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CO2 Laser-assisted Sclerectomy Surgery, Part II: Multicenter Clinical Preliminary Study Noa Geffen, MD,*w Yokrat Ton, MD,*w Joshua Degani, PhD,z and Ehud I. Assia, MD*w deep, unroofing of the Schlemm canal and exposure of the Purpose: To evaluate the efficacy of CO2 laser-assisted sclerectomy juxtacanalicular trabeculum, all of which are essential for surgery (CLASS) in primary and pseudoexfoliative open-angle allowing effective fluid percolation.6 Inadvertent perforation of the thin trabecular membrane during these manual Materials and Methods: Patients for primary filtration surgery manipulations is a frequent complication, occurring in 30% underwent CLASS with a CO to 50% of the cases during the early stages of the learning 2 laser system (OT-134-IOPtiMate, IOPtima Ltd., Ramat Gan, Israel). This self-controlled system curve,7,11 whereas, in contrast, if the tissue is not cut deep gradually ablates and removes scleral layers until percolating fluid enough, effective filtration may not be achieved.
absorbs the energy, attenuating further tissue ablation. Intraocular CO2 laser-assisted sclerectomy surgery (CLASS) pro- pressure (IOP) was measured at baseline, 1, 2, 4, and 6 weeks, and cedure offers a potential alternative to the manual NPDS 3, 6, and 12 months, respectively. Complete success was defined as procedure for the management of medically uncontrolled 5rIOPr18 mm Hg and 20% IOP reduction with no medication at glaucoma. The characteristics of the CO a 12-month endpoint visit, and qualified success as the same IOP 2 laser, when used range with or without medication.
specifically to ablate the sclera, are elaborated in part I ofthis study. The unique characteristics of this laser were used Results: Thirty of 37 patients completed 12 months of follow-up.
to develop the simplified CLASS procedure, in which Mitomycin C was used in 25 procedures (83.3%). The mean inadvertent perforations are unlikely.12,13 The CO baseline IOP of 26.3 ± 7.8 mm Hg (mean ± SD) dropped to 14.4 effect ceases once aqueous starts to percolate preventing ± 3.4 and 14.3 ± 3.1 mm Hg at 6 and 12 months, respectively, perforation. When used in conjunction with a micromani- with 42.4% and 40.7% IOP reduction at 6 and 12 months,respectively (P<0.001). Complete success was achieved by 76.7% pulating system, the OT-134 (IOPtiMate; IOPtima Ltd., and 60% of the patients at 6 and 12 months, respectively, whereas Ramat Gan, Israel), it can be used to achieve effective fluid qualified success was achieved by 83.3% and 86.6% of the patients percolation in a minimal or noninvasive procedure. The at 6 and 12 months, respectively. Complications were mild and OT-134 also offers a scanning mode that further facilitates transitory with no sequela.
precisely controlled tissue ablation.
Experimental studies in animal eyes and in human Conclusions: Short-term and intermediate results suggest thatCLASS may become a simple, safe, and effective means of choice cadaver eyes12 confirmed that the novel CLASS technique for the treatment of open-angle glaucoma.
is a relatively simple operation with a short learning curve.
After preclinical trials using the OT-134, as described in the Key Words: glaucoma, filtration, nonpenetrating deep sclerectomy, first part of this study, we evaluated the safety and efficacy of the CLASS technique in the clinical trials described here.
(J Glaucoma 2010;00:000–000) MATERIALS AND METHODS This was a prospective, nonrandomized, noncompara- he pioneering work of Krasnov1 in 1969 and the various tive, multinational, multicenter clinical research study, modifications that succeeded it2–8 have led to the conducted in accordance with the Declaration of Helsinki development of a filtration procedure known as the with the approval of the human research committee of the nonpenetrating deep sclerectomy (NPDS). Conventional participating medical centers, with applicable regulations trabeculectomy has so far remained the gold standard for pertaining to good clinical practice. All participating glaucoma surgery, despite its potential vision-threatening patients or their legal guardians signed an informed consent complications, including shallow or flat anterior chamber, document before the study was started. The clinical trials hypotony, infection, choroidal hemorrhage, and malignant were carried out in Mexico city, Mexico (Drs Carrasco and glaucoma.9 NPDS is known to have a higher safety profile Turati), in Madanapelee, India (Drs Thomas and Naveen), compared with trabeculectomy10 but one of the main and in Moscow, Russia (Dr Anisimova).
