Chapter 60 Complications of Uveitis and Their Management DEBRA A. GOLDSTEIN and HOWARD H. TESSLER Table Of Contents |
CATARACT GLAUCOMA CYSTOID MACULAR EDEMA HYPOTONY BAND KERATOPATHY REFERENCES |
The treatment of uveitis is often frustrating because of the many complications that may arise as a result of inflammation and its treatment. The most frequent complications are cataract, glaucoma, macular edema, hypotony, and band keratopathy. This chapter addresses each of these entities and highlights current methods available for their treatment. Other complications, such as rhegmatogenous and nonrhegmatogenous retinal detachments, are addressed elsewhere in these volumes. |
CATARACT |
Cataract is a frequently seen complication of uveitis, occurring in up
to 50% of patients with juvenile rheumatoid arthritis (JRA), pars planitis, and
Fuchs' iridocyclitis.1–6 The incidence in other forms of uveitis is also high and seems to be related
to both the location and duration of the inflammation, as well
as to the use of corticosteroid therapy. The contribution of steroids
to cataractogenesis is well known from the data on nonuveitis patients
receiving steroid therapy and from experimental data.7 In addition, recent reports suggest that the prevalence of cataract in
pars planitis may be as low as 10% if steroid use is limited or replaced
by other forms of treatment, such as cryotherapy or immunosuppressive
therapy.8 However, most of the complications of uveitis are more difficult to treat
than is cataract; thus, the fear of cataract formation should not
prevent the judicious use of corticosteroids. When a cataract develops in a uveitis patient, the management is more complex than in the nonuveitis patient. The presence of posterior synechiae, pupillary membranes, and inflammation may make the surgery more difficult, and the postoperative course is often stormy (Fig. 1). Much controversy still exists regarding the best method of managing the uveitis patient with a cataract. Ideally, absolute control of inflammation should be obtained for at least 3 months preceding surgery; however, there are exceptions to this rule, as in the case of lensinduced uveitis.9 The choice of surgical technique is also controversial, but it is probably not as important as the perioperative management. The patient should be treated preoperatively with topical steroid drops (e.g., prednisolone acetate or phosphate) at least four times a day for at least 3 days before surgery. Also, we often pretreat with an oral steroid (usually prednisone 1 mg/kg/day) for 3 days, if the patient's medical status permits. Adequate pupillary dilation is often difficult to achieve preoperatively because of posterior synechiae and pupillary membranes. If this is the case, a laser peripheral iridotomy can be performed preoperatively, or a surgical peripheral iridectomy can be performed at the time of surgery. The posterior synechiae can then be lysed with the aid of a cyclodialysis spatula; access is gained to the superior ones through the peripheral iridotomy. If adequate pupillary dilation is still not achieved, straight or curved long-handled retinal scissors can be used to fashion small membranotomies or sphincterotomies (1 to 2 per clock hour), and viscoelastic material can then be used to dilate the pupil. This technique has an advantage over a single large sphincterotomy in that the pupil usually remains functional afterward. If adequate pupillary dilation is still not achieved, iris hooks can be used to further dilate the pupil. In some cases, iris hooks provide sufficient dilation without the need for sphincterotomies. The lens is then removed with the use of either phacoemulsification or standard extracapsular techniques. Implantation of an intraocular lens (IOL) is still controversial. There is much evidence that an IOL can be safely implanted in cases of Fuchs' iridocyclitis10–12 and pars planitis.8,13,14 In contrast, most evidence in cases of children with JRA is in favor of lensectomy/vitrectomy with no IOL (Fig. 2).4,15–17 The use of an IOL in uveitis of other etiologies is still uncertain, but an IOL should never be inserted in a patient with inflammation that could not be adequately controlled preoperatively. If an IOL is to be inserted, we prefer an all polymethyl-methacrylate lens to one with polypropylene haptics, because this may, at least in theory, lessen the chance of postoperative inflammation.12,17 Recently, in selected cases, we had good postoperative results using foldable acrylic lenses. Placement of the IOL in the capsular bag rather than the ciliary sulcus is also preferred because this may lessen the risk of inflammation secondary to iris-haptic contact. Occasionally, even in eyes with