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Etiology
Treatment
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Cataract and IOLs

Postoperative Endophthalmitis vs. Toxic Anterior Segment Syndrome (TASS)

Brandon L. Davis, MD · Laura Kearsley MD · Nick Mamalis, MD

Postoperative endophthalmitis is a rare but potentially devastating complication of cataract surgery. Postoperative endophthalmitis can be either sterile or infectious. Sterile endophthalmitis is also known as the toxic anterior segment syndrome (TASS). The overall incidence of endophthalmitis has decreased over the past several decades. This decrease has mostly been a result of improved surgical technique and patient preparation. Modern estimates indicate that the incidence of infectious endophthalmitis ranges from 0.13% to 0.7%.1-4 Culture positive infectious endophthalmitis accounts for approximately 69% of cases.5 There are multiple potential causes of TASS including toxic effects from intraocular fluids, medications, lenses, instruments, endotoxins, and sterilization techniques. It is imperative to differentiate infectious endophthalmitis from TASS, as the treatments and positive outcomes are different.

Clinical Course

There is significant overlap between the clinical presentation of sterile and infectious endophthalmitis. The presence of negative cultures, timing of onset, and response to therapy can help distinguish between the two entities. Often, the presenting signs and symptoms of infectious endophthalmitis occur within the first 48 to 72 hours after surgery. If endophthalmitis is caused by fungal or less virulent organisms, the onset of symptoms can occur as late as weeks to months after surgery. TASS can occur immediately, usually within the first 24 hours following surgery. However, there may also be a delayed onset toxic reaction.

The most common presenting signs and symptoms of infectious endophthalmitis include decreased or blurred vision, lid swelling, conjunctival injection, and pain. There is an increased cellular reaction in the anterior chamber and a hypopyon can be seen upon presentation in almost 75% of patients.5 Ocular pain, which is usually regarded as diagnostic, is present in only three-quarters of patients. Other, more unusual presentations include retinal vasculitis, retinal periphlebitis, and mid-peripheral retinal hemorrhages.6-8

TASS usually presents sooner than infectious endophthalmitis (12 to 24 hours after surgery) and differs from infectious endophthalmitis in presentation. Patients often have decreased visual acuity, corneal edema, a nonreactive, dilated pupil, and a moderate to severe anterior chamber reaction with cells, flare, hypopyon, and especially fibrin. Pain is mild to moderate if present. Patients with TASS can have marked corneal edema and even permanent, irreversible corneal decompensation.9 The corneal edema is characteristically "limbus to limbus."

Upon presenting of infectious endophthalmitis, patients' visual acuity tends to be poor. In the endophthalmitis vitrectomy study (EVS),5 86% of patients presented with an initial visual acuity of less than 5/200, and 26% had light perception only. By 3 months, 41% of patients had an acuity of 20/40 and 69% were better than 20/100. At 9 to 12 months, these numbers improved even more, with 74% of patients with better than 20/100 vision and 53% with better than 20/40 vision. Poor outcomes tended to be associated with diabetes, worse initial vision, small pupil size after maximal dilation, presence of rubeosis irides, and an absence of a red reflex. In the EVS, only 56% of patients reached a visual acuity of 20/100 (vs. 77% of nondiabetics).10 Other factors associated with a poor outcome include a history of glaucoma, afferent pupillary defect, corneal infiltrate, ring ulcer, abnormal intraocular pressure (IOP), retinal detachment, and microbiologic factors.5 One of the most significant microbiologic factors is the type of organism. In the EVS, patients reached a visual acuity of 20/100 84% of the time with gram-positive, coagulase-negative micrococci, 56% of the time with gram-negative organisms, 50% of the time with Staphylococcus aureus, 30% of the time with streptococci, and 14% of the time with enterococci. Despite these variations, it appears that visual acuity at initial presentation is still more useful in predicting visual outcome and response to vitrectomy than biologic factors.11

