Miguel Giménez de la Linde, MD 1 ; Belén Giménez Alcántara, MSc 1 ; Rafael Barañano Alcaide, MSc 1 ARTICLE

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1 ARTICLE Acute serous neuroepithelial detachment following uncomplicated cataract surgery. Relationship with the volume of cefuroxime injected into the anterior chamber Miguel Giménez de la Linde, MD 1 ; Belén Giménez Alcántara, MSc 1 ; Rafael Barañano Alcaide, MSc 1 PURPOSE: We present a new retinal condition following uncomplicated cataract surgery, and its relationship with the injection of cefuroxime at the correct concentration (0.1 ml/1 mg), but at a volume greater than 0.1 ml. SETTING: OFTALMOCOR. Ophthalmology and ocular surgery clinic. Cordoba, Spain. METHODS: A total of 364 patients were evaluated 1, 3 and 7 days after cataract surgery, performing optical coherence tomography (OCT) at each examination. We studied 162 patients who were given an intracameral injection of a standard cefuroxime solution (0.1 ml/1 mg) and a further 202 patients who were given an injection of the same cefuroxime solution, but without controlling the amount injected into the anterior chamber and irrigating the surface with the remaining solution. RESULTS: Thirty cases ( 15%) of serous neuroepithelial detachment (SND) and oedema in the outer layers of the retina were observed in the group of patients in whom the cefuroxime was injected in an uncontrolled manner, compared to none in the patient group in which 0.1 ml/1 mg was injected. CONCLUSION: An excessive volume of cefuroxime, albeit at the correct concentration (0.1 ml/1 mg), injected following uncomplicated cataract surgery can cause SND that resolves without any apparent side effects. J Emmetropia 2016; 2: Intracameral cefuroxime injection has been shown to reduce the incidence of postoperative endophthalmitis five-fold 1, and is commonly used in the postoperative prophylaxis of bacterial endophthalmitis following cataract surgery 2. Submitted: 2/11/2016 Revised: 6/29/2016 Accepted: 7/21/ OFTALMOCOR, Ophthalmology and ocular surgery clinic. Córdoba, Spain. Financial Disclosure: None of the authors has a financial or proprietary interest in any product, material or method mentioned herein. Corresponding Author: Miguel Giménez de la Linde OFTALMOCOR C/ Francisco Rabal s/n Cordoba (Spain) oftalmocor@oftalmocor.com The European Society of Cataract and Refractive Surgeons (ESCRS) 3 found in a large multicentre study that the intracameral injection of cefuroxime (0.1 ml/1 mg) at the end of cataract surgery reduced the risk of postoperative endophthalmitis. When not used, the risk of this condition increased five-to sixfold. Since then, it has been routinely used in this procedure. Dilution errors were initially reported 4-5, but while these had no consequences in some cases 6, in others, severe toxic effects on the retina and human corneal epithelial cells were described at doses higher than 2.75 mg/ml 7. The occurrence of serous neuroepithelial detachment (SND) during the postoperative period following uncomplicated cataract surgery in some patients led us to study this complication, in an attempt to establish whether its cause could be related with the intracameral administration of cefuroxime SECOIR Sociedad Española de Cirugía Ocular Implanto-Refractiva ISSN:

80 CEFUROXIME AND SEROUS NEUROEPITHELIAL DETACHMENT MATERIALS AND METHODS This was a retrospective observational study that evaluated two homogeneous groups of patients who underwent cataract surgery