little or no preoperative inflammation, significant membranes form around an IOL (Fig. 3). This can occur even in the absence of significant anterior chamber cell and flare in the postoperative period.18 Although these cocoonlike membranes can be lysed with the Nd:YAG laser, they tend to reform. Therefore, it is imperative to be vigilant in the first 6 to 12 weeks after surgery, aggressively treating any signs of inflammatory deposits on the IOL, even in the absence of anterior chamber reaction. If laser membranectomy is required, vigorous anti-inflammatory treatment is necessary to prevent re-formation of the membrane. In severe cases, removal of the IOL may be required. It has been suggested that pars plana vitrectomy may be warranted when substantial vitreous cell and debris might preclude good postoperative visual acuity.4,8,12,19 Although we do not routinely perform pars plana vitrectomy on all uveitis patients with cataract, this procedure is considered for eyes with significant vitreous debris or inflammation. The postoperative management is similar to that of nonuveitis patients, except that inflammation is usually more severe and prolonged, often requiring depot steroid injections and systemic anti-inflammatory treatment. The results of cataract surgery in uveitis patients vary according to the preoperative diagnosis. Patients with Fuchs' iridocyclitis generally do well, with a visual acuity of 20/40 or better being the rule.10–12 Patients with pars planitis also do well, with 60% to 82% achieving a visual acuity greater than 20/40.8,18 Most pars planitis patients who fail to achieve good visual acuity do so because of cystoid macular edema.4,8,9 In these patients, perhaps more aggressive anti-inflammatory treatment, both preoperatively and postoperatively, will improve visual outcome. Patients with JRA do not tend to have as good an outcome as those with Fuchs' or pars planitis; a visual acuity greater than 20/40 is generally achieved in only about 60% of patients.15 However, one study using aggressive preoperative control of inflammation has reported a visual acuity greater than 20/40 in 75% of JRA patients.20 Finally, those patients with idiopathic and other forms of nongranulomatous anterior uveitis tend to do well postoperatively, with almost 80% achieving a visual acuity of 20/40 or better, again provided inflammation is well controlled preoperatively.9 |
GLAUCOMA |
Glaucoma is a frequent complication of uveitis, occurring in up to one
fourth of patients with chronic inflammation.21–23 Therefore, it is essential to measure the intraocular pressure (IOP) of
the uveitis patient at each visit. Elevated IOP can be seen in any type
of uveitis, but is most common in Fuchs' iridocyclitis, Vogt-Koyanagi-Harada
syndrome, JRA-associated iridocyclitis, and iritis secondary
to herpes simplex and herpes zoster.5,6,24 The glaucoma occurring with chronic uveitis can be either secondary open
angle or closed angle, or a combination of both types. Careful gonioscopy
of the uveitis patient with elevated IOP is therefore critical. Open-angle glaucoma is the type most often seen in patients with chronic uveitis.25 The chamber angle may become blocked by debris and inflammatory cells. Alternatively, the trabecular meshwork may itself become inflamed, reducing outflow facility. This is the proposed mechanism of elevated IOP in Possner-Schlossman syndrome (glaucomatocyclitic crisis). It has also been postulated that the endothelial cells of the trabecular meshwork are capable of phagocytosis and that during periods of inflammation these cells ingest debris, migrate off the trabecular beams, and eventually may be lost. This loss of endothelial cells would then be reflected in a decreased outflow facility and an increased IOP.25 Another mechanism that may be responsible for increased IOP in uveitis patients is the so-called steroid response. This elevated IOP can occur with any route of steroid administration, but it is seen most often after topical use; it is least likely with systemic treatment. The IOP rise seems to be dependent on the type, frequency, and duration of treatment, as well as on patient characteristics. It is seen in up to 30% of the general population after 3 to 4 weeks of treatment with topical steroids, and in a much higher percentage of glaucoma patients. The IOP rise in glaucoma patients tends to be faster and of a greater magnitude than in nonglaucoma patients. The incidence is also high in patients with a family history of glaucoma, suggesting a genetic basis for the response.26–31 The mechanism responsible for steroid-induced ocular hypertension is not yet clear but does seem to result from a decrease in outflow facility.26–30,32 This may result from