- Email: [email protected]
Evaluation of a multifunctional femtosecond laser for the creation of laser in situ keratomileusis flaps
280
ARTICLE
Evaluation of a multifunctional femtosecond laser for the creation of laser in situ keratomileusis flaps Stephen Slade, MD, Teresa Ignacio, MD, Scott Spector, MD
Purpose: To characterize the performance of a multifunctional femtosecond laser system (Lensx) for the creation of laser in situ keratomileusis (LASIK) flaps. Setting: Two surgical sites in the United States. Design: Prospective case series pilot study. Methods: Patients with myopia or hyperopia who were eligible for femtosecond laser-initiated LASIK surgery with corrected distance visual acuities (CDVA) correctable to at least 20/25 were enrolled. Central flap thickness accuracy (desired versus achieved) and precision (flap thickness standard deviation) were measured using anterior segment optical coherence tomography. Flap dissection quality, stromal bed quality, and amount of opaque bubble layer (OBL) formation were graded during surgery, and the refractive outcomes were evaluated postoperatively at 1-month and 3-month follow-ups.
L
aser in situ keratomileusis (LASIK) is the most commonly performed corneal refractive surgery worldwide1,2 and is used for the correction of myopia, hyperopia, and astigmatism.3 The LASIK procedure begins with the creation of a corneal flap followed by excimer stromal ablation on the corneal bed that corrects the refractive error. The first step, creation of the hinged flap, is the most critical step of the LASIK procedure because it affects safety and efficacy of the final visual outcome. It is important to produce a uniform flap with a narrow standard deviation (SD) to obtain a proper stromal bed thickness and reduce the likelihood of corneal ectasia.4 Corneal flaps were initially created using a microkeratome blade. Microkeratome flap creation subsequently
Results: The study comprised 30 patients (58 eyes). At 3 months postoperatively, the flap thickness accuracy was 1.3 mm G 2.6 (SD). A total of 78.3% of flaps were lifted with no resistance and 16.7% were lifted with minimal resistance using a blunt instrument. All (100%) stromal beds were determined to have a very smooth surface (grade 5 on a 0 to 5 scale). No OBL was observed in 73.3% of eyes; 26.7% of eyes showed an OBL occurring on less than 24% of the stromal bed surface. At 3 months postoperatively, most eyes (84.5%) had an uncorrected distance visual acuity of 20/20 and 98% had a CDVA of 20/20. The most common ocular adverse event was punctate keratitis (11.7%).
Conclusion: The multifunctional femtosecond laser system effectively created LASIK flaps that were high quality, accurate, and precise. J Cataract Refract Surg 2018; 44:280–286 Q 2018 ASCRS and ESCRS
evolved from manually guided mechanical microkeratomes to automated microkeratomes and single-use microkeratomes; however, despite refinements in the technology, complications such as buttonhole flaps and irregular incision planes can still affect the outcome of the procedure.5,6 The use of a femtosecond laser for flap creation has been commercially available since 2002, and it is the most common application of the femtosecond laser.7 The theoretical advantages of femtosecond lasers include increased precision in flap creation, a decrease in flap imperfections, and lower procedural intraocular pressure (IOP).8 Femtosecond lasers create an incision through photodisruption. The laser produces pockets of plasma with each shot that expands, displacing the surrounding tissues and leading to the
Submitted: April 19, 2017 | Final revision submitted: December 1, 2017 | Accepted: December 6, 2017 From the Slade & Baker Vision Center (Slade), Houston, Texas, Alcon Research (Ignacio), Lake Forest, California, and Spector Eye Care (Spector), Norwalk, Connecticut, USA. Presented in part at the European Society of Cataract and Refractive Surgeons, Copenhagen, Denmark, September 2016, and the ASCRS Symposium on Cataract, IOL and Refractive Surgery, Los Angeles, California, USA, May 2017. Supported by Alcon Laboratories, Inc., Fort Worth, Texas, USA. The funding organization participated in the design of the study, conducting the study, data collection, data management, data analysis, interpretation of the data, preparation, and review or approval of the manuscript. Corresponding author: Stephen Slade, MD, 3900 Essex Lane, Houston, Texas 77027, USA. E-mail: [email protected]. Q 2018 ASCRS and ESCRS Published by Elsevier Inc.
0886-3350/$ - see frontmatter https://doi.org/10.1016/j.jcrs.2017.12.016
MULTIFUNCTIONAL LASER FOR LASIK FLAP CREATION
formation of cavitation bubbles.9 An opaque bubble layer (OBL) is produced by gas bubbles that accumulate in the superficial layers of the stromal bed and an excessive OBL might interfere with flap creation.9 Some unique potential complications associated with flap creation using the femtosecond laser include suction failure during the laser treatment resulting in an incomplete cut, OBL formation, vertical gas breakthrough, and transient light sensitivity syndrome.10 The new generation of femtosecond lasers use higher frequency and lower energy than their predecessors that allow for the creation of a better cleavage plane and easier flap lift. Commercially available femtosecond lasers differ with respect to pulse energy, duration, distance, and pattern and therefore must be evaluated empirically.11 Historically, different femtosecond laser systems have been used for either cornea or refractive applications (Intralase, Abbott Medical Optics, Inc.; the FS200, Alcon Laboratories, Inc.; the Femto LDV Z6, Ziemer Ophthalmic Systems AG; and the Visumax, Carl Zeiss Meditec AG) or cataract surgery (Lensar, Lensar, Inc. and the Catalys, Abbot Medical Optics, Inc.), which increases the difficulty and cost of making both procedures available to patients in a single clinic. At present, a few systems are being used for both applications (Femto LDV Z8, Ziemer Ophthalmic Systems AG and Victus, Technolas Perfect Vision GmbH). However, no clinical data have been published regarding the performance of either system with respect to corneal flap creation. The femtosecond laser for the current study (Lensx, Alcon Laboratories, Inc.) has been in use for cataract surgery since 2010. The laser system uses tightly focused ultrashort femtosecond pulses (10 to 15 seconds) to create a continuous incision or tissue separation of the cornea. Previously, a pilot study to assess flap creation in 38 eyes of 20 patients was performed using a prototype that showed no statistically significant difference between the planned and postoperatively measured flap thickness, and with no associated adverse events.12 Herein we report the results of the first study using the commercially available femtosecond laser system with flap creation added as a capability, which evaluated the creation of LASIK flaps in 58 eyes for accuracy, precision, and safety. PATIENTS AND METHODS Study Design and Enrollment The trial was a prospective nonrandomized dual-center open-label pilot study designed to evaluate the thickness accuracy, defined as achieved flap thickness versus desired flap thickness, of LASIK flaps created with a femtosecond laser system. Patients were enrolled at 2 investigative sites (Slade & Baker Vision Center, Houston, Texas, and Spector Eye Care, Norwalk, Connecticut, USA) with 2 investigators (S. Slade and S. Spector, respectively). The patients were required to provide written informed consent before enrollment in the trial and the conduct of any trial-related procedures. The final protocol was approved by the institutional review board. This trial adhered to the provisions of the guidelines of the World Medical Association Declaration of Helsinki. This trial was performed in compliance with all federal, local, and/or regional requirements, including with the U.S. Health Insurance Portability and Accountability Act.
