The Ciliary Vasculature and Its Perturbation with Drugs and Surgery*

Home , Ciliary arteries, Ciliary muscle, Ciliary processes

THE CILIARY VASCULATURE AND ITS PERTURBATION WITH DRUGS AND SURGERY*

BY E. Michael Van Buskirk, MD

INTRODUCTION THE CILIARY BODY AND ITS VASCULATURE SERVE A WIDE VARIETY OF COM- plex functions in the eye. Three structural and functional components of the ciliary body can be identified: (1) the pars plana; (2) the pars plicata; and (3) the ciliary muscle. Approximately 70 major ciliary processes, interdigitated between an equal number of smaller minor processes, comprise the highly vascular pars plicata that is covered by a complex bilayered epithelium. Through an array ofintercellularjunctions, the ciliary processes form the inflow side of the blood-aqueous barrier and are responsible for the secretion of aqueous humor. 1-7 As such, they keep the globe inflated with aqueous humor, and provide nutrition and humoral mediators to the avascular structures of the anterior segment. The ciliary muscle controls the accommodative mechanism, provides structural support for the peripheral uvea by its attachment to the scleral spur, and modulates outflow ofaqueous humor by means of traction on the trabecular meshwork. 8-11 Physiologic studies of this small, complex tissue demonstrate a similar diversity ofits vascular perfusion with evidence ofvascular autoregulation and for regional changes in blood flow in response to pharmacologic or neurogenic stimuli. 12-20 Advances in photofluorometric measurement of aqueous humor formation in the undisturbed and experimentally altered eye are now rapidly advancing knowledge about factors affecting the formation of aqueous humor. 21-25 However, the interplay of ciliary body perfusion and aqueous formation cannot be understood entirely without a thorough understanding of the microvasculature and microcirculation of the ciliary processes and the surrounding uveal tissues. Recent emphasis on clinical alteration of the ciliary body with aqueous suppressant drugs,

*From the Department ofOphthalmology, the Oregon Health Sciences University, Portland, Oregon. Supported in part by grant EY05231 (National Eye Institute), Core grants RRC0163 and RR05694 (National Institutes of Health), and a Heed Foundation Fellowship.

TR. AM. OPHTH. Soc. vol. LXXXVI, 1988 Ciliary Vasculature 795 with cyclodestructive surgery, and for support ofintraocular lens implants by this complex tissue, has made study ofthe ciliary vasculature especially relevant. This thesis examines methods for examination ofthe ciliary vasculature, while minimizing artifactual disturbance ofthe tissue. The precise anatomic details of the ciliary vasculature are presented in primates and are compared to other nonprimate mammalian eyes. The effects on the ciliary vasculature of commonly used ocular therapeutic modalities are also examined, including pharmacologic manipulation, cyclodestruction, and intraocular lens implantation.

METHODS All of the studies for this project involved preparation of methacrylate luminal castings ofthe ocular microvasculature by intra-arterial injection of casting media. This technique, de6cribed by Batson26 in 1955, was evalu- ated intensively and modified,to minimize perturbation ofthe general and ocular physiology prior to injection ofthe plastic casting media. The initial studies of the anterior uveal angioarchitecture employed injection of commercially available Batson's compound no. 17.27 Although it is ex- tremely viscous, carefully injected Batson's compound no. 17 produces complete castings ofmicrovascular beds to the level ofthe finest capillaries, with detailed relief replication of the vascular endothelial nuclear imprint on the surface ofthe casting (Figs 1 and 2).28 Examination ofthese imprints permits differentiation of arteries with their spindle-shaped palisaded nuclei from veins with rounded randomly distributed nuclei (Fig 2). Batson's methacrylate media provides dry rigid castings that are easily handled and dissected to reveal details ofthree-dimensional architecture at a microscopic level. Moreover, plastic compounds resist high voltage and allow scrutiny by scanning electron microscopy (SEM).

INITIAL STUDIES In the initial studies, whole ocular microvascular luminal methacrylate castings were prepared by simultaneous bilateral carotid artery injection of Batson's compound no. 17 in anesthetized cynomolgus monkeys.27 The injection medium was prepared according to the manufacturer's recom- mendations. The animals were intratracheally intubated and anesthetized with halothane. The major blood vessels in the neck were isolated through a mid-line incision, the carotid arteries were cannulated with appropriately sized catheters and the jugular veins were incised. Batson's compound was hand-injected simultaneously into the carotid arteries as rapidly as possi- 796 Van Buskirk

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FIGURE 1 Gold-palladium coated methacrylate casting ofcanine ocular vasculature. ble, using multiple 10 cc syringes until clear Batson's compound egressed from the cut end ofthe incisedjugular veins. To facilitate filling ofthe ocular vessels, the intraocular pressure was reduced to ambient pressure by incising the cornea with a razor blade fragment immediately prior to injection. After polymerization of the injection material, the eyes were enucleated and fixed in formalin. The whole, methacrylate injected, fixed eyes were immersed and macerated in 6 M potassium hydroxide for at least 24 hours at 500 to 55°C, digesting away all tissue. They were then gently tumbled in running tap water to remove all residual tissue and air dried, leaving a rigid methacrylate casting of the entire ocular vasculature (Fig 1). The dried, tissue-free castings were hemisected at the equator and the anterior portions were mounted on a stub for further dissection and for SEM. Dissection ofOcular Castings The ocular castings presented a complexity of intertwined vessels that required careful and orderly methods of dissection. The ciliary processes lie internal to the rich ciliary muscle vasculature rendering them relatively inaccessible to examination without complex microdissection methods.29 Ciliary Vasculature 797

FIGURE 2 Scanning electron micrograph of contiguous artery and vein, showing palisaded spindle- shaped arterial nuclear imprints and rounded venous nuclei (x 600).

The hemisected casting ofthe anterior ocular segment was draped over a wooden disc, 2 mm thick and 8 mm in diameter, to preserve its spherical shape while mounted on the stub. The equatorial cut edge was secured to a SEM stub with silver paint. The entire specimen was then coated with gold palladium in a sputter coater and examined with an AMR 1000 scanning electron microscope. SEM of these preparations permitted identification of the anterior ciliary arteries, with their interconnections with the episcleral and perforating arteries entering the bulk ofthe ciliary muscle. By using a hooked insect dissection needle and fine scissors, the ciliary muscle capillary bed and draining veins were removed layer-by-layer without disturbing the underlying choroidal veins and the ciliary processes vessels using binocular magnification of a dissecting microscope. Subsequent SEM revealed the interconnections of the perforating anterior and long posterior ciliary arteries and their supply to the iris and ciliary processes. To examine the angioarchitecture of the individual ciliary processes, three to four contiguous processes were separated from the main casting with fine scissors and were mounted together on a separate stub. These 798 Van Buskirk specimens were then returned to the scanning electron microscope where the processes could be scanned from various angles by manipulating the microscope stage. Because the arteriolar, capillary, and venular interconnections were at the upper limit of resolution for dissecting microscope, scanning electron micrograph stereoscopic pairs were employed to deter- mine and record otherwise undetectable anatomic relationships. An initial photograph of the casting was obtained at low magnification (50 to 200 x) and repeated after tilting the stage by 6 degrees to provide a stereomicro- graph. Examination of these stereoscopic pairs of photographs revealed superficial arteriolar connections to the ciliary processes, and also indi- cated additional connections deeper within the specimen. After recording the superficial layer, individual capillaries and arterioles were cut away using a pneumatically powered ultramicroscissors that was specifically developed for this purpose. It was mounted on the arm ofa micromanipula- tor and brought into the microscopic field without disruption ofthe casting. Thus, the entire casting was examined, recorded, and microdissected layer-by-layer to reveal the complex interconnections within and between the ciliary processes.

