Lens-induced glaucoma

Documenta Ophthalmologica 81: 317-338, 1992. �9 1992 Kluwer Academic Publishers. Printed in the Netherlands.

Lens-induced glaucoma

J O N A T H A N P. E L L A N T & S T E P H E N A. O B S T B A U M Department of Ophthalmology, Lenox Hill Hospital, New York, USA

Accepted 9 July 1992

Key words: Pupillary block glaucoma, ciliary block glaucoma, phacolytic glaucoma

Abstract. The crystalline lens is implicated as a causative element in producing several forms of glaucoma. Etiologically they represent a diversity in the presentation of the glaucomatous process. These conditions include glaucoma related to: lens dislocation (ectopia lentis), lens swelling (intumescent cataract), classical pupillary block, aqueous misdirection - ciliary block, phacoanaphylaxis, lens particle, and phacolytic glaucoma. The management of elevated intraocular pressure often requires altering the intraocular relationship of anatomic structures surrounding the lens or lens removal. We will review the entities that produce these lens- induced glaucomatous conditions and suggest a rational approach to their diagnosis and treatment.

Introduct ion

The crystalline lens plays a dominant role in the causation of various types of glaucoma. The mechanism producing the glaucomatous conditions vary somewhat , but can be broadly reduced into two categories. In the first instance the crystalline lens blocks the anterior flow of aqueous humor resulting in a precipitous rise in intraocular pressure ( IOP) . The conditions associated with this mechanism are: (1) pupillary block glaucoma, e.g. classical or that produced by an intumescent lens, (2) ectopia lentis where the lens loosened f rom some or all of its zonular attachments, either shifts forward producing pupillary block or combines its abnormal position with the interposition of vitreous to produce vitreo-lenticular block, and (3) ciliary block (malignant) glaucoma, in which there is posterior aqueous misdirection resulting in ciliolenticular or ciliovitreolenticular blockage.

The second category of lens-induced glaucoma develops as a consequence of blockage of the trabecular meshwork by lens proteins, material or debris. In phacolytic (lens protein) glaucoma certain constituents of the lens, heavy molecular weight soluble proteins, block the trabecular meshwork resulting in l O P elevation. Lens material per se is also capable of obstructing aqueous outflow. This condition is te rmed lens particle glaucoma. Finally, in rare cases, a phacoanaphylact ic response to lens material has been associated with an elevation of lOP.

Glaucoma capsulate is another condition that involves the crystalline lens

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and increased IOP. Clinicopathologic evidence suggests that the fibrillar protein material that blocks the trabeculum is not elaborated by the lens capsule but that the lens serves as a repository of this material as do other ocular structures. While we acknowledge that glaucoma capsulare or exfolia- tion syndrome is also associated with loose zonules and in rare instances can produce pupillary block, this condition will not be separately discussed in this communication.

The purpose of this article is to review these entities and to discuss the pathophysiology of the glaucomas they produce.

Pupillary block glaucoma

Pupillary block glaucoma is the result of the obstruction to aqueous outflow caused by apposition of the iris root to the trabecular meshwork. Certain individuals have an anatomic predisposition to develop this entity and these biometric variables have been studied extensively. Furthermore it has been shown that repeated attacks of angle closure reduce outflow facility in otherwise normal appearing eyes, following resolution of the acute episode [1]. The use of lasers for treatment has revolutionized the care of these patients.

Anatomy

Eyes which develop angle closure glaucoma secondary to pupillary block have been observed to have several aspects of their ocular anatomy which predispose them to its occurrence. The most important physical factor in these patients is that they usually have a shallow anterior chamber. The depth of the chamber is dependent on the dimensions of the lens, the cornea and the axial length of the globe. The lens displays a greater axial thickness, and is more anteriorly located in eyes that have acute angle closure [2-5]. With aging the lens assumes greater thickness [2, 4, 5] and a greater curve of its anterior surface [6], in addition, the zonules loosen and the lens is displaced forward [5]. These factors not only cause increasing shallowness of the anterior chamber but also increase iridolenticular contact [7], resulting in greater amounts of pupillary block [4]. It is commonly recognized that hyperopic eyes have an increased risk of angle closure compared to the normal population. Their eyes have a shorter axial length and shallower anterior chamber. As a result of what has been termed 'optical co- ordination' these eyes also possess thicker lenses to compensate for their shorter axial length [2]. One may see how these factors together would create an anatomic situation which predisposes these patients to angle closure.

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Physiology

The primary physiologic factor in initiating the angle closure mechanism is relative pupillary block [8]. When this situation is present the aqueous fluid can not readily gain access to the outflow channels in the anterior chamber. As aqueous continues to be produced and accumulate in the posterior chamber, pressure builds in this compartment, causing the lens-iris dia- phragm to move forward. This situation is promoted by the continual flow of aqueous already present in the anterior chamber out through the trabecular meshwork, allowing the lens and iris to move further forward. This displacement continues until it is arrested by a larger posterior restraining force generated by the zonular apparatus. However, if the forces acting in the anterior direction are sufficiently large they will cause the iris to come into contact with the peripheral cornea and acute closure of the angle will ensue. Once this occurs, aqueous production will continue to push the angle closed. The shallower the anterior chamber at the outset, the greater the probability that this series of events will occur.

There are two antagonistic muscle groups in the iris, the dilator and sphincter muscles. They maintain a delicate balance of forces that influence the area of iridolenticular contact, and the pupillary blocking force. When the sphincter constricts, the posterior component of its force decreases. However, during mydriasis the posterior force of this muscle increases, causing an enhancement of iridolenticular contact [8]. Mapstone has shown that the major component of pupillary block force comes from the sphincter muscle group and that this force reaches its maximum value during middilation [9-11].