281
Inclusion and Exclusion Criteria Inclusion criteria allowed patients older than 21 years with myopia or hyperopia to be eligible for femtosecond laser–initiated surgery, with corrected distance visual acuity (CDVA) correctable to at least 20/25 in each eye. Exclusion criteria included previous corneal surgery, corneal lesions that would impede laser treatment, corneal edema, hypotony, glaucoma, existing corneal implant, keratoconus, irregular astigmatism, and corneal thickness values that would result in a residual stromal bed less than 280 mm when flap resection and excimer ablation were calculated. Study Treatment and Plan The planned scheduled visits for the study included the screening (day 30 to 1), surgery (day 0), and 2 postoperative visits at 1-month (day 30 to 45) and 3-month (day 90 to 105) intervals. Unscheduled visits were completed if additional follow-up was deemed necessary by the investigator. The total expected duration of participation for each patient was up to 5 months depending on the time of surgery after the preoperative/screening visit and the timing of each postoperative visit thereafter. Patients were enrolled sequentially based on the informed consent form date and time. Eligible patients who signed an informed consent form completed the screening assessments and returned to the clinic within 30 days to have bilateral LASIK surgery. Primary and Secondary Effectiveness Endpoints The primary endpoint of the study was flap thickness accuracy within the central zone at 3 months postoperatively. The secondary endpoints included flap thickness precision within the central zone at 1 month and 3 months postoperatively (variability of the achieved flap thickness), ease of flap dissection, stromal bed quality, OBL assessment, uncorrected distance visual acuity (UDVA) and CDVA, manifest refraction spherical equivalent, and prediction error between target versus achieved refraction. The results for UDVA and CDVA measurements are presented using the standard refractive graphs for reporting refractive surgery outcomes.13 An exploratory effectiveness endpoint was variability of flap thickness measured at 3 points across the central and peripheral zones of the flaps at 3 months postoperatively. Safety Endpoints Safety endpoints included reporting adverse events, findings from slitlamp evaluation, significant IOP measurement, decrease in CDVA, and reporting surgical events and device deficiencies. Flap Thickness Measurements Flap thickness was calculated by subtracting the anterior segment optical coherence tomography (AS-OCT) (Visante, Carl Zeiss Meditec AG and iVue, Optovue, Inc.) measurement from the programmed (desired) flap thickness. Each AS-OCT measurement was performed separately by 2 different technicians to ensure accuracy. They took 1 measurement at the center and then 4 measurements peripherally (6.0 mm from center) at 0-degree, 90-degree, 180-degree, and 270-degree orientations at 1 month and 3 months postoperatively. These measurements were performed by placing the cursor at the appropriate points and visualizing the edge of the flap to manually mark the thickness to be measured by the AS-OCT. This was repeated 3 times for each measurement and the mean was reported. Software centration and live AS-OCT visualization allowed for accurate centration of the flap. Assessment of Flap Dissection Quality Flap dissection quality was assessed using a scale created by the authors ranging from 0 to 5 based on the difficulty in lifting the flap and the amount of resistance encountered. Grades were indicated as follows: 0 Z unable to lift flap, 1 Z able to lift flap with aid of sharp instrument, 2 Z able to lift flap with difficulty using blunt Volume 44 Issue 3 March 2018
282
MULTIFUNCTIONAL LASER FOR LASIK FLAP CREATION
instrument, 3 Z able to lift flap with moderate resistance using blunt instrument, 4 Z able to lift flap with minimal resistance using blunt instrument, 5 Z able to lift flap without any resistance using blunt instrument.
50 eyes was considered sufficient for assessment of flap thickness accuracy.
RESULTS Demographics and Baseline Characteristics
Stromal Bed Quality Assessment The quality of the stromal bed was assessed using a scale created by the authors ranging from 0 to 5 based on roughness of the stromal bed. Grades were indicated as follows: 0 Z very rough, 1 Z moderately rough, 2 Z rough, 3 Z smooth, 4 Z moderately smooth, 5 Z very smooth. Assessment of Opaque Bubble Layer The presence and severity of an OBL was evaluated by the investigators during surgery. Grades were indicated as follows: 0 Z no OBL, 1 Z between 1% and 24% of stromal bed area, 2 Z between 25% and 49% of stromal bed area, 3 Z between 50% and 74% of stromal bed area, 4 Z between 75% and 99% of stromal bed area, 5 Z 100% of stromal bed area. Investigational Device The investigational femtosecond laser (Lensx Laser System) uses tightly focused ultrashort femtosecond pulses (10 to 15 seconds) to create a continuous incision or tissue separation of the cornea. The laser pulses are delivered through a patient interface, a sterile disposable applanation lens, and suction ring assembly that contacts the cornea and fixes the eye with respect to the delivery system. A small volume of tissue (a few microns in diameter) is photodisrupted at the laser focus. A computer-controlled scanning system directs the laser beam throughout a 3-dimensional pattern to the desired target location to produce the incision through photodisruption. The Wavelight laser system and the Visx laser were used to perform the corneal ablation. The femtosecond-laser settings were line spot separation, 7.0 mm and layer separation, and 7.0 mm. Statistical Analysis The safety analysis set was the primary analysis set, and included all patients/eyes that were exposed to the device during the study. No formal statistical hypothesis testing was planned in support of the performance objectives. All baseline, performance, and safety data were summarized using descriptive statistics. A sample size of
Table 1. Demographics and baseline characteristics of the 30 patients in the study. Parameter Age (y) Mean G SD Median Range Sex, n (%) Male Female Race, n (%) White Black or African American American Indian or Alaskan native Asian Other Ethnicity, n (%) Hispanic or Latino Not Hispanic or Latino Not reported or unknown
Volume 44 Issue 3 March 2018
Value 34.5 G 11.0 32.5 21, 61 14 (46.7) 16 (53.3) 26 (86.7) 0 (0.0) 1 (3.3) 1 (3.3) 2 (6.7) 6 (20.0) 22 (73.3) 2 (6.6)
A total of 34 patients (68 eyes) were initially enrolled. Thirty patients (4 did not meet eligibility criteria) had bilateral LASIK surgery and 58 eyes were available upon completion of the study. Of the 30 patients who had bilateral LASIK surgery, 29 completed the study (96.7%) and 1 patient (3.3%) was lost to follow-up before the 1-month visit. Table 1 shows the demographics and baseline characteristics of the study population. The distribution of men to women was balanced and the majority of the patients were identified as white and non-Hispanic or Latino. Analysis of Flap Thickness and Precision
Table 2 shows the mean flap thickness within the central zone, the flap thickness accuracy (defined as the mean difference between the achieved and desired flap thickness within the central zone), and the flap thickness precision (defined as the variation in flap thickness measured by the SD) at 1 month and 3 months postoperatively. Flap Dissection Quality
Of the 60 flaps graded, the majority (47 [78.3%]) were graded 5 (able to lift flap without any resistance using blunt instrument), whereas only 10 (16.7%) were graded 4 (able to lift flap with minimal resistance using blunt instrument and 3 (5.0%) were graded 3 (able to lift flap with moderate resistance using blunt instrument) (Figure 1). Flap Uniformity
Anterior segment OCT (AS-OCT) measurements of the flap thickness were recorded within the peripheral zone (6.0 mm diameter), at 0-degree, 90-degree, 180-degree, and 270-degree orientations. Similar means for flap
Table 2. Flap accuracy and precision. Follow-up Parameter Flap thickness within central zone (mm) Eyes, n Mean G SD Median Range 95% CI Difference between achieved and desired flap thickness (mm) Eyes, n Mean G SD Median Range 95% CI Mean flap thickness accuracy (mm) Mean flap thickness precision (mm) CI Z confidence interval
1 Mo
3 Mo
58 127.8 G 3.7 128.0 110, 134 126.9, 128.8
58 125.8 G 4.8 125.0 107, 134 124.6, 127.1
58 3.3 G 3.8 4.0 4, 10 2.3, 4.4 3.3 3.7
58 1.3 G 2.6 2.0 5, 5 0.6, 2.0 1.3 4.8
283
MULTIFUNCTIONAL LASER FOR LASIK FLAP CREATION
57 eyes were 20/20 (Figure 5). On average, low residual refractive error was observed starting at 1 month postoperatively, with a mean MRSE of 0.17 diopters (D) 3 months postoperatively. For 1 patient, a UDVA worse than 20/40 and a 2-line decrease in CDVA were reported in both eyes at the 1-month visit. This patient recovered to 20/25 by the 3-month visit. The decrease in visual acuity was attributed to a bilateral adverse event of IOP increase caused by a steroid response and conjunctivitis that led to a series of other complications throughout the study. No other eye in the study had a clinically significant decrease in CDVA. Figure 1. Analysis of ease of flap dissection rated by the investigator during surgery (grade 0 Z unable to lift flap; grade 1 Z able to lift flap with aid of sharp instrument; grade 2 Z able to lift flap with difficulty using blunt instrument; grade 3 Z able to lift flap with moderate resistance using blunt instrument; grade 4 Z able to lift flap with minimal resistance using blunt instrument; grade 5 Z able to lift flap without any resistance using blunt instrument).