IMPROVED CASTING METHODS Ocular microvascular castings, conventionally prepared with Batson's compound no. 17, produced fine luminal replication ofthe ocular microvasculature suitable for detailed determination of the ocular angioarchitecture. Once these baseline structural details were understood, methods for vascular modulation in response to physiologic, pharmacologic, or surgical influences were planned. However, because of the high viscosity of the material, high injection pressures, hand-applied to catheters in each carotid artery, were required for prolonged periods of time in order to obtain complete filling ofdistal ocular capillary beds. To study the effects of the unilateral ocular effects of drugs or operations, it was necessary to assure equal injection pressure to each eye, obtainable only by direct aortic injection. Moreover, prolonged exposure to the injection media and gradual intravascular filling could produce unwanted agonal physiologic responses and, perhaps, artifactual effects on the blood vessels. Therefore, a low viscosity casting medium was needed that would be rigid enough for microdissection and for SEM. By using a medium with a viscosity close to blood, rapid injection became possible at physiologic perfusion pressure and with control ofblood oxygen saturation right up to the time the casting material entered the ocular cerebral circulation. New Casting Media The viscosity ofBatson's compound no. 17 was reduced from 260 cp to 10 to Ciliary Vasculature 799 12 cp by the addition of 140 ml of methylmethacrylate solution (Aldricch Chemical Co, Inc, Milwaukee, WI) and 5 ml ofacetone to 95 ml ofBatson's polymethylmethacrylate. Further viscosity reductions toward the 4 cp of blood were possible, but produced inconsistently soft, friable castings unsuitable for examination. However, the 10 to 12 cp material was easily and rapidly injected into vascular lumina without appreciable resistance until it polymerized within 5 to 15 minutes. To insure complete polymerization ofthe plastic without distortion ofthe tissue, the enucleated eyes were placed in warm (38°C) formalin fixative for 24 hours before being consigned to the corrosion step in warm potassium hydroxide. The cornea was incised to permit simultaneous intraocular fixation and retention of ocular global shape. These methods consistently provided rigid, exquisitely detailed castings without significant extravasation and with good preservation ofthe endothelial nuclear imprint. Laboratory Animals Preliminary studies were carried out in the Old World monkey (Macaca fascicularis), whose eyes are anatomically similar to human eyes. More- over, there already exists a body of physiologic literature regarding blood flow and aqueous humor production in monkeys and humans to which the anatomic data from these experiments can be compared. In addition to primate studies, the ciliary vasculature was examined in nine other mammalian species, concentrating on the rabbit but also including other commonly used laboratory animals, such as the rat (20 eyes), guinea pig (4 eyes), dog (34 eyes), cat (8 eyes), and pig (4 eyes).30'3' Although significant differences occur, rabbit eyes proved to have enough similarities to primate eyes that they were useful to study. The rabbit ciliary vasculature is much easier to study than that ofthe primate because it has no ciliary muscle capillary bed to obscure visualization of internal microvasculature, thus obviating the need for lengthy lamellar microdissection. Consequently, all preliminary studies on the physiologic control ofthe injection techniques and the quantitative pharmacologic studies were done in adult New Zealand Albino rabbits. Anesthesia The monkeys were anesthetized with intravenous thiamylal sodium and the rabbits and other nonprimates received intravenous pentobarbital sodium. All animals were intratracheally intubated and connected to a Harvard small animal respirator with room air. Despite the experimental surgical manipulation required to prepare the animals for injection, ocular and cerebral perfusion and oxygenation were maintained to the moment of 800 Van Buskirk methacrylate injection. Blood gases monitored during multiple procedures remained in the normal range. Blood Pressure and Methacrylate Arterial Perfusion Pressure Arterial blood pressure was monitored during preinjection surgery and during injection to assure adequate preinjection vascular perfusion and to control methacrylate injection pressure. This step was initially accom- plished with an electronic pressure transducer connected to a catheter in the brachial artery in monkeys and in the ear or brachial artery in rabbits. However, by simultaneous monitoring at several sites, it was recently determined that intra-aortic monitoring of both blood and methacrylate perfusion pressures can keep arterial injection pressure between 100 and 120 mm Hg. Injection Technique The animals were supine. An intravenous line was inserted into the antecubital vein in monkeys or an ear vein in rabbits. After administration ofanesthesia and endotracheal intubation, both internaljugular veins were isolated through a midline nuchal incision and encircled with ligatures to permit rapid transsection at the time of injection. The abdomen was opened and the abdominal aorta was cannulated to retrograde fashion with a 7 French plastic catheter. Its tip was advanced to the midthoracic level and secured in place with silk ligatures. Three-way stopcocks permitted withdrawal of arterial blood for blood gas determination, connection to pressure transducers, and injection ofintravascular perfusate or methacrylate. Immediately before intra-aortic methacrylate injection, the chest was opened and a ligature was placed around the aorta with its indwelling catheter to prevent retrograde refluxing of injected plastic. Coincident with the start ofinjection, the jugular veins were opened and the heart was cross-clamped to restrict perfusion to the head and arms. The methacrylate solution was injected at 370 to 38°C and the injection pressure was maintained at 100 to 120 mm Hg until the plastic polymerized to arrest flow in the system. After 1 hour the eyes were enucleated, fixed, and macerated. Casting Analysis A total of 49 rabbits were used for these studies. Many of these animals were studied with a variety ofmonitoring devices and injection solutions at various injection pressures, temperatures, viscosities, and intraocular pressures to develop a reliable injection technique under the best physiologic conditions possible. After obtaining suitable castings ofthe rabbit ciliary vasculature with or Ciliary Vasculature 801 without ocular perturbation, the anterior halves ofthe ocular castings were separated from the remainder ofthe globe and divided into quadrants. The specimens were mounted on scanning microscope stubs with a small supportive balsa wood block under the concavity of the sample. The specimens were dissected under the high power ofa dissection microscope for the best display of the vessels of the anterior uvea. They were then sputter coated with gold and examined in an AMR 1000 scanning electron microscope. Because no ciliary muscle capillary bed obscures the major arterial circle in rabbits, this preparation was particularly favorable for observing the arteriolar branches to the iris and ciliary processes in sufficient numbers to generate statistically valid data. These arterioles at their branch points from the major arterial circle, designated the "branch zone," regularly displayed some degree of focal constriction compared to downstream vessel caliber (Fig 3). The diameter at the constriction, evidently a contractile cuffjust beyond the branching point ofthe arteriole from the major arterial circle, was then compared to that of the same vessel about 50 ,um downstream, that is, well beyond the region of the cuff (Fig 4). The difference was expressed as a percentage ([constricted diameter/nonconstricted diameter x 100] -), with negative

FIGURE 3 Focal constriction (arrow) in rabbit ciliary process arteriole at branch zone from the major arterial circle (x 560). 802 Van Buskirk

FIGURE 4 Rabbit major arterial circle with iridial and ciliary process arterioles (a) branching from the major arterial circle (M). Measurements taken at branching point and 50 ,u downstream (x 60). values indicating a constriction and positive values indicating a gradual taper from the parent vessel. This approach provides a measure ofperfor- mance ofthe technique that is independent ofthe absolute diameters ofthe arterioles, which can vary under different conditions and in animals of different sizes, but can also be compared directly. For group comparisons, we combined data from three different eyes, taking measurements from about 100 arterioles, all ofthem equivalent anterior or posterior branches from the major arterial circle (statistical comparisons between anterior and posterior arterioles have never shown any difference). The Student's t-test was used for analysis of paired data of the constricted and downstream values on individual arterioles, the ungrouped t-test was used for comparisons between eyes. Adrenergic Agonist Effects on the Ciliary Vasculature Eight adult rabbits were given 1 drop of 2.5% phenylephrine eyedrops to the left eye 1 hour before intravascular methacrylate castings were prepared. In all cases, the ipsilateral pupil was widely dilated and the contralateral pupil was normal. The first four rabbits received no drug in the fellow eye and were cast in the usual manner. To evaluate the effect of chronic alpha-adrenergic stimulation, the Ciliary Vasculature 803 second group offour rabbits received 1 drop daily of2.55 phenylephrine to the left eye for 1 month prior to casting, while the fellow eye received nothing. On the day ofthe casting, both eyes received 2.5% phenylephrine eyedrops 1 hour before the injection. These experiments permitted evalua- tion of the influence of chronic drug therapy on the effect of acute stimulation. Intraocular Pressure Intraocular pressure was not controlled in the majority ofanimals studied, but remained at the usual pressure under barbiturate anesthesia, usually less than 15 mm Hg. Some ofthe earlier studies in monkeys were done with intraocular pressure reduced to 0. Consequently, some rabbit eyes were studied after the cornea was incised during the intra-aortic methacrylate injection. The reduced intraocular pressure produced better filling of the ciliary and iris capillaries. Because better capillary filling occurred when the intraocular pressure was reduced to ambient pressure simultaneously with intravascular methacrylate injection, one rabbit eye was cast after unilateral intracameral paracentesis. It was then prepared for casting. Just as the methacrylate was injected into the aorta, the left cornea was incised with a razor blade fragment to reduce intraocular pressure to 0 mm Hg. The diameters of44 contiguous posterior and anterior ciliary process arterioles at the branch and downstream zones were measured on the low pressure eye and 29 were measured on the normotensive eye.

INTRAOCULAR LENS IMPLANTATION Three adult cynomolgus monkeys underwent bilateral extracapsular lens extraction and received a posterior chamber intraocular lens with non- angled "C"-looped proline haptics (Intermedics, Pharmacia, Ophthalmics, Pasadena, CA). Special effort was made in each case to assure that the haptics were placed anterior to the lens capsular bag to rest against the iridociliaryjunction (Fig 5). In all cases, a fornix-based conjunctival flap was created and a small limbal incision was made. The pupil was dilated preoperatively with tropicamide and cyclopentylate. An anterior capsulot- omy was performed and the lens was then aspirated from the eye with a double lumen infusion-aspiration needle apparatus. An 11.5 mm diameter intraocular lens (haptic to haptic) was then implanted into the posterior chamber, taking care to avoid insertion ofeither haptic into the capsule and assuring that both haptics rested within the ciliary sulcus (Fig 5). The corneoscleral and conjunctival wounds were closed with 10-0 nylon su- tures. The animals received 0.5 cc betamethasone subconjunctivally following the procedures. 804 Van Buskirk

FIGURE 5 Prolene intraocular lens haptic fixed in ciliary sulcus ofcynomolgus monkey eye.

No vitreous was lost. The wounds healed well with no uveal prolapse or leakage. Thirty days after the posterior chamber lens implantation, each animal exhibited no significant external or intraocular inflammation and was sacrificed using the methacrylate injection technique. After methacrylate polymerization, the eyes were enucleated and fixed in formalin. The posterior segments were removed and, with the cornea down, the ciliary body and lens implant were examined from the posterior side, while the optics were excised and discarded. The haptics were left in the ciliary sulcus. The location ofone haptic in each eye was marked with a nylon suture through the sclera and ciliary muscle. Also, its location was noted relative to the meridian of the globe. All eyes but one were macerated in potassium hydroxide. The haptics of the intraocular lenses apparently dropped out of the sulcus during maceration and were lost in the macerated tissue. Their location was identified with the nylon suture, but the imprint ofthe lens haptic in the sulcus was easily observed with the dissecting microscope. The castings were examined by SEM. The other eye, not cast, was prepared for light microscopy.

