Chapter 178 – Phacoantigenic Uveitis
DAVID J. FORSTER
• Intraocular inflammation induced by lens protein, usually after surgical or traumatic rupture of the lens capsule.
• Anterior uveitis that occurs days to weeks after capsular disruption.
• Acute, more severe cases are associated with redness, pain, photophobia, and possibly hypopyon formation.
• Chronic low-grade inflammation may be seen with milder cases or may be related to intraocular lens, anaerobic infection, or fungal endophthalmitis.
Phacoantigenic, or lens-induced, uveitis is a term used to describe several entities that may have overlapping clinical features. All are believed to be caused by immune reaction to lens protein. Phacoanaphylactic endophthalmitis is an acute granulomatous anterior uveitis that occurs after surgical or traumatic rupture of the lens capsule. Phacogenic nongranulomatous uveitis (previously called “phacotoxic” uveitis) is a more chronic form of uveitis that can be seen after cataract surgery and is the result of immunological reaction to retained lens material. The third entity, phacolytic glaucoma, is not a true uveitis but may present clinically as a lens-induced uveitis. It is the result of leakage of lens protein through the intact capsule of a hypermature cataract. Recognition of these entities is important, since prompt removal of lens material is usually curative. In addition, they must be differentiated from postoperative endophthalmitis, which requires prompt intervention and antibiotic treatment to minimize visual loss.
EPIDEMIOLOGY AND PATHOGENESIS
The incidence of phacoantigenic uveitis is low. Most series report that phacoanaphylactic endophthalmitis and phacogenic nongranulomatous uveitis account for less than 1% of all cases of uveitis. Likewise, intraocular lens (IOL)–related uveitis accounts for only about 1% of uveitis cases.    Postsurgical infectious endophthalmitis, which may mimic phacoanaphylactic endophthalmitis, is rare as well, occurring in 0.10–0.35% of surgical cases.
The pathogenesis of lens-induced uveitis is hypothesized to be an immunological response to lens proteins that occurs after surgical or nonsurgical traumatic rupture of the lens capsule. In the past, it was thought that lens protein was organ specific and that it was sequestered from the immune system in normal individuals by an intact lens capsule.  However, studies have since shown that the majority of healthy persons have measurable anti-lens antibodies in the circulation, even in the absence of eye disease. Development of phacoanaphylactic endophthalmitis may depend more on altered tolerance to lens protein than on an immune reaction to “sequestered” lens antigens.  Most likely, phacoanaphylactic endophthalmitis represents an immune complex–mediated phenomenon related to traumatically released lens protein, facilitated by B cells that have been stimulated by bacterial lipopolysaccharides. 
Phacogenic nongranulomatous uveitis was once referred to as phacotoxic uveitis because it was believed that the inflammation was caused by the release of toxic substances into the anterior chamber after disruption of the lens capsule.   However, there is no evidence to support the hypothesis that lens proteins are directly toxic to ocular tissues.  Most likely, this type of uveitis, if it exists at all, represents a variant of phacoanaphylactic endophthalmitis, or it may represent undiagnosed cases of IOL-related uveitis or low-grade bacterial endophthalmitis.
Phacolytic glaucoma results from leakage of protein through an intact lens capsule and is generally seen in the setting of a hypermature lens. Protein that leaks into the anterior chamber is engulfed by macrophages, which in turn cause blockage of the trabecular meshwork, resulting in the elevation of intraocular pressure, which is characteristic of this entity (see Chapter 230 ).
IOL-associated uveitis, though not strictly a subset of phacoantigenic uveitis, is mentioned here because it may be the cause of chronic postoperative inflammation in patients who have undergone cataract extraction. A number of factors can result in IOL-related uveitis, including lens–iris or lens–ciliary body contact, or complement activation in the aqueous by certain types of lens materials (e.g., polypropylene haptics).  Likewise, chronic uveitis may be seen in patients who have low-grade endophthalmitis postoperatively. Agents responsible for these cases include Propionibacterium acnes, Staphylococcus epidermidis, Candida parapsilosis, and Torulopsis candida.   