thickness were observed within the 4 sectors, indicating uniformity of flap thickness across the peripheral zone (Table 3). Stromal Bed Quality
Surface quality of the stromal bed after flap creation was assessed using a 6-point grading scale ranging from 0 (very rough surface) to 5 (very smooth surface). All 60 stromal beds were graded as 5 by the investigators (Figure 2). Opaque Bubble Layer
No OBL was observed in 44 eyes whereas 16 eyes showed an OBL occurring on less than 24% of the stromal bed surface (grade 1) (Figure 3). Furthermore, no surgical complications were reported in any eyes as a result of OBL formation. Visual Acuity
The UDVA was assessed for the 58 eyes that completed the study. At 1 month postoperatively, 47 eyes had a UDVA of 20/20, and at 3 months postoperatively, 49 eyes had a UDVA of 20/20 (Figure 4). The CDVA was assessed for all 60 eyes; patients were manually refracted to their best correction before CDVA testing. At 1 month postoperatively, 53 eyes were 20/20, and at 3 months postoperatively,
Prediction Refraction Error
Figure 6 shows the results of the prediction refraction error analysis (defined as the difference between the actual postoperative refractive error and the intended formula-derived refractive target). The prediction error was 0.5 D or less in 54 eyes at 1 month postoperatively, and in 53 eyes at 3 months postoperatively. Furthermore, the prediction error was 1.0 D in 57 eyes at 1 month postoperatively, and in all 58 eyes at 3 months postoperatively. Safety
The safety analysis set included all patients exposed to the device during the study. Table 4 shows the ocular treatment-emergent adverse events. No adverse event or serious adverse event related to the device was reported. The 1 serious adverse event that did occur was flap microstriae of mild severity, which required a surgical intervention of flap refloat. The investigator reported that the corneal flap microstriae had resolved at an unscheduled visit 2 days postoperatively. Table 5 shows the incidence and details of the ocular treatment-emergent adverse events. Surgical Events and Device Deficiencies
Two incidences of surgical events were reported, both of which related to a patient interface suction failure. In both cases the patient interface was replaced and the surgery completed. DISCUSSION Femtosecond lasers have been shown to reduce postoperative complications and improve the smoothness and accuracy of flap creation compared with mechanical microkeratome use.10 Following the initial data on a
Table 3. Flap uniformity in 58 eyes. Degree Parameter Flap thickness in peripheral zone (mm) Mean G SD Median Range 95% CI
0
90
180
270
126.4 G 4.9 126.5 109, 133 125.1, 127.6
125.9 G 4.7 126.0 108, 133 124.7, 127.2
126.2 G 5.2 126.0 106, 135 124.9, 127.6
126.1 G 5.0 126.5 106, 133 124.8, 127.4
CI Z confidence interval
Volume 44 Issue 3 March 2018
284
MULTIFUNCTIONAL LASER FOR LASIK FLAP CREATION
Figure 2. Analysis of stromal bed quality rated by the investigator during surgery based on a roughness scale (grade 0 Z very rough; grade 1 Z moderately rough; grade 2 Z rough; grade 3 Z smooth; grade 4 Z moderately smooth; grade 5 Z very smooth).
femtosecond laser prototype, the current study was conducted to characterize the accuracy, precision, and safety of the commercially available system (differences between the 2 systems include the patient interface and software). The current study was designed for 3 months of followup, in contrast to similar studies that were followed for 1 month.14,15 In this study, AS-OCT measurements of flap thickness were 127.8 G 3.7 mm at 1 month postoperatively, and 125.8 G 4.8 mm at 3 months postoperatively, which were comparable to femtosecond lasers dedicated only to corneal and refractive applications. A previous pilot study using the same laser system reported a mean postoperative flap thickness of 140.28 G 8.0 mm.12 Two other studies using another femtosecond laser system (LDV Z6)14,15 found mean postoperative flap thicknesses of 90.1 G 2.7 mm and 89.6 G 2.0 mm, respectively. In the current study, the measurements of flap thickness accuracy within the central zone at 1 and 3 months were 3.3 G 3.8 mm and 1.3 G 2.6 mm, respectively, showing that flaps can be created accurately and precisely with a multiplatform femtosecond laser. The advantages of creating an accurate flap are well documented. Thick flaps can increase the probability of residual corneal stroma
Figure 4. The UDVA (Snellen) was assessed for each patient at baseline and at 1 month and 3 months postoperatively. The preoperative CDVA is presented for comparison. Analysis was performed on the safety set (CDVA Z corrected distance visual acuity; UDVA = uncorrected distance visual acuity).
Volume 44 Issue 3 March 2018
Figure 3. The presence and severity of the OBL graded by the investigator during surgery (grade 0 Z no OBL; grade 1 Z between 1% and 24% of stromal bed area; grade 2 Z between 25% and 49% of stromal bed area; grade 3 Z between 50% and 74% of stromal bed area; grade 4 Z between 75% and 99% of stromal bed area; grade 5 Z 100% of stromal bed area).
less than 250 mm, which increases the risk for postoperative corneal ectasia. In addition to accuracy, flaps in this study were shown to be very uniform across all 4 sectors of the peripheral zone. More planar flap morphology has been shown to improve LASIK outcomes.16,17 The visual acuity results were also comparable to other flap creation studies, although it is unclear whether those studies used the same excimer laser to perform the corneal ablation. At 1 month postoperatively, 81% of the patients in our study had a UDVA of 20/20 or better, compared with a study showing 82.2% (LDV Z6) at 3 months.18 The average efficacy (visual acuity %20/20) for femtosecond lasers tested in multiple studies was 79.1% (Visumax, average of 3 studies), 83.6% (FS200, average of 2 studies), and 85.1% (Intralase 60 kHz, average of 7 studies), systems that are dedicated to corneal and refractive applications.19 No serious adverse events were reported in the current study. Only 1 adverse event was reported to occur in more than 4% of patients (punctate keratitis, 11.7%), and no serious complications occurred, as has been reported in other studies.14,18 There were 2 instances of increased IOP because of a bilateral steroid response in 1 patient; the patient’s IOP was controlled after the steroid was discontinued. The serious adverse event (flap microstriae) was reported to be of mild severity and had resolved spontaneously by 2 days postoperatively. Only 2 incidences of
Figure 5. The CDVA (Snellen) was assessed for each patient at baseline and at 1 month and 3 months postoperatively. The patients were manually refracted to their best correction before testing (CDVA Z corrected distance visual acuity).
285
MULTIFUNCTIONAL LASER FOR LASIK FLAP CREATION
Table 5. Incidence of ocular treatment-emergent adverse events in the 60 study eyes by preferred term. Parameter Any AE Punctate keratitis Conjunctivitis viral Eye allergy IOP increase Corneal epithelial defect Flap microstriae
Figure 6. Analysis of prediction refraction error at 1 month and 3 months postoperatively. Analysis was performed on the safety set (SEQ Z spherical equivalent).
surgical events were reported that were related to suction failure, with no complications such as flap tears, corneal ectasia, buttonholes, and incomplete passes reported. A metaanalysis of femtosecond laser use in LASIK flap creation19 found that intraoperative and postoperative complication rates ranged from 0% to 37.5%, depending on the system and the study. In the current study, stromal bed quality was uniformly rated very smooth, with approximately three-quarters of the eyes showing no OBL and no eye had an OBL occurring on more than one fourth of the stromal bed surface. Published literature supports that the quality of the stromal bed in terms of smoothness correlates positively with better visual outcomes and limiting higher-order aberrations.16 Real-time OCT visualization aided in centering the flap to guarantee that the horizontal overlap was in contact with the limbus, allowing gas to evacuate in a timely manner. Because an OBL is generally formed from gas that cannot escape, this placement helped avoid OBL formation. Other femtosecond laser systems use different methods for gas evacuation to minimize OBL appearance. For example, the FS200 laser uses a chimney-like tunnel system for gas evacuation in which a venting dissection corridor is created by the surgeon within the flap hinge.20 The Intralase creates a vertical gas pocket for gas removal; however, this might incur a risk for gas breakthrough into the anterior chamber.21 Strengths of the study include a 3-month follow-up (versus only 1 month), the use of AS-OCT rather than Table 4. Ocular treatment-emergent adverse events in the 60 study eyes. Parameter Any AE AE related to device Any serious AE Serious AE related to device AE leading to discontinuation Serious AE leading to discontinuation AE leading to death
AE (N)
AE (%)
Eyes (N)
13 0 1 0 0 0
21.7 0.0 1.7 0.0 0.0 0.0
16 0 1 0 0 0
0
0.0
0
AE (N)
AE (%)
Eyes (N)
13 7 2 2 2 1 1
21.7 11.7 3.3 3.3 3.3 1.7 1.7
16 7 2 2 2 2 1
AE Z adverse event; IOP Z intraocular pressure
pachymetry to measure flap thickness, and having 2 independent observers perform the AS-OCT readings. Limitations of the study include the difficulty in using objective standards to measure the ease of flap lifting and the standardization of evaluation between different surgeons. The only way to perform an objective assessment for these parameters would involve in vitro testing. Therefore, subjective measurements were used for evaluation of flap dissection quality. Limitations of AS-OCT measurements include decreased accuracy after surgery, overestimation of flap thickness, and difficulty in achieving the same position with the OCT during each measurement.22–24 In addition, the use of 3 different OCT units (Visante, iVue, and Optovue) introduces the possibility for variation in flap thickness measurements. To account for these limitations and maximize accuracy, measurements were repeated 3 times for each assessment. Software centration and live OCT visualization were important for centration of the flap during OCT measurement; however, it was not within the scope of this study to record the centration of every flap. Future studies might address this by evaluating the location of each flap. The femtosecond laser in the current study can create flaps that are accurate, precise, uniform, and easy to lift, with the creation of a smooth stromal bed with minimum OBL. The expanded capability to include cornea and refractive applications in addition to cataract procedures facilitates patient access within a single clinic and creates economic value. The results from this study can be used to plan further comparative studies in the future.
