Histopathology

Histopathologic examination of eyes with neovascular glaucoma, regardless of etiology, reveals that the new vessels arise from the microvascular bed (capillaries or venules) in the iris and ciliary body. The new vessels appear first as endothelial buds from capillaries of the minor arterial circle; new buds may then appear from vessels anywhere in the iris. Changes occur within the microstructure of the endothelial cells and in the extracellular matrix surrounding them. The buds then become vascular tufts not unlike tiny glomeruli. The new vessels have thin walls with irregular endothelia and pericytes. The junctions between the endothelial cells appear to be open, which accounts for their leakiness on angiography.

With time, a clinically invisible fibrous membrane develops along the vessels. The membrane contains myofibroblasts that have contractile properties. The contraction of the myofibroblasts pulls the posterior pigment layer of the iris epithelium anteriorly, producing ectropion uveae, and pulls the peripheral iris into the chamber angle, producing PAS. There is one report that new vessels developing after central retinal vein occlusion are larger in diameter and more irregular than those associated with diabetes mellitus.

Despite the variety of underlying diseases, the clinical appearance and histopathologic findings of neovascular glaucoma do not vary greatly. However, there may be some variation in the acuteness of the onset and the rate of progression, depending on the underlying condition. For example, neovascular glaucoma associated with central retinal vein occlusion may progress more rapidly than that associated with diabetes mellitus, and often depends on the predominance of either an ischemic or hemorrhagic retinal insult.

Pathogenesis

The pathogenesis of neovascular glaucoma is that retinal ischemia liberates angiogenic factors that diffuse forward and induce new vessel formation on the iris and in the angle. Capillary occlusion or ischemia appears to be the initiating event in this process, which seems to be similar to the production of an angiogenic factor or factors by solid tumors. Angiogenic substances (or substance) from tumors implanted in the eye but at a distance from the retina and iris have been shown to cause neovascularization of both. Angiogenic factors are produced by hypoxic retinal tissue in vitro . Angiogenic factors have been detected in mammalian retina and in aqueous humor samples from patients with neovascular glaucoma. In laboratory experiments, this factor (or factors) is capable of stimulating capillary endothelial proliferation, corneal neovascularization, and retinal neovascularization. Vasoproliferative factors have been detected in increased amounts in the eyes of both animal models and patients with neovascular glaucoma. And most recently is the impressive regression of new vessels induced by molecular-specific antiangiogenic factors, such as bevacizumab.

Historically, a number of substances have been proposed as the angiogenic factor. Some of the families of compounds having angiogenic activity include fibroblast growth factor, vascular endothelial growth factor (VEGF), angiogenin, platelet-derived endothelial cell growth factor, transforming growth factor-α, transforming growth factor-β, and tumor necrosis factor-α. Vascular endothelial growth factor is thought to be a primary culprit. It is found in concentrations 40–100 times normal in the aqueous humor of patients with neovascular glaucoma. Tolentino and co-workers showed that intravitreal injection of VEGF can produce iris neovascularization and neovascular glaucoma in primates. Some consider that angiogenesis is most likely a process (not unlike the clotting or inflammatory cascades) involving several families of agents, including polypeptides, amines, lipids, and other low molecular weight compounds.

The above theory explains many observations about neovascular glaucoma. Diffusible molecules from the retina enter the anterior chamber through the pupil, with their highest concentration near this site. This may explain the initial appearance of rubeosis iridis at the pupillary margin. This mechanism also accounts for why rubeosis iridis and neovascular glaucoma are more common after cataract extraction with capsular disruption and after vitrectomy in eyes with vascular retinopathy. The lens and vitreous may serve as mechanical barriers to the diffusion of an angiogenic substance. Furthermore, the vitreous humor apparently also contains an endogenous inhibitor of angiogenesis. Finally, vitrectomy and cataract surgery cause inflammation, which may further serve as a stimulus to neovascularization. Lastly, this theory explains the efficacy of panretinal photocoagulation or retinal cryoablation in neovascular glaucoma, treatments which destroy ischemic retina that had been synthesizing the angiogenic factor(s). Aiello and co-workers have found a marked decrease in VEGF in the vitreous of patients after panretinal photocoagulation. These treatments may also liberate inhibitory factors that counteract the vasoproliferative stimulus.