drawbacks of the procedure is its technical difficulty. The Eligible candidates were adults (aged 18 years or procedure requires dissection of 2 scleral flaps; superficial and above) of both sexes, with primary open-angle glaucomaor pseudoexfoliative glaucoma in the eye scheduled forsurgery. The clinical diagnosis was based on the findings of Received for publication February 7, 2010; accepted August 16, 2010.
glaucomatous optic neuropathy and of reliable and From the *Department of Ophthalmology, Meir Medical Center, Kfar reproducible evidence of visual field defects typical of Saba; wSackler Faculty of Medicine, Tel Aviv University, Tel Aviv; glaucoma. The criteria for glaucoma diagnosis were an and zIOPtima Ltd, Ramat-Gan, Israel.
Supported by a grant from IOPtima Ltd, Ramat-Gan, Israel.
open-angle and glaucomatous appearance of the optic Reprints: Ehud I. Assia, MD, Department of Ophthalmology, Meir nerve head, including thinning or notching of the neuro- Medical Center, 59 Tchernichovsky Street, 44281 Kfar Saba, Israel retinal rim accompanied by localized or diffuse retinal nerve fiber layer loss, cup/disc ratios being higher vertically Copyright r 2010 by Lippincott Williams & WilkinsDOI:10.1097/IJG.0b013e3181f7b14f compared with horizontally, and accompanied by correlated J Glaucoma  Volume 00, Number 00, '' 2010 Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

J Glaucoma  Volume 00, Number 00, '' 2010 typical glaucomatous visual field loss. Primary filtration threshold 24-2 Humphrey perimetry tests, the last of which surgery was indicated in each participant, all of whom were was carried out within 2 weeks before surgery.
on maximal tolerated ocular hypotensive medications and Complications, both intraoperative and postoperative had an intraocular pressure (IOP) in the study eye of 18 mm (early, through day 7, and late, beyond 1 wk), were classified Hg or higher, as measured with a Goldmann applanation according to severity and their relationship to the studied tonometer during 3 consecutive visits over a 90-day period device. In addition, the incidence of intraoperative macro- before enrollment. In addition, inclusion criteria were a perforations, defined as perforations accompanied by iris phakic or pseudophakic study eye with a Shaffer angle prolapse or anterior chamber shallowing or both, was wider than grade 2, no associated ocular disorders other than cataract, and no earlier surgical or laser interventionin the study eye other than clear corneal incision cataract Surgical Technique All the operations were performed under subconjuncti- Patients with a history of an earlier intraocular surgery val anesthesia with 2% lidocaine without epinephrine. A but clear corneal cataract extraction, a history of ocular 5.5-mm superior fornix-based incision was made and the laser procedures, or with a history of severe eye trauma Tenon capsule was dissected to expose the sclera. A partial were excluded from the study. Patients with any media thickness (one-third to one-half) rectangular limbal-based opacity, which may interfere with optic nerve evaluation, 5 5-mm superior scleral flap was dissected at the limbus into and patients with a pupillary dilation diameter of <2 mm, the clear cornea. The desired scanning area and the shape a best-corrected visual acuity of 20/200 or less in the fellow were set, the laser beam was focused, and the area to be eye, known allergy to the study medications, with severe treated was verified with a red laser (HeNe)-aiming beam systemic disease or disabling conditions, or pregnant or (Fig. 1A). The CO2 laser beam was then applied over an area nursing women were excluded from the study. Data from that included the Schlemm canal until the outer wall of the patients, who were followed up for less than 6 months, were canal was ablated and a scleral bed was formed. The residual excluded from the study.
