In 2008, image-guided femtosecond lasers became available for cataract surgery.1 These systems led to several benefits, including a reduction in used ultrasound energy and more precise capsulotomies as a basis for capsule-fixated intraocular lenses (IOLs).2–5 For the first time, these devices also treated intraocular tissue. Therefore, triggered intraocular effects are largely unknown and have not been sufficiently investigated. Several studies reported laser-induced miosis occurred shortly after laser treatment, with varying frequencies.6–8 Narrowing of the pupil is potentially associated with a higher complication rate.9 In a previous study, intraocular prostaglandin concentration increased immediately after laser treatment. This was confirmed in two independent study arms.10
Prostaglandins (especially increased prostaglandin E2) are known to play a role in inflammation-induced miosis. However, it is unclear which partial step of laser-assisted cataract surgery leads to the observed prostaglandin release. To reduce the occurrence, a further understanding of the mechanism is needed. The aim of the current study was to investigate if the fragmentation of the lens or capsulotomy induced inflammation after laser-assisted cataract surgery.11–14 Therefore, aqueous humor prostaglandin levels were analyzed right after laser-assisted cataract surgery and laser-assisted capsulotomy or fragmentation only.
Patients and Methods
Aqueous humor samples were obtained from patients undergoing routine microincision cataract surgery and three laser-assisted cataract surgery groups. The samples were collected at the beginning of the surgery and stored at −80°C until used. All tenets of the Declaration of Helsinki were observed. The Lens Opacities Classification System III (LOCS III) was used and preoperative nuclear opalescence was estimated by one independent physician using a Haag Streit BQ 900 slit lamp (Bern, Switzerland) at maximum illumination.
Patients who were scheduled for cataract surgery on one eye and were willing to volunteer for the trial after giving informed consent were randomly allocated to one of four study groups based on the following inclusion criteria.
In the control group, patients with a significant cataract (LOCS III nuclear opalescence grading score, grades II to IV) and without any other ocular diseases were scheduled for traditional microincision phacoemulsification. Similarly, patients with significant cataract and no ocular diseases were included in the laser-assisted cataract surgery groups.
Patients with serious coexisting ocular disease, history of inflammatory eye disease, previous ocular surgery or trauma, relevant corneal opacities, age-related macular degeneration, diabetic and hypertensive retinopathy, any kind of glaucoma, pseudoexfoliation, dilated pupil size smaller than 6 mm, and rheumatic and metabolic diseases were excluded. Age younger than 22 years, pregnancy, the use of nonsteroidal anti-inflammatory drugs or steroids in the past 6 months, and participation in another clinical study were also considered exclusion criteria.
Based on these criteria, 67 patients were included in this prospective study.
Laser-Assisted Cataract and Control Surgery
All surgeries were performed at the Institute for Vision Science, Ruhr University Eye Clinic, Bochum, Germany. Manual and femtosecond laser surgeries were performed by one experienced surgeon (HBD) in all cases. Preoperatively, all groups received the same topical medication. Medical mydriasis was induced using topical 0.5% tropicamide eye drops (Mydriaticum; Stulln Pharma, Stulln, Germany) and 5.0% phenylepherine eye drops (Neo-Synephrine; Ursapharm, Saarbrücken, Germany) instilled three times within 1 hour prior to surgery. Oxybuprocaine eye drops (Conjuncain EDO 0.4%; Dr. Mann Pharma and Bausch & Lomb, Berlin, Germany) were applied three times for topical anesthesia 30 minutes prior to surgery.
In the three laser-assisted cataract surgery groups (capsulotomy, fragmentation, and combination), different steps of the procedure were performed with the Catalys Precision Laser System (Abbott Medical Optics, Santa Ana, CA). In the capsulotomy group, only the capsulotomy was performed with the laser system. In the fragmentation group, only lens fragmentation was performed with the laser system. In the combination group, both capsulotomy and lens fragmentation were performed with the laser system (capsulotomy prior to fragmentation). No corneal incisions were performed with the laser system. In all capsulotomy cases, the set capsulotomy size was 5.0 mm and the programmed pulse energy was 4 µJ, with an incision depth of 600 µm (treatment time 1.6 sec). The iris safety distance zone was set at 500 µm.
In the two lens treatment groups, an extensive segmentation and softening pattern was used (waffle pattern, grid spacing 350 µm, central cross repetition rate of 3, anterior and posterior safety zone 500 µm, and 10-µJ pulse energy). Four to 5 minutes after laser treatment, a paracentesis was made at the 11-o’clock position and approximately 100 µL of aqueous humor was collected. The samples were directly stored at −80°C in a freezer located in the operating room. In the fragmentation group, a manual capsulotomy was performed. In all groups, subsequent nuclear disassembly was conducted and an IOL was implanted.
In the control group, a 1.2-mm paracentesis was created in the same manner as described for the laser-assisted cataract surgery groups. Similar to the other groups, approximately 100 µL of aqueous humor was collected and immediately stored at −80°C. Routine manual cataract surgery with implantation of an IOL was then performed.