Conditions and diseases commonly associated with neovascular glaucoma

Neovascular glaucoma is associated with a large number of diseases and conditions ( Box 16–1 ). As noted above, most of these conditions have some relation to either retinal or ocular ischemia or to chronic inflammation. In a large comprehensive survey, diabetes mellitus was associated with about one-third of the cases of neovascular glaucoma; central retinal vein occlusion with another third; and a variety of conditions with the last third – with carotid occlusive disease being the most common in the last group. The discussion here is limited to a few of the more common entities, such as central retinal vein occlusion and diabetes mellitus, from among a wide variety of predisposing conditions.

Clinical presentation

Neovascular glaucoma often presents with an acute onset of pain, tearing, redness, and blurred vision. In some cases, depending on the underlying disease, patients report diminished vision for weeks to months before the onset of the pain and redness. When first seen, an affected eye may have ciliary injection, a hazy cornea from epithelial edema, a deep anterior chamber with moderate flare, a hyphema, a small pupil, and new vessels on the iris and in the angle. The first sign of rubeosis iridis is increased permeability of the blood vessels at the pupillary margin as detected by fluorescein angiography or fluorophotometry. Clinically the new vessels are first detected as small tufts at the pupillary margin. Occasionally new vessels are seen first in the angle if the tufts near the pupil are obscured by dark iris pigment ( Fig. 16–4A ). The neovascularization progresses over the iris surface and into the angle. The new vessels extend from the iris root across the ciliary body and scleral spur, where they arborize over the trabecular meshwork ( Fig. 16–4B ). At times it may be difficult to distinguish new vessels from normal iris vessels, especially in inflamed eyes. Normal iris vessels have a uniform size and a radial course, and they do not branch within the iris. In contrast, new vessels have an irregular size and an irregular course, and they branch frequently. New vessels also lie on the iris surface rather than in the stroma as normal vessels do.

Stages of neovascular glaucoma. (A) Pre-glaucoma stage with new vessels appearing at pupillary margin and in angle. (B) Open-angle glaucoma stage with new vessels spreading and fibrovascular tissue covering angle. (C) Heavy neovascularization and extensive peripheral anterior synechiae. (D) Regression stage with angle sealed and vessels less visible.

Modified from Hoskins HD Jr: Trans Am Acad Ophthalmol Otolaryngol 78:330, 1974.

When the fibrovascular membrane covers a substantial portion of the trabecular meshwork, outflow facility falls and IOP rises. With time, the membrane pulls the peripheral iris up into the angle ( Fig. 16–4C ). The rate at which this occurs is quite variable, ranging from days to years.

In the late stages of neovascular glaucoma the eye is painful with bullous keratopathy, a sealed angle, and intractable glaucoma. Traction from the fibrovascular membrane lifts the iris anteriorly, gives the stroma a compacted appearance, and produces ectropion uveae and a fixed, dilated pupil. At this stage, the new vessels may be much less visible, especially those in the angle ( Fig. 16–4D ).

Treatment

Historically, eyes with neovascular glaucoma had a poor prognosis, and enucleation for chronic pain was a frequent outcome. This dismal picture has changed remarkably over the past several decades, and in many instances neovascular glaucoma can be prevented or treated satisfactorily in terms of patient comfort, although restoration of visual function is uncommon.

Despite recent improvements in therapy, it is always far more effective to prevent neovascular glaucoma than to treat the disease once it is established. We have already mentioned the use of prophylactic panretinal photocoagulation (or retinal cryoablation) to deter neovascular glaucoma following ischemic central retinal vein occlusion. In similar fashion, photocoagulation can prevent neovascular glaucoma in eyes with proliferative diabetic retinopathy or non-proliferative retinopathy and large areas of capillary non-perfusion. Immediate panretinal photocoagulation may also prevent rubeosis iridis from progressing to neovascular glaucoma.