CYCLOCRYOTHERAPY Two adult cynomolgus monkeys received cyclocryotherapy to the ciliary Ciliary Vasculature 805 body using parameters commonly employed in clinical practice. The first monkey received three applications of a 2 mm nitrous oxide cryoprobe at - 80°C for 60 seconds. The applications were placed 3 mm posterior to the limbus at 1 clock-hour apart. Castings were made of the left eye 3 weeks after cryotherapy and of the right eye 5 weeks after cryotherapy. The second monkey received two applications to the superior limbal quadrant between 10:30 and 1:30 o'clock at 1 clock-hour apart, followed by treatment of the opposite inferior quadrant 30 days later. Sixty days after the start of the study, the fellow eye was treated in a similar manner to the superior quadrant, followed by inferior,treatment 30 days later. Ten days after the final treatment, castings were made of both eyes. This sequence of treatments provided castings of ciliary body segments 10, 40, 70, and 100 days after cyclocryotherapy.

RESULTS

PRIMATE ANTERIOR UVEAL VASCULATURE A dual arterial supply, from both the anterior and posterior ciliary arteries, uniquely characterizes the higher primate anterior uveal vasculature. Two long posterior ciliary arteries travel intrasclerally along the horizontal meridian of the globe to enter the uvea through the ciliary muscle and to terminate at an anastomotic arterial circle in the anterior ciliary body. Seven anterior ciliary arteries pass anteriorly from the terminations ofthe rectus muscles (two from each of the retus muscles, except the lateral rectus muscle with only one) to supply the episcleral tissues before perforating the sclera to anastomose with branches ofthe posterior arteries of the anterior ciliary vasculature (Fig 6). Initial studies identified three levels ofextensive arterial anastomosis within the anterior segment: (1) the episcleral circle; (2) the ciliary intramuscular circle; and, to a lesser extent, (3) the major circle of the iris. Episcleral Circle After leaving the rectus muscle tendons, the anterior ciliary arteries branch within the episclera to interconnect with adjacent anterior ciliary arteries often forming a complete anastomotic ring to supply the episclera. Other anterior ciliary artery branches, as well as some branches directly from this episcleral circle, perforate the scleral wall to enter the ciliary muscle. Ten to 20 of these perforating branches occur per eye (Figs 6 to 8). They are generally randomly distributed around the circumference of the eye, but usually are more sparse in areas between the rectus muscles thanjust distal to the muscle insertions. Moreover, these perforating arterioles are more 806 Van Buskirk

FIGURE 6 Anterior uveal vasculature showing three levels of anastomotic arterial circles with relative discontinuity of major arterial circle of iris. Anterior ciliary arteries run along borders of rectus muscles, while long posterior ciliary arteries perforate sclera posteriorly to merge with intramuscular circle within ciliary muscle. Small scleral perforating arteries join episcleral and intramuscular circles. Also evident is solitary anterior ciliary artery from lateral rectus and relative paucity of temporal scleral perforating arteries. common nasally than temporally where they arise most commonly as branches from the vertical recti, rather than from the lateral rectus. Thus, not only does the lateral rectus provide only one anterior ciliary artery, it often contributes few, if any, perforating arterioles to the anterior uvea. Intramuscular Circle and the Major Circle ofthe Iris After passing through the sclera, the majority of the perforating anterior Ciliary Vasculature 807

FIGURE 7 Montage of superficial anterior ciliary vasculature. Episcleral circle (e), anterior ciliary arteries (a), ciliary muscle capillaries (c), and long posterior ciliary arteries (p) entering ciliary muscle are shown (x 22). (Reprinted from Ophthalmology27.) ciliary arterial branches arborize anteriorly within the ciliary muscle toward the root ofthe iris. The most lateral ofthese join with each other and with similar branches for the long posterior ciliary arteries to form the second arterial circle, the intramuscular circle, the most consistently continuous of the three arterial rings (Fig 9). It provides capillaries to the ciliary muscle (Fig 10), as well as to recurrent ciliary arteries that travel posteriorly to supply the anterior choriocapillaris (Fig 9). Other branches extend anteriorly to the iris root. Here they abruptly bend at right angles, forming multiple circumferentially oriented serial segments that comprise the major circle ofthe iris (Fig 11). The "major" circle is the least continuous ofthe three anastomotic arterial circles ofthe anterior uvea. After sending branches to the ciliary processes, these arterial segments end as a single iris arteriole or as a tuft of arterioles to supply a ciliary process. 808 Van Buskirk

FIGURE 8 Anterior ciliary artery and scleral perforating branch. After perforating sclera (arrowhead), artery turns posteriorly to enter ciliary muscle (m) (x 62.5).

Iris Vasculature The iris arterioles may arise as terminations of major iris circle segments, may branch from the major circle, or occasionally may branch directly from the intramuscular circle. They travel centripetally toward the pupillary border. Numerous capillaries emanate from these vessels to form a convo- luted iris capillary network that drains into iris venules. These venules coalesce into veins that extend to the iris periphery before passing, without further branching, between the major circle and the bases of the ciliary processes to enter the choroidal venous system (Fig 12). Ciliary Process Vasculature Like the anterior uvea as a whole, the ciliary processes also possess a complex and highly anastomotic microvasculature. These studies demonstrate four separate pathways for blood to go as it enters the ciliary process vasculature (Fig 13). The major processes themselves have a dual arteriolar supply emanating from the branches of the major circle, and the anterior and posterior ciliary process arterioles (Fig 14). Branches exist to supply the minor processes, while others pass without further branching along the base of the process to enter the anterior choroid (Figs 14 and 15). The anterior arterioles ofthe major ciliary processes consistently branch into tufts, with several of them supplying the tips of each process and Ciliary Vasculature 809

FIGURE 9 Montage ofdeep anterior ciliary vasculature with ciliary muscle dissected away. Continuous intramuscular circle (i), long posterior ciliary arteries (p), and anterior ciliary perforating arteries (a) and discontinuous major circle (arrow) are shown. A recurrent anterior choroidal artery (arrowhead) can also be seen (x 22). (Reprinted from Ophthalmology27.) sending connecting branches to adjacent processes (Fig 16). A short distance from their branching from the major circle, they nearly always exhibit a focal constriction in their diameter that extends a finite length before giving way to unconstricted distended capillaries ofthe anterior and inner portion of the ciliary process (Fig 17). The posterior arterioles also emanate from the major circle to supply the base or hilum ofthe ciliary processes (Fig 16). These are fewer, less tufted branches and never show the focal luminal constrictions observed in the anterior arterioles (Fig 16). Capillaries from these posterior vessels supply the central portion ofthe major ciliary processes. In addition, the adjacent, smaller (or minor) ciliary processes derive their arteriolar supply from the small branches from these posterior arterioles, forming, in effect, an 810 Van Buskirk

FIGURE 10 Arterial supply to ciliary muscle from intramuscular arterial circle (x 170).

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FIGURE 11 Arteriolar branches (i) from intramuscular circle comprising discontinuous major circle ofiris (m). Discontinuities are highlighted with arrows (x 76). Ciliary Vasculature 811

FIGURE 12 Iris vasculature showing arterioles (arrowhead) branching from major circle segments and large iris veins (arrow) passing internally to major circle (x 120).

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FIGURE 13 Drawing of a major and contiguous minor ciliary process showing four possible routes for incoming blood: (1) anterior ciliary process arterioles; (2) posterior ciliary proces arterioles; (3) minor ciliary process arterioles; and (4) "shunt" arterioles to choroid. , 812 Van Buskirk

FIGURE 14 Profile view of a single major ciliary process showing anterior (a) and posterior (p) arterioles and shunt branches to choroid (c) (x 143).

FIGURE 15 Branch (arrowhead) from posterior ciliary arteriole ofmajor process on the left supplying the minor ciliary process on the right. Anterior portions of ciliary process have been dissected away (x 320). Ciliary Vasculature 813

FIGURE 16 Arteriolar supply to ciliary process showing focally constricted anterior arterioles (arrowheads) supplying anterior tip of process and posterior non-constricted arterioles (arrow) to base or hilum ofprocess (x 260).

FIGURE 17 Focal constrictions (arrowheads) in anterior ciliary process arterioles as they enter the process tip (x 440). 814 Van Buskirk interprocess arcade (Fig 15). Some branches from both anterior and posterior interprocesses connections communicate directly via arterioles to the peripheral choroid to bypass the ciliary process altogether (Fig 14). Although some variation exists, capillaries ofthe ciliary processes generally pass concentrically posterior to empty into peripheral choroidal veins (Figs 13 and 14). The minor ciliary process capillaries supplied by nonconstricted posterior arterioles are similar to those at the base ofthe major processes, being smaller and projecting less far into the anterior chamber than the inner portion of the major processes.