a stabilization of lysosomal membranes, which in turn could cause an increased deposition of glycosaminoglycans in the trabecular meshwork, because lysosomal enzymes are, at least in part, responsible for glycosaminoglycan breakdown.33 Not all IOP increases seen with steroid use constitute a true “steroid response.” During episodes of acute anterior uveitis, the IOP is often low secondary to hyposecretion by an inflamed ciliary body. With a reduction of this inflammation, aqueous production may return to normal, resulting in an elevation of IOP. Angle-closure glaucoma is another possible sequela of chronic uveitis. Inflammatory peripheral anterior synechiae may close off the chamber angle, resulting in an elevation of IOP. The angle may also be closed by rubeosis iridis, which can occur as a consequence of chronic inflammation. Angle closure can also result from pupillary block, which can arise when extensive posterior synechiae prevent the flow of aqueous from the posterior to the anterior chamber. This results in iris bombe, because aqueous trapped in the posterior chamber causes the iris to be displaced anteriorly, mechanically closing the angle. One final cause of angle-closure glaucoma in the uveitis patient is anterior rotation of the ciliary body. This can occur secondary to ciliary body swelling or extensive exudative retinal detachment. The treatment of uveitic glaucoma depends on its etiology. Steroid-induced pressure rises usually respond to withdrawal of, or a reduction in dose of, the offending agent.26–28,32 In general, those steroids with better anti-inflammatory activity result in a greater pressure rise.34 Patients with steroid-induced glaucoma may therefore benefit from a change in medication from a more potent steroid, such as prednisolone acetate, to one with a lesser effect on IOP, such as fluorometholone alcohol or acetate. There are also newer topical steroid preparations, such as rimexolone, that are purported to have less of an effect on IOP.35 In addition, a decrease in drug concentration or frequency of administration may suffice to lower IOP. The medical management of uveitic glaucoma is similar to that of other types of glaucoma, except that miotics and epinephrine-based compounds should be avoided because they may increase inflammation and the risk of synechia formation. In addition, the glaucoma seen with certain types of uveitis, such as Fuchs' heterochromic iridocyclitis, may be refractory to medical treatment.22 If the glaucoma cannot be medically managed, argon laser trabeculoplasty should probably be avoided. It has a low success rate in uveitic glaucoma and may cause a significant increase in IOP and inflammation.36 The success rate of trabeculectomy is lower in uveitic patients than in patients with primary open-angle glaucoma,23 but it may be increased with the use of antimetabolites.25 Both postoperatively administered subconjunctival 5-fluorouracil and intraoperatively administered mitomycin C have been demonstrated to increase the success rate of filtration surgery in uveitic glaucoma.37–40 Another surgical alternative for the treatment of uveitic glaucoma is placement of a seton, such as the Molteno implant.39 Like other forms of pupillary block, uveitic pupil-block glaucoma is treated with a laser peripheral iridotomy. In uveitis patients, however, there is a tendency for the iridotomy to close because of the inflammatory reaction. We therefore tend to fashion multiple, large iridotomies, often using the argon as well as the Nd:YAG laser. In heavily pigmented eyes, which often have a more marked inflammatory reaction, a surgical peripheral iridectomy may be required (Fig. 4). |
CYSTOID MACULAR EDEMA | |
Cystoid macular edema (CME) is by far the most common macular sequela of
chronic inflammation, although retinal and subretinal neovascularization, preretinal
membranes, macular ischemia, and macular holes can also
occur.41–43 Chronic CME and its sequelae are a significant cause of visual morbidity
and probably account for the majority of cases of low visual acuity (20/40) in
uveitis patients (Fig. 5).44–46 The main symptoms experienced by patients with CME are decreased vision
and metamorphopsia, often with marked fluctuations in acuity. The diagnosis
of CME is often difficult and may require careful stereoscopic
examination at the slit lamp with a contact, Hruby, 78 or 90 D lens. Frank
cystoid changes may not be present, and often only a loss of the
normal foveal reflex is seen. For cases in which the diagnosis is not
clear, fluorescein angiography is a helpful tool. This demonstrates leakage
from perifoveal capillaries, with or without the characteristic
petaloid hyperfluorescence in the late phases of the angiogram.