When a patient is seen with an acute episode of neovascular glaucoma, including markedly elevated IOP, the initial treatment consists of maximal IOP-reduction medical therapy, atropine for relief and to maximally dilate the pupil before iris mobility is lost, and corticosteroid. In this situation, miotic agents, prostaglandins, and adrenaline (epinephrine) are usually ineffective in lowering IOP, and may exacerbate pain and conjunctival injection. In most cases it is important to proceed rapidly with panretinal photocoagulation or retinal cryoablation to prevent total angle closure. Following this treatment, new vessels in the angle begin to regress within a few days to a few weeks. Depending on the extent of the PAS, the retinal treatment may abort the glaucoma, or leave a stable form of residual angle closure that may be responsive to medical therapy or surgery.

If extensive PAS are present after retinal ablation, and if IOP is not controlled by medical treatment, the clinician’s choice of therapy is usually based on the visual potential of the eye. If the eye has good visual potential, and if the neovascular membrane has regressed, filtering surgery can be successful, especially when augmented with antimetabolites. Wet field cautery or underwater diathermy to the sclera and iris may be useful to reduce intraoperative bleeding; but particularly helpful is preoperative intravitreal bevacizimab. Postoperatively, these eyes are often inflamed and require extensive topical, periocular, and systemic corticosteroid treatment.

Other authorities believe that there is a high failure rate of standard filtering surgery in eyes with neovascular glaucoma, even after the angiogenic stimulus has been reduced or eliminated, and despite antimetabolite agents. Today, many clinicians attempt to control the glaucoma with some type of posterior glaucoma drainage device. Glaucoma drainage implants appear to be successful in controlling pressures and preserving vision in approximately two-thirds of patients with neovascular glaucoma, dramatically reducing the need for enucleation in these otherwise doomed eyes. In aphakic eyes it is possible to implant the tube through the pars plana, so long as the anterior vitreal skirt has been removed by pars palna vitrectomy.

There are a number of therapeutic options for eyes with neovascular glaucoma and poor visual potential. Eyes with limited or no vision can often be made comfortable using cycloplegic agents and topical corticosteroids regardless of the IOP. Cyclodestructive procedures may be appropriate if the patient is too infirm for surgery, has too little visual potential to procede with filtration or tube surgery, or requires immediate pain relief. The history of attempting to reduce aqueous production by means of ciliary destruction is a long one.

Cyclocryotherapy often reduces IOP and makes patients more comfortable after an initial period of pain lasting 1–7 days, but this treatment is less effective in maintaining vision. Cyclocryotherapy is usually applied at −60°C to −80°C, using a large-tip probe with its anterior edge 2.5 mm posterior to the limbus. Six to eight 60–second freezes are placed over half of the circumference of the ciliary body. Frequent complications of this treatment include iridocyclitis, hypotony, pain, cataract, and phthisis bulbi. If cyclocryotherapy fails to reduce IOP, the treatment can be repeated over the same quadrants of the ciliary body and extended slightly. At least one-quarter of the ciliary body should remain untouched to reduce the incidence of phthisis bulbi. In the past, cyclodiathermy was used for the same purpose as cyclocryotherapy. Cyclodiathermy was largely abandoned and replaced by cryotherapy, which had a higher rate of success and a lower rate of complications. More recently, cyclocryotherapy itself has been replaced by either trans-scleral laser cyclophotocoagulation or endocyclophotocoagulation. One can expect approximately 65% success after 1 year in controlling pressures and pain with this modality. The results seem comparable with those achieved with posterior glaucoma drainage device implantation. In our hands, diode laser cyclodestruction with a contact delivery probe is a relatively safe and effective procedure for patients with poor vision or poor visual prognosis and for those for whom a glaucoma drainage device operation may be inadvisable (e.g., previous encircling band, poor physical condition). Retrobulbar alcohol injections and enucleation are appropriate treatments for eyes either with no useful vision or with intractable pain that does not respond to medical therapy and ciliodestructive procedures.