The iris dilator force acts from its point of contact with the lens toward the insertion of the iris. The greater the pupillary dilation, the smaller the force acting posteriorly to push the iris against the lens. This force ap- proaches zero at full dilation. Any increase in lenticular diameter or forward position of the lens will increase the pupillary blocking force. The elasticity of the iris acts with the dilator force to balance sphincter forces. At any stage in pupillary dilation, the iris dilator and elastic forces act in one direction and the force of the sphincter acts equally in the opposite direction. In an eye with a short axial length, and an anteriorly placed thick lens, the posterior forces of the iris against the lens may be sufficient to overcome the pressure gradient between the anterior and posterior cham- bers and pupillary block may result [8-10].

Another important factor in this process is the tendency for the peripheral iris to bow against the trabecular meshwork. The greatest potential for this appears to be during mid-dilation. This is the same position that the major component of pupillary block, the iris sphincter force, is maximally acting [12].

Although relative pupillary block is entirely theoretical, the observations

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that peripheral iridectomy is often curative implicates this mechanism as the most important factor acting in acute angle closure glaucoma. After iridectomy the depth of the anterior chamber often increases as the aqueous may now bypass the pupillary resistance and reach the outflow channels of the trabeculum.

Signs and symptoms

Symptoms of angle closure glaucoma are related to the marked elevation of intraocular pressure. They include ocular pain and headache, blurred vision, and the perception of halos around lights (secondary to corneal edema). The increase in intraocular pressure may cause a vasovagal response which leads to nausea and vomiting, bradycardia, and diaphoresis. Approximately one third of patients give a history of previous intermittent or sub-acute attacks often relieved by periods of sleep [13]. Patients often describe that their symptoms occur at night. Photographic measurements of the eyes of normal individuals have shown that the anterior chamber shows an even more significant decrease in depth compared to the central region [14]. One may see how this variation, when combined with the middilation of the pupil present in the evening may facilitate closure of the angle in predisposed eyes.

Signs of angle closure include reduced central visual acuity secondary to corneal edema. The lids may be swollen and conjunctival injection is common. The pupil is usually in a middilated position and may assume a vertically oval orientation because of iris ischemia. The anterior chamber is flat peripherally and one may observe areas of iridocorneal contact. Cell and flare are often present. In the case of lens swelling a mature cataract may be seen bowing the iris forward. Examination of the fellow eye typically reveals a shallow anterior chamber, narrow angle, and often a cataract.

Lens intumescence secondary to continual growth of the lens as a person ages is a well recognized precipitating factor to angle closure glaucoma. The lens matures by the continual deposition of new lens fibers thus increasing its antero-posterior diameter [15]. A less well recognized cause of lens intumescence is caused by an idiosyncratic reaction to systemic medications that result in swelling of the lens, a transient myopic shift, and rarely angle closure glaucoma. More than twenty different drugs, most commonly diuretics, are recognized to induce transient myopia [12, 16]. The swelling of the lens may be compared to the increase in myopia secondary to lenticular swelling seen in diabetic patients. Febrile illness (hemorrhagic fever with renal syndrome) has also been implicated in a number of cases of transient myopia and shallowing of the anterior chamber [17]. It is not known if these cases share a common pathophysiologic mechanism as the drug-related ones. Miotics have also been implicated in precipitating angle closure glaucoma but by a different mechanism [18]. This class of drugs constricts the pupil, and contraction of the ciliary muscle resulting in slackening of the

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zonules and forward movement of the lens. Both of these mechanisms result in an increase of relative pupillary block and may lead to acute angle closure in anatomically predisposed eyes. Closure of the angle has also been described secondary to anterior rotation of the ciliary body in patients with cicatricial retinopathy of prematurity without a retrolental mass, and in patients with AIDS who also have ciliochoroidal effusions [19, 20].

Treatment

Treatment of angle closure glaucoma has three goals (1) to lower intraocular pressure quickly so as to limit damage to the optic nerve and anterior chamber structures, (2) protect the fellow eye from developing an acute attack as it is usually similarly anatomically predisposed to the condition, and (3) perform definitive treatment in the involved eye and in the fellow eye to prophylactic against future attacks [21].

Initially, attempts are made to lower intraocular pressure medically. Topical beta blockers, carbonic anhydrase inhibitors, and hyperosmotic agents are administered. The use of parasympathometic agents such as pilocarpine 1%-2% may also be used to constrict the pupil and pull the iris periphery away from the trabecular meshwork; however, the agents also tend to increase pupillary block, so they must be used judiciously [18].

Occasionally an attack of angle closure secondary to pupillary block proves resistant to medical management. When this occurs mechanical means of lowering the pressure are instituted: (a) corneal depression using a Zeiss 4 mirror lens or a moist cotton swab, (b) iridectomy with the Nd : YAG laser, (c) gonioplasty with an argon laser, (d) coreoplasty with the argon laser, and (e) apply digital massage [17, 21-23].

