49 Toxic Anterior Segment Syndrome Toxic anterior segment syndrome (TASS) is a rare, yet serious complication that typically develops acutely following exposure of a toxic substance to the anterior segment of the eye. It is a sterile, postoperative, inflammatory reaction of the anterior segment. Though cataract surgery is the most common surgery leading to the development of TASS, it can theoretically occur after any anterior segment surgery, including cornea transplant or glaucoma surgeries. Any substance used during or immediately after anterior segment surgery can potentially cause TASS, as the tissues of the anterior segment of the eye are very sensitive structures. The extent and intensity of the inflammatory reaction depends on the type of toxin and the duration the toxin remains in the anterior segment. A common end point of the toxic insult is the widespread breakdown of the blood–aqueous barrier, resulting in significant anterior segment inflammation with increased aqueous cell and flair as well as possible fibrin and hypopyon formation. Prompt recognition and treatment of TASS is critical. It is important to distinguish TASS from other causes of postoperative inflammation, especially infectious endophthalmitis, though this is often difficult. Any uncertainty of diagnosis should result in the collection of vitreous and aqueous fluid for further infectious workup. Although prevention is the most effective method of minimizing the incidence of TASS, topical corticosteroids remain the mainstay of treatment in positive cases. Outcomes vary depending on the type of toxic substance that enters the eye, the duration of exposure to the substance, and the amount of time before initiation of treatment, and can resolve completely or result in significant sequelae including permanent corneal edema, or medically refractive glaucoma. Toxic anterior segment syndrome typically develops 12 to 48 hours following anterior segment surgery, though a rare, delayed-onset TASS has been reported.1 The inflammation is sterile and is triggered by a substance that enters the anterior segment of the eye. The occurrence of TASS is rare, though it is difficult to estimate its exact incidence. A retrospective case series conducted at the Aravind Eye Hospital in India reported an incidence of 0.23% (60 eyes from 26,408 cataract surgeries).2 Cases of TASS often occur in clusters, though individual cases have been seen. Sporadic cases of TASS are often overlooked, given the lack of awareness of available registries for reporting outbreaks. In response to TASS outbreaks, the American Society of Cataract and Refractive Surgery (ASCRS) created a TASS task force, to educate anterior segment surgeons regarding TASS and to help investigate outbreaks of TASS. Questionnaires are available on the ASCRS Web site to aid in the reporting of TASS cases.3 The pathophysiology of TASS involves a toxic insult that damages the corneal endothelial cell layer, iris, or trabecular mesh-work, resulting in a marked inflammatory reaction. The extent and intensity of the inflammatory reaction depends on the type of toxin and the duration that the toxin remains in the anterior segment. A common end point of the toxic insult is the wide-spread breakdown of the blood–aqueous barrier, resulting in significant anterior segment inflammation with increased aqueous cell and flair as well as possible fibrin and hypopyon formation. The etiologies of TASS are broad, as any substance used during or immediately after anterior segment surgery can potentially cause TASS. Upon entering the anterior segment, the toxic substance causes injury to the sensitive tissues of the eye, particularly the corneal endothelium, iris, and trabecular meshwork. A recent retrospective analysis by Bodnar et al4 of surveys reporting cases of TASS from June 2007 through March 2012 evaluated the most common risk factors for TASS. The study identified inadequate cleaning and sterilization of ophthalmic instruments as the most commonly identified risk factor for TASS. Other causes include the use of medications or solutions containing incorrect formulations or toxic additives, mishandling of intraocular lenses or instrument tips, and poor maintenance of equipment used for cleaning surgical instruments. The etiologies of TASS can be categorized as (1) intraocular medications and solutions, and (2) cleaning and sterilization of ophthalmic instruments. Virtually all cataract procedures use balanced salt solution (BSS) as an irrigating solution intraoperatively. Abnormalities in the composition of BSS, including pH, osmolarity, or ionic composition, can lead to the development of TASS. Specifically, pH values less than 6.5 or greater than 8.5 are toxic to tissues in the anterior chamber. Osmolarity values less than 200 mOsm or greater than 400 mOsm may cause cellular damage to tissues in the anterior chamber. Furthermore, any substance added to BSS during surgery (i.e., epinephrine or antibiotics) may also cause TASS, especially those containing preservatives. Many topical eyedrops contain preservatives or stabilizing agents intended to maintain the efficacy of the medication for an extended period of time. These agents may be toxic to the corneal endothelium if they gain access to the anterior chamber of the eye. The most common preservative in topical ophthalmic drops is benzalkonium chloride. There are reports of patients developing significant corneal edema or endothelial cell damage after being treated with solutions containing this substance.5 Another preservative to be wary of is methyl paraben, which is used in lidocaine. Though these preservatives are relatively safe when used on the surface of the eye, they are toxic to anterior segment tissue and should be avoided during anterior segment surgery. Stabilizing agents, such as bisulfites and metasulfites in a high enough concentration, are also potentially toxic to anterior segment tissues, especially corneal endothelium. Addition of a stabilizing agent, such as bisulfite, to epinephrine prevents the degradation and efficacy of the medication. However, these additives are known to cause corneal endothelial damage, resulting in TASS when not properly diluted. Intracameral epinephrine containing 0.1% bisulfite has been associated with corneal edema, whereas epinephrine containing 0.05% bisulfite