Phacoanaphylactic endophthalmitis usually develops days to weeks (or sometimes months) after surgical or nonsurgical trauma or surgical disruption of the lens capsule. It may occur within 24 hours of cataract surgery in a patient who has been previously sensitized to lens protein (i.e., if the fellow eye has undergone cataract extraction). It typically has an abrupt onset, with a granulomatous type of inflammatory response. Mutton-fat keratic precipitates and posterior synechiae are common. Anterior chamber reaction is moderate to severe, and hypopyon formation may be seen. Lens debris may be seen floating in the anterior chamber, and intraocular pressure may be elevated from blockage of the trabecular meshwork. There may be an associated vitritis, but typically there is no involvement of the retina, choroid, or optic nerve. Some cases, however, have been seen in association with sympathetic uveitis. Visual acuity is usually diminished, but generally less pain occurs than with acute infectious endophthalmitis.
Phacogenic nongranulomatous uveitis may share features of phacoanaphylactic endophthalmitis, but the inflammation is usually less severe or acute than with the latter. It typically
develops within 2–3 weeks of lens capsule disruption (either surgical or traumatic). Retained lens material may elicit an ongoing inflammatory response, with cells and flare in the anterior chamber and posterior synechiae formation. Unlike with phacoanaphylactic endophthalmitis, however, the inflammation is nongranulomatous; the mutton-fat keratic precipitates seen with phacoanaphylactic endophthalmitis are absent in this condition. Intraocular pressure may be elevated from plugging of the trabecular meshwork by inflammatory cells or lens material.
Phacolytic glaucoma is seen in patients who have a hypermature lens and an intact lens capsule. Large cells and protein (flare) are seen in the anterior chamber, but keratic precipitates and posterior synechiae are usually absent. Intraocular pressure is elevated, sometimes markedly, and may result in corneal edema.
A chronic form of uveitis may be elicited by IOLs themselves. Patients may have persistent anterior chamber reaction, keratic precipitates, or inflammatory precipitates on the IOL surface. Most types of posterior chamber lenses in use today rarely cause such problems, but the presence of iris chafing by either the optic or haptic portion of the IOL may result in chronic inflammation. This is more common with anterior chamber lenses. As mentioned earlier, certain materials in the prosthesis (e.g., polypropylene) may activate complement, which leads to recruitment of inflammatory cells into the anterior chamber.
In acute cases of postoperative inflammation, the possibility of infectious endophthalmitis must be considered. Generally, these patients present within a week after surgery with pain and visual loss; usually moderate to severe inflammation is seen in the anterior chamber and vitreous cavity, with possible hypopyon formation. Lid edema, chemosis, and corneal clouding also may be present. However, certain types of infectious endophthalmitis may have a much more insidious onset, not manifesting until weeks or months after surgery. Frequently, this is the case with infections caused by S. epidermidis or anaerobic bacteria and fungi. This type of infectious endophthalmitis is commonly referred to as delayed or localized endophthalmitis.
One causative organism that has become important in such delayed types of infections is P. acnes, an anaerobic bacterium.  Infection with P. acnes usually manifests as chronic low-grade inflammation postoperatively. Often the inflammation is responsive transiently to topical corticosteroids, but typically it flares up as the corticosteroids are tapered. Findings may include granulomatous keratic precipitates or hypopyon. Frequently, a white fibrous plaque is evident on the posterior capsule or between the capsule and the IOL ( Fig. 178-1 ). It is possible that P. acnes organisms become sequestered within this fibrous pocket, which results in the chronic low-grade inflammatory reaction. Cases of exacerbation of intraocular inflammation following neodymium:yttrium-aluminum-garnet capsulotomy have been associated with P. acnes infection.   Presumably, the laser-induced capsular disruption liberates the previously sequestered organisms, which results in an acute increase in inflammation. Other organisms that may produce a picture similar to that seen with P. acnes include S. epidermidis, C. parapsilosis, and T. candida.