WHAT WAS KNOWN Femtosecond lasers are commonly used for LASIK flap creation; however, few femtosecond lasers are in use for both corneal/refractive and cataract applications.
WHAT THIS PAPER ADDS A multifunctional, commercially available femtosecond laser system safely and effectively created LASIK flaps that were high quality, accurate, and precise. The majority of the flaps were lifted with no or minimal resistance. All the flaps had a very smooth stromal bed with minimum OBL.
AE Z adverse event
Volume 44 Issue 3 March 2018
286
MULTIFUNCTIONAL LASER FOR LASIK FLAP CREATION
REFERENCES 1. Mitka M. FDA focuses on quality-of-life issues for patients following LASIK surgery. JAMA 2009; 302:2420–2422 2. Sugar A, Rapuano CJ, Culbertson WW, Huang D, Varley GA, Agapitos PJ, de Luise VP, Koch DD. Laser in situ keratomileusis for myopia and astigmatism: safety and efficacy; a report by the American Academy of Ophthalmology (Ophthalmic Technology Assessment). Ophthalmology 2002; 109:175–187 3. Duffey RJ, Leaming D. US trends in refractive surgery: 2004 ISRS/AAO survey. J Refract Surg 2005; 21:742–748 4. Ou RJ, Shaw EL, Glasgow BJ. Keratectasia after laser in situ keratomileusis (LASIK): evaluation of the calculated residual stromal bed thickness. Am J Ophthalmol 2002; 134:771–773 5. Knorz MC. Flap and interface complications in LASIK. Curr Opin Ophthalmol 2002; 13:242–245 6. Lichter H, Stulting RD, Waring GO III, Russell GE, Carr J. Buttonholes during LASIK: etiology and outcome. J Refract Surg 2007; 23:472–476 7. Soong HK, Malta JB. Femtosecond lasers in ophthalmology. Am J Ophthalmol 2009; 147:189–197 8. Santhiago MR, Kara-Junior N, Waring GO IV. Microkeratome versus femtosecond flaps: Accuracy and complications. Curr Opin Ophthalmol 2014; 25:270–274 9. Liu C-H, Sun C-C, Ma DH-K, Huang JC-C, Liu C-F, Chen H-F, Hsiao C-H. Opaque bubble layer: incidence, risk factors, and clinical relevance. J Cataract Refract Surg 2014; 40:435–440 10. Kohnen T, Schwarz L, Remy M, Shajari M. Short-term complications of femtosecond laser–assisted laser in situ keratomileusis cuts: review of 1210 consecutive cases. J Cataract Refract Surg 2016; 42:1797–1803 11. Kymionis GD, Kontadakis GA, Naoumidi I, Kankariya VP, Panagopoulou S, Manousaki A, Grentzelos MA, Pallikaris IG. Comparative study of stromal bed of LASIK flaps created with femtosecond lasers (IntraLase FS150, WaveLight FS200) and mechanical microkeratome. Br J Ophthalmol 2014; 98:133–137 12. Juhasz E, Filkorn T, Kranitz K, Sandor GL, Gyenes A, Nagy ZZ. Analysis of planned and postoperatively measured flap thickness after LASIK using the LenSx multifunctional femtosecond laser system. J Refract Surg 2014; 30:622–626 13. Reinstein DZ, Archer TJ, Randleman JB. JRS standard for reporting astigmatism outcomes of refractive surgery [editorial]. J Refract Surg 2014; 30:654–659. erratum 2015; 31:129. Available at: https://www.healio .com/ophthalmology/journals/jrs/2014-10-30-10/%7B8222b603-d8a1-4b 64-846c-d3ddd026b1ff%7D/jrs-standard-for-reporting-astigmatism-out comes-of-refractive-surgery#. Accessed December 13, 2017 €kinen P, Salmenhaara K, Uusitalo H. Laser-assisted 14. Pietil€ a J, Huhtala A, Ma in situ keratomileusis flap creation with the three-dimensional, transportable Ziemer FEMTO LDV model Z6 I femtosecond laser. Acta Ophthalmol 2014; 92:650–655. Available at: http://onlinelibrary.wiley.com/doi/10.1111/aos .12333/epdf. Accessed December 13, 2017 15. Pietil€ a J, Huhtala A, M€ akinen P, Uusitalo H. Flap characteristics, predictability, and safety of the Ziemer FEMTO LDV femtosecond laser with the disposable suction ring for LASIK. Eye 2014; 28:66–71. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890769/pdf/eye20132 44a.pdf. Accessed December 13, 2017
Volume 44 Issue 3 March 2018
16. Salomao MQ, Wilson SE. Femtosecond laser in laser in situ keratomileusis. J Cataract Refract Surg 2010; 36:1024–1032 17. Zhang X-X, Zhong X-W, Wu J-S, Wang Z, Yu K-M, Liu Q, Yang B. Corneal flap morphological analysis using anterior segment optical coherence tomography in laser keratomileusis with femtosecond lasers versus mechanical microkeratome. Int J Ophthalmol 2012; 5:69–73. Available at: http: //www.ncbi.nlm.nih.gov/pmc/articles/PMC3340831/pdf/ijo-05-01-069.pdf. Accessed December 13, 2017 18. Kasetsuwan N, Satitpitakul V, Puangsricharern V, Reinprayoon U, Pariyakanok L. Comparison of performances of femtosecond laser and microkeratome for thin-flap laser in situ keratomileusis. Lasers Surg Med 2016; 48:596–601 € J, Ma €kinen P, Uusitalo H. Femtosecond lasers for laser 19. Huhtala A, Pietila in situ keratomileusis: a systematic review and meta-analysis. Clin Ophthalmol 2016; 10:393–404. Available at: https://www.ncbi.nlm.nih.gov/pmc /articles/PMC4788361/pdf/opth-10-393.pdf. Accessed December 13, 2017 20. Kymionis GD, Tsoulnaras KI, Tsakalis NG, Grentzelos MA. Diffuse lamellar keratitis in the femtosecond-assisted LASIK flap tunnel. Clin Ophthalmol 2014; 8:1065–1067. Available at: https://www.ncbi.nlm.nih.gov/pmc /articles/PMC4051804/pdf/opth-8-1065.pdf. Accessed December 13, 2017 21. Kanellopoulos AJ, Asimellis G. Digital analysis of flap parameter accuracy and objective assessment of opaque bubble layer in femtosecond laserassisted LASIK: a novel technique. Clin Ophthalmol 2013; 7:343–351. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577012 /pdf/opth-7-343.pdf. Accessed December 13, 2017 22. Kim J-H, Lee D, Rhee K-I. Flap thickness reproducibility in laser in situ keratomileusis with a femtosecond laser: optical coherence tomography measurement. J Cataract Refract Surg 2008; 34:132–136 23. Cheng ACK, Ho T, Lau S, Wong AL, Leung C, Lam DSC. Measurement of LASIK flap thickness with anterior segment optical coherence tomography. J Refract Surg 2008; 24:879–884 24. Huang D, Swanson EA, Lin CP, Schuman JS, Stinson WG, Chang W, Hee MR, Flotte T, Gregory K, Puliafito CA, Fujimoto JG. Optical coherence tomography. Science 1991; 254:1178–1181
Disclosures: Dr. Slade is a consultant to Alcon Laboratories, Inc. Dr. Ignacio was an Alcon employee at the time of the study. Dr. Spector receives personal fees from Alcon Laboratories, Inc.
