Assessing the impact of FLACS on surgical outcomes

The femtosecond laser is an infrared laser with a wavelength of 1,053 nm that operates at high energy levels and very short, femtosecond range, pulses. Femtolasers, such as the Nd:YAG laser, work by producing photodisruption or photoionization of the optically transparent tissue, such as the cornea.¹

Femtosecond lasers were previously used primarily for corneal surgery. However, technical development enabled the first application in cataract surgery for capsulorrhexis and lens fragmentation in August 2008, which was achieved by Dr Zoltan Z. Nagy at Semmelweis University in Budapest.² The initial results demonstrated higher precision of capsulorrhexis and reduced phacoemulsification power in porcine and human eyes.³

Femtosecond lasers were believed to have revolutionised cataract surgery. However, despite the promise, the assessment of perceived benefits has proven to be far more complicated than was initially thought. In a recent review by Popovic et al.⁴, no statistically significant differences were detected between femtosecond laser-assisted cataract surgery (FLACS) and manual phacoemulsification cataract surgery (PCS) in terms of patient-important visual and refractive outcomes and overall complications.

However, FLACS showed statistically significant differences for several secondary surgical outcomes, i.e., decreased effective phacoemulsification time; enhanced capsulotomy circularity; lower postoperative central corneal thickness; and corneal endothelial cell reduction.

Cystoid macular oedema

Cystoid macular oedema (CME) (Figure 1) following cataract surgery remains the most common cause of poor visual outcome. Whereas acute pseudophakic CME may resolve spontaneously, some patients will suffer from vision impairment and will be difficult to treat.

Published studies use different methodologies, which primarily depend on clinical observation of cystoid changes; leakage shown by fluorescein angiography; or increased thickness shown by OCT along with some degree of visual impairment.⁵

Although pseudophakic CME was described about 50 years ago, the pathophysiology remains uncertain and various pathomechanisms were suggested.⁶ Most researchers agree that postoperative inflammation seems to be a major cause of CME.

It is postulated that surgical manipulation within the anterior chamber may lead to the release of arachidonic acid from uveal tissue, with the production of either leukotrienes via the lipoxygenase pathway or prostaglandins (PGs) via the cyclooxygenase pathway.

Subsequently, the mediators of inflammation might diffuse posteriorly into the vitreous resulting in breakdown of the blood-retinal barrier. This disruption results in increased permeability of the perifoveal capillaries and fluid accumulation within the retina.⁷ As the FLACS procedure requires additional manoeuvres (e.g., for docking) and the eye is exposed to an energy other than ultrasound, concerns regarding the safety of FLACS have been raised.

The first report on the influence of FLACS on macular thickness was published by Ecsedy et al.⁸ The study compared macular thickness in an OCT device (Stratus OCT, Carl Zeiss Meditec) in 20 eyes of 20 patients undergoing FLACS versus 20 eyes of 20 patients undergoing standard ultrasound PCS.

The difference in the inner macular ring thickness between groups was 21.68 μm 1 week after surgery and 17.56 μm after 1 month. Although the disparity did not achieve statistical significance, multivariable modelling showed lower macular thickness in the inner retinal ring in the laser group after adjusting for age and preoperative thickness.

Another study by the same authors compared the outer nerve layer thickness in 12 eyes of 12 patients undergoing FLACS versus 13 eyes of 13 patients undergoing PCS.⁹ The study revealed that after cataract surgery, macular oedema was detectable mainly in the outer nuclear layer in both groups but was significantly less using the femtosecond laser platform.

Femtosecond theories

The mechanisms leading to CME in FLACS are unknown. It is presumed that, in general, near-infrared lasers, such as the femtosecond laser, pass easily with little absorption through the nonpigmented tissues i.e., the cornea, aqueous humour or lens. However, as a result of the absorption by melanosomes in the pigmented layer of the retina and choroid there might be an increased risk of damage.

Furthermore, femtosecond laser pulses during pretreatment may cause shockwaves that communicate with surrounding anterior ocular structures (e.g., the iris and ciliary body), leading to mechanical microtrauma.¹⁰

The formerly mentioned factors might result in PG release during FLACS. A study by Schultz et al.¹¹ assessed total PG and PG E₂ (PGE₂) levels in the anterior chamber fluid in four independent patient populations.