Measurements of Prostaglandin in Aqueous Humor
All samples from the four groups were measured at the same time by the same investigator with the same standard preparation to avoid inter-user or plate variability. Prostaglandin concentrations were determined using a commercially available enzyme immunoassay kit (Cayman Chemicals, Ann Arbor, MI) as previously described.10 The enzyme immunoassay kits were used according to the provided manufacturer instructions. Briefly, assays were performed on 96 well plates by adding 50 µL of standards, controls, and samples (aqueous humor) into the wells, followed by a prostaglandin–acetylcholinesterase conjugated tracer and an anti-prostaglandin antibody. After incubation, the plates were rinsed, Ellmans reagent was added, and measurements were performed at a wavelength of 405 µm using a microplate reader (AESKU Reader with Gen5 ELISA Software; AESKU.Diagnostics, Wendelsheim, Germany).
All statistical analyses were performed using Statistica software version 10 (Statsoft, Tulsa, OK). Significant differences in prostaglandin concentration between the groups were calculated using Student’s t test. P values of less than .05 were considered statistically significant.
Patients were randomly placed in one of the four study groups. After positioning the patient on the operating bed, the surgeon opened the corresponding envelope indicating which of the four procedures to choose. In total, 67 aqueous humor samples were analyzed (49 samples of patients undergoing laser-assisted cataract surgery and 18 samples of patients before conventional cataract surgery) (Table 1). There was no difference between the laser-assisted cataract surgery groups and the control group with regard to sex or cataract density.
Clinical Patient Data for the Four Groups
Prostaglandin Concentrations in Aqueous Humor
The prostaglandin level in the human aqueous humor was detected in three different laser-assisted cataract surgery groups and in the control group (conventional cataract surgery). In the control group, total prostaglandin concentration (mean ± standard error of mean; 52.5 ± 8.1 pg/mL) was lower than in all of the laser-assisted cataract surgery groups. Prostaglandin concentration in the capsulotomy group (362.4 ± 117.5 pg/mL) was significantly higher than that in the control group (P = .01). Levels in the combination group (330.6 ± 110.6 pg/mL) were also significantly higher than those in the control group (P = .01) (Figure 1). No difference was found between the fragmentation (186.8 ± 114.0 pg/mL) and control (P = .14) groups (Figure 1). Mean prostaglandin levels in the capsulotomy and combination groups were approximately 80% to 98% higher than those in the fragmentation group.
Mean prostaglandin levels in aqueous humor of all four groups: control, fragmentation, capsulotomy, and combination (fragmentation and capsulotomy). Measured prostaglandin levels were significantly higher in the capsulotomy (P = .01) and combination (P = .01) groups compared with the control group, whereas no significant increase was observed in the fragmentation group (P = .14). Values are median ±25% to ±75% range.
The number of laser-assisted cataract surgeries is increasing worldwide. A laser-induced miosis was described in multiple studies and prostaglandins have been identified as potential inflammatory mediators.6 However, until now, it was unknown which step of the treatment induces miosis.
In the current study, intraocular prostaglandin release after different partial steps of laser-assisted cataract surgery was investigated. In comparison to the control group, significantly higher prostaglandin levels were observed after laser-assisted cataract surgery capsulotomy alone and after capsulotomy in combination with lens fragmentation. The measured prostaglandin levels were comparable to concentrations in the precursor trial.10 Lens fragmentation alone did not result in an increased intraocular prostaglandin concentration.
Surprisingly, the results of this study indicate that the anterior laser capsulotomy stimulates prostaglandin release. It was postulated that prostaglandins are released by the ciliary body due to an increase in temperature, vibrations, or shockwaves.15 Because significantly more energy was used for the fragmentation of the lens than for the capsulotomy (fragmentation: 10 µJ, capsulotomy: 4 µJ) and treatment time for fragmentation was up to 20 times longer, an increase in temperature is not likely responsible for the inflammation. Most likely, laser spots passing the aqueous humor induced vibrations or shockwaves and may represent the main trigger for miosis. Therefore, optimized capsulotomy laser settings have great potential to reduce the described phenomenon and a complete fragmentation of the lens (eg, a waffle pattern) seems to be uncritical. A reduced incision depth in the anterior chamber during capsulotomy in combination with lower pulse energy is especially necessary. Furthermore, we assume that the safety distance of the capsulotomy to the iris needs to be sufficient. A further decrease in the incidence of laser-induced miosis seems possible in combination with nonsteroidal anti-inflammatory drug pretreatment.
The influence of penetrating corneal laser incisions was not investigated in the current study. Similar to the anterior capsulotomy, the laser fires into the anterior chamber during this treatment. Potential vibrations or shockwaves are created and could lead to a higher prostaglandin release. However, in the precursor trial, prostaglandin concentration was not significantly higher with corneal incisions.10 Maybe the greater distance between laser treatment zone and ciliary body reduces this effect. Interestingly, a capsular block syndrome occurred in none of the laser-assisted cataract surgery cases with fragmentation alone. This observation allows the assumption that this complication does not occur or only rarely occurs with current laser system settings. One possible explanation is the fact that the smaller numerical aperture of the Catalys Precision Laser System results in less gas release.