First author: Stephen Slade, MD Slade & Baker Vision Center, Houston, Texas, USA
ARTICLE
Evaluation of a multifunctional femtosecond laser for the creation of laser in situ keratomileusis flaps Stephen Slade, MD, Teresa Ignacio, MD, Scott Spector, MD
Purpose: To characterize the performance of a multifunctional femtosecond laser system (Lensx) for the creation of laser in situ keratomileusis (LASIK) flaps. Setting: Two surgical sites in the United States. Design: Prospective case series pilot study. Methods: Patients with myopia or hyperopia who were eligible for femtosecond laser-initiated LASIK surgery with corrected distance visual acuities (CDVA) correctable to at least 20/25 were enrolled. Central flap thickness accuracy (desired versus achieved) and precision (flap thickness standard deviation) were measured using anterior segment optical coherence tomography. Flap dissection quality, stromal bed quality, and amount of opaque bubble layer (OBL) formation were graded during surgery, and the refractive outcomes were evaluated postoperatively at 1-month and 3-month follow-ups.
L
aser in situ keratomileusis (LASIK) is the most commonly performed corneal refractive surgery worldwide1,2 and is used for the correction of myopia, hyperopia, and astigmatism.3 The LASIK procedure begins with the creation of a corneal flap followed by excimer stromal ablation on the corneal bed that corrects the refractive error. The first step, creation of the hinged flap, is the most critical step of the LASIK procedure because it affects safety and efficacy of the final visual outcome. It is important to produce a uniform flap with a narrow standard deviation (SD) to obtain a proper stromal bed thickness and reduce the likelihood of corneal ectasia.4 Corneal flaps were initially created using a microkeratome blade. Microkeratome flap creation subsequently
Results: The study comprised 30 patients (58 eyes). At 3 months postoperatively, the flap thickness accuracy was 1.3 mm G 2.6 (SD). A total of 78.3% of flaps were lifted with no resistance and 16.7% were lifted with minimal resistance using a blunt instrument. All (100%) stromal beds were determined to have a very smooth surface (grade 5 on a 0 to 5 scale). No OBL was observed in 73.3% of eyes; 26.7% of eyes showed an OBL occurring on less than 24% of the stromal bed surface. At 3 months postoperatively, most eyes (84.5%) had an uncorrected distance visual acuity of 20/20 and 98% had a CDVA of 20/20. The most common ocular adverse event was punctate keratitis (11.7%).
Conclusion: The multifunctional femtosecond laser system effectively created LASIK flaps that were high quality, accurate, and precise. J Cataract Refract Surg 2018; 44:280–286 Q 2018 ASCRS and ESCRS
evolved from manually guided mechanical microkeratomes to automated microkeratomes and single-use microkeratomes; however, despite refinements in the technology, complications such as buttonhole flaps and irregular incision planes can still affect the outcome of the procedure.5,6 The use of a femtosecond laser for flap creation has been commercially available since 2002, and it is the most common application of the femtosecond laser.7 The theoretical advantages of femtosecond lasers include increased precision in flap creation, a decrease in flap imperfections, and lower procedural intraocular pressure (IOP).8 Femtosecond lasers create an incision through photodisruption. The laser produces pockets of plasma with each shot that expands, displacing the surrounding tissues and leading to the
Submitted: April 19, 2017 | Final revision submitted: December 1, 2017 | Accepted: December 6, 2017 From the Slade & Baker Vision Center (Slade), Houston, Texas, Alcon Research (Ignacio), Lake Forest, California, and Spector Eye Care (Spector), Norwalk, Connecticut, USA. Presented in part at the European Society of Cataract and Refractive Surgeons, Copenhagen, Denmark, September 2016, and the ASCRS Symposium on Cataract, IOL and Refractive Surgery, Los Angeles, California, USA, May 2017. Supported by Alcon Laboratories, Inc., Fort Worth, Texas, USA. The funding organization participated in the design of the study, conducting the study, data collection, data management, data analysis, interpretation of the data, preparation, and review or approval of the manuscript. Corresponding author: Stephen Slade, MD, 3900 Essex Lane, Houston, Texas 77027, USA. E-mail: [email protected]. Q 2018 ASCRS and ESCRS Published by Elsevier Inc.
0886-3350/$ - see frontmatter https://doi.org/10.1016/j.jcrs.2017.12.016
MULTIFUNCTIONAL LASER FOR LASIK FLAP CREATION
formation of cavitation bubbles.9 An opaque bubble layer (OBL) is produced by gas bubbles that accumulate in the superficial layers of the stromal bed and an excessive OBL might interfere with flap creation.9 Some unique potential complications associated with flap creation using the femtosecond laser include suction failure during the laser treatment resulting in an incomplete cut, OBL formation, vertical gas breakthrough, and transient light sensitivity syndrome.10 The new generation of femtosecond lasers use higher frequency and lower energy than their predecessors that allow for the creation of a better cleavage plane and easier flap lift. Commercially available femtosecond lasers differ with respect to pulse energy, duration, distance, and pattern and therefore must be evaluated empirically.11 Historically, different femtosecond laser systems have been used for either cornea or refractive applications (Intralase, Abbott Medical Optics, Inc.; the FS200, Alcon Laboratories, Inc.; the Femto LDV Z6, Ziemer Ophthalmic Systems AG; and the Visumax, Carl Zeiss Meditec AG) or cataract surgery (Lensar, Lensar, Inc. and the Catalys, Abbot Medical Optics, Inc.), which increases the difficulty and cost of making both procedures available to patients in a single clinic. At present, a few systems are being used for both applications (Femto LDV Z8, Ziemer Ophthalmic Systems AG and Victus, Technolas Perfect Vision GmbH). However, no clinical data have been published regarding the performance of either system with respect to corneal flap creation. The femtosecond laser for the current study (Lensx, Alcon Laboratories, Inc.) has been in use for cataract surgery since 2010. The laser system uses tightly focused ultrashort femtosecond pulses (10 to 15 seconds) to create a continuous incision or tissue separation of the cornea. Previously, a pilot study to assess flap creation in 38 eyes of 20 patients was performed using a prototype that showed no statistically significant difference between the planned and postoperatively measured flap thickness, and with no associated adverse events.12 Herein we report the results of the first study using the commercially available femtosecond laser system with flap creation added as a capability, which evaluated the creation of LASIK flaps in 58 eyes for accuracy, precision, and safety. PATIENTS AND METHODS Study Design and Enrollment The trial was a prospective nonrandomized dual-center open-label pilot study designed to evaluate the thickness accuracy, defined as achieved flap thickness versus desired flap thickness, of LASIK flaps created with a femtosecond laser system. Patients were enrolled at 2 investigative sites (Slade & Baker Vision Center, Houston, Texas, and Spector Eye Care, Norwalk, Connecticut, USA) with 2 investigators (S. Slade and S. Spector, respectively). The patients were required to provide written informed consent before enrollment in the trial and the conduct of any trial-related procedures. The final protocol was approved by the institutional review board. This trial adhered to the provisions of the guidelines of the World Medical Association Declaration of Helsinki. This trial was performed in compliance with all federal, local, and/or regional requirements, including with the U.S. Health Insurance Portability and Accountability Act.
