Laser-in situ keratomileusis (LASIK) is considered the most common form of refractive surgery performed nowadays and provides stable refractive and visual results but has uncommon but potentially dangerous complications such as post-LASIK ectasia. The exact mechanism of post-LASIK ectasia is unknown, but it is thought that the formation of a corneal flap during the LASIK procedure weakens the corneal biomechanical structure, causing post-LASIK ectasia in some cases [1, 2].

Corneal collagen cross-linking (CXL) acts by increasing the chemical bonds between collagen fibers of the cornea with an increase in mechanical stiffness with stoppage of progression of keratoconus and post-LASIK ectasia [3, 4]. Simultaneous LASIK and accelerated CXL (LASIK Xtra) have recently been proposed as a way to reduce the risk of post-LASIK ectasia and regression [5-7].

Although not yet FDA approved, LASIK Xtra is used in many countries around the world and is frequently performed on patients who are at high risk of post-LASIK regression, such as those with high degrees of myopia, younger patients, and those with low residual stromal bed thickness [8-10]

The cornea is kept all the time in a state of continuous dehydration via the active fluid pump and barrier function in the corneal endothelium. Any disturbance in these activities leads to the affection of the corneal transparency [11].

Diabetes mellitus (DM) is considered one of the most morbid chronic diseases affecting millions of patients all over the world [12]. DM could reduce ECD and the percentage of hexagonal cells but increase coefficient of variation (CV), indicating that diabetes causes the corneal endothelial cell to be unstable [13].

The specular microscope is a useful non-contact instrument that can image corneal endothelium under very high magnification. It can also be used for the measurement of corneal thickness [14].

Our study analyzed the effect of LASIK Xtra on corneal endothelium in diabetic myopic patients by specular microscopy.

In a prospective comparative interventional case series study, 120 eyes of 60 myopic patients were treated with LASIK and accelerated CXL at the International Eye Centre and Roaa Laser Vision Correction Centre between October 2019 and March 2021 January; they were divided into 2 groups:

Group A: Involved 60 eyes of 30 diabetic patients

Group B: Involved 60 eyes of 30 nondiabetic patients. Approval of the ethical committee of the Minia faculty of medicine was obtained, and after a thorough overview of the study's benefits and risks, each patient signed an informed written consent form.

Postoperative ectasia is considered a rare but visually debilitating problem after LASIK in some myopic patients, particularly moderate to high myopia in young patients, so LASIK is a major challenge in these patients. Hence, the combined application of simultaneous accelerated CXL and LASIK is used to reduce the risk of Post-LASIK ectasia and regression [15].

But the corneal endothelium is affected to some extent by accelerated CXL; the energy of UV-A is 3 mW/cm², which was used for 30 min together with hydrophilic riboflavin 0.1% application resulting in up to 95% decrease in energy of UV-A reaching the corneal endothelium in the standard CXL treatment. To reduce the procedure period, 9 mW/cm² for 10 min or 30 mW/cm² for 3 min are used which is equal to 3 mW/cm² for 30 min. The high dose of UV-A light energy damages the sub-basal nerve plexus, harming the endothelial pump function [16, 17].

DM affects all structural layers of the cornea, including the corneal epithelium, corneal nerves, tear film, and corneal endothelium, with morphological and functional changes and an increased risk of endothelial complications after intraocular surgery. Although the pathophysiological mechanisms behind diabetic corneal endothelium damage are still unknown, osmotic damage owing to excessive sorbitol build up and oxidative damage due to glycation end-product accumulation have both been implicated [18].

The endothelium has been studied in both diabetic patients and healthy people in a number of researches. The corneal endothelium of diabetic individuals alters morphologically, according to the majority of them. In type 2 DM patients, other investigations found a significant drop in ECD and hexagonality, as well as an increase in CV. Several investigations, however, reported no change between diabetic and non-diabetic participants' ECDs. The impact of DM on the corneal endothelium is still up for debate [19].

Nowadays, LASIK is considered a relative contraindication in diabetic patients due to the pathologic changes in the cornea of these patients. Also, the immune response is weak, and wound healing is delayed with the need for more follow-up in these patients [20, 21].