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Etiology

Infectious endophthalmitis
When postoperative endophthalmitis is culture-positive, the primary source of bacteria is believed to be the ocular surface and adnexa. In fact, associations between external bacterial flora and bacteria isolated from vitrectomy specimens have been reported to be as high as 82%.12 In the EVS, isolates from intraocular and conjunctival specimens were indistinguishable in 67.7% of cases.13 Most cases of infectious endophthalmitis are caused by bacteria, with Staphylococcus epidermidis being the most likely organism. Seventy percent of patients are infected with coagulase-negative organisms (mostly S. epidermidis), 10% with S. aureus, 9% with Streptococcus, 2% with enterococcus, 3% with other gram-positive species, and 6% with gram-negative species.14-16

It appears that microbiological spectrum and clinical presentation are often related. In the endophthalmitis vitrectomy study, patients with gram-positive, coagulase-negative micrococci tended to present later than patients with other gram-positive or more virulent gram-negative organisms. In addition, the more virulent strains tended to be associated with more significant findings including corneal infiltrates, cataract wound abnormalities, afferent pupillary defects, loss of a red reflex, and initial light perception only vision.5 Other possible microbacterial factors affecting presentation include bacterial adhesion to lens surface irregularities, electrostatic charge, or the lens material. It has been suggested that the intercellular adhesion locus carried by S. epidermidis may play a role in the pathogenesis of some forms of endophthalmitis.16

Preoperative risk factors for infectious endophthalmitis include blepharitis, conjunctivitis, canaliculitis, lacrimal duct obstruction, contact lens wear, and an ocular prosthesis in the fellow orbit. Implantation of a secondary intraocular lens (IOL) increases the incidence of endophthalmitis, but is most likely the result of other factors. These factors include diabetes, trans-scleral suture fixation, polypropylene haptics, preoperative eyelid abnormalities, reentrance through a previous wound, and postoperative wound defects.17

It is easy to assume that intraocular contamination is the primary cause of infectious endophthalmitis. Although endophthalmitis is rare, intraocular contamination is common after uncomplicated cataract surgery. In two studies, intraocular aspirates were positive in 13.7% to 43% of cases.18,19 No patients developed endophthalmitis in either of these studies. It can be concluded that other factors that influence the presence or absence of ensuing endophthalmitis must exist. Some theories on the inciting factors include the patient's history, aspects of cataract surgery itself, wound abnormalities, use of an IOL without a heparinized surface, and immunosuppression.20 In Germany, a survey found that most ophthalmologists view scleral incisions, diabetes mellitus, occlusion of the lacrimal sac, and skin diseases as risk factors for endophthalmitis.21

Certain intraoperative factors have been found to be associated with an increased risk for infectious endophthalmitis. These factors include inadequate sterilization of the eyelid and conjunctiva, surgery longer than 60 minutes, vitreous loss, use of prolene-haptic IOLs, and unplanned or nonapparent ocular penetration.22 Other possibilities include wound leak or dehiscence, incarceration of the vitreous into the surgical wound, inadequately buried sutures or suture removal, and a postoperative filtering bleb. Controversy exists about the influence of the type of incision. In a retrospective chart review, Colleaux and colleagues found that the incidence of endophthalmitis did not differ with clear corneal versus scleral tunnel incisions.24

TASS
TASS is implicated when no obvious cause for postoperative inflammation can be found. As opposed to being infectious, these cases are believed to be secondary to nonphysiologic factors. Cases of TASS tend to be clustered and are often a result of patients' reaction to abnormal solutions, contamination of equipment, and/or IOLs. Potential causes for intraocular reactions include abnormal irrigation solutions (abnormal pH or ionic composition), denatured viscoelastic, residual detergent in reusable equipment, and chemical residues left after sterilization. Patients can also have reactions to residual lens cortex, preservatives in ophthalmic solutions, and endotoxins not destroyed by the sterilization process. Kreisler and coauthors24 described an outbreak of TASS secondary to Klebsiella endotoxin. The ultrasound bath used to clean the instruments became contaminated with bacteria. Sterilization killed the bacteria, but a heat-stable endotoxin remained on the instruments and caused an outbreak of TASS. Other sources include reactions to the finish, design, chemical structure, or sterilization of an IOL.25