281
Inclusion and Exclusion Criteria Inclusion criteria allowed patients older than 21 years with myopia or hyperopia to be eligible for femtosecond laser–initiated surgery, with corrected distance visual acuity (CDVA) correctable to at least 20/25 in each eye. Exclusion criteria included previous corneal surgery, corneal lesions that would impede laser treatment, corneal edema, hypotony, glaucoma, existing corneal implant, keratoconus, irregular astigmatism, and corneal thickness values that would result in a residual stromal bed less than 280 mm when flap resection and excimer ablation were calculated. Study Treatment and Plan The planned scheduled visits for the study included the screening (day 30 to 1), surgery (day 0), and 2 postoperative visits at 1-month (day 30 to 45) and 3-month (day 90 to 105) intervals. Unscheduled visits were completed if additional follow-up was deemed necessary by the investigator. The total expected duration of participation for each patient was up to 5 months depending on the time of surgery after the preoperative/screening visit and the timing of each postoperative visit thereafter. Patients were enrolled sequentially based on the informed consent form date and time. Eligible patients who signed an informed consent form completed the screening assessments and returned to the clinic within 30 days to have bilateral LASIK surgery. Primary and Secondary Effectiveness Endpoints The primary endpoint of the study was flap thickness accuracy within the central zone at 3 months postoperatively. The secondary endpoints included flap thickness precision within the central zone at 1 month and 3 months postoperatively (variability of the achieved flap thickness), ease of flap dissection, stromal bed quality, OBL assessment, uncorrected distance visual acuity (UDVA) and CDVA, manifest refraction spherical equivalent, and prediction error between target versus achieved refraction. The results for UDVA and CDVA measurements are presented using the standard refractive graphs for reporting refractive surgery outcomes.13 An exploratory effectiveness endpoint was variability of flap thickness measured at 3 points across the central and peripheral zones of the flaps at 3 months postoperatively. Safety Endpoints Safety endpoints included reporting adverse events, findings from slitlamp evaluation, significant IOP measurement, decrease in CDVA, and reporting surgical events and device deficiencies. Flap Thickness Measurements Flap thickness was calculated by subtracting the anterior segment optical coherence tomography (AS-OCT) (Visante, Carl Zeiss Meditec AG and iVue, Optovue, Inc.) measurement from the programmed (desired) flap thickness. Each AS-OCT measurement was performed separately by 2 different technicians to ensure accuracy. They took 1 measurement at the center and then 4 measurements peripherally (6.0 mm from center) at 0-degree, 90-degree, 180-degree, and 270-degree orientations at 1 month and 3 months postoperatively. These measurements were performed by placing the cursor at the appropriate points and visualizing the edge of the flap to manually mark the thickness to be measured by the AS-OCT. This was repeated 3 times for each measurement and the mean was reported. Software centration and live AS-OCT visualization allowed for accurate centration of the flap. Assessment of Flap Dissection Quality Flap dissection quality was assessed using a scale created by the authors ranging from 0 to 5 based on the difficulty in lifting the flap and the amount of resistance encountered. Grades were indicated as follows: 0 Z unable to lift flap, 1 Z able to lift flap with aid of sharp instrument, 2 Z able to lift flap with difficulty using blunt Volume 44 Issue 3 March 2018
282
MULTIFUNCTIONAL LASER FOR LASIK FLAP CREATION
instrument, 3 Z able to lift flap with moderate resistance using blunt instrument, 4 Z able to lift flap with minimal resistance using blunt instrument, 5 Z able to lift flap without any resistance using blunt instrument.
50 eyes was considered sufficient for assessment of flap thickness accuracy.
RESULTS Demographics and Baseline Characteristics
Stromal Bed Quality Assessment The quality of the stromal bed was assessed using a scale created by the authors ranging from 0 to 5 based on roughness of the stromal bed. Grades were indicated as follows: 0 Z very rough, 1 Z moderately rough, 2 Z rough, 3 Z smooth, 4 Z moderately smooth, 5 Z very smooth. Assessment of Opaque Bubble Layer The presence and severity of an OBL was evaluated by the investigators during surgery. Grades were indicated as follows: 0 Z no OBL, 1 Z between 1% and 24% of stromal bed area, 2 Z between 25% and 49% of stromal bed area, 3 Z between 50% and 74% of stromal bed area, 4 Z between 75% and 99% of stromal bed area, 5 Z 100% of stromal bed area. Investigational Device The investigational femtosecond laser (Lensx Laser System) uses tightly focused ultrashort femtosecond pulses (10 to 15 seconds) to create a continuous incision or tissue separation of the cornea. The laser pulses are delivered through a patient interface, a sterile disposable applanation lens, and suction ring assembly that contacts the cornea and fixes the eye with respect to the delivery system. A small volume of tissue (a few microns in diameter) is photodisrupted at the laser focus. A computer-controlled scanning system directs the laser beam throughout a 3-dimensional pattern to the desired target location to produce the incision through photodisruption. The Wavelight laser system and the Visx laser were used to perform the corneal ablation. The femtosecond-laser settings were line spot separation, 7.0 mm and layer separation, and 7.0 mm. Statistical Analysis The safety analysis set was the primary analysis set, and included all patients/eyes that were exposed to the device during the study. No formal statistical hypothesis testing was planned in support of the performance objectives. All baseline, performance, and safety data were summarized using descriptive statistics. A sample size of
Table 1. Demographics and baseline characteristics of the 30 patients in the study. Parameter Age (y) Mean G SD Median Range Sex, n (%) Male Female Race, n (%) White Black or African American American Indian or Alaskan native Asian Other Ethnicity, n (%) Hispanic or Latino Not Hispanic or Latino Not reported or unknown
Volume 44 Issue 3 March 2018
Value 34.5 G 11.0 32.5 21, 61 14 (46.7) 16 (53.3) 26 (86.7) 0 (0.0) 1 (3.3) 1 (3.3) 2 (6.7) 6 (20.0) 22 (73.3) 2 (6.6)
A total of 34 patients (68 eyes) were initially enrolled. Thirty patients (4 did not meet eligibility criteria) had bilateral LASIK surgery and 58 eyes were available upon completion of the study. Of the 30 patients who had bilateral LASIK surgery, 29 completed the study (96.7%) and 1 patient (3.3%) was lost to follow-up before the 1-month visit. Table 1 shows the demographics and baseline characteristics of the study population. The distribution of men to women was balanced and the majority of the patients were identified as white and non-Hispanic or Latino. Analysis of Flap Thickness and Precision
Table 2 shows the mean flap thickness within the central zone, the flap thickness accuracy (defined as the mean difference between the achieved and desired flap thickness within the central zone), and the flap thickness precision (defined as the variation in flap thickness measured by the SD) at 1 month and 3 months postoperatively. Flap Dissection Quality
Of the 60 flaps graded, the majority (47 [78.3%]) were graded 5 (able to lift flap without any resistance using blunt instrument), whereas only 10 (16.7%) were graded 4 (able to lift flap with minimal resistance using blunt instrument and 3 (5.0%) were graded 3 (able to lift flap with moderate resistance using blunt instrument) (Figure 1). Flap Uniformity
Anterior segment OCT (AS-OCT) measurements of the flap thickness were recorded within the peripheral zone (6.0 mm diameter), at 0-degree, 90-degree, 180-degree, and 270-degree orientations. Similar means for flap
Table 2. Flap accuracy and precision. Follow-up Parameter Flap thickness within central zone (mm) Eyes, n Mean G SD Median Range 95% CI Difference between achieved and desired flap thickness (mm) Eyes, n Mean G SD Median Range 95% CI Mean flap thickness accuracy (mm) Mean flap thickness precision (mm) CI Z confidence interval
1 Mo
3 Mo
58 127.8 G 3.7 128.0 110, 134 126.9, 128.8
58 125.8 G 4.8 125.0 107, 134 124.6, 127.1
58 3.3 G 3.8 4.0 4, 10 2.3, 4.4 3.3 3.7
58 1.3 G 2.6 2.0 5, 5 0.6, 2.0 1.3 4.8
283
MULTIFUNCTIONAL LASER FOR LASIK FLAP CREATION
57 eyes were 20/20 (Figure 5). On average, low residual refractive error was observed starting at 1 month postoperatively, with a mean MRSE of 0.17 diopters (D) 3 months postoperatively. For 1 patient, a UDVA worse than 20/40 and a 2-line decrease in CDVA were reported in both eyes at the 1-month visit. This patient recovered to 20/25 by the 3-month visit. The decrease in visual acuity was attributed to a bilateral adverse event of IOP increase caused by a steroid response and conjunctivitis that led to a series of other complications throughout the study. No other eye in the study had a clinically significant decrease in CDVA. Figure 1. Analysis of ease of flap dissection rated by the investigator during surgery (grade 0 Z unable to lift flap; grade 1 Z able to lift flap with aid of sharp instrument; grade 2 Z able to lift flap with difficulty using blunt instrument; grade 3 Z able to lift flap with moderate resistance using blunt instrument; grade 4 Z able to lift flap with minimal resistance using blunt instrument; grade 5 Z able to lift flap without any resistance using blunt instrument).