Iridectomy is the definite treatment for angle closure secondary to pupillary block [18, 24]. The formation of a new pathway for aqueous flow to the anterior chamber by-passes the obstruction caused by pupillary block and relieves the pressure in the posterior chamber, allowing the peripheral iris to fall away from the trabecular meshwork, thereby facilitating aqueous outflow. Iridectomy may be performed during the acute attack. If the cornea is too edematous to permit adequate visualization of the iris, the application of topical glycerin to the cornea may clear the cornea sufficiently to allow treatment. Some ophthalmologists prefer to wait 1-2 days after the acute attack is controlled to allow the corneal edema to clear and intraocular inflammation to subside before proceeding with laser iridectomy. In the past, surgical iridectomy was the standard procedure to definitely treat pupillary block. The availability and relative safety of the laser iridectomy has largely replaced the surgical iridectomy except in certain circumstances where the surgical approach is still indicated [21].

If the fellow eye is also anatomically predisposed to angle closure, prophylactic laser iridectomy should be performed on that eye at some later date.

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When pupillary block is caused by an intumescent cataract that is visually significant, an alternative surgical approach is warranted. If intraocular pressure can be controlled pre-operatively, then cataract extraction and iridectomy may be performed.

Ciliary block glaucoma

Malignant glaucoma (MG) was first described in 1869 by Von Graefe. The condition derived its name not because of its relation to a neoplastic process, but because it was traditionally difficult to diagnose and was extremely resistant to the earliest forms of treatment attempted. In its classic form MG is seen after surgery for glaucoma in which some or all of the anterior chamber angle is closed by synechiae [25]. It usually occurs a few days following the surgery but has been reported to occur sixteen years later [26, 27]. Its development is not related to the intraocular pressure at the time of surgery or to the type of surgical procedure performed, and has been observed following filtering surgery, placement of Nd:YAG cyclophotocoagulation, scleral buckle, argon laser release of scleral flap sutures and iridectomy [28-31]. In recent years eyes have been examined with pathology very similar to that of classic MG even though they have not undergone previous glaucoma surgery [32-36]. These eyes respond to similar medical and surgical management and referred to as ciliary block glaucoma (CBG), reflecting the anatomic basis of the abnormality. These cases have resulted in a re-examination of the presumed pathophysiology of the condition as well as an attempt to redefine and expand the definition of MG to include all cases of ciliary block regardless of their etiology [37].

The ability to recognize the various forms of CBG and to institute appropriate treatment is essential if these eyes are to be saved. Ciliary block glaucoma is characterized by the misdirection of aqueous fluid into the vitreous cavity. The accumulating fluid acts as an enlarging space-occupying mass which pushes the anterior hyaloid, lens, and iris forward, thus flatten- ing the anterior chamber and causing the anterior angle to close. The fluid continues to accumulate without a channel of drainage and the pressure within the eye rises. The initiating sequence has not been fully elucidated and remains a matter of controversy. It has become apparent that several factors may be responsible for this pathological process/condition. Anterior movement of the lens with shallowing of the anterior chamber can usually be seen. The fellow eye may have normal depth of the anterior chamber. The relationship of the ciliary processes to the lens equator and anterior hyaloid membrane has been the focus of recent attempts to determine the inciting event [38]. It appears that the tips of the ciliary processes become misdirected and/or swollen and direct the flow of aqueous in a posterior direction. This theory is supported by the clinical observation that the ciliary processes may be seen to touch the lens through iris coloboma in a number

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of cases of CBG. These tips may be rotated anteriorly with their tips flattened against the lens [25, 29]. Some investigators have suggested that inflammation of the ciliary processes may alter their anatomic relationship with the lens sufficiently to incite aqueous misdirection [32-34].

Patients usually present with a red and painful eye with recent onset of blurred vision. Examination of these eyes may reveal variable chemosis, a shallow or flat anterior chamber, elevated intraocular pressure, corneal edema and decreased pupillary reactivity to light. Occasionally slit lamp examination of the vitreous shows clear zones within the vitreous gel thought to represent accumulations of aqueous fluid in this space.

Studies by Epstein et al. have demonstrated that although normal vitreous offers very little resistance to aqueous flow through its body, as pressure builds within the vitreous cavity the vitreous exhibits increased resistance to flow [39]. If this situation is present in the aqueous misdirection syndrome as fluid collects and pressure builds in the vitreous cavity the vitreous humor may increasingly inhibit the aqueous from escaping from this abnormal location. The vicious cycle prohibits the relief of the pressure build-up. He postulates that the increased pressure may somehow alter the composition of the vitreous by increasing its viscosity or by changing the anatomic position of the anterior hyaloid by pressing it against the pars plana, decreasing the available hyaloid surface area available for fluid flow, thereby occluding an area which otherwise allows fluid to flow freely. In a related paper Grant showed that decreasing the free surface area of the anterior hyaloid can significantly increase the resistance to outflow from the vitreous body [40].

Differential diagnosis

The differential diagnosis of CBG includes classic pupillary block glaucoma, choroidal separation, and suprachoroidal hemorrhage. Pupillary block may present with a very similar clinical picture of a red and painful eye, flat anterior chamber, and corneal edema. Pupillary block is far more common than CBG and must be ruled out. The key to the differential is the presence or absence of a patent peripheral iridectomy. If no iridectomy is present the differential may be very difficult.

Since pupillary block is relieved by a patent iridectomy a careful search for one must be made. If none is found or if some question exists as to the patency of one that is found, a laser iridectomy should be attempted. This serves two purposes, one of the diagnosis and one of the treatment. If the glaucoma and block are relieved by the creation of the iridectomy with forward flow of aqueous fluid the diagnosis of pupillary block is made and the appropriate therapy administered. If the patient does not respond to iridectomy then pupillary block is ruled out as the cause of elevated intraocular pressure, and further diagnostic evaluation is necessary.