COMPARATIVE ANATOMY Lacking the large ciliary muscle ofthe primate eye, the anterior uveal and ciliary process vasculatures ofthe nonprimate mammalian eye are easier to study. As expected, of the ten mammalian species studied (including the monkey), only the primary had anterior ciliary arteries extending from the insertions ofthe rectus muscles. Thus, the ciliary body of the nonprimate mammalian eye is supplied entirely by branches ofthe major arterial circle ofthe iris, itself originating solely from the long posterior ciliary arteries. However, some interesting and appealing similarities between primates and other mammalian eyes do exist that are potentially useful for investiga- tion. While most mammals have only a single form of arteriole branching off the major circle to supply the ciliary process, the rabbit, like the primate, exhibits a dual arteriolar supply, anterior and posterior to the ciliary processes (Figs 4 and 18). The rabbit ciliary processes extend well

FIGURE 18 Profile ofiridociliary process ofrabbit showing iridial portion (i), ciliary portion (c), and dual arteriolar supply (arrowheads) branching from the major circle (x 60). Ciliary Vasculature 815 onto the posterior surface ofthe iris, forming iridial processes that play an important role in the formation of aqueous humor (Fig 18). Arterioles branching anteriorly from the major circle supply these iridociliary processes as well as the iris stroma. Posterior branches from the major circle supply the more posterior portion of the ciliary processes completing the duality ofthe ciliary process supply. Despite other interesting interspecies variations, the ciliary processes of the other eight species studied were consistently supplied by only one type ofarteriole. These arterioles varied in location from the anterior portion of the process in rodents and carni- vores to the core or hilum of the process in the ungulate eye (Figs 19 and 20). Other interesting similarities to the primate eye exist in the rabbit and rodent eyes. Both the rat and the rabbit exhibit focal constrictions in arterioles supplying the ciliary processes, suggestive of precapillary "sphincter" agonal spasm as exhibited in the primate (Figs 20 and 21). This observation made it possible to pursue confidently pharmacologic studies in these lower mammalian eyes. By the same token, the dual arteriolar supply to the ciliary processes, the existence ofprecapillary sphincter-like activity, and the ready visualization ofthe ciliary processes without extensive microdissection, makes the rabbit eye ideal for studying pharmacologic manipulation of the ciliary vasculature.

CLINICAL PERTURBATION OF THE CIIARY VASCULATURE Intraocular Pressure Reduction The eye receiving paracentesis during injection showed subjectively better capillary filling and measurably greater arteriolar diameters than the eye that was injected at normal intraocular pressure. For example, the mean downstream diameter was 62 ,um with low intraocular pressure and 47 ,um in the unperturbed eye, a significant different (P <. 01). However, reduced intraocular pressure neither stimulated nor inhibited the branch zone focal constriction, with a mean constriction of -6.61% + 1.86% in the low pressure eye and -6.61% + 2.93% in the normotensive eye not a significant different (P = . 713). Hence, reduction ofintraocular pressure to ambient pressure resulted in somewhat greater vessel diameter, in general, but no increase in sphincter activity. Alpha-Adrenergic Stimulation Rabbit eyes that received topical phenylephrine, regularly exhibited pro- found constriction at the ciliary arteriolar branch zones, and generally, in large and small caliber vessels (Fig 21). The graph in Fig 22 shows the percent ofconstriction, comparing branch zones to the downstream zones 816 Van Buskirk

FIGURE 19 Profile of feline (above) and hircine (below) ciliary process vasculatures showing arteriolar supply anteriorly in the cat and posteriorly in the goat (arrows) (x 60).

FIGURE 20 Profile (above) and enface (below) view ofrat ciliary process microvasculature showing marked focal constriction (arrowheads) in arterioles supplying each process (x 280). Ciliary Vasculature 817

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FIGURE 21 Branch zone from ciliary process arterioles branching from the major circle showing the focal constriction (arrow) in the phenylephrine treated eye (below; x 640) and no constriction in the control eye (above; x 560). Ciliary Vasculature 819 in 101 arterioles in three eyes of three different animals, with - 28. 0% + 2.05% (mean + standard error of the mean) of focal constriction in the phenylephrine-treated eye. By contrast, the control eyes showed only - 6.2% ± 1.26% constriction (Fig 22). Ifany artifactual skewing occurred, it would be in favor of less constriction since the most acutely narrowed arteriolar branches often interrupted the flow of plastic, leaving a blind- ended tapered stump that could not be counted. Many ofthese specimens treated with phenylephrine showed reduced filling ofthe ciliary processes presumably from reduced downstream arteriolar flow but the major circle and its immediate branches usually filled sufficiently for analysis. Chronic Adrenergic Stimulation Chronic exposure to phenylephrine for 30 days prior to casting only minimally diminished the response to preinjection alpha-adrenergic stimulation (Fig 23). In all cases, the degree of constriction was slightly, but insignificantly, less than in the previous untreated fellow eye with a maximum difference ofonly 11%. The graphs in Fig 23 compare the percent of focal constriction at the branch zone to the downstream zones in a representative rabbit. The chronically treated eye exhibited a mean focal constriction of - 30.4% + 3.42% after it was cast, 1 hour after the last phenylephrine dose. The control eye, that received no chronic drug exposure but was also cast 1 hour after a single drop, exhibited a mean focal constriction of - 33.28% + 2.94%, not a significant difference (P = .538). Intraocular Lens Implantation The multiple steps taken to assure identification of the sites of the intraocular lens haptics after tissue digestion, proved unnecessary, in retrospect, because the haptic locations were readily identifiable in the casting ofthe anterior segment by inspection ofthe iridociliary junction or ciliary sulcus. A well defined groove lies between the iris vessels anteriorly and the ciliary process arterioles posteriorly in the areas where the lens haptic rested (Fig 24). As described above, the unperturbed ciliary sulcus is a highly vascular area. Superiorly, iris veins pass through the sulcus toward the choroid, while inferiorly the anterior ciliary process arterioles branch supplies the ciliary processes. In addition, the vast ciliary muscle capillary bed lies just external to the sulcus (Figs 25 and 26). The intraocular lens haptics of these eyes with ciliary sulcus fixation appeared to displace the vessels that traverse the sulcus externally, compressing them against the ciliary muscle and sclera (Fig 27). This compression separated iridial vessels from ciliary process vessels by mechanical displacement of some vessels and constriction ofothers to create the relatively hypovascular groove (Figs 24 to 27). The anterior ciliary process vessels were posteriorly 820 Van Buskirk ConltroC 20

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0 -100 -60 -20 0 20 60 100 Percent FocaL Arteriolar Constriction FIGURE 22 A comparison ofthe degree ofvasoconstriction in normal rabbit eyes and those exposed to one drop ofphenylephrine 1 hour before casting. The control graph shows minimal deviation from normal distribution about a mean of 6% constriction (n = 99 arterioles from 3 eyes). After phenylephrine the mean level ofarteriolar constriction is markedly higher (about 28%; n = 101 arterioles from 3 eyes). Ciliary Vasculature 821 Rcute Exposure 8

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LUILU. . . .. -i . lll nI -100 -60 -20 0 20 60 1 00 Percent Focac Artzrio(ar Constriction FIGURE 23 A comparison ofthe degree ofvasoconstriction in the eyes ofone rabbit, ofwhich one eye was exposed chronically for 37 days to phenylephrine administration, whereas the other eye received one drop before the casting procedure. The two eyes, with mean levels of vasoconstriction of - 33% (n = 45 arterioles) and - 30% (n = 25 arterioles), respectively, are not significantly different. 822 Van Buskirk

FIGURE 24 Monkey ciliary sulcus compressed by intraocular lens haptic displacing and compressing neighboring vessels to create a relatively hypovascular groove (arrowheads). Iris vessels lie above and ciliary processes below distended sulcus (x 70).

FIGURE 25 Profile view of ciliary sulcus showing compression of anterior ciliary process arterioles and capillaries against the process hilum by intraocular lens haptic (x 120). Ciliary Vasculature 823

FIGURE 26 Cross-section of methacrylate injected monkey ciliary sulcus with a posterior chamber intraocular lens. Fibroblast encapsulated lens haptic (H), embedded in sulcus, compresses (arrowheads) methacrylate filled iris vein (M). 824 Van Buskirk

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FIGURE 27 Monkey ciliary sulcus with (above) and without (below) intraocular lens haptic. Compressed area shows retrodisplacement of the sulcus and its vessels well behind the insertion of the ciliary muscle (c) with thinning and elongation of the vessels in the region (arrowheads) (x 120). displaced behind the ciliary muscle insertion, compared to areas not compressed by the haptic (Fig 27). The ciliary process tips were flattened with posterior depression of the anterior arterioles against the hilum or basal core of the process (Figs 25 and 27). Ciliary Vasculature 825 The initial studies of unoperated monkeys showed focal constrictions of the anterior arterioles suggesting a possible mechanism for modulation of regional blood flow to this critical portion ofthe process (Fig 17). The eyes with intraocular lenses showed, in addition to generalized compression of the anterior ciliary processes, a high incidence and degree of focally constricted areas in the anterior ciliary process arterioles in the areas ofthe sulcus compressed by the lens haptics (Fig 28). The focal constrictions were more numerous and marked in these haptic compressed areas than in uncompressed areas in the same eye or in the fellow eye, which did not receive an intraocular lens. In addition to the ciliary process arterioles, veins from the iris also often showed localized constriction as they passed through the ciliary sulcus posteriorly toward the choroid (Fig 29). Despite the obvious displacement ofvessels, generalized vascular compression, and localized constriction of many of the vessels to the anterior ciliary processes, the capillary beds of the processes seemed to fill normally; that is, despite constriction of the anterior arterioles and compression ofthe ciliary process tips, all ofthe vessels ofthe ciliary processes were well filled with methacrylate. Since interconnections exist between the anterior and posterior areas of the ciliary process, it could not be determined ifanterior capillary filling resulted as the anterior arterioles filled or artifactually via back filling from the posterior vessels. Cyclocryotherapy Extensive vascular destruction was well demonstrated by the studies of cryotherapy upon the ciliary vasculature. Severe alterations in the ciliary body vasculature were evident in all eyes treated but there was no consistent pattern ofdamage, recanalization, or repair among the four eyes treated. Despite rigid efforts to maintain a consistent location and duration ofa single application ofcryotherapy, there was no observable relationship between the effect produced and the amount of treatment given or the length of time between treatment and casting preparation. In the initially treated monkey, the ciliary muscle capillaries were entirely destroyed, as early as 3 weeks after therapy, leaving discrete avascular "holes" corre- sponding to the sites ofcryotherapy (Fig 30). Adjacent capillaries exhibited signs of severe injury with marked extravasation of plastic through dis- rupted unstable vessel walls. The ciliary process in the areas of treatment showed no capillary filling at all, suggesting complete destruction of their vasculature. However, neighboring, untreated regions of the ciliary body showed remarkably normal microvasculature, suggesting surprising localization of the destructive process (Figs 30 and 31). Indeed, a normally injected ciliary process can be seen adjacent to a completely destroyed 826 Van Buskirk

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FIGURE 28 Profile (above) and enface (below) views of monkey ciliary sulcus compressed by intraocular lens haptic with elongated constricted zones (arrowheads) in ciliary process anterior arterioles as they curve around the haptic (x 280). Ciliary Vasculature 827

FIGURE 29 Iris vein compressed (arrowhead) by intraocular lens haptic in the ciliary sulcus ofa monkey ( x 280).