charred tissue was wiped away with a BSS damp Weck-Cel The patients underwent a baseline examination within sponge and ablation was continued until sufficient percola- 2 weeks before surgery, and 1 day, 1, 2, 4, and 6 weeks, and tion was achieved along a region of at least 3 mm in length 3, 6, and 12 months after surgery. Baseline examination (Figs. 1B–D). The scleral flap was repositioned and secured included refraction, best-corrected visual acuity measured with 2 interrupted 10-0 nylon sutures and a high-molecular with a Snellen chart, comprehensive biomicroscopy, IOP weight ophthalmic viscosurgical device (Healon 5; Abbott assessment with a calibrated Goldmann applanation tono- Medical Optics, Santa Ana, CA) was applied beneath the meter (average of 3 repeated measurements taken at the flap. The conjunctiva was adequately secured with 10-0 nylon same time of the day ± 1 h), and fundus examination buried sutures (2 to 4), and the eye was patched with including optic disc evaluation. The patients also under- antibiotic and steroid ointments.
went gonioscopy, assessment of central corneal thickness The application of mitomycin C (MMC) and its (average of 3 repeated measurements), and 3 consecutive concentration were left to the surgeon's discretion. The FIGURE 1. Surgical steps: (A) a carbon dioxide laser beam is applied under a scleral flap. Red aiming beams indicate the area to beablated. When the lateral anterior dots are positioned at the surgical limbus (transition of transparent to gray zones) the ablated area willinclude the Schlem canal. B, Percolating aqueous is beginning to be seen at the ablated area. C, The desired surgical endpoint isachieved, percolation without scleral perforation. D, The superficial flap is sutured to its original position. E, Postoperative image of theconjunctival bleb 1 month later in the patient.
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J Glaucoma  Volume 00, Number 00, '' 2010 CO2 Laser-assisted Sclerectomy Surgery, Part II patients were treated postoperatively with prednisolone deep, causing perforation, or too small). In 1 of these acetate 1% drops (Pred Forte; Allergan, Irvine, CA) 6 times 4 cases the ablation zone was larger than the dissected flap, daily for 4 weeks and with moxyfloxacin 0.5% drops and in the other 3 cases the surgeons opted to convert to (Vigamox; Alcon Laboratories, Fort Worth, TX) 4 times conventional trabeculectomy. One patient was excluded daily for 2 weeks.
as he underwent laser treatment (iridectomy) before this Surgeons working on their first cases with the CLASS procedure, a major violation of the protocol. Moreover, procedure were permitted to convert to conventional this patient had Fuch endothelial dystrophy leading to trabeculectomy at any stage of the operation.
corneal decompensation, which was another protocolviolation. Although all 5 patients were excluded from the Postoperative Analysis performance analysis, those who had received at least "Complete success" was defined as IOP values partial laser treatment were included in the safety analysis.
measured at the 6-month visit and 12-month endpoint, All the patients were followed in the prospective ranging between 5 and 18 mm Hg and IOP reduction prescribed manner apart from 1 patient who was lost to Z20% compared with baseline IOP without additional follow-up 6 weeks after the procedure and another patient hypotensive medication or repeat filtration surgery. The who died, 4 weeks after the procedure, from causes same finding, but also including patients who required unrelated to the glaucoma surgery (complications of long- hypotensive medications postoperatively, was defined as standing severe diabetes mellitus).
"qualified success." Failure was defined as an IOP value MMC was used in 25 patients (83.3%), of which 15 <5 mm Hg and >18 mm Hg, IOP reduction of <20% patients at a concentration of 0.02% for 2 minutes and 10 compared with baseline IOP, severe loss of vision, or the patients at a concentration of 0.04% for 1 minute. Shallow need to undergo additional glaucoma surgery other than diffuse blebs were observed in all the cases (Fig. 1E).
goniopuncture or needling. Goniopuncture and needlingwere not considered to be failures or adverse events, as both are commonly used as normal postoperative interventions Data on all 37 enrolled patients were used in the that are required to maintain or augment the operative analysis of safety outcomes. No device malfunctions results of glaucoma surgeries.13–15 The number of hypo- occurred. There were no device-related macroperforations.
tensive medications being used by each patient at the time Four cases of microperforation, defined as small trabeculo- of the 6-month and the 12-month visits was compared with Descemet holes with no loss of depth of the anterior the baseline situation.
chamber, and no iris prolapse, were recorded. The anteriorchamber remained deep and stable in all cases.