In patients with choroidal separation the intraocular pressure is usually

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normal or low. This entity is commonly seen following filtration surgery or ocular trauma. The diagnosis is made by careful ophthalmoscopic examination where one sees elevation of the choroid during fundus examination or by B-scan ultrasonography. The treatment of this condition consists of drainage of the fluid through one or more sclerotomy sites. Commonly straw-colored fluid is drained during this procedure.

Suprachorodial hemorrhage is sometimes found after glaucoma surgery. The patient usually presents one to three days following surgery with normal to elevated intraocular pressure, a shallow or flat anterior chamber, and occasionally with pain. The suprachoroidal hemorrhage acts as a posterior enlarging mass, similar to this situation of malignant glaucoma, but this entity has more in common with choroidal separation, both in its diagnosis and therapy. The diagnosis is made by ophthalmoscopy or ultrasonography where one sees choroidal elevation. Classically the elevation is dark red in color which helps to differentiate it from separation of the choroid. The therapy, as for choroidal separation is drainage of the fluid by sclerotomy. These sites will drain dark red to black liquid blood and/or clots. On rare occasions the hemorrhage is located in an intrachoroidal space and no material drains from the sclerotomy sites. If this is the case the blood will resorb spontaneously with time [13].

Therapy

For many years, miotics were used in the treatment of malignant glaucoma with little to no success. In the 1950's carbonic anhydrase inhibitors and hyperosmotic agents were added to this regimen but without significant improvement in efficacy. In 1962 the first well known therapeutic trial of mydriatic-cycloplegic therapy was published in a landmark paper by Chand- ler & Grant [42]. This regimen was uniformly successful in the first eight patients who received it. This treatment works by relaxing the ciliary muscle, thus tightening the zonules, pulling the lens posteriorly against the

face of t h e anterior hyaloid and reestablishing a more normal anatomic orientation of the ciliary processes. Additionally by pulling the lens back away from the iris it diminishes any component of pupillary block if present. The success of this therapeutic modality highlighted the previous failure of miotics, which constrict the ciliary muscle, loosening the zonules and allowing the lens to move anteriorly, increasing the contact of the lens with the ciliary processes and increasing the amount of pupillary block. Since that time several case reports have demonstrated the initiation of miotic therapy as the cause of CBG in some patients [31,33, 43]. Continued use of mydriatic-cycloplegic also appears important as recurrence of the malignant condition has occurred when these agents are discontinued, and relieved upon reinstitution of them [44].

Some patients must be continued on mydriatic therapy chronically. If

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cycloplegic-mydriatic therapy does not relieve the CBG, current recom- mendations suggest the addition of carbonic anhydrase inhibitors, hyperosmotic agents, and topical beta-blockers [25]. It is believed that the hyperosmotic agents dehydrate the vitreous an-"d allow the lens to move posteriorly. Some investigators suggest that all of these agents be used once the diagnosis of CBG is made [13]. Chandler & Grant state that the above medical regimen will adequately treat 50% of the cases of CBG with reformation of the anterior chamber and lowering of the intraocular pressure within 5 days of initiating treatment [12].

Several investigators have advocated the use of the argon laser at this point if medical therapy is not successful in breaking the attack, provided that the ciliary processes are visible through an iris coloboma. Herschler reports success in 5 out of 6 of these patients. If the ciliary processes are visible he recommends direct treatment of two to four processes with the laser through a gonioscopy lens [44]. Several questions regarding the mechanism of this treatment were put forth in the editorial discussion of this paper [45]. These include: Does the laser alter the anterior hyaloid adjacent to the ciliary process? Does the heat of the laser rupture the adjacent anterior hyaloid membrane? Does it act via the lysis of zonules in the area of treatment? Do the additional few days of observation following laser treatment as recommended by the author allow the medications additional time in which to achieve effective results? These questions remain unanswered and further research into the mechanism of the laser's efficacy is needed.

The first attempts at surgical treatment for MG was intracapsular cataract extraction. This therapy highlighted the early focus on the lens in the pathogenesis of this disease. Although this treatment saved many eyes, Shaffer observed in 1954 that vitreous loss accompanied those cataract extractions that relieved the MG. And those cases in which the glaucoma was not relieved were not accompanied by vitreous loss [46]. This was a very significant step in the understanding of MG and shifted the focus toward the vitreous as the ocular structure to which therapy should be aimed.

In 1964 Chandler proposed a surgical technique involving puncture and aspiration of the vitreous without removal of the lens [47]. The technique he described involved a needle puncture of the anterior and posterior hyaloid membranes with aspiration of a small volume of the vitreous-aqueous fluid present behind the lens. This served two purposes (a) decompression of the eye and (b) formation of a channel to allow posteriorly trapped aqueous fluid back to the anterior chamber. Additionally the anterior chamber was reformed with an air bubble. Several modifications of the original procedure have been made since that time. Disruption of the hyaloid membranes and aspiration of the fluid using the technique of pars plana vitrectomy is now favored by some as the safest and most effective surgical modality [48, 48A1.

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Ectopia lentis

Ectopia lentis was first described by Berryat in 1749 in a young patient with both lenses in the anterior chamber. It is a condition in which the lens is displaced from its normal location within the pupillary axis. The extent of the displacement may vary, it may be minimal resulting from the fracture of only a few of the zonules with the lens remaining more or less in its normal position (subluxation), or the displacement may be more severe with rupture of all the zonules resulting in total dislocation of the lens.