On the other side, some studies revealed that corneal complications after LASIK did not increase in patients with well-controlled DM and the visual outcomes between the diabetic and non-diabetic patients showed no significant difference, so LASIK could be performed safely in only selected cases provided that DM is well controlled with no ocular or systemic complications as nephropathy or peripheral neuropathy according to the American Academy of Ophthalmology recommendations [22, 23].

Most studies on diabetic patients showed that the cornea has more thickness, more polymegathism, and less pleomorphism than non-diabetic patients; these changes could be correlated to the duration of diabetes and/or the metabolic control status [24, 25].

Our study studied the effect of accelerated CXL on corneal endothelium in diabetic myopic patients in comparison with non-diabetic myopic patients. In reviewing the literature, we found no previous studies on the effect of LASIK Xtra on corneal endothelium in diabetic patients. 120 eyes with borderline CCT or residual stromal bed were evaluated, 60 eyes had DM with normal blood glucose level and HbA1c. Complete ocular examination was done to exclude ocular complications of DM; also FA and OCT were done to exclude early retinal affection.

In the non-diabetic population, there was no significant change in the mean ECD by the end of the 6-month follow-up period (p-value= 0.103), but there was a significant change in the diabetic group (p-value <0.001). Furthermore, when both groups were compared, there was no substantial difference (p value= 0.219) at the end of 6 months follow-up. These findings agreed with other studies on the effect of CXL and refractive surgery on the corneal endothelium.

Regarding pleomorphism, there were significant changes in the diabetic patients at the end of 6 months follow-up (p-value <0.001) with no significant changes in the non-diabetic group (p-value=0.884), our study showed that no significant differences between both groups preoperatively and postoperatively at 6 months (p value<0.001).

CV represents an indicator of the uniformity of endothelial cell size. In the diabetic group, there was a significant change between the preoperative value and after 6 months postoperatively (p-value<0.001) while no significant change in the non-diabetic group after 6 months of surgery (p-value= 0.178), there is a significant difference preoperatively and postoperatively at 6 months on comparing both groups (p-value<0.001).

During the follow-up period, we noticed stable postoperative refraction without cases of post LASIK ectasia or regression, which was the main indication of associated cross-linking with LASIK (Figs. 4 and 5).

Fig. (4). Specular microscopy in the diabetic group. The cell density (CD) was decreased significantly after 3 months. Pleomorphism was represented by hexagonal cells (HEX), which changed markedly after 3 months, and polymegathism, which was represented by CV changed significantly at 3 and 6 months. (a: preoperative- b:after 3 months- c: after 6 months).

Fig. (5). Specular microscopy in the non-diabetic group. Notice the fewer changes in CD, pleomorphism (HEX), and polymegathism (CV) (a: preoperative- b: after 3 months- c: after 6 months).

Similar research, such as Tohamey M's study on the effect of LASIK Xtra in non-diabetic patients, found that accelerated cross-linking had no significant effect on corneal endothelium during 6 months follow-up [26].Also, a study was done by Wu Y which concluded that ECD did not differ between LASIK and LASIK Xtra in non-diabetic patients [17].

Also, our results were consistent with other studies of the effect of LASIK Xtra, although there were some changes in the parameters of the irradiance as Cingü et al. who studied the effect of accelerated CXL (18 mW/cm2) for 5 minutes and found that ECD decreased postoperatively then returned to the preoperative value at 6 months, while CV returned to their preoperative value only at 3 months [27]. Another study by Bhandari used more power of UVA irradiance (30 mW/cm2) for 3 minutes and found that ECD and CV changed significantly up to 12 months follow-up [28].

Other studies on the effect of accelerated cross-linking in keratoconus and Post-LASIK ectasia as Badawi et al., who used UV-A irradiance of 30 mW/cm² for 3 min and found that the changes in ECD and CV were persistent up to 12 months follow-up [29]. Kanellopoulos compared standard CXL (3 mW/cm² for 30 min) in one eye and accelerated CXL (7 mW/cm² for 15 min) in the fellow eye of 21 patients and found that there were no significant changes in the corneal endothelium between accelerated and standard CXL [30].

LASIK with accelerated cross-linking is safe on the corneal endothelium count and morphology in diabetic patients, and this potentiates the use of LASIK Xtra in the diabetic myopic patient's especially in high errors but more prolonged follow-up was needed to ensure long-term safety.

The research has some drawbacks, such as a limited sample size, a short follow-up time, and the lack of distinction between type 1 and type 2 DM.