thickness were observed within the 4 sectors, indicating uniformity of flap thickness across the peripheral zone (Table 3). Stromal Bed Quality
Surface quality of the stromal bed after flap creation was assessed using a 6-point grading scale ranging from 0 (very rough surface) to 5 (very smooth surface). All 60 stromal beds were graded as 5 by the investigators (Figure 2). Opaque Bubble Layer
No OBL was observed in 44 eyes whereas 16 eyes showed an OBL occurring on less than 24% of the stromal bed surface (grade 1) (Figure 3). Furthermore, no surgical complications were reported in any eyes as a result of OBL formation. Visual Acuity
The UDVA was assessed for the 58 eyes that completed the study. At 1 month postoperatively, 47 eyes had a UDVA of 20/20, and at 3 months postoperatively, 49 eyes had a UDVA of 20/20 (Figure 4). The CDVA was assessed for all 60 eyes; patients were manually refracted to their best correction before CDVA testing. At 1 month postoperatively, 53 eyes were 20/20, and at 3 months postoperatively,
Prediction Refraction Error
Figure 6 shows the results of the prediction refraction error analysis (defined as the difference between the actual postoperative refractive error and the intended formula-derived refractive target). The prediction error was 0.5 D or less in 54 eyes at 1 month postoperatively, and in 53 eyes at 3 months postoperatively. Furthermore, the prediction error was 1.0 D in 57 eyes at 1 month postoperatively, and in all 58 eyes at 3 months postoperatively. Safety
The safety analysis set included all patients exposed to the device during the study. Table 4 shows the ocular treatment-emergent adverse events. No adverse event or serious adverse event related to the device was reported. The 1 serious adverse event that did occur was flap microstriae of mild severity, which required a surgical intervention of flap refloat. The investigator reported that the corneal flap microstriae had resolved at an unscheduled visit 2 days postoperatively. Table 5 shows the incidence and details of the ocular treatment-emergent adverse events. Surgical Events and Device Deficiencies
Two incidences of surgical events were reported, both of which related to a patient interface suction failure. In both cases the patient interface was replaced and the surgery completed. DISCUSSION Femtosecond lasers have been shown to reduce postoperative complications and improve the smoothness and accuracy of flap creation compared with mechanical microkeratome use.10 Following the initial data on a
Table 3. Flap uniformity in 58 eyes. Degree Parameter Flap thickness in peripheral zone (mm) Mean G SD Median Range 95% CI
0
90
180
270
126.4 G 4.9 126.5 109, 133 125.1, 127.6
125.9 G 4.7 126.0 108, 133 124.7, 127.2
126.2 G 5.2 126.0 106, 135 124.9, 127.6
126.1 G 5.0 126.5 106, 133 124.8, 127.4
CI Z confidence interval
Volume 44 Issue 3 March 2018
284
MULTIFUNCTIONAL LASER FOR LASIK FLAP CREATION
Figure 2. Analysis of stromal bed quality rated by the investigator during surgery based on a roughness scale (grade 0 Z very rough; grade 1 Z moderately rough; grade 2 Z rough; grade 3 Z smooth; grade 4 Z moderately smooth; grade 5 Z very smooth).
femtosecond laser prototype, the current study was conducted to characterize the accuracy, precision, and safety of the commercially available system (differences between the 2 systems include the patient interface and software). The current study was designed for 3 months of followup, in contrast to similar studies that were followed for 1 month.14,15 In this study, AS-OCT measurements of flap thickness were 127.8 G 3.7 mm at 1 month postoperatively, and 125.8 G 4.8 mm at 3 months postoperatively, which were comparable to femtosecond lasers dedicated only to corneal and refractive applications. A previous pilot study using the same laser system reported a mean postoperative flap thickness of 140.28 G 8.0 mm.12 Two other studies using another femtosecond laser system (LDV Z6)14,15 found mean postoperative flap thicknesses of 90.1 G 2.7 mm and 89.6 G 2.0 mm, respectively. In the current study, the measurements of flap thickness accuracy within the central zone at 1 and 3 months were 3.3 G 3.8 mm and 1.3 G 2.6 mm, respectively, showing that flaps can be created accurately and precisely with a multiplatform femtosecond laser. The advantages of creating an accurate flap are well documented. Thick flaps can increase the probability of residual corneal stroma
Figure 4. The UDVA (Snellen) was assessed for each patient at baseline and at 1 month and 3 months postoperatively. The preoperative CDVA is presented for comparison. Analysis was performed on the safety set (CDVA Z corrected distance visual acuity; UDVA = uncorrected distance visual acuity).
Volume 44 Issue 3 March 2018
Figure 3. The presence and severity of the OBL graded by the investigator during surgery (grade 0 Z no OBL; grade 1 Z between 1% and 24% of stromal bed area; grade 2 Z between 25% and 49% of stromal bed area; grade 3 Z between 50% and 74% of stromal bed area; grade 4 Z between 75% and 99% of stromal bed area; grade 5 Z 100% of stromal bed area).
less than 250 mm, which increases the risk for postoperative corneal ectasia. In addition to accuracy, flaps in this study were shown to be very uniform across all 4 sectors of the peripheral zone. More planar flap morphology has been shown to improve LASIK outcomes.16,17 The visual acuity results were also comparable to other flap creation studies, although it is unclear whether those studies used the same excimer laser to perform the corneal ablation. At 1 month postoperatively, 81% of the patients in our study had a UDVA of 20/20 or better, compared with a study showing 82.2% (LDV Z6) at 3 months.18 The average efficacy (visual acuity %20/20) for femtosecond lasers tested in multiple studies was 79.1% (Visumax, average of 3 studies), 83.6% (FS200, average of 2 studies), and 85.1% (Intralase 60 kHz, average of 7 studies), systems that are dedicated to corneal and refractive applications.19 No serious adverse events were reported in the current study. Only 1 adverse event was reported to occur in more than 4% of patients (punctate keratitis, 11.7%), and no serious complications occurred, as has been reported in other studies.14,18 There were 2 instances of increased IOP because of a bilateral steroid response in 1 patient; the patient’s IOP was controlled after the steroid was discontinued. The serious adverse event (flap microstriae) was reported to be of mild severity and had resolved spontaneously by 2 days postoperatively. Only 2 incidences of
Figure 5. The CDVA (Snellen) was assessed for each patient at baseline and at 1 month and 3 months postoperatively. The patients were manually refracted to their best correction before testing (CDVA Z corrected distance visual acuity).
285
MULTIFUNCTIONAL LASER FOR LASIK FLAP CREATION
Table 5. Incidence of ocular treatment-emergent adverse events in the 60 study eyes by preferred term. Parameter Any AE Punctate keratitis Conjunctivitis viral Eye allergy IOP increase Corneal epithelial defect Flap microstriae
Figure 6. Analysis of prediction refraction error at 1 month and 3 months postoperatively. Analysis was performed on the safety set (SEQ Z spherical equivalent).
surgical events were reported that were related to suction failure, with no complications such as flap tears, corneal ectasia, buttonholes, and incomplete passes reported. A metaanalysis of femtosecond laser use in LASIK flap creation19 found that intraoperative and postoperative complication rates ranged from 0% to 37.5%, depending on the system and the study. In the current study, stromal bed quality was uniformly rated very smooth, with approximately three-quarters of the eyes showing no OBL and no eye had an OBL occurring on more than one fourth of the stromal bed surface. Published literature supports that the quality of the stromal bed in terms of smoothness correlates positively with better visual outcomes and limiting higher-order aberrations.16 Real-time OCT visualization aided in centering the flap to guarantee that the horizontal overlap was in contact with the limbus, allowing gas to evacuate in a timely manner. Because an OBL is generally formed from gas that cannot escape, this placement helped avoid OBL formation. Other femtosecond laser systems use different methods for gas evacuation to minimize OBL appearance. For example, the FS200 laser uses a chimney-like tunnel system for gas evacuation in which a venting dissection corridor is created by the surgeon within the flap hinge.20 The Intralase creates a vertical gas pocket for gas removal; however, this might incur a risk for gas breakthrough into the anterior chamber.21 Strengths of the study include a 3-month follow-up (versus only 1 month), the use of AS-OCT rather than Table 4. Ocular treatment-emergent adverse events in the 60 study eyes. Parameter Any AE AE related to device Any serious AE Serious AE related to device AE leading to discontinuation Serious AE leading to discontinuation AE leading to death
AE (N)
AE (%)
Eyes (N)
13 0 1 0 0 0
21.7 0.0 1.7 0.0 0.0 0.0
16 0 1 0 0 0
0
0.0
0
AE (N)
AE (%)
Eyes (N)
13 7 2 2 2 1 1
21.7 11.7 3.3 3.3 3.3 1.7 1.7
16 7 2 2 2 2 1
AE Z adverse event; IOP Z intraocular pressure
pachymetry to measure flap thickness, and having 2 independent observers perform the AS-OCT readings. Limitations of the study include the difficulty in using objective standards to measure the ease of flap lifting and the standardization of evaluation between different surgeons. The only way to perform an objective assessment for these parameters would involve in vitro testing. Therefore, subjective measurements were used for evaluation of flap dissection quality. Limitations of AS-OCT measurements include decreased accuracy after surgery, overestimation of flap thickness, and difficulty in achieving the same position with the OCT during each measurement.22–24 In addition, the use of 3 different OCT units (Visante, iVue, and Optovue) introduces the possibility for variation in flap thickness measurements. To account for these limitations and maximize accuracy, measurements were repeated 3 times for each assessment. Software centration and live OCT visualization were important for centration of the flap during OCT measurement; however, it was not within the scope of this study to record the centration of every flap. Future studies might address this by evaluating the location of each flap. The femtosecond laser in the current study can create flaps that are accurate, precise, uniform, and easy to lift, with the creation of a smooth stromal bed with minimum OBL. The expanded capability to include cornea and refractive applications in addition to cataract procedures facilitates patient access within a single clinic and creates economic value. The results from this study can be used to plan further comparative studies in the future.