Statistical Methods Mild transitory complications were recorded in some Continuous variables were summarized in terms of of the 30 patients who were included in the final analysis.
the mean, median, standard errors, and minimum and maxi- These included 4 cases of superficial punctuate keratitis, mum values. Categorical variables were derived from fre- microhyphema (1 case), infectious conjunctivitis (1 case), quency counts and percentages.
wound dehiscence (1 case), and wound leaks (2 cases, both The 95% confidence intervals (CIs) were calculated for at 1 surgical center in which the surgeon did not suture the the mean IOP measurements and for the success rates at scleral flap in half of the procedures, including those 6-month follow-up and the 12-month endpoint. A paired 2 cases). All complications resolved spontaneously or with t test was used to determine the significance of the changes conservative treatment in 1 month after the surgery. None in IOP. All the tests applied were 2 tailed, and a P value of of these ill effects was attributed specifically to the laser r0.05 was considered significant. The data were analyzed treatment. One patient developed choroidal detachment using the SAS software (SAS Institute, Cary, NC).
1 week postoperatively; this was treated by drainage andwas completely resolved.
Performance Analysis Between December 2007 and June 2008, 37 consecu- The preoperative IOP of 26.3 ± 7.8 mm Hg (mean ± tive patients (37 eyes) who met the inclusion/exclusion SD) dropped to 14.4 ± 3.4 mm Hg at 6 months and 14.3 ± criteria were enrolled in the study. Demographic data and 3.1 mm Hg at 12 months postoperatively (Fig. 2), yielding baseline information on the recruited patients are summar- average IOP reductions at 6 and 12 months of 11.9± ized in Table 1.
7.4 mm Hg (42.4%) and 11.6 ± 8.4 mm Hg (40.7%), Five patients were excluded from the performance respectively (P<0.001). Kaplan-Meier survival curves for analysis; in 4 cases because of inappropriate size and probability of CLASS success are presented in Figure 3.
configuration of the manually performed scleral flap (too The patterns of IOP reduction were similar at all 3 surgical TABLE 1. Demographic Details and Baseline Data Hispanic, 14 (37.8%); Indian, 13 (35.2%); Caucasian, 10 (27%) CCT indicates central corneal thickness; C/D, cup-to-disc ratio; PEXG, pseudoexfoliative glaucoma; POAG, primary open-angle glaucoma.
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J Glaucoma  Volume 00, Number 00, '' 2010 Average IOP by site
FIGURE 2. Cumulative intraocular pressure (IOP) ± SD measure- ments of 33 patients taken from the preoperative stage up to 12 months postoperatively. Average IOP reduction at 12 months = FIGURE 4. Intraocular pressure results at each of the participat- 41%. Dashed line indicates preoperative IOP level minus 20%.
ing surgical centers. The intraocular pressure patterns are almostidentical in the 3 centers in the 3 different continents.
Nonpenetrating filtration surgery is a promising surgical centers in Asia (India), America (Mexico), and Europe procedure for open-angle glaucoma treatment. A review of (Russia) (Fig. 4). Defining success as 5rIOPr18, and 20% the literature shows contradictory findings, however, with IOP reduction, the complete success rates after 6 and 12 some studies describing NPDS as superior2–4 and others as months were 76.7% (95% CI, 0.58-0.90) and 60% (95% CI, similar or inferior-to-standard trabeculectomy.16–18 Despite 0.40-0.77), respectively, whereas qualified success were its possible advantages, mainly its higher safety profile 83.3% (95% CI, 0.65-0.94) and 86.6% (95% CI, 0.69- compared with those of other filtration procedures, many surgeons are reluctant to use this procedure. A meta-analysis The complete success rates after 12 months with and of the results of manual NPDS19 showed that a mean IOP of without MMC were 68.2% and 42.9%, respectively, not 21 mm Hg or lower at a mean follow-up of 31.3 months was showing statistically significant difference (P = 0.375), achieved by 48.6% of patients without any implant or whereas the rates of qualified success were 95.5% and antimetabolite medications, by 68.7% of patients with an 71.4%, respectively, not showing statistically significant implant, and by 67.1% of patients on use of antimetabolites.
difference either (P = 0.136).