The levels of both PG and PGE₂ increased following FLACS compared with PCS in all populations. No correlation between PG/PGE₂ ratio and cataract density; corneal incision; suction time; or laser time was found. The authors concluded that PG levels rise immediately after FLACS.

Another study¹² by the same group assessed aqueous humour PG levels at different timepoints and in different applications of the femtosecond laser: pre-cataract surgery; after FLACS fragmentation; after FLACS capsulotomy; and after both capsulotomy and fragmentation.

Anterior capsulotomy was found to be the main trigger for increased aqueous humour PG levels. With that, Wang et al.¹³ found that FLACS results in increased PGE₂ and also IL-1β and IL-6 anterior chamber levels (Table 1).

Further investigations focused on the inhibition of PG release. A study by Kiss et al.¹⁴ assessed humour PG concentrations in three age-matched groups: after FLACS procedure with capsulotomy and laser lens fragmentation without nepafenac; with nepafenac; and before PCS.

In the FLACS surgery group, nepafenac was administered three times daily on the day before surgery and on the morning of the surgery day. Preoperative 1-day-long nepafenac treatment prior to FLACS prevented the rise of intracameral PG concentration.

The final PG concentration following FLACS was lower than before PCS. Another consecutive case series was conducted by Jun et al.¹⁵ In 90 eyes the authors have compared PGE₂ levels after PCS without a topical non-steroidal anti-inflammatory drug (NSAID); FLACS without previous ketorolac application; and FLACS preceded by topical ketorolac. Preoperative topical ketorolac inhibited aqueous humour PGE₂ elevation.

Miosis is a major disadvantage of FLACS versus PCS because miosis during the phacoemulsification can substantially increase surgical complications. PGE₂ release has been suggested as an underlying causative factor, although a precise mechanism has not been fully determined.

Jun et al.¹⁵ found that the administration of ketorolac tromethamine 0.45% eyedrops four times during 1 hour before surgery reduced miosis induced by FLACS pretreatment.

A study by Conrad-Hengerer et al.¹⁶ assessed the postoperative flare severity and central macular thickness up to 6 months after surgery. Higher levels of laser flare photometry in PCS (2 hours after surgery) compared with the FLACS. No difference in OCT CMT between FLACS and PCS was observed. The authors concluded that FLACS does not have an influence on the incidence of postoperative macular oedema.

In a study by Levitz et al.¹⁷, postoperative analysis of clinically CME was conducted including OCT examination with a follow-up of 2 to 24 months after surgery. CME occurred in 7 of 713 eyes (0.98%) in the PCS group, and in 8 of 677 eyes (1.18%) in the FLACS group. The difference was not statistically significant. However, the limitation of the study was an increased risk profile of the pre-existing conditions-two patients in each cohort developed bilateral CME.

Contrast studies by Ewe et al. revealed an increased risk for CME after FLACS. In their first study¹⁰ published in 2015, the incidence of CME with FLACS versus PCS was evaluated. Of 833 eyes undergoing FLACS, seven developed postoperative CME (0.8%), and of 458 eyes undergoing PCS, one case imvolved the development of postoperative CME (0.2%).

A trend toward greater CME in the FLACS group was found (p = 0.07). A limitation of the study was the nonspecified number of cases with diabetic retinopathy or retinal disease. Furthermore, of the seven cases developing CME subsequently to FLACS, four occurred in two patients.

In 2016¹⁸ , the authors evaluated visual outcomes up to 6 months after cataract surgery. CME was found in eight of 988 eyes that underwent FLACS (0.81%) and in one of 888 eyes that underwent PCS (0.1%). The difference was statistically significant (p = 0.041).

As OCT can detect early, subclinical retinal thickening in people without a significant macular oedema, it plays a dominant role in modern practice, particularly in macular oedema. The results of the formerly mentioned study were based solely on clinical examination, without OCT assessment.

Conclusions

As a summary, the Cochrane review comparing the outcomes of FLACS versus PCS can be presented.¹⁹ Sixteen randomised controlled trials were included for analysis. It was not possible to determine the equivalence or superiority of FLACS versus PCS.

Another conclusion was that complications occur rarely. For CME the evidence was inconclusive-the odds ratio was 0.58 (95% confidence interval 0.20 to 1.68). However, the nine included studies on CME manifested low certainty of evidence.