Ectopia lentis has been extensively studied and a number of clinical entities have been described. These include isolated inherited forms (ectopia lentis and ectopia lentis et pupillae), inherited forms associated with systemic disorders (Marfan's Syndrome, Homocystinuria, and Weill- Marchesani Syndrome), an inherited form associated with progressive myopia, and dislocation secondary to trauma. Although the underlying pathophysiology may be different among these etiologies they all may cause glaucoma through similar common final pathways including pupillary block and phacolytic process.

Symptoms of this disorder are primarily complaints relating to changes in visual acuity. Minimal subluxation may be asymptomatic. Progressive disruption of the zonules allows the lens to assume a more spherical shape, resulting in increasing degrees of myopia. If enough zonules have broken to allow the lens to shift within the pupillary axis the patient may experience monocular diplopia, or quadropia if the condition is bilateral. The loss of zonular support may result in difficulties with accommodation and near vision. If the lens dislocates completely from the pupillary axis the patient becomes hyperopic secondary to a functionally aphakic optical condition. When glaucoma is caused by dislocation of the lens and pupillary block the patient experiences symptoms consistent with angle closure glaucoma, a red and painful eye with elevated intraocular pressure and decreased visual acuity, oftentimes accompanied by headache, nausea, and vomiting.

Signs of ectopia lentis include phacodonesis, subluxation of the lens (which may sometimes only be observed following dilation of the pupil), and iridodonesis. Forward movement of the lens may result in a shallowing of the anterior chamber either symmetrically or asymmetrically (eccentric to the pupillary axis). During an attack of glaucoma the anterior chamber angle is closed, the chamber is shallow and elevated intraocular pressure results in edema of the cornea. A difference in anterior chamber depth between the two eyes should raise the examiner's suspicion of an ectopic lens. Gonio- scopically the iris may be seen to assume the shape of a volcano with the pupil forming the central crater. This is the result of the anterior movement of the lens and increased contact with the middle third of the iris.

The simple form of ectopia lentis is inherited as an autosomal dominant trait [49, 50]. However, a few case reports have demonstrated a recessive pattern of inheritance, the latter occurring in families in which consanguinity

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has been documented [51]. The displacement of the lens is usually upward and temporal in this set of patients.

Ectopia lentis et Pupillae is a similar disorder which in addition to lens subluxation patients also express displacement of the pupil. The displacement of the lens is reported to be in the direction opposite the displacement of the pupil. This condition is quite rare and inheritance has been observed to be autosomal recessive, usually in families in which consanguinity has been documented or suspected [52-54], as in the case with simple ectopia lentis. In a few families certain offspring have demonstrated simple ectopia lentis without any observable abnormality of the iris, this may represent an incomplete expression of the genotype. Ectopia lentis et Pupillae is a disorder affecting the whole eye, associated findings include axial myopia, retinal detachment, cataract, abnormal iris illumination, persistent pupillary membranes, iridohyaloid adhesions, and prominent iris processes in the anterior chamber angle [54].

The glaucoma seen in these two subsets of patients is usually the result of a pupillary block mechanism with forward movement of the lens and increasing iridolenticular contact. This results in obstruction of flow of aqueous humor to the anterior chamber. Pressure builds in the posterior chamber and causes an angle closure glaucoma. The treatment for angle closure secondary to pupillary block is discussed elsewhere in this paper. Occasionally the lens may wedge itself into the pupillary axis and the vitreous humor may come forward to obstruct the remaining space in the pupil causing a vitreo-lenticular pupillary block, resulting in angle closure glaucoma by similar mechanism.

It is possible for the lens to dislocate posteriorly into the vitreous cavity. If this occurs and the lens is hypermature, or over the course of time becomes cataractous, lens proteins may leak through a defect in the lens capsule and a phacolytic glaucoma may result. The anterior chamber will have a dense cell and flare, with open anterior chamber angle, elevated intraocular pressure and corneal edema. This diagnosis is a difficult one to make and must be kept in mind in patients with dislocated lens and severe intraocular inflammation and glaucoma. Diagnosis may be facilitated by paracentesis aspiration of aqueous humor showing the typical enlarged macrophage of the phacolytic response [55]. Alternatively analysis of the fluid may demonstrate heavy molecular weight proteins specific to the lens. The treatment is the same as for other presentations of phacolytic glaucoma requiring first medical management to decrease inflammation and intraocular pressure, and then removal of the lens.

In the genetic spontaneous late subluxation of the lens (GSLSL) syndrome patients often present with symptoms of progressive myopia or intermittent acute angle closure. This entity was first described by Vogt in 1905 in which a pedigree of 16 of 46 family members were affected with lens luxation without any known cause and onset of symptoms between the ages of 20 to 70. Malbran et al. describes two families with this condition. In both

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families an autosomal dominant mode of inheritance is demonstrated. Progressive pupillary block in these patients causes angle closure glaucoma. Each of the affected patients in this series had intracapsular cataract extraction with resolution of their glaucoma. Scanning electron microscopy of the zonules in two of these patients showed them to be fragmented, disrupted and irregular. The lenses in the patients were essentially normal. The changing refractive error in affected family members is secondary to forward movement of the lens and increasing spherical shape and not from axial elongation of the eyes. Iridectomy may alleviate the pupillary block and the onset of glaucoma in these patients, however the lens continues to migrate anteriorly making cataract extraction eventually necessary in all of them [56].

Another form of acute angle closure glaucoma with transient myopia secondary to swelling of the lens has also been described. These patients have normal zonular apparatus and do not exhibit subluxation of the lens and so they will not be discussed here. This condition will be described in the section on pupillary block glaucoma.