does not cause endothelial changes.6 Given that bisulfite-free epinephrine is not available in the Unites States, and that the need for epinephrine to combat miosis is critical, commercially available epinephrine is appropriate for use, but only when it is diluted at least 1:4 in BSS or in a preservative-free anesthetic. Intraocular anesthetics are increasingly used to reduce intraoperative and postoperative pain and to supplement topical anesthetics. The most common intracameral anesthetic currently used in surgery is 1% methylparaben-free (MPF) lidocaine. Low concentrations of preservative-free anesthetics do not seem to cause endothelial toxicity. Higher concentrations (i.e., > 2.0% lidocaine) or preservative-containing anesthetics are toxic to endothelial tissue. For example, 2.0% lidocaine has been associated with significant postoperative corneal thickening and opacification. Therefore, it is critical that intracameral anesthetics be preservative-free and of the appropriate concentration. Although the practice of mixing antibiotics into BSS has largely fallen out of favor due to the unproven efficacy in preventing endophthalmitis, it is still being practiced by numerous surgical centers, as reported by Bodnar et al.4 The lack of a commercially available injectable solution approved for endophthalmitis prophylaxis increases the risk of developing TASS secondary to improperly mixed, diluted, or prepared antibiotics. In addition, the narrow therapeutic index of antibiotics in general increases the incidence of poor outcomes with intracameral antibiotic use. Antibiotics such as gentamicin and cefuroxime have been associated with anterior and posterior segment inflammation, including TASS, cystoid macular edema, and macular infarction, when inadequately prepared or used in too high a concentration.7–10 Because no injectable prophylactic antibiotic solution exists in the United States, any intracameral antibiotic must be mixed, diluted, and prepared appropriately prior to use in surgery. Improper preparation of these antibiotics has been associated with both anterior and posterior segment inflammation.10 Several studies found intracameral cefuroxime to be associated with a reduction in the occurrence of endophthalmitis when used in the proper concentration (1 mg/0.1 cc).11–13 However, even with a strict protocol, achieving a consistent dilution for intracameral use is difficult.14 The Intermountain Ocular Research Center recently became involved in a TASS outbreak in which 12 patients were administered a commercially available 0.5% moxifloxacin product called Moxeza (Alcon, Fort Worth, TX). This topical drug contains ingredients such as xanthan gum, sorbitol, and tyloxapol, which are toxic to sensitive structures within the anterior chamber. Any surgeon considering using intracameral antibiotics must proceed with caution and ensure that any intracameral antibiotic is properly mixed. Ophthalmic viscosurgical devices (OVDs) are potentially toxic to corneal endothelial cells, especially when residual OVD remains in the anterior segment at the conclusion of surgery. The incidence of retained OVD is higher in cases with posterior capsular rupture and vitreous loss, in which OVD may remain in the remnant capsular bag or posterior to the iris. In addition, poorly flushed and cleaned reusable cannulas and handpieces are a source of contamination. If OVD is retained in phaco equipment and is broken down during sterilization processes and subsequently flushed into the anterior segment during subsequent surgeries, it can cause TASS. As previously mentioned, problems with the instrument-cleaning process was found to be the most common identified risk factor in a recent retrospective analysis.4 The instrument cleaning process entails the use of sufficient volume for flushing equipment, flushing of the handpieces and reusable cannulas with deionized/distilled water, and the use of enzymatic detergents and ultrasonic baths. Small-bore instruments, such as cannulas, ultrasound, and irrigation/aspiration handpieces, are particularly susceptible to retained material, given their small internal diameters and openings. Residual OVD as well as cortex can build up in these instruments and within the equipment’s lumen. The OVD that remains within the lumen becomes denatured by autoclaving and could result in TASS when these instruments are used in subsequent surgeries. To avoid OVD and cortical buildup, it is critical to flush reusable cannulas and handpieces with at least 120 mL of deionized/distilled water. Deionized/distilled water ensures that the instruments do not become contaminated with solutes or endotoxins. This flushing should be done either manually with a syringe or an automated unit that is set to deliver the appropriate flush volume. Consideration should be given to using disposable cannulas whenever possible, especially with OVD cannulas. There are two commonly used methods to remove bioburden from surgical instruments: washing with enzymes and detergents, and placing instruments in an ultrasound bath. However, compared with most other general surgical instruments, ophthalmic instruments accumulate very little bioburden. Therefore, the cleaning process should be different for instruments used in anterior segment surgery. The use of enzymes and detergents remains debatable, but they should be avoided because they have been shown to be toxic to corneal endothelial cells in human and animal studies.15 Enzymatic detergents are not deactivated during sterilization by autoclave, and can cause inflammation if not thoroughly flushed out of the lumen of handpieces and cannulas. Similarly, ultrasound baths require strict and regular cleaning. If not maintained adequately, they can become colonized with gram-negative bacteria that produce endotoxin. The heat-stable endotoxin survives despite the autoclave sterilization and can cause TASS when the contaminated instruments are used in subsequent anterior segment surgeries.4,16
Etiology
Intraocular Medications and Solutions
Balanced Salt Solution
Topical Ophthalmic Eyedrops
Stabilizing Agents
Intraocular Anesthetics
Intraocular Antibiotics
Ophthalmic Viscosurgical Devices
Cleaning and Sterilization of Ophthalmic Instruments
Enzymatic Detergents and Ultrasound Baths
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