In conclusion,  FLACS is related to an increase of anterior chamber PG and cytokines, resulting in intra-operative miosis. This can be prevented by pre-operative NSAID application. As a result of methodological problems, several studies on the association between FLACS and CME are inconclusive.

References

1.     Chung SH, Mazur E. Surgical applications of femtosecond lasers. J Biophotonics. 2009;2:557–572.

2.     Nagy ZZ, Szaflik JP. The role of femtolaser in cataract surgery. Klin Oczna. 2012;114:324–327.

3.     Nagy Z et al. Initial clinical evaluation of an intraocular femtosecond laser in cataract surgery.  J Refract Surg. 2009;25;1053-1060.

4.     Popovic M et al. Efficacy and Safety of Femtosecond Laser-Assisted Cataract Surgery Compared with Manual Cataract Surgery: A Meta-Analysis of 14 567 Eyes. Ophthalmology. 2016;123:2113-2126.

5.     Kim SJ et al. A method of reporting macular edema after cataract surgery using optical coherence tomography. Retina. 2008;28:870-876.

6.     Tsangaridou MA et al. Controversies in NSAIDs Use in Cataract Surgery.  Curr Pharm Des. 2015;21:4707-4717.

7.     Grzybowski A et al. Pseudophakic cystoid macular edema: update 2016.  Clin Interv Aging. 2016;11:1221-1229.

8.     Ecsedy M et al. Effect of femtosecond laser cataract surgery on the macula. J Refract Surg. 2011;27:717-722.

9.     Nagy ZZ et al. Macular morphology assessed by optical coherence tomography image segmentation after femtosecond laser-assisted and standard cataract surgery. J Cataract Refract Surg. 2012;38:941-946.

10.   Ewe SYP et al. Cystoid macular edema after femtosecond laser-assisted versus phacoemulsification cataract surgery.  J Cataract Refract Surg. 2015;41:2373-2378.

11.   Schultz T et al. Changes in prostaglandin levels in patients undergoing femtosecond laser-assisted cataract surgery.  J Refract Surg. 2013;29:742-747.

12.   Schultz T et al.. Prostaglandin release during femtosecond laser-assisted cataract surgery: main inducer.  J Refract Surg. 2015;31:78-81.

13.   Wang L et al. Anterior chamber interleukin 1β, interleukin 6 and prostaglandin E2 in patients undergoing femtosecond laser-assisted cataract surgery.  Br J Ophthalmol. 2016;100:579-582.

14.   Kiss HJ et al. One-Day Use of Preoperative Topical Nonsteroidal Anti-Inflammatory Drug Prevents Intraoperative Prostaglandin Level Elevation During Femtosecond Laser-Assisted Cataract Surgery. Curr Eye Res. 2016;41:1064-1067.

15.   Jun JH et al. Effects of topical ketorolac tromethamine 0.45% on intraoperative miosis and prostaglandin E2 release during femtosecond laser-assisted cataract surgery.  J Cataract Refract Surg. 2017;43:492-497.

16.   Conrad-Hengerer I et al. Femtosecond laser-induced macular changes and anterior segment inflammation in cataract surgery.  J Refract Surg. 2014;30:222-226.

17.   Levitz L et al. Incidence of cystoid macular edema: femtosecond laser-assisted cataract surgery versus manual cataract surgery.  J Cataract Refract Surg. 2015;41:683-686.

18.   Ewe SYP et al. A Comparative Cohort Study of Visual Outcomes in Femtosecond Laser-Assisted versus Phacoemulsification Cataract Surgery. Ophthalmology. 2016;123:178-182.

19.   Day AC et al. Laser-assisted cataract surgery versus standard ultrasound phacoemulsification cataract surgery. in Cochrane Database of Systematic Reviews (2016).                 

Dr Andrzej Grzybowski, MD, PhD, MBA

E: ae.grzybowski@gmail.com

Dr Grzybowski is a professor of ophthalmology and chairman of the Department of Ophthalmology, University of Warmia and Mazury, Olsztyn, Poland. He is also head of Department of Ophthalmology at Poznań City Hospital, Poland. Dr Grzybowski reports grants, personal fees and non-financial support from Bayer; non-financial support from Novartis; non-financial support from Alcon Laboratories; non-financial support from Thea; personal fees and non-financial support from Valeant; and non-financial support from Santen, outside of the submitted work.