Some have advocated direct laser treatment to new vessels in the angle, a technique referred to as goniophotocoagulation, if neovascularization of the iris is encountered before PAS have formed. Low-energy argon laser treatments (0.2 seconds, 50–100 μm, 100–200 mW) are applied to the neovascular tufts as they cross the scleral spur. The laser therapy often must be repeated because these vessels may re-open minutes to days after treatment. Although goniophotocoagulation is inadequate treatment for neovascular glaucoma by itself, it may be a useful adjunct to panretinal photocoagulation in certain situations. For example, goniophotocoagulation can reduce angle neovascularization and synechia formation temporarily while panretinal photocoagulation takes effect and reduces the angiogenic stimulus. Finally, goniophotocoagulation can be applied when full panretinal photocoagulation is not totally successful in reducing the angiogenic stimulus. Its efficacy, however, is perhaps less than that of intravitreal angiogenic inhibitors; both modalities, however, may provide only temporary relief of weeks to months.

In neovascular glaucoma eyes secondary to central retinal vein occlusion, clinicians recommend intravitreal bevacizumab (1.25 mg/0.05 ml) (Avastin) to be administered through the pars plana 24–78 hours preceding surgery, with near total regression of iris neovascularization within 48 hours and some IOP lowering, an effect lasting for some weeks. This rapid regression of new vessels allows both for panretinal photocoagulation and glaucoma surgery with reduced risk of bleeding. Similarly focal laser or intraocular surgery can be enhanced with temporary regression of new vessels by such intervention. When used with combined surgical approaches such as pars plana vitrectomy with panretinal endolaser and filtration surgery, the outlook for greater surgical success in treating neovascular glaucoma in the short-to-medium term appears brighter.

Histopathology

Histopathologic examination of eyes affected by the ICE syndrome reveals a thin, abnormal corneal endothelium and Descemet’s membrane separated by a thick accumulation of collagen. These tissues form a multilayered membrane that covers the angle and extends onto the anterior surface of the iris. The endothelial cells develop the epithelial-like characteristics of desmosomes, microvilli, tonofilaments (contractile elements), and proliferation – none of which occur in normal corneal endothelium. Most authorities believe this to be a metaplasia of endothelium into cells with epithelial characteristics, from an unknown trigger. These histopathologic changes are manifest on clinical examination by a ‘beaten silver’ appearance to the endothelium on slit-lamp examination; a loss of the normal, regular endothelial mosaic on specular reflection; and alterations in the size and shape of endothelial cells on specular microscopy. The size and shape of endothelial cells show great variation – some may be necrotic, and the findings are often patchy in the early stages of the condition. Even with the variation in clinical presentation, the endothelial findings are usually there if looked for carefully enough.

Pathogenesis

The most commonly accepted theory on the pathogenesis of the ICE syndrome proposes that the fundamental defect is in the corneal endothelium, whose dysfunction results in corneal edema. Furthermore, the corneal endothelium in this condition elaborates a membrane which causes a secondary angle closure. When the membrane contracts, it forms PAS leading to glaucoma, as well as iris defects such as corectopia, ‘stretch holes’, and iris nodules. Ischemia may be a secondary phenomenon producing ‘melt holes.’ At present we do not understand what causes the corneal endothelium to behave in this unusual manner. A few investigators postulate that there is an abnormal proliferation of neural crest cells or a fetal crest of epithelial cells. Other authorities suggest the endothelium proliferates because of inflammation. Electron micrographic, immunohistochemical, and serologic studies have suggested herpes simplex virus and, in another laboratory, Epstein-Barr virus. The viral theory is attractive and might explain the unilaterality of this syndrome in the vast majority of patients. In the past it was proposed that the ICE syndrome was a primary iris defect or that the disease occurred because of vascular insufficiency. These latter theories no longer seem tenable.

Clinical presentation

The PAS are more extensive in the quadrant toward which the pupil is displaced. The iris in the opposite quadrant has thinner stroma and full-thickness holes in some cases. In the Cogan-Reese syndrome, pigmented lesions project anteriorly from the iris surface and are surrounded by the multilayered membrane. The nodules are actually small portions of iris stroma that have been pinched off by the membrane.