In many cases, the cause of TASS outbreaks is not known, but a few case reports have been published specifically linking cause and effect. The first report of an adverse toxic or inflammatory reaction was in 1987, in which a series of patients developed a reaction to the viscoelastic. It appears that the viscoelastic, sodium hyaluronate, within reusable cannulas was denatured during heat sterilization.26 Other early cases were believed to be due to detergent and viscoelastic residues trapped inside irrigating cannulas, miotic agents such as 1% Miochol (acetylcholine chloride, CIBA Vision) and aminoglycoside antibiotics inadvertently penetrating through the surgical wound.27

A more recent study postulated an association between TASS and the MemoryLens (Bausch & Lomb, Claremont, Calif.). In the report, 10 patients developed sterile endophthalmitis at a mean of 8 days postoperatively. All patients responded to steroids and were consistent with a delayed-onset, acute toxic reaction. Jehan and colleagues25 postulated that the hydrophilic nature of the lens allowed for a water-soluble inflammatory agent to penetrate the IOL and cause an inflammatory reaction. The authors also considered the possibility that materials used during the manufacturing, polishing or packaging process could have caused this outbreak. The MemoryLens has since been recalled (April 2000) secondary to similar reports of inflammation.

Another case series found an association between toxic endothelial cell destruction and intraocular benzalkonium chloride (a cationic detergent that is commonly used as a preservative in topical ophthalmic solutions). In this series, 12 of 19 patients developed corneal edema after using balanced salt solution preserved with benzalkonium chloride at 0.001%. Other toxic preservatives include sodium bisulfite at 0.1% and thimerosal at 0.01%. Corneal endothelial damage can easily occur if any hospital staff mistakenly replaces irrigating solutions with increased amounts of preservative.9

Another case series reported nine cases of sterile endophthalmitis after use of refrigerated balanced salt solution. Before this outbreak, it was believed that cold balanced salt solution might decrease endothelial cell loss and postoperative inflammation. Sixty-eight cases were performed under these conditions and nine patients developed TASS. The only common technique in this series was the use of cold balanced salt solution. The authors postulated that the cold balanced salt solution decreased tissue swelling, allowing for entry of potentially toxic subconjunctival fluid.28

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Treatment

Infectious endophthalmitis
Standards of treatment for infectious endophthalmitis include intravitreal antibiotics, with or without pars plana vitrectomy, topical and subconjunctival antibiotics, and corticosteroid therapy. If no clinical improvement is noted within the first 48 to 72 hours, vitreous tap and intravitreal antibiotic injection should be repeated, and pars plana vitrectomy performed.29

Originally, intravenous antibiotics and pars plana vitrectomy were the most common treatments for infectious endophthalmitis. Given the fact that systemic antibiotics generally do not penetrate the eye well, intravitreal antibiotics are also used. Since the offending organism is usually not known at the time of intravitreal injection, antibiotic coverage must be broad and must cover both gram-positive and gram-negative bacteria. Vancomycin 1 mg/0.1 mL is the preferred treatment for gram-positive bacteria. Injections of 2 mg/0.1 mL can occasionally result in retinotoxic drug levels.30 As of 1995, vancomycin was found to cover the majority of gram-positive organisms in endophthalmitis, including the methicillin-resistant S. aureus.11

The most common treatment for gram-negative organisms is the aminoglycoside, amikacin, given at a dose of 0.4 mg/0.1 mL. The third-generation cephalosporin, ceftazidime, given at a dose of 2.25 mg/0.1 mL, has gained popularity in recent years because of its broad coverage and decreased potential for retinotoxicity. In 1992, one study found that 100% of gram-negative organisms in endophthalmitis were sensitive to ceftazidime, whereas only 97 % were sensitive to amikacin.31 The only disadvantage to using ceftazidime is that it must be injected in a different syringe than vancomycin (they tend to precipitate when combined).