Diagnosis of phacoantigenic uveitis is usually made on a clinical basis. However, in cases of acute inflammation after a penetrating injury or surgery, differentiation of an immune-mediated process (e.g., phacoanaphylactic endophthalmitis) from an infectious process (e.g., acute bacterial endophthalmitis) may be difficult or impossible based on clinical findings alone. Characteristically, the inflammation associated with phacoanaphylactic endophthalmitis is granulomatous in nature, with mutton-fat keratic precipitates; these are much less common in bacterial endophthalmitis. Also, the severe pain caused by infectious
Figure 178-1 Propionibacterium acnes endophthalmitis. A, Note the typical fibrous white plaque between the intraocular lens and the posterior capsule. B, Examination of a surgically removed plaque shows a mass of P. acnes. (Courtesy of Dr. A. H. Friedman.)
endophthalmitis is not characteristic of phacoanaphylactic endophthalmitis. Nonetheless, when the diagnosis is unclear, diagnostic vitrectomy should be performed as soon as possible because of the rapidity with which bacterial endophthalmitis can destroy ocular tissues. Culture of vitrectomy specimens is preferred to that of anterior chamber fluid because of the higher yield of positive results with the former.
Cases of delayed bacterial (e.g., P. acnes) or chronic fungal endophthalmitis often do not become apparent until months after surgery. In any patient who has ongoing inflammation postoperatively and is only partially responsive to topical corticosteroids, P. acnes should be suspected, particularly if hypopyon develops after corticosteroid withdrawal or in the presence of plaque-like material on the posterior capsule. It also should be strongly suspected when the uveitis is exacerbated by laser capsulectomy.  Diagnosis of P. acnes endophthalmitis usually requires vitrectomy; posterior capsulectomy, particularly if any plaques are present, may be necessary to demonstrate the organisms ( Fig. 178-2 ). Since P. acnes is very slow growing, the laboratory should be instructed to hold the plates for at least 2 weeks before reading the culture as negative. Fungal endophthalmitis may present with a similar picture of chronic low-grade inflammation and may progress to the point of forming vitreous “fluff balls” or foci of retinochoroiditis. In particular, this entity should be considered in patients who are immunocompromised or iatrogenically immunosuppressed. Diagnosis also is made by culture of vitrectomy specimens; the yield can be increased by first passing the fluid through a Millipore filter and sending the filter for culture as well.
Figure 178-2 Reaction to Propionibacterium acnes. Capsulectomy specimen reveals the presence of bacteria and remnants of lens fibers in the lens capsule.
Differential Diagnosis of Phacoantigenic Uveitis
Early (within first week of surgery or trauma)
Bacterial endophthalmitis (usually aerobes)
Late (weeks to months)
Phacogenic nongranulomatous uveitis
Anaerobic endophthalmitis (e.g., P. acnes)
Low-grade bacterial endophthalmitis (e.g., S. epidermidis)
Retained intraocular foreign body
Hypermature cataract (no history of surgery or trauma)
The differential diagnosis of phacoantigenic uveitis is outlined in Box 178-1 . The distinguishing features of these entities were discussed earlier. One entity that is not discussed here, although it is covered in detail in Chapter 179 , is sympathetic uveitis. This is a rare bilateral granulomatous type of panuveitis that occurs after injury to one eye (the “exciting eye”). After weeks or years, the patient develops inflammation in the fellow (“sympathizing”) eye as well. Ninety percent of cases occur between 2 weeks and 1 year after injury. The inflammation is characterized by mutton-fat keratic precipitates, anterior chamber and vitreous cellular infiltration, choroidal thickening, disc edema, serous retinal detachments, and characteristic yellow-white infiltrates at the level of the retinal pigment epithelium (Dalen-Fuchs nodules). Histopathologically, eyes with sympathetic uveitis may show signs of phacoanaphylactic endophthalmitis as well. The key distinguishing features between sympathetic uveitis and the other types of post-traumatic uveitis discussed earlier are that sympathetic uveitis causes a panuveitis as opposed to merely an anterior uveitis, and it is always bilateral, whereas the others usually affect only the traumatized eye. Fluorescein angiography and ultrasonography can be useful in demonstrating the posterior uveal involvement of sympathetic uveitis.