FIGURE 30 Anterior view of iris and ciliary muscle vasculature 3 weeks after cyclocryotherapy showing complete vascular disruption and lack ofmethacrylate filling in discrete area oftreatment with relative preservation ofcontiguous areas to extreme right. Extravasation at injury site and into anterior chamber (arrowheads), presumably from disruption ofciliary muscle capillaries, can be seen. Iris vasculature (i) is preserved (x 95). 828 Van Buskirk

FIGURE 31 Junction between cryotreated and untreated ciliary processes in monkey 3 weeks after cyclocryotherapy showing completely avascular process (arrowhead) adjacent to a normally filled one (x 165). ciliary process stump (Fig 31). Also remarkable in the first eye treated was that the iris showed little, if any, disruption of its vasculature, even overlying a severely destroyed ciliary muscle and ciliary process (Fig 30). The second monkey received two cryotherapy treatments 30 days apart to opposite quadrants in each eye. The first eye was cast 70 and 100 days after treatment and the second was cast 10 and 40 days after treatment. These eyes manifested considerably more vascular damage than the first monkey, despite the fact that each treatment consisted ofonly two applications rather than the three applications received by the first monkey. Grossly, the ciliary processes appeared completely flat in the enucleated eye before maceration. In addition, the first eye treated, cast 70 days after its second treatment, exhibited hypotony and chronic choroidal detachment. Less than ten ofthe ciliary processes located nasally in the horizontal axis filled at all. The fellow eye also showed complete avascularity of the treated areas, but normal filling of the horizontal processes (Fig 32). Interestingly, this specimen showed extensive destruction of the ciliary Ciliary Vasculature 829

FIGURE 32 Low magnification ofmonkey eye cast 40 days after second cyclocryotherapy. Iris, peripheral choroidal, and ciliary vasculature are completely destroyed in vertical meridians where treatment was applied (arrows). Untreated ciliary processes (arrowheads) in horizontal meridians are well preserved (x 16.5). muscular vasculature and midperipheral choroidal vasculature so that few vascular connections persisted between the posterior and anterior segments.

DISCUSSION Recent years have brought renewed interest in both pharmacologic and surgical manipulation of the ciliary body. Prior to 1980, medical glaucoma therapy relied primarily on enhancement of aqueous humor outflow with cholinergic compounds. The introduction of beta-adrenergic antagonists and topical carbonic anhydrase inhibitors has now shifted that strategy toward the suppression of aqueous humor formation.32-35 By the same token, new methods of surgical aqueous suppression have also been developed. Cyclodestructive procedures, such as cyclocryotherapy or transscleral cyclodiathermy, have long been used in advanced glaucoma, but were unpredictable and sometimes complicated by prolonged uveitis, macular edema, choroidal detachment, hypotony, or phthisis bulbi.36-38 830 Van Buskirk Because of the unpredictability of cyclocryotherapy, a variety of new cyclodestructive procedures involving ultrasound, new applications of lasers, and surgery have been developed in recent years for more selective destruction ofthe ciliary processes.39-47 The recent shift in cataract surgery toward implantation of intraocular lenses into the posterior chamber has also introduced a new and common variety ofciliary body surgical manipulation.48,49 Despite this increased clinical emphasis on the ciliary body, the exact details ofits baseline vasculature have been difficult to discern by conventional methods of anatomic study. Although the anastomosis of the posterior and anterior ciliary arteries to form the major arterial circle was observed nearly a century ago by Leber,50 the precise vascular interconnections and relationships remained obscured from direct observation by the surrounding tissue of the ciliary body. In order to understand the vascular effects of alteration of the ciliary body with drugs or surgery, the complexities of the ciliary body microvasculature were examined with a refined intraluminal casting technique.

INTRALUMINAL MICROVASCULAR CASTING The technique used for these studies, developed over the past 10 years, has combined intravascular casting with low viscosity methacrylate material, tissue corrosion, stereoscopic microdissection, and SEM.27305152 Al- though various intravascular injection techniques have been used for centuries to study vascular anatomy, three-dimensional analysis first became practical in the early 1950s when Ashton5'3 54and Ashton and Smith55 combined latex luminal injection with tissue corrosion for examination of ocular vessels. SEM of rigid methacrylate casting allows prolonged examination ofcomplex vascular interconnections at magnifications beyond the capability ofconventional dissecting microscopes. 26,28,56-58 One limitation of SEM is that only surface vessels can be viewed clearly. However, by combining precise sequential methods of microdissection with stereoscopic SEM, the three-dimensional spatial relationship ofcomplex microvascular systems, such as the ciliary body, could be determined.29 Rigid methodology has limited artifactual alteration or distortion of the vessels by the plastic itself, but intra-arterial injection ofmethacrylate can never be interpreted as a physiologic event. Reduction of the viscosity to near that of blood has helped to maintain peripheral arterial pressure at physiologic levels while injecting at physiologic blood pressure levels. It is possible that differences in surface tension and viscosity between blood and methacrylate may cause regional differences in intraluminal pressures in plastic perfused specimens, producing some luminal dilation in some Ciliary Vasculature 831 vessels. Scrutiny of the nuclear imprint pattern replicated on the luminal casting surface (Fig 2) suggested that the endothelium remained grossly preserved through the plastic polymerization process. Maintenance of normal peripheral perfusion and oxygenation to within seconds ofthe rapid intra-arterial plastic injection also helped to preserve the integrity ofvessel walls.

ANTERIOR UVEAL CIRCULATION The anterior uveal circulation in the primate eye proved to proceed through a highly complex microvascular network interconnecting both the anterior and the long posterior ciliary arterial systems (Fig 6). This unusual arrangement, similar to the cerebral arterial circle of Willis, results in the potential for collateral and bi-directional blood flow within the ocular anterior segment. The episcleral anastomotic arborization from the anterior ciliary arteries was observed by Ashton and Smith55 with neoprene castings. In the old world monkeys studied, the plexus ofvessels from the seven anterior ciliary arteries were interconnected to form a complete anastomotic ring at the level ofthe episclera. The second, or intramuscular circle, was actually first discussed by Leber5O in the early 20th century. Subsequently the intramuscular circle received little attention as a potential collateral channel, perhaps because it is primarily a primate feature appreciated only after laborious dissection of the surrounding ciliary muscle capillary bed. This intramuscular circle proved to be the most complete anastomotic circle providing the greatest potential for collateral flow within the anterior uvea, with large caliber anastomosis between the long posterior ciliary arteries and the perforating branches of the anterior ciliary arteries. The major circle of the iris, composed of multiple discontinuous segments arising from the intramuscular circle, appeared less important for anterior segment collateral blood flow.

ANTERIOR CIIARY ARTERIES The relationship of the anterior ciliary arteries to anterior segment blood flow remains incompletely understood. Nonprimate mammals apparently perfuse their anterior segments quite adequately from the long posterior ciliary supply alone, but also lack the bulky and vascular ciliary muscle that may compete with the anterior uvea for circulatory needs. Perhaps randomly occurring anterior ciliary arterial extensions from the rectus muscles offered some early primitive primates an evolutionary advantage, perhaps a better developed accommodative apparatus, for survival over their less endowed competitors. The contemporary role of anterior ciliary arteries in the primate eye is 832 Van Buskirk unknown. As with all mammalian eyes, the posterior ciliary arteries enter the uvea in the horizontal meridian more richly supplying the horizontal than the vertical portions ofthe uvea. The 12 o'clock and 6 o'clock positions of the iris, the terminations of the iridial extensions of the long posterior ciliary arteries, become relatively hypoperfused "watershed" zones, as seen in the canine eye (Fig 1). In the primate eye, these areas can also derive blood from the anterior ciliary circulation, ifnecessary. The temporal horizontal quadrant of the primate anterior segment receives little anatomic contribution from the anterior ciliary branches of the lateral rectus with only one branch that contributes little to the episcleral circle. Thus, the superior and inferior areas of the anterior uveal vasculature appear to be more dependent on the anterior ciliary arteries than the medial and lateral portions. Incision of the insertions of the horizontal rectus muscles alone, as in conventional strabismus surgery, has not been associated with anterior segment ischemia in otherwise healthy individu- als, but separation of the vertical recti poses a more significant risk.59 By the same token, separation of the vertical rectus muscle insertions in monkeys caused delayed vascular filling ofthe superior and inferior iris as seen with fluorescein angiography.60 Reverse flow in the anterior ciliary arteries, that is, from within the eye through the sclera toward the rectus muscle, has been demonstrated by fluorescein angiography in normal human volunteers.61-63 Nanba and Schwartz63 further demonstrated increased temporal anterior ciliary artery diameter with increased intraocular pressure. The anatomic data from methacrylate castings cannot deter- mine direction of flow in these vessels, but do document that anatomic connections and anastomoses exist to permit bi-directional flow under appropriate circumstances. Indeed, flow direction in the cerebral circle of Willis can reverse when intraluminal occlusions alter relative pressure relationships in the cerebral vascular system. Moreover, regional shifts in cerebral blood flow have been demonstrated with localized cerebral activity.64-68By the same token, it could be postulated that increased ciliary muscle activity may divert posterior ciliary arterial flow to the ciliary muscle, placing more uveal demand on the anterior supply, while increased intraocular pressure may divert blood flow toward the anterior ciliary arteries as observed by Nanba and Schwartz.63 Since at least two complete anterior anastomotic circles exist in the anterior segment, each fed by diverse arterial trunks, spontaneous changes in flow direction may occur in response to tissue demands ofthe extraocular muscles, the ciliary muscle, the anterior uvea, intraocular pressure, and arterial blood pressure within the individual arterial trunks. In methacrylate castings of the human ocular microvasculature, Morrison and Wilson observed direct Ciliary Vasculature 833 connections between the perforating anterior ciliary arterial branches and the major circle of the iris (personal communication, 1987). These may facilitate development of"reverse" flow in the anterior ciliary arteries with increased pressure within the eye or in the long posterior ciliary artery.