Ectopia lentis is associated with a number of systemic disorders which include Marfan's Syndrome, Homocystinuria, Weill-Marchesani Syndrome, Hyperlysinemia, and Sulfite Oxidase deficiency. The biochemical defects in these conditions result in defective zonular apparatus and subluxation/ dislocation of the lens often occurs.

Marfan's Syndrome is inherited as an autosomal dominant condition with variable expression. The prevalence is 1 in 15,000 births and shows no racial or ethnic predilection [57]. It is associated with musculoskeletal (arachnodactyly), cardiovascular and ocular abnormalities and is caused by a defect in the cross linking of collagen resulting in subnormal connective tissue tensile strength. Recently, some patients with the syndrome were found to a point mutation in the fibrillin type I gene [58]. Ocular abnormalities include enophthalmos, ectopia lentis, reduced visual acuity usually moderate to high myopia (which if uncorrected often results in amblyopia), retinal detachments and various anterior chamber angle anomalies which

�9 consist o f bridging pectinate strands, inconspicuous Schwalbe's line, and irregular fraying of the iris root [49, 59, 60].

Ectopia lentis occurs in 50-80% of patients with Marfan's [51]. It is usually bilateral and symmetric with displacement occurring in the superior temporal direction. The glaucoma in these patients results from dislocation of the lens with lenticulopupillary of vitreopupillary block causing closure of the anterior chamber. Some authors believe that the anterior chamber abnormalities in these patients may cause poor outflow facility, the extent of this contribution is not known [51,52]. Cross & Jensen in their study of 142 patients with Marfan's failed to observe any significant increase in open angle glaucoma compared with the normal population [60].

Homocystinuria is an inborn error in the metabolism of the sulfur containing amino acids caused by a deficiency of the enzyme cystathione

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beta synthetase. It is inherited in an autosomal recessive manner [59, 61]. Screening of newborn infants indicates a minimal prevalence of 1 in 200,000 [57]. Like Marfan's it is associated with musculoskeletal (arachnodactyly), cardiovascular and ocular anomalies. In addition it is associated with mental retardation in nearly 50% of those affected [54, 63]. Patients with homocystinuria also suffer from thrombotic vascular occlusions, thought to be secondary to increased platelet adhesiveness. Because of the phenotypic similarities between these two diseases, many early studies of ectopia lentis combined these two populations of patients as it was not appreciated that two separate biochemical pathways were affected [60]. A simple test of the urine, the sodium nitroprusside test is now available to diagnose patients with homocystinuria [54, 61].

Ocular manifestations of this disorder include lens subluxation which is classically inferiorly or inferonasally. Lens subluxation is found in approximately 80-90% of these patients [49, 60]. Myopia is also common and lecticular myopia may be the first sign of lens dislocation. Others have observed retinal detachment, microphthalmos and albinism in patients with homocystinuria, though whether these represent true associations or random associations is a matter of controversy.

Patients with Weill-Marchesani syndrome have morphologic characteris- tics that are dissimilar to patients with Marfan's syndrome or homocystinuria. Affected individuals display brachydactyly and are typically of Short stature with stubby spade-like hands which exhibit marked limitation of mobility in contradistinction to the hyperflexability observed in the other two diseases. This syndrome may be inherited in an autosomal dominant or recessive pattern. Consanguinity is often observed [62-64].

The prominent ocular manifestation is microspherophakia which is consid- ered a prerequisite to the diagnosis [62]. Sagittal diameters have been measured to be 25% greater than normal, and mass of the lens is reduced by 20-25% [64]. The pathological lenticutar shape may be progressive and is responsible for the significant myopia found in these patients [62]. Clinically the zonules in these patients appear abnormally elongated and lax and allow the lens to move anteriorly, resulting in pupillary block and in angle closure glaucoma. Lens dislocation is common and occurs at an early age in these patients [65]. Anomalies of the anterior chamber are found in these patients but are not felt to be related to the development of glaucoma [65].

Treatment

Patients with Marfan's Syndrome who have partial luxation of the lens within the pupillary space that does not cause significant visual impairment or pupillary block glaucoma should be followed conservatively. Partial luxation within the pupillary space producing pupillary block can be treated with laser peripheral iridectomy. If the lens becomes partially luxated within the pupil and produces visual distortion because of the abnormal position of

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the lens then iris photocoagulation to enlarge the phakic zone may be attempted. Total anterior dislocation of the lens requires removal. If the lens becomes dislocated into the vitreous cavity and is not hypermature, producing inflammation, or glaucoma, then it should remain in situ; if any of these do occur removal of the lens is indicated [66]. A similar approach may be taken in patients with homocystinuria who exhibit lens dislocation and acute angle closure glaucoma. However, even with recurrent attacks of angle closure glaucoma a more conservative approach is warranted in these patients because of their predisposition to thrombotic vascular occlusion including pulmonary embolism and cerebral vascular accidents [67]. The physician must have increased tolerance for these glaucomatous attacks before surgical removal of the lens with its inherent risks is undertaken in these patients. Several investigators have suggested various anticoagulation regimens in an attempt to protect against these fatal complications should lens extraction be necessary.