The use of laser technology to improve surgical accuracy is The preoperative use of hypotensive medications per therefore a highly appealing option.12 patient dropped from an average of 2.5 ± 1.3 to 0.1 ± 0.4 at The CO2 laser is most commonly used in laser-assisted 6 months and 0.6 ± 0.9 at 12 months (P<0.001) (Fig. 5).
operations.20 It has been used for tissue dissection in Eight needling procedures were carried out in 7 filtration procedures using either a continuous wave or a patients between 1 and 4 weeks (mean, 3.8 wk) after rapid superpulse mode.21 The CLASS technique is con- surgery. Two patients needed to undergo YAG laser venient because the microdissection is performed under goniopuncture procedures, carried out 2 and 4 weeks after direct microscopic observation, and the safety profile is the initial surgery.
high as the anterior chamber is not penetrated.
FIGURE 3. Kaplan-Meier survival curves for probability of CO2laser-assisted sclerectomy surgery success. Solid line indicates FIGURE 5. Average number of hypotensive medications ± SD qualified success and dashed line indicates complete success.
from the preoperative stage up to 12 months postoperatively.
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J Glaucoma  Volume 00, Number 00, '' 2010 CO2 Laser-assisted Sclerectomy Surgery, Part II The CO2 laser has certain qualities that confer The limitations of this study include the absence of a significant advantages when it is used specifically to facilitate control group and the limited follow-up period (12 mo).
deep sclerectomy filtration surgeries. These include photo- Longer-term follow-up is required to further evaluate and ablation of dry tissues, coagulation of bleeding vessels, and substantiate the safety and long-term efficacy of the CLASS, almost complete absorption of the laser energy by even and to assess its usefulness in a wider spectrum of indications.
minute amount of water. As the emitted radiation is readily Despite these limitations, the results are sufficiently promising absorbed by the percolating aqueous humor, the trabecular to suggest that the CLASS is a simple surgical procedure to meshwork is effectively protected from the laser energy perform, which appears to be relatively safe and effective in when percolation takes place. Thus, perforation of the thin the short and intermediate term.
trabeculo-Descemet membrane during deep sclerectomy,which is the most frequent intraoperative complication of manual NPDS, is substantially minimized.7,11 Study group: Svetlana Anisimova, MD, Ehud I. Assia, The feasibility and safety of the earlier CO2 laser MD, Michael Belkin, MD, Felix Gil Carrasco MD, Elie prototype (model OT-133) for CLASS procedure were Dahan, MD, Noa Geffen, MD, Orna Geyer, MD, Dvora examined in experimental models12 and in a clinical trial.22 Kidron, MD, Guy Kleinman, MD, Shimon Kurtz, MD, Shoba Although the results were usually satisfactory, localized Naveen, MD, Mark Sherwood, MD, Ravi Thomas, MD, heating and tissue photocoagulation resulted in several Yokrat Ton, MD, Mauricio Turati, MD, and Miriam Zalish, cases in early fibrosis and adhesions, with consequent failure of the filtration. The improved version (OT-134)provides faster scanning, higher power focused laser beam, evenly distributed over the scanned area with somebeam overlap to ensure uniform, effective ablation with 1. Krasnov MM. Microsurgery of glaucoma: indications and minimal coagulative thermal damage to adjacent tissues.
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- I, OM OG MED MATEMATIK OG FYSIK I, OM OG MED MATEMA Semi-Mechanistic Pharmacokinetic and Pharmacodynamic Modelling of a Novel Human Recombinant Follicle Stimulating Hormone Trine Høyer Rose Roskilde University Department of Science and Environment nr. 502 - 2016 DK - 4000 Roskilde Roskilde University,