Patients who present with chronic inflammation after penetrating injury also need to be examined carefully for a retained intraocular foreign body. Ultrasonography and computed tomography scanning are helpful in ruling this out as a cause of prolonged post-traumatic uveitis.
Figure 178-3 Phacoanaphylactic endophthalmitis. The zonal type of granulomatous inflammation seen in phacoanaphylactic endophthalmitis is evident here. A lens remnant is surrounded by a zone of neutrophils, which in turn is surrounded by a zone of macrophages, epithelioid cells, and giant cells; the outermost layer is composed of lymphocytes and plasma cells.
No identified associations exist between post-traumatic uveitis and systemic disease. As mentioned earlier, however, immunocompromised patients who present with persistent inflammation postoperatively should cause an increased level of suspicion of fungal endophthalmitis.
Phacoanaphylactic endophthalmitis is characterized histopathologically by a zonal type of granulomatous inflammation centered around lens remnants ( Fig. 178-3 ). Polymorphonuclear leukocytes immediately surround the lens material. These in turn are surrounded by a zone of granulomatous reaction, which consists of macrophages, epithelioid cells, and giant cells. Lymphocytes and plasma cells make up the outermost area of inflammation.
Phacoantigenic nongranulomatous uveitis, as its name implies, typically exhibits a nongranulomatous inflammatory reaction around the lens material.  The cellular infiltrate consists of lymphocytes, histiocytes, and polymorphonuclear leukocytes, but epithelioid and giant cells are absent.
Histopathology of specimens taken from eyes infected with P. acnes usually shows the presence of neutrophils, admixed with macrophages. However, the inflammatory reaction around pockets of P. acnes organisms is often surprisingly minimal (see Fig. 178-2 ). This may be because of the organism’s low virulence.
Mild postsurgical inflammation is normal in the first few weeks and usually responds well to topical corticosteroids or topical nonsteroidal anti-inflammatory medications. Retained lens material, however, is frequently associated with more severe or prolonged postoperative inflammation. Most of these cases eventually resolve with prolonged corticosteroid therapy. Topical therapy is often sufficient, but in more severe cases, systemic or periocular corticosteroids may be necessary. Cases that persist in spite of such therapy usually require surgical removal of the remaining lens material. Phacoanaphylactic endophthalmitis, in contrast, should be treated as soon as possible with removal of all lens material. Intensive corticosteroid therapy should also be employed, but it is usually insufficient to control the inflammation if the inciting lens material is not removed.
Prolonged topical corticosteroid therapy also may be required for IOL-related uveitis. If the uveitis is persistent, repositioning of the IOL (particularly if there is iris touch or pupillary capture) or complete removal of the IOL may be necessary. Other potential causes of prolonged postoperative inflammation (e.g., iris or vitreous incarceration in the wound) should be corrected surgically if inflammation or secondary cystoid macular edema does not respond to corticosteroid therapy.
Mild cases of P. acnes endophthalmitis may respond to intravitreal vancomycin (1?mg), which can be given at the same time as vitreous cultures are obtained. More severe cases, or cases that do not respond to this treatment, require pars plana vitrectomy and posterior capsulectomy with repeat injection of vancomycin. Removal of the IOL is not necessary in many cases, but it may be required in severe cases that are unresponsive to the previously mentioned measures. Topical and systemic antibiotic therapy (e.g., cephalosporins) also may be helpful.
COURSE AND OUTCOME
Mild cases of lens-induced uveitis usually do well with corticosteroid therapy. In more severe cases or in cases of phacoanaphylactic endophthalmitis, prompt removal of all lens material is usually curative. The same is true with phacolytic glaucoma. Low-grade endophthalmitis from organisms such as S. epidermidis or P. acnes often has a favorable outcome if appropriate therapy is instituted in a timely manner. In one series of 16 patients with P. acnes endophthalmitis, 11 had final visual acuity of 20/40 (6/13) or better.
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