Within the spectrum of the ICE syndrome there are three well-characterized clinical entities – progressive iris atrophy, Chandler’s syndrome, and Cogan-Reese syndrome – as well as a variety of intermediate forms. All of the variants of this syndrome appear in early to mid adult life, occur in whites more often than blacks, and affect women more commonly than men. The patients usually are seen after noticing a change in the appearance of their iris or pupil, a disturbance in their vision, or mild ocular discomfort. Although there are a few reports of familial cases, in most individuals the medical and family histories are unrevealing. The ICE syndrome almost always involves one eye, although the fellow eye may have subclinical abnormalities of the iris or corneal endothelium. Furthermore, there have been a few well-documented reports of individuals with bilateral involvement. Some degree of corneal endothelial abnormality is usually seen on slit-lamp examination in most patients with abnormal specular microscopy in all.

Progressive (essential) iris atrophy

In progressive iris atrophy (known as essential iris atrophy in the past) the clinical picture is dominated by corectopia and progressive dissolution of the iris ( Fig. 16–6 ). The iris dissolution begins as a patchy disappearance of the stroma and progresses to full-thickness holes ( Fig. 16–7 ). Some of the holes occur in quadrants away from the direction of pupillary displacement and are thought to be caused by traction (‘stretch holes’). Other holes occur without corectopia and are ischemic in nature (‘melt holes’), as demonstrated on fluorescein angiography of the iris. Broad patchy PAS form attachments anterior to Schwalbe’s line. The synechiae lift the iris off the surface of the lens, and also produce ectopion uveae and corectopia. Depending on the distribution of the synechiae, the pupil can be displaced to one side or pulled into a pear, oval, or slit shape. As the PAS become more extensive, IOP rises. The severity of the glaucoma is usually related to the extent of the synechiae. On occasion, elevated IOP is noted despite open angles; in this situation the membrane has covered the angle but not yet contracted to form permanent adhesions. The corneal endothelium may appear normal but more often has the appearance of tiny guttata. The cornea may become edematous when IOP is elevated.

(A) Early essential iris atrophy. (B) Goniophotograph of characteristic peripheral anterior synechia associated with iridocorneal endothelial syndrome.

Advanced essential iris atrophy with polycoria.

Treatment

The treatment of the ICE syndrome is as variable as the clinical picture. If corneal edema produces pain or reduced vision, the patient may be helped by hypertonic solutions or soft contact lenses. In many cases corneal edema is improved if IOP is reduced by medical or surgical therapy. Some patients with the ICE syndrome eventually require penetrating keratoplasty.

Glaucoma is initially treated with the full range of medical therapy. Laser trabeculoplasty offers no help in this condition because most of the angle is covered by a membrane or sealed with synechiae. Short-term success has been reported with a goniotomy procedure. But as the entire angle is progressively covered by a membrane or sealed by synechiae, medical therapy or angle surgery eventually fail because of relentless angle closure. Filtering surgery or glaucoma drainage devices are often required to control glaucoma in patients with the ICE syndrome. However, clinicians should be aware that functioning filtering blebs often fail after 2–5 years, perhaps related to proliferation of a membrane over the internal opening of the sclerostomy, despite the use of adjunctive antimetabolite therapy. In such cases, some would attempt a repeat trabeculectomy with mitomycin application or tube operation. In most cases, corneal edema clears after successful filtering surgery; in other cases, edema persists, presumably because of corneal endothelial dysfunction. At one time it was proposed that eyes with the ICE syndrome undergo a wide basal iridectomy to prevent total closure of the angle by PAS. This approach has not proved to be useful. Ultimately, the discovery of the stimulus to epithelialization of the corneal endothelium will lead to inhibitors, and possibly prevent this difficult angle-closure disease.

Histopathology

Histopathologic study of eyes from individuals with posterior polymorphous dystrophy reveals a thin Descemet’s membrane covered by multiple layers of collagen. This is lined by a layer of cells that various investigators have stated resembles endothelium, epithelium, or fibroblasts. In some cases a membrane has been noted in the angle and on the anterior surface of the iris.

Pathogenesis

The cause of posterior polymorphous dystrophy remains controversial. Analogous to the ICE syndrome, some investigators postulate that a dysplastic corneal endothelium produces a basement membrane-like material that extends into the angle and onto the iris. When the membrane contracts, it causes iris atrophy, corectopia, and iridocorneal adhesions. Most authorities believe posterior polymorphous dystrophy is a developmental disorder; a few authorities have postulated that a viral infection, perhaps herpes simplex, causes metaplasia of the corneal endothelium. Perhaps several different stimuli can produce similar epithelialization of endothelium.