In the Weill Marchesani syndrome since the zonules are generally still intact and the subluxation of the lens is into the pupillary space, the situation may be managed with mydriatics which cause the relaxation of the ciliary apparatus resulting in increased tension on the zonules, pulling the lens back to its normal position. Miotics are contraindicated in this condition as they cause relaxation of the zonular apparatus and may thereby enhance pupillary block. Prophylactic laser peripheral iridectomy is indicated in these patients to prevent angle closure glaucoma secondary to pupillary block. Repeated attacks of acute angle closure glaucoma in these patients may result in the formation of peripheral anterior synechiae, resulting in a picture of chronic angle closure glaucoma. If this occurs the patient may require filtering surgery in the affected eye to control the intraocular pressure [12].

Free lens material

Three distinct clinical entities are recognized which cause elevation of intraocular pressure by the liberation of lenticular material into the eye. They are phacolytic glaucoma, phacoanaphylactic glaucoma and lens particle glaucoma. Each has a specific clinical presentation and displays different pathophysiologic mechanisms which cause increased intraocular pressure. However, considerable overlap may occur clinically as more than one of them may be present in the same eye, making accurate diagnosis difficult at times. The ability to take a careful history and a thorough understanding of these conditions will facilitate diagnosis and appropriate management of these patients.

Phacolytic glaucoma

Our understanding of phacolytic glaucoma has undergone considerable evolution in the past two decades. This potentially devastating condition was

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much more prevalent at one time, but is rarely seen today. It is the result of the leakage of lenticular material from hypermature or Morgagnian cataracts through intact lens capsule. Recent improvements in the tech- niques of cataract extraction have encouraged earlier removal of cataractous lenses so that today, fewer lenses progress to the hypermature state.

Individuals (usually elderly patients) classically present with a red and painful eye caused by the acute rise in intraocular pressure [68]. The disease is nearly always unilateral. Systemic signs such as headache, nausea and vomiting are sometimes present, similar to those seen in acute angle closure glaucoma. Patients often describe a gradual decline of visual acuity in the affected eye, reflecting the slow maturation process of the cataract. Visual acuity at the time of presentation is a poor indicator of visual potential in this condition. Eyes with poor light perception without projection often obtain good acuity after treatment. This is because the lens is believed to act as a diffusion screen in these patients causing considerable scattering of light [691.

On slit lamp examination one sees a mature or hypermature cataract, corneal edema secondary to elevated intraocular pressure, intense cell and flare and an open anterior chamber angle. The aqueous cells are larger than the lymphocytes typically seen in cases of uveitis. They have been demonstrated to be macrophages swollen with eosinophilic lenticular material which they have engulfed [70]. Use of the millipore filter as described by Goldberg may facilitate identification of these cells [55]. One may observe soft white patches on the lens capsule of these patients. These patches are aggregates of macrophages attracted to the site of leaking lens material and may serve as a valuable clinical sign in the differential diagnosis [68]. Keratitic precipitates are not seen in these patients. In one study, 25% of patients were observed to also have angle recession, the significance of this finding is not known [71]. The fellow eye is usually observed to have a mature cataract and a deep anterior chamber.

The classical teaching regarding phacolytic glaucoma was that the macrophages were responsible for the elevation of intraocular pressure by blocking the flow of aqueous fluid to the trabecular meshwork [68, 69]. Support for this theory came from the repeated observation of these cells in and around the meshwork in histologic specimens. Research by Epstein et al. has had a profound effect upon our understanding of this condition [72]. He analyzed aqueous fluid from patients with mature or hypermature cataracts and the presumed diagnosis of phacolytic glaucoma who were undergoing cataract extraction. He identified extremely high levels of soluble heavy molecular weight (HMW) proteins in these eyes compared with control subjects. In previous experiments on cadaver eyes he had shown these proteins to cause decreased outflow facility by blocking the trabecular meshwork, resulting in elevated intraocular pressure [73]. Several eyes with suspected phacolytic glaucoma had extreme elevations of intraocular pressure despite a paucity of macrophages, suggesting that the role of the cells

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were less important in the pathogenesis than previously believed. Yanoff & Scheie observed that although phacolytic glaucoma displays a nearly pure macrophagic response, that in pediatric patients with congenital cataracts large numbers of macrophages may be seen after these lenses are needled and aspirated, without causing elevation of intraocular pressure. Similarly in an animal model, Dueker instilled macrophages that had engulfed oil into the anterior chamber and did not observe any significant elevation of intraocular pressure [12].

HMW proteins are present in much higher concentrations in cataractous lenses than in normal lenses, this difference is especially marked in patients over 75 years old [74]. The soluble HMW proteins are believed to leak through an intact lens capsule and clog the trabecular meshwork by nature of their large size. It is now thought that the macrophages observed in the trabecular meshwork of patients with phacolytic glaucoma are acting as scavengers, attempting to remove the lenticular material and reestablish normal aqueous outflow. These studies have greatly de-emphasized the contribution of the macrophages in the pathogenesis of this condition.

The goal of therapy is to remove the source of the HMW proteins from the eye. After attempts are made to lower intraocular pressure medically, cataract extraction is indicated. In the past intracapsular capsular extraction (ICCE) with copious irrigation of the anterior chamber was uniformly advocated [68]. Recently, investigators have shown that extra capsular cataract extraction (ECCE) with posterior chamber intraocular lens (PCIOL) implantation to be equally efficacious in the treatment of these patients [75]. The indicated method of cataract extraction therefore depends on the preference of the surgeon given the individual clinical situation.

Lens particle glaucoma

Occasionally as increase in intraocular pressure is seen following ECCE, penetrating lens injury or Nd : YAG posterior capsulotomy. It is thought that the obstruction to aqueous flow in these cases is caused by a mechanical blockage of the trabecular meshwork by 'normal' lens particles [70]. The severity of the glaucoma is usually related to the amount of free cortical material seen in the aqueous fluid [13]. Epstein et al. has shown that small amounts of particulate homogenate of the lens are capable of causing severe decrease in aqueous outflow [73]. This is the entity known as lens particle glaucoma.