CILIARY PROCESS CIRCULATION Like the anterior uveal vasculature as a whole, the ciliary processes ofthe primate eye also manifest a complex microvasculature with a potential for multi-directional, regionally modulated flow. The approximately 70 major ciliary processes in the primate eye are interdigitated with an equal number ofsmaller minor processes69 and are more extensively involved in the formation of aqueous humor in the anterior tip region.6 Here, they exhibit increased numbers of capillary fenestration and epithelial mito- chondria, indicative of specialization for aqueous humor formation. 6,7 The precise significance ofthe two different types ofprocesses is unknown. The methacrylate casting studies, however, show that the minor processes derive their arterial supply from an interprocess vascular arcade that branches from the basal or core portion of the adjacent major process, arterioles that typically do not show sphincter-like focal constrictions. Thus, the minor processes and basal or core portion ofthe major processes appear to derive their blood flow dependent directly on anterior uveal flow. On the other hand, the anterior portions of the major processes may have some regulatory capacity by way of the sphincters observed in their anterior arterioles. Although focal constrictions were observed in the ciliary process only in rabbits, rodents, and primates, Macri70'71 postulated and later demonstrated their existence in cats based on physiologic studies ofaqueous flow. Funk72 observed similar focal constriction in hypertensive rats, as demonstrated in the present study. Two findings are especially important in the primate ciliary vasculature: (1) the dual arteriolar supply to the major processes and (2) the observation of localized luminal constrictions consistent with sphincter control of the anterior ciliary microcirculation. In addition to arteriolar connections to the major and minor processes, some connections were observed directly from the anterior arteriolar branches to the choroid, bypassing the ciliary process altogether (Figs 13 and 14). These pathways may become functional under conditions of hypotony or choroidal detachment but their physiologic significance remains unproven. If such shunt vessels were activated they would divert arterial blood away from the ciliary process while increasing pressure in the peripheral choroidal veins. 834 Van Buskirk

COMPARATIVE ANATOMY Examination of a total of ten mammalian species showed that the dual arterial supply to the anterior uvea was unique to the primate eye and that only the rabbit and primate had dual arteriolar supply to the individual ciliary processes.3' However, the rabbit ciliary processes extend well onto the iris, forming iridociliary processes, as observed by Troncoso.73 The iridial portion and the iris share a common arteriolar supply. Other data suggest that these iridial processes in the rabbit, like the anterior ciliary process tips in the primate, are primarily important for formation of aqueous humor. 74-77 Other interesting similarities exist between the rabbit and primate. Focal constrictions can be demonstrated in ciliary process arterioles in the rabbit without pharmacologic stimulation, suggesting that some localized vasoconstriction at branch points to the ciliary processes occurs spontaneously, either as an agonal response or as a manifestation of normal vasomotor tone.30 The present study found that these focal constrictions occurred in the rabbit in both the anterior and posterior arterioles with equal frequency. This observation in the rabbit is in contrast to the primate where the posterior arterioles do not show any localized constriction. Therefore, the rabbit is not exactly analogous to the primate, but seems to have the potential for vasoactive control of the entire ciliary process. Just as the primate eye seems to have evolved a complex duality for anterior uveal blood supply, vascular specialization of the anterior ciliary process tips also seems to have developed in higher primates.

DRUG EFFECTS Eventually a wide variety ofdrugs will be studied with casting methods to understand mechanisms of pharmacologic alteration of ciliary blood flow, but these initial studies concentrated on alpha-adrenergic stimulation in the rabbit. Since vasoconstriction appeared to develop during the agonal response to the intravascular injection of methacrylate, it seemed likely that alpha-adrenergic stimulation may be active and could be experimentally studied.'7"8 It is possible that these constrictions occurred as a physiologic or pharmacologic response to the methacrylate itself, but artifactual alterations in pressure, oxygenation, perfusion, or viscosity were minimized aS much as possible. Alpha-adrenergic stimulation regularly constricted sphincter-like structures in the rabbit vessel lumen, just as the ciliary process arterioles branched from the major circle ofthe iris. Moreover, this constriction was associated with the downstream luminal narrowing either in response to reduced pressure or diffuse vasoconstriction, resulting in poor ciliary process capillary filling. This finding suggests that alpha-adrenergic stimu- Ciliary Vasculature 835 lation of the rabbit eye would reduce ciliary body perfusion, as demonstrated in rabbits with both topical administration of the drug phenylephrine and sympathetic nerve stimulation.78-84 Despite the mild vasoconstriction often seen even in untreated eyes, phenylephrine administration markedly increased both the incidence of observed constricted areas and the degree ofconstriction at each location. Although some tachyphylaxis to alpha-adrenergic stimulation was possible with chronic stimulation, the chronically treated eyes continued to show greater focal vasoconstriction than did untreated eyes. These findings support the hypothesis that ciliary blood flow is under some adrenergic control by means ofmural sphincters in the arterioles supplying the ciliary processes.

INTRAOCULAR LENSES The iridociliary junction, commonly referred to as the ciliary sulcus, seems to be a convenient place to support the haptics of the posterior chamber intraocular lens, but is in fact a complex, delicate and highly vascular tissue52'69,85 (Fig 27). Many cataract surgeons specifically select the ciliary sulcus for haptic fixation, while others advocate implantation within the lens capsular bag.85-89 Despite their preferences, surgeons frequently are unable to predict the location ofthe lens haptics as shown by histopathologic studies in postmortem eyes with implants. McDonnell et a189 observed that 84% of 110 eyes with posterior chamber lenses had at least one haptic outside the capsular bag. Once placed in the sulcus, such haptics soon erode into the soft tissues ofthe ciliary body and usually become encapsulated in a fibrous sheath.85'87,89 McDonnell et a189 observed at least one haptic totally embedded within the uveal tissues ofthe ciliary sulcus in 37% ofeyes with posterior chamber intraocular lenses. Ciliary sulcus intraocular lens fixation appears to be well tolerated clinically in most patients, considering the multitude of asymptomatic patients with posterior chamber intraocular lenses. 49,85 However, erosion into the soft tissues of the iridociliary tissues can occasionally lead to clinically adverse consequences, such as inflammation, edema, thrombosis, bleeding, pigment dispersion, and perhaps localized ischemia.85,87'89-91 Chronic inflammation and iris edema occasionally follow clinically uncom- plicated posterior chamber lens implantation. Bioincompatibility, chronic tissue chafing, poor wound healing, premature discontinuation of topical corticosteroids, and retained crystalline lens material all can lead to chronic inflammation after cataract surgery. 85 To that list, perhaps, should be added compression ofiris veins, as this study demonstrated in monkey eyes with posterior chamber intraocular lenses (Fig 33). McDonnell et al89'9' and 836 Van Buskirk

FIGURE 33 Slitlamp photograph showing posterior chamber hemorrhage (arrows) after sulcus fixation ofa posterior chamber intraocular lens.

Apple et al87 also observed, histologically in postmortem eyes, local vascular compression with thrombosis. Since the major circle of the iris is segmental rather than a continuous anastomotic circle, obliteration of a segment could produce localized hypoperfusion, but probably would not compromise total blood flow to the anterior segment or anterior uveal collateral flow. Although not observed histologically, erosion of the haptic into the lumen of a vessel could cause tearing of the vessel wall and hemorrhage into the posterior chamber (Fig 33). Other clinical correlates likely exist with tissue erosion ofthe lens haptics into the ciliary sulcus. Although not a vascular phenomenon, tissue chafing can lead to pigment dispersion and glaucoma.9092 Three patients with seemingly well tolerated posterior chamber lenses developed synechiae, localized to the area of the lens haptics several months after the original implantation.93 These eyes may have developed localized iris ischemia and inflammation leading to the late synechiae without other manifestations of more diffuse uveitis.