WHAT WAS KNOWN Femtosecond lasers are commonly used for LASIK flap creation; however, few femtosecond lasers are in use for both corneal/refractive and cataract applications.
WHAT THIS PAPER ADDS A multifunctional, commercially available femtosecond laser system safely and effectively created LASIK flaps that were high quality, accurate, and precise. The majority of the flaps were lifted with no or minimal resistance. All the flaps had a very smooth stromal bed with minimum OBL.
AE Z adverse event
Volume 44 Issue 3 March 2018
286
MULTIFUNCTIONAL LASER FOR LASIK FLAP CREATION
REFERENCES 1. Mitka M. FDA focuses on quality-of-life issues for patients following LASIK surgery. JAMA 2009; 302:2420–2422 2. Sugar A, Rapuano CJ, Culbertson WW, Huang D, Varley GA, Agapitos PJ, de Luise VP, Koch DD. Laser in situ keratomileusis for myopia and astigmatism: safety and efficacy; a report by the American Academy of Ophthalmology (Ophthalmic Technology Assessment). Ophthalmology 2002; 109:175–187 3. Duffey RJ, Leaming D. US trends in refractive surgery: 2004 ISRS/AAO survey. J Refract Surg 2005; 21:742–748 4. Ou RJ, Shaw EL, Glasgow BJ. Keratectasia after laser in situ keratomileusis (LASIK): evaluation of the calculated residual stromal bed thickness. Am J Ophthalmol 2002; 134:771–773 5. Knorz MC. Flap and interface complications in LASIK. Curr Opin Ophthalmol 2002; 13:242–245 6. Lichter H, Stulting RD, Waring GO III, Russell GE, Carr J. Buttonholes during LASIK: etiology and outcome. J Refract Surg 2007; 23:472–476 7. Soong HK, Malta JB. Femtosecond lasers in ophthalmology. Am J Ophthalmol 2009; 147:189–197 8. Santhiago MR, Kara-Junior N, Waring GO IV. Microkeratome versus femtosecond flaps: Accuracy and complications. Curr Opin Ophthalmol 2014; 25:270–274 9. Liu C-H, Sun C-C, Ma DH-K, Huang JC-C, Liu C-F, Chen H-F, Hsiao C-H. Opaque bubble layer: incidence, risk factors, and clinical relevance. J Cataract Refract Surg 2014; 40:435–440 10. Kohnen T, Schwarz L, Remy M, Shajari M. Short-term complications of femtosecond laser–assisted laser in situ keratomileusis cuts: review of 1210 consecutive cases. J Cataract Refract Surg 2016; 42:1797–1803 11. Kymionis GD, Kontadakis GA, Naoumidi I, Kankariya VP, Panagopoulou S, Manousaki A, Grentzelos MA, Pallikaris IG. Comparative study of stromal bed of LASIK flaps created with femtosecond lasers (IntraLase FS150, WaveLight FS200) and mechanical microkeratome. Br J Ophthalmol 2014; 98:133–137 12. Juhasz E, Filkorn T, Kranitz K, Sandor GL, Gyenes A, Nagy ZZ. Analysis of planned and postoperatively measured flap thickness after LASIK using the LenSx multifunctional femtosecond laser system. J Refract Surg 2014; 30:622–626 13. Reinstein DZ, Archer TJ, Randleman JB. JRS standard for reporting astigmatism outcomes of refractive surgery [editorial]. J Refract Surg 2014; 30:654–659. erratum 2015; 31:129. Available at: https://www.healio .com/ophthalmology/journals/jrs/2014-10-30-10/%7B8222b603-d8a1-4b 64-846c-d3ddd026b1ff%7D/jrs-standard-for-reporting-astigmatism-out comes-of-refractive-surgery#. Accessed December 13, 2017 €kinen P, Salmenhaara K, Uusitalo H. Laser-assisted 14. Pietil€ a J, Huhtala A, Ma in situ keratomileusis flap creation with the three-dimensional, transportable Ziemer FEMTO LDV model Z6 I femtosecond laser. Acta Ophthalmol 2014; 92:650–655. Available at: http://onlinelibrary.wiley.com/doi/10.1111/aos .12333/epdf. Accessed December 13, 2017 15. Pietil€ a J, Huhtala A, M€ akinen P, Uusitalo H. Flap characteristics, predictability, and safety of the Ziemer FEMTO LDV femtosecond laser with the disposable suction ring for LASIK. Eye 2014; 28:66–71. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3890769/pdf/eye20132 44a.pdf. Accessed December 13, 2017
Volume 44 Issue 3 March 2018
16. Salomao MQ, Wilson SE. Femtosecond laser in laser in situ keratomileusis. J Cataract Refract Surg 2010; 36:1024–1032 17. Zhang X-X, Zhong X-W, Wu J-S, Wang Z, Yu K-M, Liu Q, Yang B. Corneal flap morphological analysis using anterior segment optical coherence tomography in laser keratomileusis with femtosecond lasers versus mechanical microkeratome. Int J Ophthalmol 2012; 5:69–73. Available at: http: //www.ncbi.nlm.nih.gov/pmc/articles/PMC3340831/pdf/ijo-05-01-069.pdf. Accessed December 13, 2017 18. Kasetsuwan N, Satitpitakul V, Puangsricharern V, Reinprayoon U, Pariyakanok L. Comparison of performances of femtosecond laser and microkeratome for thin-flap laser in situ keratomileusis. Lasers Surg Med 2016; 48:596–601 € J, Ma €kinen P, Uusitalo H. Femtosecond lasers for laser 19. Huhtala A, Pietila in situ keratomileusis: a systematic review and meta-analysis. Clin Ophthalmol 2016; 10:393–404. Available at: https://www.ncbi.nlm.nih.gov/pmc /articles/PMC4788361/pdf/opth-10-393.pdf. Accessed December 13, 2017 20. Kymionis GD, Tsoulnaras KI, Tsakalis NG, Grentzelos MA. Diffuse lamellar keratitis in the femtosecond-assisted LASIK flap tunnel. Clin Ophthalmol 2014; 8:1065–1067. Available at: https://www.ncbi.nlm.nih.gov/pmc /articles/PMC4051804/pdf/opth-8-1065.pdf. Accessed December 13, 2017 21. Kanellopoulos AJ, Asimellis G. Digital analysis of flap parameter accuracy and objective assessment of opaque bubble layer in femtosecond laserassisted LASIK: a novel technique. Clin Ophthalmol 2013; 7:343–351. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577012 /pdf/opth-7-343.pdf. Accessed December 13, 2017 22. Kim J-H, Lee D, Rhee K-I. Flap thickness reproducibility in laser in situ keratomileusis with a femtosecond laser: optical coherence tomography measurement. J Cataract Refract Surg 2008; 34:132–136 23. Cheng ACK, Ho T, Lau S, Wong AL, Leung C, Lam DSC. Measurement of LASIK flap thickness with anterior segment optical coherence tomography. J Refract Surg 2008; 24:879–884 24. Huang D, Swanson EA, Lin CP, Schuman JS, Stinson WG, Chang W, Hee MR, Flotte T, Gregory K, Puliafito CA, Fujimoto JG. Optical coherence tomography. Science 1991; 254:1178–1181
Disclosures: Dr. Slade is a consultant to Alcon Laboratories, Inc. Dr. Ignacio was an Alcon employee at the time of the study. Dr. Spector receives personal fees from Alcon Laboratories, Inc.
First author: Stephen Slade, MD Slade & Baker Vision Center, Houston, Texas, USA