In 1995, the results of the EVS made the use of intravenous antibiotics obsolete. They found that systemic antibiotics were not useful adjuncts to intravitreal antibiotics. Despite potential limitations in study design, discontinuing the use of systemic antibiotics decreases potential toxic side effects, cost, and length of hospital stay for these patients.5,32 Originally, vitrectomy was believed to be beneficial because it removed vitreous membranes, debris, and possibly the infecting organisms and associated toxins. The EVS further classified this treatment by finding that doing a vitrectomy is only beneficial for patients with light perception only or worse vision. These patients achieved a three-fold chance of achieving 20/40 vision if they received a vitrectomy.5 The study then went on to sub-classify treatment even further. They found that diabetics tended to do better with a vitrectomy, regardless of their initial vision. These results were not statistically significant, leaving the decision for biopsy/tap vs. vitrectomy up to the clinician.10

Topical and subconjunctival antibiotics can also be used as a supplement to intravitreal antibiotics. Although topical and subconjunctival antibiotics are used in an attempt to increase the concentration of antibiotics in the anterior chamber, added benefit is questionable. Unfortunately, topical antibiotics do not penetrate the vitreous well, and subconjunctival injection is risky and highly associated with pain. Recommended topical antibiotics include hourly applications of fortified vancomycin in a dose of 50 mg/mL, and amikacin in a dose of 50 mg/mL or ceftazidime in a dose of 100 mg/mL.

Corticosteroid therapy can be used in conjunction with antibiotics to further reduce inflammation and its possible destructive effects on the retina. Corticosteroid therapy can be given topically, orally, or intravitreally. Intravitreal injection has been shown to reduce intraocular inflammation and secondary complications, but has not been shown to have any affect on visual outcome.1,33,34 One study by Shah and colleagues found that intravitreal steroids had a negative effect on visual outcome. The nonrandomized nature of the study and the slight (not statistically significant) baseline difference between treatment groups makes this study difficult to interpret.35,36 If intravitreal corticosteroid therapy is used, the recommended dosage includes injection of dexamethasone (400 mg per 0.1 mL) at the time of biopsy or vitrectomy. Prednisolone acetate 1% is the preferred topical steroid. The recommended oral steroid is prednisone at 30 mg per day for 5 to 10 days.5

TASS
Treatment of TASS has not been as thoroughly studied as infectious endophthalmitis. Part of this difference is due to the fact that TASS is often believed to be infectious upon presentation. Often, the diagnosis of TASS is only assigned after cultures are found to be negative or a cause is discovered. Several cases described in the literature were defined as TASS secondary to negative cultures and improvement despite discontinuation of antibiotics.27 Treatments used in published case reports vary considerably, making generalized recommendations difficult. The most common factor among case reports includes use of corticosteroids to decrease inflammation.25,28,37 This consists of an intense regimen of hourly topical steroids (prednisolone acetate 1%) with or without a course of oral steroids (prednisone). If intravitreal corticosteroids are used, dexamethasone at 400 mg per 0.1 mL is recommended.

The patients should be followed closely, especially if there is any question of an infectious etiology. Inflammation secondary to TASS will respond readily to topical steroid treatment, which may then be tapered accordingly. These patients may also have concomitant trabecular meshwork damage and must be monitored closely for IOP increases. Last, diffuse corneal edema occurs secondary to endothelial damage and may result in permanent corneal clouding requiring subsequent penetrating keratoplasty.

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Prevention

Infectious endophthalmitis
Many methods of reducing preoperative and operative bacteria have been advocated to decrease the incidence of infectious endophthalmitis. Prophylaxis usually includes antisepsis (adequate draping of eyelid, lashes, and lid margins), topical preoperative antibiotics, intracameral antibiotics, subconjunctival antibiotics, systemic antibiotics, and postoperative antibiotics. Multiple studies have shown a decreased bacterial load with prophylaxis, but no definitive decrease in endophthalmitis.38 Care must be taken to avoid contamination of surgical equipment. Preventative measures include adequate sterilization of reusable equipment and/or the use of disposable tubing when possible.