Unfortunately, patients in the lens fragmentation group were significantly older when compared to the combination group (analysis of variance). An influence on the measured values cannot be excluded. However, in vivo prostaglandin measurements always show inter-individual variations. Nonetheless, higher prostaglandin concentrations were measured in the combination and capsulotomy groups and compared with the control group, and the ages in these three groups were comparable.
This study is the first to identify anterior capsulotomy as the main trigger for an increase of prostaglandins in the aqueous humor immediately after laser-assisted cataract surgery. Consequently, an anterior capsulotomy with optimized settings in combination with nonsteroidal anti-inflammatory drug pretreatment may reduce the incidence of laser-induced miosis.
- Nagy Z, Takacs A, Filkorn T, Sarayba M. Initial clinical evaluation of an intraocular femtosecond laser in cataract surgery. J Refract Surg. 2009;25:1053–1060. doi:10.3928/1081597X-20091117-04 [CrossRef]
- Dick HB, Schultz T. Intraocular lens fixated in the anterior capsulotomy created in the line of sight by a femtosecond laser. J Refract Surg. 2014;30:198–201. doi:10.3928/1081597X-20140217-06 [CrossRef]
- Conrad-Hengerer I, Hengerer FH, Schultz T, Dick HB. Effect of femtosecond laser fragmentation on effective phacoemulsification time in cataract surgery. J Refract Surg. 2012;28:879–883. doi:10.3928/1081597X-20121116-02 [CrossRef]
- Dick HB, Schultz T. On the way to zero phaco. J Cataract Refract Surg. 2013;39:1442–1444.
- Friedman NJ, Palanker DV, Schuele G, et al. Femtosecond laser capsulotomy. J Cataract Refract Surg. 2011;37:1189–1198. doi:10.1016/j.jcrs.2011.04.022 [CrossRef]
- Dick HB, Gerste RD, Schultz T. Laser cataract surgery: curse of the small pupil. J Refract Surg. 2013;29:662. doi:10.3928/1081597X-20130920-01 [CrossRef]
- Yeoh R. Intraoperative miosis in femtosecond laser-assisted cataract surgery. J Cataract Refract Surg. 2014;40:852–853. doi:10.1016/j.jcrs.2014.02.026 [CrossRef]
- Bali SJ, Hodge C, Lawless M, Roberts TV, Sutton G. Early experience with the femtosecond laser for cataract surgery. Ophthalmology. 2012;119:891–899. doi:10.1016/j.ophtha.2011.12.025 [CrossRef]
- Artzen D, Lundstrom M, Behndig A, Stenevi U, Lydahl E, Montan P. Capsule complication during cataract surgery: case-control study of preoperative and intraoperative risk factors. Swedish Capsule Rupture Study Group report 2. J Cataract Refract Surg. 2009;35:1688–1693. doi:10.1016/j.jcrs.2009.05.026 [CrossRef]
- Schultz T, Joachim SC, Kuehn M, Dick HB. Changes in prostaglandin levels in patients undergoing femtosecond laser-assisted cataract surgery. J Refract Surg. 2013;29:742–747. doi:10.3928/1081597X-20131021-03 [CrossRef]
- Solomon KD, Turkalj JW, Whiteside SB, Stewart JA, Apple DJ. Topical 0.5% ketorolac vs 0.03% flurbiprofen for inhibition of miosis during cataract surgery. Arch Ophthalmol. 1997;115:1119–1122. doi:10.1001/archopht.1997.01100160289004 [CrossRef]
- Keulen-de Vos HC, van Rij G, Renardel de Lavalette JC, Jansen JT. Effect of indomethacin in preventing surgically induced miosis. Br J Ophthalmol. 1983;67:94–96. doi:10.1136/bjo.67.2.94 [CrossRef]
- Gimbel HV. The effect of treatment with topical nonsteroidal anti-inflammatory drugs with and without intraoperative epinephrine on the maintenance of mydriasis during cataract surgery. Ophthalmology. 1989;96:585–588. doi:10.1016/S0161-6420(89)32845-4 [CrossRef]
- Bucci FA Jr, Waterbury LD. Aqueous prostaglandin E(2) of cataract patients at trough ketorolac and bromfenac levels after 2 days dosing. Adv Therapy. 2009;26:645–650. doi:10.1007/s12325-009-0042-5 [CrossRef]
- Maihofner C, Schlotzer-Schrehardt U, Guhring H, et al. Expression of cyclooxygenase-1 and -2 in normal and glaucomatous human eyes. Invest Ophthalmol Vis Sci. 2001;42:2616–2624.
Clinical Patient Data for the Four Groups
|No. of patients (n = 67)||18||19||11||19|
|Mean age ± standard deviation, y||74.3 ± 7.4||74.0 ± 4.9||81.0 ± 11.1||67.6 ± 10.7|
|Mean cataract grade ± standard deviation||3.1 ± 0.8||3.1 ± 0.6||3.9 ± 1.0||3.1 ± 0.9|