The diagnosis is usually made in postoperative or post traumatic patients who display considerable free lens material in the anterior chamber associated with elevated intraocular pressure. Paracentesis of the aqueous may show fragments of lens particles and swollen macrophages. The macrophages are not necessary for diagnosis and as in the case with phacolytic glaucoma their presence probably reflects their role as scavengers of debris in the body. Initial therapy includes topical beta blockers and carbonic

333

anhydrase inhibitors to lower the intraocular pressure and cycloplegics to dilate the pupil. Miotics should be avoided as these patients often form synechiae. Topical steroids are used to reduce inflammation. If glaucoma and inflammation persist despite attempts at medical management, then removal of remaining cortical material should be undertaken without delay. Potential consequences of allowing the inflammation to persist include chronic glaucoma secondary to peripheral anterior synechiae (PAS), formation of dense pupillary membrane which may lead to pupillary block, and cystic degeneration of the macula, resulting in loss of central vision [12].

Phacoanaphylactic glaucoma

Phacoanaphylactic glaucoma is a severe inflammatory reaction directed against lenticular antigens. It may cause elevation of intraocular pressure when the trabecular meshwork is affected by the inflammatory processes, or becomes obstructed by inflammatory cells. Alternatively, formation of synechiae may result in pupillary block. In some cases hypotony is seen with hyposecretion by the ciliary body secondary to persistent inflammation.

Phacoanaphylaxis is an unusual condition which is rarely diagnosed in the living eye [74, 76]. Classically it is seen following operative or other trauma to the lens capsule in a patient previously sensitized to lens antigens. These proteins usually maintain an immunologically privileged site within the lens capsule. When exposed to the circulation they may be recognized as "foreign" by the individual's immune system and incite an inflammatory response. The glaucoma observed in these patients may be the result of a combination of mechanisms, as lens particles and phacolytic processes may be observed concurrently in involved eyes. Why some patients develop phacoanaphylaxis while others do not is not understood at the present time.

The onset of inflammation is usually 24 hours to 14 days after damage to the lens capsule [77, 78], However, it has been observed up to one year after cataract extraction, and up to fifty-nine years following ocular injury [76]. The intense reaction is manifest clinically as lid edema, chemosis, injection of the conjunctiva, corneal edema, heavy chamber anterior cell flare, posterior synechiae, and mutton fat keratitic precipitates [75]. Sterile hypo- pyon is common. The vitreous, retina and choroid are classically not involved, however in a large series by Thach et al. the choroid was involved in 76% of eases [76].

Phacoanaphylaxis is a unilateral zonal inflammation centered around the lens. Pathologically the sine qua non of this condition is a granulomatous reaction with polymorphonuclear, epitheliod, and giant cells surrounding degenerating lenticular material. The term phacoanaphylaxis is somewhat misleading as the condition is not a true allergy to lens proteins. Although eosinophils may be seen, IgE has not been found to cause the inflammatory reaction. Marak et al has developed an experimental animal model which is

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histologically identical to the inflammation found in the human eyes. The mechanism responsible appears to be an arthus-type immune complex reaction mediated by IgG and the complement system [76,79]. Several authors believe that an adjuvant such as the staphylococcal antigen, P. acnes antigen or vitreous humor may play an important role in the process [76, 78, 80].

In the past many eyes with this condition were believed to have sympathetic ophthalmia and were enucleated [81, 82]. Eyes with the latter condition exhibit an autoimmune reaction to uveal tissue and the inflammation extends to all layers of the eye. It may be difficult to differentiate between these two entities, and both may be seen in the same eye. However, phacoanaphylactic reactions are limited to the anterior segment of the eye and these patients usually retain good visual potential despite the severity of the inflammation.

Therapy is initially directed at controlling inflammation and lowering intraocular pressure by medical means. If this proves unsuccessful then surgical removal of the remaining lens material is indicated. In 1965 Riise was the first investigator to demonstrate that removal of cortical lens material in these patients may result in a striking resolution of the inflammation and surprisingly good post-operative visual acuity [83]. Since that publication others have shown that removal of the posterior capsule in patients with suspected phacoanaphylaxis following ECCE may result in resolution of persistent inflammation, presumably by removing residual cortical material, thereby eliminating the inciting stimulus [84, 85]. If cataract develops in the fellow eye, ICCE is indicated, as any residual lens proteins following ECCE would result in an accelerated course of inflammation in the second eye [75, 86].

Conclusions

The lens is capable of inducing glaucoma by a number of different mechanisms. The flow of aqueous fluid may be inhibited from reaching its normal outflow channels by (1) the pupillary block mechanism when an intumescent lens pushes against the iris, (2) aqueous misdirection when the ciliary processes alter their anatomic relationship relative to the lens equator, and (3) when a subluxated lens enters the pupillary space and blocks the flow aqueous. Alternatively, lenticular material and the inflammatory cells that may react to it obstruct the trabecular meshwork. The ability to take a precise ocular history, exacting powers of observation, and a thorough understanding of the pathophysiology of these conditions is essential to make an accurate diagnosis and to institute appropriate treatment.

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Address for correspondence: Dr. Jonathan P. Ellant, MD, Department of Ophthalmology, Lenox Hill Hospital, 100 East 77th Street, New York, NY 10021, USA

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