The pathogenesis of uveitic CME is not completely understood, but it seems to be primarily related to a disturbance in the blood-retinal barrier; however, other factors such as vitreoretinal traction may also be involved.46 The cause of the breakdown of the blood-retinal barrier is unclear, but it may be the result of action by inflammatory mediators, such as cytokines and arachidonic acid metabolites. Also, a role has been postulated for oxygen free radicals within the vitreous cavity.47,48 The mainstay of treatment for uveitic CME thus far consists of steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and carbonic anhydrase inhibitors. Vitrectomy, cryotherapy, and immunosuppressive agents may also be indicated in selected cases. Because prostaglandins have been implicated in the development of uveitic CME, the use of systemic NSAIDs in its treatment is theoretically appealing. However, data supporting their use in uveitic CME are not yet available.46 Topical NSAIDs have shown much promise in aphakic and pseudophakic CME49,50 but have not proved to be of much benefit in CME secondary to chronic inflammation.51 Topical steroids are of little benefit in uveitic CME, although a short course may be indicated to assess their therapeutic effect and, more importantly, to determine if the patient is a “steroid responder.” If there is no significant rise in IOP with topical steroids, posterior subtenon injections of steroid (e.g., triamcinolone diacetate or triamcinolone acetonide) are probably the best choice of treatment. The injections are performed using the technique described by Smith and Nozik,52 in which the injection is placed in the posterosuperior subtenon space with a short 25-gauge needle. This placement facilitates delivery of the drug (which is believed to be absorbed transsclerally) to the macular area.53 The injections are repeated every 3 weeks until a response is obtained, or until three injections have not resulted in any improvement. Thereafter, the injections are repeated every few months as needed. Patients who cannot tolerate or do not respond to steroid injections may benefit from systemic steroids, although their use in most cases should be limited to a maximum of 6 months because of their numerous side effects. Some patients do, however, seem to tolerate long-term, low-dose oral steroid treatment (e.g., prednisone 20 mg qod). These patients, like all patients on systemic treatment, must be warned of the possible side effects and followed appropriately. Some studies have shown a reduction in uveitic CME in patients treated with systemic carbonic anhydrase inhibitors (CAIs),54,55 although others have failed to demonstrate this effect.51,56 Therefore, these agents should be considered for patients in whom steroid injections are not an option, or as an adjunct to therapy in patients receiving steroids. In some patients, standard pharmacologic therapy is not effective in decreasing CME or improving visual acuity. Many of these patients may benefit from more aggressive therapy, especially if the visual loss is severe. There is evidence that cryotherapy of the pars plana results in a decrease in vitritis and presumably CME in patients with pars planitis who have neovascularization of the vitreous base and pars plana.57,58 Although this treatment may be beneficial in selected patients, one must remember that it carries the risk of complications such as retinal detachment and proliferative vitreoretinopathy.59 Peripheral laser may be as effective as cryotherapy with a lower rate of complications. Pars plana vitrectomy has been advocated as a treatment option for refractory uveitic CME because it has been postulated that the vitreous may harbor antigen-antibody complexes and immunocompetent cells that may be responsible for the development or persistence of CME.60–63 In addition, vitrectomy serves to relieve vitreous traction, which may play a role in the development of CME. Although the subgroup of patients who would most benefit from this treatment has yet to be defined, the initial results of pars plana vitrectomy for uveitic patients intolerant of or unresponsive to steroid treatment have been promising.60,63 Finally, immunosuppressive therapy remains an option for selected patients with severe, bilateral, sight-threatening uveitis. Cyclosporin (CSA), a specific modulator of T-cell function, has been used to treat a variety of forms of uveitis, often with good results; however, visual acuity may worsen when the drug is stopped.64–66 The most significant side effect of CSA is nephrotoxicity; renal function must therefore be closely monitored.67 Other drugs that have been used to treat uveitis are antimetabolites, such as methotrexate and azathioprine, and alkylating agents, such as cyclophosphamide and chlorambucil. All of these agents have serious side effects, and their use should be reserved for specific patients with severe, bilateral, blinding disease who are nonresponsive to or intolerant of conventional therapy. When following uveitis patients with CME, it is important to realize that an improvement in visual acuity may occur before there is a decrease in capillary leakage on fluorescein angiography or a change in blood-retinal barrier permeability as measured with vitreous fluorophotometry.63,64,68 In fact, only retinal thickness has proved to correlate well with visual acuity.69 Thus, although fluorescein angiography is very helpful in making the diagnosis of CME, stereophotographs of the macula coupled with a good clinical examination may be a better way to follow a patient's response to treatment. |
HYPOTONY | |
The definition of ocular hypotony is not as exact as that of glaucoma, but
it can probably be said to exist when repeated tonometry reveals an
IOP 4 mmHg, or when the IOP is low enough that complications ensue. The
complications of hypotony include keratopathy with Descemet's
folds, optic disc edema, maculopathy, and, eventually, phthisis bulbi (Fig. 6).