CYCLOCRYOTrHERAPY Transscleral cyclodestructive procedures have been employed since the Ciliary Vasculature 837 introduction of penetrating cyclodiathermy in 1936.37 Cyclocryotherapy has been highly successful when applied to the aphakic eye with an open chamber angle, but less so in eyes with extensive peripheral anterior synechiae or complicated secondary glaucomas.94'95 Cyclocryotherapy also is sometimes unpredictably complicated by phthisis bulbi, though less so when only 180 degrees ofthe limbal circumference is treated. 94-96 Chronic macular edema and choroidal detachment, serous or hemorrhagic, occasionally complicate cyclocryotherapy in glaucoma patients. Consistent with previously reported clinical series, ocular castings ofthe two monkeys after cryotherapy revealed highly variable effects despite efforts to provide a constant degree oftreatment. Quigley97 also observed a variable degree of cyclodestruction from similar treatments in experimental animals. Consistent with Quigley's histologic study, complete destruction of the ciliary process vasculature was observed in the areas treated. However, in the first eye injected there was good preservation of adjacent untreated processes, while the subsequent monkey developed extensive loss of vascularity in contiguous processes as well. In addition to cryodestruction ofthe vasculature, the poor methacrylate filling in the first eye could have resulted from intravascular clotting and edema, as reported by Quigley.97 However, the persistence, indeed exacerbation, of unfilled ciliary processes many months after the procedures, confirms that the vessels were actually destroyed by the freezing. Perhaps combining the two procedures, despite their separate limbal locations, accelerated this more global vascular destruction. Like Quigley's97 histological study in the monkey, no tendency toward vascular regeneration or recanalization after cyclocryotherapy was observed.

Functionally, the ciliary process appears to be the most complex tissue in the anterior uvea. Ciliary process blood flow could directly affect aqueous humor formation by controlling capillary hydrostatic pressure and, therefore, ultrafiltration. In addition, perfusion could indirectly influence secretion, both by governing the availability ofplasma for ultrafiltration and by supplying the nutrients required for this active metabolic process. The complex anatomy of the ciliary process microvasculature provides multiple avenues for regional modulation of ciliary perfusion that could contribute to aqueous humor regulation. With multiple potential routes for arterial blood flow within the anterior uvea as awhole and within individual ciliary processes, the ciliary vasculature would seem readily susceptible to physiologic regulation and clinical manipulation with drugs or surgery, as the methacrylate luminal castings demonstrated. 838 Van Buskirk

REFERENCES 1. Raviola G: The structural basis of the blood-ocular barriers. Exp Eye Res (Suppl) 1977; 25:27-63. 2. Raviola G, Raviola E: Intercellular junctions in the ciliary epithelium. Invest Ophthalmol Vis Sci 1978; 17:958-981. 3. Sears ML: The aqueous, in RA Moses (ed): Adler's Physiology of the Eye: Clinical Applications. St Louis, CV Mosby, 1981, p 204. 4. Shabo AL, Maxwell DS: The blood-aqueous barrier to tracer protein: A light and electron microscopic study of the primary ciliary process. MicrovascRes 1972; 4:142-158. 5. Smith RS, Rudt LA: Ultrastructural studies of the blood-aqueous barrier. 2: The barrier to horseradish peroxidase in primates. AmJ Ophthalmol 1973; 76:937-947. 6. Hara K, Lutjen-Drecoll E, Prestele H, et al: Structural differences between regions of the ciliary body in primates. Invest Ophthalmol Vis Sci 1977; 16:912-924. 7. Lutjen-Drecoll E: Morphological basis for aqueous humor formation, in SM Drance, AH Neufeld (eds): Glaucoma: Applied Pharmacology in Medical Treatment. Orlando, Grune & Stratton, 1984, p 23. 8. Henderson T: The cribriform ligament of the ciliary muscle: A demonstration of the comparative anatomy of the angle of the anterior chamber in man and monkeys. Trans Ophthalmol Soc UK 1921; 41:465-481. 9. The Doyne Memorial Lecture: The anatomy and physiology ofaccommodation in mammalia. Trans Ophthalmol Soc UK 1926; 46:280. 10. Rohen J: The histologic structure of the chamber angle in primates. AmJ Ophthalmol 1961; 52:529-539. 11. Kaufinan PL, Barany EH: Loss of acute pilocarpine effet on outflow facility following surgical disinsertion and retrodisplacement of the ciliary muscle from the scleral spur in the cynomolgus monkey. Invest Ophthalmol 1976; 15:793-807. 12. Ehinger B: Adrenergic nerves to the eye and to the related structures in man and in the cynomolgus monkey (Macaca irus). Invest Ophthalmol 1966; 5:42-52. 13. Connections between adrenergic nerves and other tissue components in the eye. Acta Physiol Scand 1966; 67:57-64. 14. Malmfors T: The adrenergic innervation of the eye as demonstrated by fluorescence microscopy. Acta Physiol Scand 1965; 65:259-267. 15. Laties AM, Jacobowitz D: A comparative study ofthe autonomic innervation ofthe eye in monkey, cat, and rabbit. Anat Rec 1966; 156:383-395. 16. Mittag T, Tormay A: Adrenergic receptors in iris-ciliary body: Direct ligand binding studies. Invest Ophthalmol Vis Sci (Suppl) 1981; 20:198. 17. Bill A, Linder M, Linder J: The protective role ofocular sympathetic vasomotor nerves in acute arterial hypertension. 9th European Conference on Microcirculation, Antwerp, 1976. Bibl Anat 1977; 16:3035. 18. Beausang-Linder M: Effects ofsympathetic stimulation on cerebral and ocular blood flow: Modification by hypertension, hypercapnia, acetazolamide, PGI-2, and papaverine. Acta Physiol Scand 1982; 114:217-224. 19. Bill A: Autonomic nervous control ofuveal blood flow. Acta Physiol Scand 1962; 56:70-81. 20. Stjernschantz J, Bill A: Effect ofintracranial stimulation ofthe oculomotor nerve on ocular blood flow in the monkey, cat, and rabbit. Invest Ophthalmol Vis Sci 1979; 18:99-103. 21. Goldman H: Uber Fluorescein in der menschlichen Vorderkammer: Das Kammerwasser- Minutenvolumen des Menschen. Ophthalmologica 1950; 119:65-95. 22. Jones RF, Maurice DM: New methods ofmeasuring the rate ofaqueous flow in man with fluorescein. Exp Eye Res 1966; 5:208-220. 23. Nagataki S: Aqueous humour dynamics ofhuman eyes as studied using fluorescein. JpnJ Ophthalmol 1975; 19:235-249. 24. Johnson SB, Coakes RL, Brubaker RF: A simple photogrammetric method of measuring anterior chamber volume. AmJ Ophthalmol 1978; 85:469-474. Ciliary Vasculature 839

25. Coakes RL, Brubaker RF: (1979) Method of measuring aqueous humor flow and corneal endothelial permeability using a fluorophotometry nomogram. Invest Ophthalmol Vis Sci 1979; 18:288-302. 26. Batson OV: Corrosion specimens prepared with a new material. Anat Rec 1955; 121:425A. 27. Morrison JC, Van Buskirk EM: Anterior collateral circulation in the primate eye. Ophthalmology 1983; 90:707-715. 28. Hodde KC, Miodonski A, Bakker C, et al: Scanning electron microscopy of microcorro- sion casts with special attention on arterio-venous differences and application to the rat's cochlea. SEM 1977; 2:477. 29. Morrison JC, Van Buskirk EM: Sequential microdissection and scanning electron microscopy of ciliary microvascular castings. SEM 1984; 2:857-865. 30. Morrison JC, DeFrank MP, Van Buskirk EM: Regional microvascular anatomy of the rabbit ciliary body. Invest Ophthalmol Vis Sci 1987; 28:1314-1324. 31. Comparative microvascular anatomy of mammalian ciliary processes. Invest Ophthalmol Vis Sci 1987; 28:1325-1340. 32. Phillips CI, Howitt G, Rowland DJ: Propranolol as ocular hypotensive agent. Br J Ophthalmol 1967; 51:222-226. 33. Zimmerman T, Kaufman H: Timolol: A beta-adrenergic blocking agent for the treatment of glaucoma. Arch Ophthalmol 1977; 95:601-604. 34. Stein A, Pinke R, Krupin T, et al: The effect oftopically administered carbonic anhydrase inhibitors on aqueous humor dynamics in rabbits. AmJ Ophthalmol 1983; 95:222-228. 35. Lewis RA, Schoenwald RD, Eller M, et al: Ethoxzolamide analogue gel: A topical carbonic anhydrase inhibitor. Arch Ophthalmol 1984; 102:1821-1824. 36. Weve H: Die zyklodiatermie das corpus diliare bei glaukom. Zentralbl Ophthalmol 1933; 29:562. 37. Vogt A: Versuche zur intraokularen druckherabsetzung mittels diatermieschadigung des corpus ciliare (zyklodiatermiestichelung). Schweiz Med Wochenschr 1936; 66:593. 38. Bietti G: Surgical intervention on the ciliary body: New trends for the reliefofglaucoma. JAMA 1950; 142:889-897. 39. Weekers R, Lavergne G, Watillon M, et al: (1961) Effects of photocoagulation of ciliary body upon ocular tension. AmJ Ophthalmol 1961; 52:156-163. 40. Beckman H, Sugar HS: Neodymium laser cyclocoagulation. Arch Ophthalmol 1973; 90:27-28. 41. Beckman H, Waeltermann J: Transscleral ruby laser cyclocoagulation. AmJ Ophthalmol 1984; 98:788-795. 42. Purnell EW, Sokollu A, Torchia R, et al: Focal chorioretinitis produced by ultrasound. Invest Ophthalmol 1964; 3:657-664. 43. Coleman DJ, Lizzi FL, Driller J, et al: (1985) Therapeutic ultrasound in the treatment of glaucoma. I. Experimental model. Ophthalmology 1985; 92:339-346. 44. Coleman DJ, Lizzi FL, Driller J, et al: Therapeutic ultrasound in the treatment of glaucoma. II. Clinical applications. Ophthalmology 1985; 92:347-353. 45. Lee PF, Pomerantzeff 0: Transpupillary cyclophotocoagulation of rabbit eyes: An experimental approach to glaucoma surgery. AmJ Ophthalmol 1971; 71:911-920. 46. Shields MB: Cyclodestructive surgery for glaucoma: Past, present, and future. Trans Am Ophthalmol Soc 1985; 83:285-303. 47. Freyler H, Scheimbauer I: Excision ofthe ciliary body (Sautter procedure) as a last resort in secondary glaucoma. Klin Monatsbl Augenheilkd 1981; 17:473-477. 48. Stark WJ, Leske MC, Worthen DM, et al: Trends in cataract surgery and intraocular lenses in the United States. AmJ Ophthalmol 1983; 96:304-310. 49. Stark WJ, Terry AC, Worthen D, et al: Update of intraocular lenses implanted in the United States. AmJ Ophthalmol 1984; 98:238-239. 50. Leber T: Die cirkulation und ernahrungsverhaltnisse des auges, in T Saemisch (ed): Graefe-Saemisch Handbuch der Gesamten augenheilkunde. 2nd ed, Vol 2, Leipzig, Wilhelm Engelmann, 1903, Chap11. 840 Van Buskirk