2 80 CEFUROXIME AND SEROUS NEUROEPITHELIAL DETACHMENT MATERIALS AND METHODS This was a retrospective observational study that evaluated two homogeneous groups of patients who underwent cataract surgery by phacoemulsification and intraocular lens (IOL) implantation, applying a presurgical periocular and conjunctival and final hygiene protocol with povidone-iodine 5% (Betadine ). All patients received topical and intracameral anaesthesia with lidocaine ( ml) and intracameral cefuroxime (0.1 ml/1 mg). A total of 364 patients (mean age ± 9.30 years) were studied, in whom an IOL with a mean power of ± 4.54 dioptres (D) was implanted. Group 1 consisted of 162 patients (91 women and 71 men) who were given an intracameral injection of a standard cefuroxime solution (0.1 ml/1 mg), while group 2 consisted of 202 patients (122 women and 80 men) who were also injected with the same cefuroxime solution, but without controlling the volume injected into the anterior chamber, and irrigating the surface with the remaining solution. All patients underwent macular optical coherence tomography (OCT) (3D OCT-1000, Topcon) 1, 3 and 7 days after the cataract surgery. RESULTS In the 162 patients in group 1, who were given the controlled dose of cefuroxime (0.1 ml/1 mg), SND was not observed in any case (p = 0.000). In the 202 patients in group 2, in which the amount of cefuroxime at the same concentration was not controlled, SND occurred in 30 eyes (14.85%) (Table 1). In all cases, the onset of SND occurred within 24 hours (1 st check-up). Three types were considered, depending on the area of the retina where they appeared: central (macular) (11 cases, 36.67%), peripheral (perimacular) (10 cases, 33.33%) and both areas (9 cases, 30.0%). The mean height was ± μm in the central areas (Figure 1) and ± μm in the peripheral areas (Figures 2 and 3).The SND resolved within 1 week in all cases. We did not find any relationship between the onset of SND and sex ( 2 = 0.923, p = 0.337), age (t = 0.13, p = 0.900) or power of the IOL implanted (t = 0.08, p = 0.938), nor were there any significant differences between myopic and non-myopic patients. Table 1. Frequencies of serous neuroepithelial detachment (SND) according to control of cefuroxime. Group 1 Cefuroxime controlled Group 2 Cefuroxime not controlled NO SND SND All All Pearson s Chi-square = ; degrees of freedom = 1; p value = Likelihood ratio Chi-square = ; degrees of freedom = 1; p value = Figure 1. A. Retinography and OCT image 24 hours after surgery, showing SND microns thick. B. Retinography and OCT image showing resolution of the SND 5 days after surgery.

CEFUROXIME AND SEROUS NEUROEPITHELIAL DETACHMENT 81 DISCUSSION A study with rabbits 8 showed that a dose of 1 mg/0.1 ml of cefuroxime administered intravitreally was not toxic to the rabbit retina.

1 ml dose injected intravitreally induced transient physiological effects, due to the permanent reduction in electroretinogram (ERG) responses and structural damage to the retina, with signs of glial

3 CEFUROXIME AND SEROUS NEUROEPITHELIAL DETACHMENT 81 DISCUSSION A study with rabbits 8 showed that a dose of 1 mg/0.1 ml of cefuroxime administered intravitreally was not toxic to the rabbit retina. In contrast, a 10 mg/0.1 ml dose injected intravitreally induced transient physiological effects, due to the permanent reduction in electroretinogram (ERG) responses and structural damage to the retina, with signs of glial activation. Cataract surgery has been linked to macular thickening with no serous detachment 9. Similarly, postsurgical cystic macular oedema (CME) and the serous central chorioretinopathy syndrome associated with CME can occur relatively late after surgery 10. Kasparova et al. 11 injected various drugs at the appropriate concentration and at lower doses than recommended into the anterior chamber of rabbit eyes; no toxic effects occurred in the anterior segment. Grupta et al. 12 reported that the use of 1 mg of intracameral cefuroxime in cataract surgery was not associated with increased macular thickness in the 4-6 weeks following the operation, compared to an injection of balanced saline solution only. In our cases, initial diagnosis was made upon encountering a refractive surprise following surgery, with hyperopias of +4 D, confirming the macular oedema with OCT (Figure 1). One characteristic of our cases that we did not find described in the literature was the occurrence of SND indiscriminately in the central area (Figure 2), peripheral area (Figure 3) or both. We divided the SND according to the area in which it appeared, and found that there were no significant differences between these areas. An incidence of 33% was found in each area. In the cases of peripheral SND (Figure 3) in which the macular area was attached, with a normal appearance, the peripheral SNDs appeared in both the nasal and temporal side of the central area. The rapid response to treatment (acetazolamide 250 mg every 8 hours and topical ketolorac) of our cases both central and peripheral suggests that the initial prognosis for this complication is good. The vulnerability of the retina to cefuroxime has been analysed at standard doses, and no alterations in retinal tolerance have been reported 13. The toxic effects of cefuroxime during cataract surgery have been described due to dilution errors 4,14 (injection of mg in the anterior chamber) causing serous retinal detachment, anterior chamber toxicity and corneal oedema. The cases resolved within 5 days. The authors concluded that the toxicity of the drug at these concentrations is 100%. Other authors 15,16 have described this complication with established doses of 0.1 ml/1 mg. In our study, this complication did not arise in any patients when the volume injected was 0.1 ml, so we thought that a higher volume had inadvertently been administered. Wong et al. 17 reported that in 6 eyes (46%), intracameral injection of an erroneously diluted solution of cefuroxime (0.1 ml/9 mg) was associated with macular oedema and diminished visual acuity, which resolved within 1 week. Figure 2. OCT image of peripheral SND. Macular OCT image (A) showing no alteration, and image (B) and 3D map (C) showing the peripheral alteration. Figure 3. OCT image of central and peripheral SND, showing lifting in both slices, and 3D map.

