris neovascularization IV. Causes of iris neovascularization A. Reports of series B. Central retinal vein obstruction C. Central retinal artery obstruction

SW Ophthalmol 22 (5) March-April 1978

312

D. E. F. G. H.

Diabetes Glaucoma Progressive essential iris atrophy Carotid artery occlusion Carcinoma metastatic to the eye and orbit I. Retinoblastoma J. Malignant melanoma K. Pseudoexfoliation of lens capsule L. Coats’ disease V. Special features of iris anatomy A. Spongy structure

GARTNRR,

HENIGND

B. Iris blood vessels VI. Pathology VII. Extension of cornea1 endothelium and Descemet’s membrane onto the anterior surface of the iris: The role of neovascularization VIII. Theories of the pathogenesis of iris neovascularization IX. Experimental production of iris neovascularization X. Therapy of neovascularization of the iris XI. Summary