Hypotony may be the end result of a number of mechanisms, including decreased aqueous production because of ciliary body inflammation, ciliary body detachment by a cyclitic membrane, or secretory failure by an atrophic or fibrotic ciliary body. Hypotony secondary to inflammation usually responds to steroid treatment. In these cases, the IOP may be increased because of an increased aqueous production by the ciliary body and because of a decreased outflow facility as a result of the steroids. Hypotony due to ciliary body detachment by cyclitic membranes may respond to pars plana vitrectomy with membranectomy and reattachment of the ciliary body. Unfortunately, the hypotony caused by ciliary body fibrosis or atrophy has no specific treatment. Often, the IOP can be maintained for a short while with aggressive steroid therapy, but eventually this treatment may fail and aqueous production completely cease. Pars plana vitrectomy with silicone oil injection has been used in a number of patients with intractable hypotony, with improvement in both IOP and visual acuity.70 Repeated intravitreal injection of viscoelastic material has also been reported in one patient with chronic hypotony in whom visual acuity and IOP were maintained over a period of 6 years. The patient received injections through the limbus under general anesthesia every 4 to 5 months, as the viscoelastic cleared from the eye.71 Viscoelastic injection through the pars plana under local anesthesia has also been used successfully in two patients with chronic hypotony, again maintaining IOP and visual acuity.72 The use of viscoelastic material instead of silicone oil eliminates the corneal decompensation seen with oil but has the disadvantage of requiring repeated injections, with each injection carrying the risk of infection and retinal detachment. Despite these drawbacks, both of these techniques can serve as last-ditch efforts to save eyes that might otherwise be lost to phthisis bulbi. |
BAND KERATOPATHY | |
Calcific band keratopathy results from the deposition of calcium hydroxyapatite
in the cornea at the level of Bowman's membrane. Histologically, there
is basophilia and calcification of Bowman's layer. Eventually, there
is fragmentation of Bowman's layer, with deposition
of hyaline material beneath the epithelium.73,74 The differential diagnosis of band keratopathy is long, reflecting systemic
and local ocular disease. It is probably most commonly associated
with JRA, where it is found in 30% to 55% of patients.1,2,75 Band keratopathy usually occurs in the interpalpebral area. It typically begins at the periphery as grayish white opacities. The opacification may spread centrally and in time may form a complete band in the interpalpebral zone. A lucid interval is noted between the band and the limbus, because Bowman's layer does not extend to the absolute limbus.75 Small lucid areas are noted in the opacity, representing regions where corneal nerves penetrate Bowman's layer. The presence of these holes imparts a “Swiss cheese” appearance to band keratopathy when examined at the slit lamp. The reason for the deposition of calcium in the interpalpebral area is unclear, but it may result from an elevation of pH in this area because of tear evaporation.74,76 Band keratopathy does not need to be treated unless there is a decrease in visual acuity or significant foreign body sensation or discomfort. If treatment is desired, it can be accomplished with disodium ethylenediamine tetraacetate (EDTA). Calcium EDTA should not be used. The corneal epithelium must first be removed with a blade or a spatula. A 2% to 3% solution of EDTA is then applied to the area of band keratopathy. This is most easily accomplished by rubbing the affected corneal surface with a cellulose sponge dipped in the EDTA solution. The cornea is repetitively wiped in this fashion, removing the abnormal deposits. Care must be taken to avoid application to uninvolved areas of cornea or to the conjunctiva, because EDTA is very irritating to the ocular surface. This procedure can be repeated as often as is necessary to maintain vision and prevent discomfort (Fig. 7).
The treatment of patients with uveitis can be both very rewarding and very frustrating. The disease itself, its complications, and the complications of treatment make each patient a unique and interesting challenge. A knowledge of the potential complications of uveitis and the treatment options available enable the physician to best manage the patient and preserve vision in a potentially blinding disease. |