4 82 CEFUROXIME AND SEROUS NEUROEPITHELIAL DETACHMENT Haemorrhagic retinal infarctions have also been described 18, attributable to an accidental overdose of cefuroxime following cataract surgery with posterior capsule rupture. Çakir et al. 19 reported toxic anterior segment syndrome after uncomplicated cataract surgery due to the use of cefuroxime. A case of serous macular detachment related with the subconjunctival injection of cefuroxime 0.1 ml/1 mg has also been described 20. Glial fibrillary acidic protein immunoreactivity in Müller cells has been considered in an attempt to explain the cause of SND, and has been observed in rabbits with high cefuroxime doses. This alteration in the Müller cells was also shown in the study by Faure et al. 15, which detected major changes with a schisis-like appearance of the outer nuclear layer and a large retinal serous detachment. However, the three-line complex formed by the external limiting membrane, ellipsoid zone and interdigitation zone was not affected. The hypothesis has been raised that niacin causes a disturbance in the function of the Müller cells, without interrupting the blood-retinal barrier 15. The pattern of SND observed may be related to the anatomy in the Müller cell layer. The most remarkable effect of the cefuroxime on the ERG responses was the transient selective reduction of the ERG b-wave, which was sometimes accompanied by an increase in the ERG a-wave, leading to the development of a typical electronegative pattern of the ERG responses. This was more evident in the eyes injected with the high dose of cefuroxime when they were examined shortly after the injection. This alteration in ERG also disappeared over time 14,15. We think that cefuroxime should be delivered at a dose of 0.1 ml/1 mg, but that manoeuvres such as hydration of the incisions or irrigation of the corneal surface with any surplus drug should be avoided. We have added OCT to our protocol for all patients undergoing cataract and/or implantable collamer lens or implant surgery. In conclusion, an excessive dose of intracamerular cefuroxime can cause SND and oedema in the outer layers of the retina after cataract surgery that resolves without apparent side effects. The SND can appear in the central area of the retina, the periphery or in both areas. It can go unnoticed if an OCT scan is not performed and only the central area of the macula is examined. After controlling the dilution and volume of solution injected during the surgery, no new cases of SND appeared. This confirms that when a controlled volume of cefuroxime solution is injected intracamerally, SND is highly unlikely to occur (p = 0.00). REFERENCES 1. Irvin SR. A newly defined vitreous syndrome following cataract surgery, interpreted according to recent concepts of the structure of the vitreous. Am J Ophthalmol. 1953; 36: Barry P, Seal DV, Gettinby G, Lees F, Peterson M, Revie CW, for the ESCRS Endophthalmitis Study Group. ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery; preliminary results from a European multicenter study. J Cataract Refract Surg. 2006; 32: ESCRS Endophthalmitis Study Group. Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors. J Cataract Refract Surg. 2007; 33: Olavi P. Ocular toxicity in cataract surgery because of inaccurate preparation and erroneous use of 50 mg/ml intracameral cefuroxime. Acta Ophthalmol. 2012; 90:e Qureshi F, Clark D. Macular infarction after inadvertent intracameral cefuroxime. J Cataract Refract Surg. 2011; 37: Sakarya Y, Sakarya R. Cefuroxime dilution error. Eur J Ophthalmol. 2010; 20: Yoeruek E, Spitzer MS, Saygili O, et al. Comparison of in vitro safety profiles of vancomycin and cefuroxime on human corneal endothelial cells for intracameral use. J Cataract Refract Surg. 2008; 34: Shahar J, Zemel E, Perlman I, Loewenstein A. Physiological and toxicological effects of cefuroxime on the albino rabbit retina. Invest Ophthalmol Vis Sci. 2012; 53: Pareja-Esteban J, Moreno-Arrones JP, Drake Rodríguez- Casanova P, Gutiérrez-Ortiz C, Teus MA. Cambios morfológicos maculares tras cirugía de cataratas: factores de riesgo. Arch Soc Esp Oftalmol. 2009; 84: Boulanger G, Weber M. Irvine Gass syndrome and central serous chorioretinipathy, pure coincidence or non-fortuitous association. J Fran Ophtalmol. 2009; 32: Kasparova EA, Fedorov AA, Shutsiun V, Zaĭtsev AV. Ocular toxicity of intracamerally injected antibacterial and antifungal drugs (experimental and morphological study). Vestn Oftalmol. 2015; 131: Gupta MS, McKee HD, Saldaña M, Stewart OG. Macular thickness after cataract surgery with intracameral cefuroxime. J Cataract Refract Surg. 2005; 31: Gass JDM, Norton EWD. Cystoid macular edema and papiledema following cataract extraction: a fluorescein fundoscopic and angiographic study. Arch Ophthalmol. 1966; 76: Delyfer MN, Rougier MB, Leoni S, et al. Ocular toxicity after intracameral injection of very high doses of cefuroxime during cataract surgery. J Cataract Refract Surg. 2011; 37: Faure C, Perreira D, Audo I. Retinal toxicity after intracameral use of a standard dose of cefuroxime during cataract surgery. Doc Ophthalmol. 2015; 130:57-63.