Clinical presentation

Although the clinical picture of posterior polymorphous dystrophy is quite variable, the most typical physical finding is a cluster or linear arrangement of vesicles in the posterior cornea surrounded by a gray haze. The deep corneal stroma and Descemet’s membrane may also have band-like thickenings, white patches, peau d’orange appearance, or excrescences that project into the anterior chamber. Posterior polymorphous dystrophy may also have associated corneal edema, iris atrophy, mild corectopia, and iridocorneal adhesions. Most cases of this syndrome are non-progressive, and the individuals affected maintain good vision throughout their lives. These eyes are often asymptomatic. The diagnosis is made on routine examination or because other members of the family have been affected.

A minority of the individuals with posterior polymorphous dystrophy develop progressive corneal changes including corneal edema. Glaucoma occurs in 10–15% of patients with this disorder. In some cases glaucoma occurs in eyes with iris atrophy, corectopia, and iridocorneal adhesions. However, in other cases glaucoma occurs in eyes with open angles and an anterior insertion of the iris into the ciliary body, which resembles congenital glaucoma.

The differential diagnosis of posterior polymorphous dystrophy includes Fuchs’ corneal dystrophy, congenital hereditary corneal dystrophy, Axenfeld’s syndrome or Rieger’s syndrome, and congenital glaucoma. These conditions should be distinguished readily by slit-lamp examination. The Haab’s striae of congenital glaucoma are thin areas surrounded by a thickened, retracted Descemet’s membrane. In contrast, the corneal involvement of posterior polymorphous dystrophy consists of thickened areas without breaks in Descemet’s membrane.

Treatment

Most cases of posterior polymorphous dystrophy require no treatment. If the cornea becomes edematous, the patient should be treated with hypertonic solutions, soft contact lenses, and penetrating keratoplasty as needed. The presence of iridocorneal adhesions is a risk factor for failure of keratoplasty. Eyes with glaucoma are treated with medication and then filtering surgery as necessary.

Pathophysiology

Epithelial downgrowth (also called epithelial ingrowth) occurs when an epithelial membrane enters an eye through a wound and then proliferates over the corneal endothelium, trabecular meshwork, anterior iris surface, and vitreous face ( Fig. 16–8 ). The epithelial membrane in the angle contracts, producing PAS and severe angle-closure glaucoma without pupillary block.

(A) Epithelialization of anterior chamber angle. (B) High-power view.

Courtesy of Ramesh C Tripathi, MD, PhD and Brenda J Tripathi, PhD, Chicago, Ill.

Cataract surgery is the most common cause of epithelial downgrowth. In the past it was estimated that this complication occurred in about 1 in 1000 ICCE cataract operations. A relatively recent review cites a 0.12% incidence decreasing to 0.08% in the decade of the 1980s. Furthermore, epithelial downgrowth was found in 8–26% of eyes enucleated for complications of cataract surgery. In recent years epithelial downgrowth has been encountered less commonly because of the wide adoption of microsurgery and better techniques of cataract extraction. Epithelial downgrowth has also been reported after penetrating keratoplasty, glaucoma surgery, penetrating trauma, and unsuccessful removal of epithelial cysts of the anterior segment.

In most cases the epithelium invades the eye through a fistula or a wound gape; fistulas have been detected in 23–50% of such eyes. It is also possible that epithelium can grow into a suture tract, or it can be introduced into an eye at the time of surgery or trauma. Epithelial downgrowth can occur after uncomplicated surgery but is more likely to occur if surgery is associated with hemorrhage, inflammation, vitreous loss, or incarcerated tissue. Other factors seem to be endothelial damage and stromal vascularization. In the past it was observed that epithelial downgrowth occurred more frequently when cataract surgery was performed with a corneal section rather than with a limbal section. Furthermore, many authorities believed that epithelial downgrowth was less common when the cataract wound was covered with a limbus-based conjunctival flap rather than with a fornix-based conjunctival flap. These observations came from uncontrolled studies, and their significance is not clear. Furthermore, modern cataract extraction techniques have markedly reduced the incidence but have not eliminated the problem.