Antibiotics can be applied subconjunctivally and topically, both in the preoperative and postoperative periods. There is a distinct lack of evidence proving any benefit for postoperative topical antibiotics, despite its widespread use among ophthalmologists.24 The most thoroughly studied topical preoperative antiseptic is 5% povidone-iodine solution. It has been applied in the immediate preoperative period, for 3 consecutive days preoperatively or at the conclusion of surgery. In some studies, 5% povidone-iodine solution has been shown to decrease conjunctival bacterial load and possibly reduce the incidence of culture-positive endophthalmitis,21,39-42 whereas others show no difference.35

Many surgeons dilute antibiotics in the irrigating fluid in an effort to decrease bacterial load. Mendivil and colleagues found, in a randomized control trial, that the half-life of vancomycin after cataract surgery was less than 2 hours: levels decreased from 20.1 µg/mL to 9.4 µg/mL (minimum inhibitory concentration [MIC] between 0.5 µg/mL and 2.0 µg/mL). Although the time of antibiotic exposure was short, the researchers found that the number of positive intraocular cultures had decreased 2 hours after surgery. No patients in this study developed endophthalmitis, making accurate conclusions difficult.43 Other studies published concerning the use of vancomycin in irrigating fluids were surveys, and cannot be easily interpreted.21,44

Vancomycin prophylaxis continues to be fiercely debated. Much of this debate stems from the fact that there is a theoretical risk of increasing antibiotic resistance with routine use of vancomycin.45 In 1995, after noting an increased incidence of vancomycin-resistant bugs, the Centers for Disease Control and Prevention issued guidelines discouraging use of prophylactic vancomycin in surgical procedures. Vancomycin may be theoretically useful and, until sufficient studies are done to fully evaluate the subsequent incidence of endophthalmitis, the decision will be based on surgeon preference.46 Recently, the effects of cefotaxime on the corneal endothelium were examined and cefotaxime was found to be safe.47 Although this drug does not have as good gram-positive coverage as the first-generation cephalosporins, it has a greater extended spectrum than vancomycin and may be an alternative for infection prophylaxis.

Factors that should be considered when choosing prophylactic antibiotics include the spectrum of activity and the toxic or allergenic potential. Fluoroquinolones have less toxicity and a broader spectrum of activity against gram-positive and gram-negative organisms than the aminoglycosides.48 Recommended preoperative antibiotics thus include a broad-spectrum fluoroquinolone such as ofloxacin or ciprofloxacin. Ciprofloxacin drops are usually given at the same time as the dilating drops to ensure that they are on board at the time of the surgery. To help prevent resistance, topical antibiotics should be applied on a four times daily dosing schedule, continued for no more than 5 to 7 days, and should not be tapered. If ofloxacin is used, patients can be given prescriptions to use these drops four times a day beginning 3 days before surgery. The second alternative to postoperative fluoroquinolone drops would be to place a 12-hour collagen shield, which has been soaked in a soluble antibiotic such as cefazolin.

TASS
The most critical step in preventing toxic anterior segment syndrome is to minimize the possibility of contamination with potentially toxic substances. In many cases, removing all toxic substances is impossible. However, careful surgical preparation can identify and prevent many potential cases.

First, surgical equipment can be examined. The sterilization process can be periodically reviewed to avoid unwanted residues left on equipment. All instruments must be carefully cleaned and dried prior to placing them in the autoclave. Disposable tubing can be used to avoid contamination with residues from previous surgeries. This includes viscoelastic cannulas. Phacoemulsification machines can be periodically checked for back flush or other sources for contamination. Ultrasound water or milk baths must be changed at least biweekly.

As mentioned above, solutions used during surgery can also be sources of toxicity. Preservatives such as benzalkonium chloride, sodium bisulfite, and thimerosal should be avoided. Balanced salt solution should be at room temperature. The pH and ionic composition of irrigation solutions can be checked and denatured viscoelastic should be avoided.

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Conclusion

Endophthalmitis, whether sterile or infectious, is a serious and potentially devastating complication of cataract surgery. Significant advances have been made to both identify potential causes and improve subsequent outcomes. Although the rarity of endophthalmitis makes research difficult, advances with regard to cause and most appropriate treatment will most likely be discovered in the future.

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References

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  40. Apt L, Isenberg S, Yoshimori R. The effect of povidone-iodine solution applied at the conclusion of ophthalmic surgery. Am J Ophthalmol. 1998;1199:701-705.
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  43. Mendivil-Soto A, Medivil MP. The effect of topical povidone-iodine, intraocular vancomycin, or both on aqueous humor cultures at the time of cataract surgery. Am J Ophthalmol. 2001;131:293-300.
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