CEFUROXIME AND SEROUS NEUROEPITHELIAL DETACHMENT 83 16. Le Dûa, V. Pierre-Kahnb. Early macular edema after phacoemulsification and suspected overdose of cefuroxime: Report of six cases.

5 CEFUROXIME AND SEROUS NEUROEPITHELIAL DETACHMENT Le Dûa, V. Pierre-Kahnb. Early macular edema after phacoemulsification and suspected overdose of cefuroxime: Report of six cases. J Fran Opthalmol. 2014; 37: Wong, David C. Transient Macular Edema after Intracameral Injection of a Moderately Elevated Dose of Cefuroxime during Phacoemulsification Surgery. JAMA Ophthalmol. 2015; 133: Çiftçi S, Çiftçi L, Dag V. Hemorrhagic retinal infarction due to inadvertent overdose of cefuroxime in cases of complicated cataract surgery: retrospective case series. Am J Ophthalmol. 2014; 157: Çakır B, Celik E, Aksoy NÖ, et al. Toxic anterior segment syndrome after uncomplicated cataract surgery possibly associated with intracameral use of cefuroxime. Clinical Ophthalmology. 2015; 9: Kontos, A. Mitry D, Althauser S, Jain S. Acute serous macular detachment and cystoid macular edema after uncomplicated phacoemulsification using standard dose subconjunctival cefuroxime. Cutaneous Ocular Toxicol. 2014; 33: First author: Miguel Giménez de la Linde, MD OFTALMOCOR, Ophthalmology and ocular surgery clinic. Córdoba, Spain.

Optometric Postoperative Cataract Surgery Management

Financial Disclosures Optometric Postoperative Cataract Surgery Management David Dinh, OD Oak Cliff Eye Clinic Dallas Eye Consultants March 10, 2015 Comanagement Joint cooperation between two or more specialists