Histopathology

Histopathologic study of biopsy specimens and enucleated globes reveals the presence of stratified squamous epithelium on the corneal endothelium, iris, and angle structures. The epithelium, which resembles conjunctival epithelium, is one to three cells thick except at the advancing corneal edge, where it may be five cells thick. However, the epithelium may also originate from cornea. The epithelial membrane passes posteriorly in some eyes to cover the ciliary processes, pars plana, and retina. If a fistula is present, it is also lined by stratified squamous epithelium.

Clinical presentation

Epithelial downgrowth usually is seen as a low-grade persistent postoperative inflammation, including conjunctival injection, photophobia, discomfort, and aqueous humor cells. Careful examination may reveal large whitish cells floating in the anterior chamber. Affected eyes often have some evidence of current or past wound leak and are hypotonic if the fistula is still functional. The key to diagnosing this condition is finding a grayish white membrane with a scalloped, thickened leading edge on the posterosuperior corneal surface. The cornea overlying the membrane may be edematous, and the iris may be drawn up to the old wound or incision. The anterior surface of the iris often appears compacted, with loss of its normal architecture. In advanced cases the eye is painful with bullous keratopathy and intractable glaucoma.

The diagnosis of epithelial downgrowth is usually made on clinical grounds as indicated above. Specular microscopy may be helpful in some cases, but this technique requires a clear cornea overlying the membrane. Involvement of the iris is dramatically demonstrated when it is treated with large, low-energy argon laser burns (200–500 μm, 100–400 mW, 0.1 second), which turn the epithelial membrane white. (Normal iris does not respond this way.) Because of the gravity of the situation, it is usually desirable to confirm the diagnosis histopathologically. Aqueous humor can be aspirated, passed through a Millipore filter, and then examined to identify epithelial cells. An alternative approach is to obtain a specimen by scraping a small portion of the posterior cornea with a blunt spatula. If these approaches are unfeasible or inadequate, biopsies should be taken of the posterior cornea and iris.

Most cases of epithelial downgrowth are associated with severe glaucoma. Usually the glaucoma is caused by a membrane that lines the angle and contracts to form PAS. Other factors contributing to the glaucoma include chronic inflammation, pupillary block, and obstruction of the trabecular meshwork by desquamating epithelial cells.

Treatment

The treatment of epithelial downgrowth is often difficult and unrewarding. All of the techniques in current use attempt to close the fistula and then to excise or destroy the epithelium in the eye. It is common to determine the extent of iris involvement using the argon laser as described above. The corneal portion of the membrane can then be destroyed with cryotherapy or chemical cauterization. The affected iris can be excised, and cryotherapy can be applied to any remaining membrane on the ciliary body and retina. An alternative approach is to do an en-bloc excision of all involved tissues. Others have excised the involved iris and vitreous with a vitrectomy instrument and destroyed any remaining membrane with cryotherapy after the eye has been filled with air. Yet another approach involves excision of involved tissues, a penetrating keratoplasty, and implantation of a glaucoma shunt. One case report using adjunctive 5–fluorouracil, both for glaucoma control and in an attempt to control the epithelialization, was unsuccessful. Many other techniques have been described in the past for treating epithelial ingrowth, including X-radiation, beta-irradiation, curettage with alcohol, and photocoagulation. These have been largely abandoned as ineffective. Immunotoxin has been shown to inhibit epithelial proliferation in tissue culture; perhaps an agent like this may find some use in the future in this very frustrating condition.

All of the current techniques have been reported to salvage some eyes with epithelial downgrowth and even to maintain good vision in a few cases. However, recurrences of the downgrowth are common, and surgery is frequently associated with complications that include corneal edema, chronic inflammation, macular edema, and phthisis bulbi. The results of treatment are better if the condition is diagnosed early. However, it must be stressed that preventing epithelial downgrowth is far more effective than treating established disease. Surgical and traumatic wounds must be cleaned of epithelial tissue fragments and foreign material and then sutured meticulously.