51. Van Buskirk EM: The canine eye: The vessels ofaqueous drainage. Invest Ophthalmol Vis Sci 1979; 18:223-230. 52. Morrison JC, Van Buskirk EM: Ciliary process microvasculature ofthe primate eye. AmJ Ophthalmol 1984; 97:372-383. 53. Ashton N: Anatomical study of Schlemm's canal and aqueous veins by means ofneoprene casts. Part I. Aqueous veins. BrJ Ophthalmol 1951; 35:291-303. 54. Observations on the choroidal circulation. BrJ Ophthalmol 1952; 36:465-481. 55. Ashton N, Smith R: Anatomical study ofSchlemm's canal and aqueous veins by means of neoprene cats. III. Arterial relations of Schlemm's canal. Br J Ophthalmol 1953; 37: 577-586. 56. Murakami XX: Application of the scanning electron microscope to the study of the fine distribution of the blood vessels. Arch Histol Jpn 1971; 32:445-454. 57. Shimizu K, Ujiie XX: Structure of Ocular Vessels. New York, Igaku-Shoin, Ltd, 1978. 58. Risco JM, Grimson BS, Johnson PT: angioarchitecture ofthe ciliary artery circulation of the posterior pole. Arch Ophthalmol 1981; 99:864-868. 59. Jacobs DS, Vastine DS, Urist MJ: Anterior segment ischemia and sector iris atrophy after strabismus surgery in a patient with chronic lymphocytic leukemia. Ophthalmic Surg 1976; 7:42-48. 60. Hayreh SS, Scott WE: Fluorescein iris angiography. II. Disturbances in iris circulation following strabismus operation on the various recti. Arch Ophthalmol 1978; 96:1390-1400. 61. Talusan ED, Schwartz B: Fluorescein angiography: Demonstration of flow pattern of anterior ciliary arteries. Arch Ophthalmol 1981; 99:1074-1080. 62. Watson PG, Bovey E: Anterior segment fluorescein angiography in the diagnosis of scleral inflammation. Ophthalmology 1985; 92:1-11. 63. Nanba K, Schwartz B: Increased diameter of the anterior ciliary artery with increased intraocular pressure. Arch Ophthalmol 1986; 104:1652-1655. 64. Gur RC, Gur RE, Obrist WD, et al: Sex and handedness differences in cerebral blood flow during rest and cognitive activity. Science 1982; 217:659-661. 65. Ginsberg MD, Howard BE, Hassel WR: Emission tomographic measurement of local cerebral blood flow in humans by an in vivo autoradiographic strategy. Ann Neurol (Suppl) 1984; 15:S12. 66. Reivich M, Alavi A, Gur RC: Positron emission tomographic studies ofperceptual tasks. Ann Neurol (Suppl) 1984; 15:s61. 67. Raichle ME, Herscovitch P, Mintun MA, et al: Dynamic measurements of local blood flow and metabolism in the study of higher cortical function in humans with positron emission tomography. Ann Neurol (Suppl) 1984; 15:S48. 68. Roland PE, Friberg L: Localization ofcortical areas activated by thinking. JNeurophysiol 1985; 53:1219-1243. 69. Hogan MJ, Alvarado JE, Weddell JE: Histology of the Human Eye. Philadelphia, WB Saunders, 1971, p 269. 70. Macri FJ: The formation and inhibition of aqueous humor prodution: A proposed mechanism of action. Arch Ophthalmol 1978; 96:1664-1667. 71. Vasoconstriction produced in the iris-ciliary body ofthe cat's eye by stimulation of local ganglion-like receptors. Invest Ophthalnol 1971; 10:581-588. 72. Funk R: Elektronenmikroskopoische untersuchungen uber die postnatale entwicklung des ziliarkorpers bei spontan hypertensiven ratten. Med Welt 1985; 36:745. 73. Troncoso MU: Microanatomy of the eye with the slitlamp microscope. II. Comparative anatomy ofthe ciliary body, zonulaand related structures in mammalia. AmJ Ophthalmol 1942; 25:1-31. 74. Wegner K: Regional differences in ultrastructure ofthe rabbit ciliary processes: The effect of anesthetics and fixation procedurs. Invest Ophthalmol 1967; 6:177-191. 75. Kozart DM: Light and electron microscopic study ofregional morphologic differences in the processes of the ciliary body in the rabbit. Invest Ophthalmol 1968; 7:15-33. Ciliary Vasculature 841

76. Ober M, Lutjen-Drecoll E, Lonnerholm G: Regional differences in the fine structure and localization ofcarbonic anhydrase in the ciliary body ofthe rabbit eye. Invest Ophthalmol Vis Sci (Suppl) 1979; 18:14. 77. Lutjen-Drecoll E, Lonnerholm G: Carbonic anhydrase distribution in the rabbit eye by light and electron microscopy. Invest Ophthalmol Vis Sci 1981; 56:70-81. 78. Bill A: Autonomic nervous control ofuveal blood flow. Acta Physiol Scand 1962; 56:70-81. 79. Langham ME, Rosenthal AR: Role ofcervical sympathetic nerve in regulating intraocular pressure and circulation. AmJ Physiol 1966; 210:786-794. 80. Cole DF, Rumble R: Responses of iris flow to stimulation of the cervical sympathetic in the rabbit. Exp Eye Res 1970; 10:183-191. 81. Beausang-Linder M: Sympathetic effects on cerebral and ocular blood flow in rabbits pretreated with indomethacin. Acta Physiol Scand 1982; 114:211-215. 82. Effects of sympathetic stimulation on cerebral and ocular blood flow: Modifica- tion by hypertension, hypercapnia, acetazolamide, PGI-2, and papaverine. Acta Physiol Scand 1982; 114:217-224. 83. Linder J: Cerebral and ocular blood flow during alpha-2 blockade: Evidence for a modulated sympathetic response. Acta Physiol Scand 1981; 113:511-517. 84. Morgan TR, Green K, Bowman K: Effects of adrenergic agonists upon regional ocular blood flow in normal and ganglionectomized rabbits. Exp Eye Res 1981; 32:691-697. 85. Apple DJ, Mamalis N, Loftfield K, et al: Complications ofintraocular lenses: A historical and histopathological review. Surv Ophthalmol 1984; 29:1-54. 86. Miyake K, Miyake C: Intraoperative posterior chamber lens haptic fixation in the human cadaver eye. Ophthalmic Surg 1985; 16:230-236. 87. Apple DJ, Reidy JJ, Googe JM, et al: A comparison of ciliary sulcus and capsular bag fixation of posterior chamber intraocular lenses. J Am Intraocul Implant Soc 1985; 11:44-63. 88. Apple DJ: Intraocular lenses: Notes from an interested observer. Arch Ophthalmol 1986; 104:1150-1152. 89. McDonnell PJ, Champion R, Green WR: Location and composition ofhaptics ofposterior chamber intraocular lenses: Histopathologic study ofpostmortem eyes. Ophthalmology 1987; 94:136-142. 90. Samples JR, Van Buskirk EM: Pigmentary glaucoma associated with posterior chamber intraocular lenses. AmJ Ophthalmol 1985; 100:385-388. 91. McDonnell PJ, Green WR, Maumenee AE, et al: Pathology of intraocular lenses in 33 eyes examined postmortem. Ophthalmology 1983; 90:386-403. 92. Van Buskirk EM: Pseudophakic glaucoma, in GW Weinstein (ed): Open Angle Glaucoma: Contemporary Issues in Ophthalmology. Vol 3, New York, Livingstone, 1986, pp 133-154. 93. : Late onset, progressive, peripheral anterior synechiae with posterior chamber intraocular lenses. Ophthalmic Surg 1987; 18:115-117. 94. Bellows AR, Grant WM: Cyclocryotherapy of chronic open-angle glaucoma in aphakic eyes. AmJ Ophthalmol 1977; 84:426-428. 95. Krupin T, Johnson MF, Becker B: Anterior segment ischemia after cyclocryotherapy. Am J Ophthalmol 1977; 84:426-428. 96. Krupin T, Mitchell KB, Becker B: Cyclocryotherapy in neovascular glaucoma. Am J Ophthalnol 1978; 86:24-26. 97. Quigley HA: Histological and physiological studies of cyclocryotherapy in primate and human eyes. AmJ Ophthalmol 1976; 82:722-732.